Datasets:

rookshanks

/

small-the_pile

like 1

We've heard a lot about rookie Liberal Leader Philippe Couillard over the years. He's 56, a former university professor and a trained brain surgeon. Couillard served as Quebec's health minister for five years in Jean Charest's government. He has also dropped a few personal details in campaign speeches: he used to play hockey (defence) and his wife calls him "Bear". Philippe Couillard takes his first ever "selfie" in a one on one chat with CBC reporter Salimah Shivji. (Philippe Couillard) But what is the leader really like? And what is he doing to make it through this long election campaign? I joined him on his campaign bus for a few minutes to find out. 1. He's into music. The Liberal leader has an extensive and diverse playlist on his iPad, everything ranging from opera and classical to rock and reggae – even liturgical music by a 12th century mystic nun who had visions. Couillard often sings along to his favourites, such as this classic reggae tune: Philippe Couillard sings along to his favourite tune: Desmond Dekker's Israelites. 0:22 And here's what Couillard plays to get pumped up for a rally: Hint: it starts and ends with Led Zeppelin 0:16 2. He's not into light reading. I asked Couillard if he had time for some light reading during the gruelling campaign. His answer: "I don't do light reading, I'm afraid." He refuses to peruse the morning newspapers on the campaign trail — which helped him get through the campaign — but he does make time to read for pleasure. His current choice: Le mythe de Napoléon au Canada français by Serge Joyal. Couillard told me he had just polished off a history of Paris during the Franco-Prussian War of 1870. Philippe Couillard says before he was the leader of the Quebec Liberal Party, he was often mistaken for Gil Grissom, a character from the TV crime drama CSI. (CBS, Robert Voets/AP) 3. He is a red wine lover, but only drinks orange juice and water on the campaign trail. And campaign or not, he goes to bed by 8:30 or 9 p.m. but wakes up very early. Training, he says, from his days in the operating room. 4. His hands are cold-resistant. Over the campaign, I've noticed that Couillard does not wear gloves while making announcements outdoors — despite the frigid March temperatures. I asked him if there were studies that showed a politician in gloves is not to be trusted. He laughed in surprise and said that he knew of none. He says when he was young, he used to play hockey outside without gloves and all the neighbourhood kids would marvel at how warm his hands stayed. Couillard says he only gets cold ears and feet. 5. He's proud of his beard. He has trimmed it for the campaign, but Couillard wears his beard proudly, despite some suggesting beards and politics don't mix. In fact, Couillard is convinced facial hair is back in fashion. I asked him for proof. He told me that before he ran for Liberal leader, he was approached numerous times by women asking for his autograph, thinking he was the (bearded) actor who played Gil Grissom on the popular TV show CSI.

IN THE UNITED STATES COURT OF APPEALS FOR THE FIFTH CIRCUIT United States Court of Appeals Fifth Circuit FILED January 14, 2008 No. 07-10219 Summary Calendar Charles R. Fulbruge III Clerk ALEX KOJO BLANKSON Petitioner-Appellant v. MICHAEL B MUKASEY, U S ATTORNEY GENERAL; JOHN SOURKARIS, Director Post Order Detention Unit, U S (ICE); NURIA PRENDES, Director of Detention and Field Operations Dallas, Texas (ICE); JILL WATSON, Warden of RPRDC Respondents-Appellees Appeal from the United States District Court for the Northern District of Texas USDC No. 1:06-CV-155 Before WIENER, GARZA, and BENAVIDES, Circuit Judges. PER CURIAM:* Alex Kojo Blankson appeals the district court’s dismissal of his 28 U.S.C. § 2241 petition on the grounds that his detention by the Department of Homeland Security/Bureau of Immigration and Customs Enforcement (DHS) is unconstitutional in light of Zadvydas v. Davis, 533 U.S. 678 (2001). * Pursuant to 5TH CIR. R. 47.5, the court has determined that this opinion should not be published and is not precedent except under the limited circumstances set forth in 5TH CIR. R. 47.5.4.  No. 07-10219 The district court noted that 8 U.S.C. § 1231(a)(1)(C) provides that the removal period shall be extended if the alien fails or refuses to make a good faith effort to obtain a travel document or acts to prevent his removal and concluded that Blankson’s own actions and conflicting claims of citizenship hampered the DHS’s ability to effectuate his removal. The district court also found that Blankson failed to show that there is no significant likelihood of removal in the foreseeable future. The district court did not err in denying the petition. Blankson’s frequently changing claims of citizenship hampered the DHS’s ability to effectuate removal and, under § 1231(a)(1)(C), has served to extend the removal period of§ 1231(a)(1)(A). See Balogun v. INS, 9 F.3d 347, 350-51 (5th Cir. 1993). Blankson has failed to show that under the circumstances his continued detention violates his constitutional rights and that “there is no significant likelihood of removal in the reasonably foreseeable future.” Zadvydas, 533 U.S. at 701. The judgment of the district court is AFFIRMED; Blankson’s motion to enter exhibit lists is DENIED. 2

--- abstract: 'A new method is presented for the construction of a natural continuous wavelet transform on the sphere. It incorporates the analysis and synthesis with the same wavelet and the definition of translations and dilations on the sphere through the spherical harmonic coefficients. We construct a couple of wavelets as an extension of the flat [*Mexican Hat Wavelet*]{} to the sphere and we apply them to the detection of sources on the sphere. We remark that no projections are used with this methodology.' address: | $^1$ Instituto de Fí[sica]{} de Cantabria (CSIC-UC), 39005, Santander, Spain\ email: [email protected]\ $^2$ Departamento de Fí[sica]{} Moderna, Universidad de Cantabria, 39005, Santander, Spain\ $^3$ Departamento de Matemáticas, Universidad de Oviedo, 33007, Oviedo, Spain title: | Wavelets on the sphere.\ Application to the detection problem --- Introduction ============ Multiscaling analysis techniques dealing with the analysis/synthesis of nD-images defined on intervals of $R^n$ have been applied in many fields of physics in the last 15 years. For instance, in the case $n = 1$ one has electronics and audio signals, in the case $n = 2$ one has optical or infrared images whereas for $n = 3$ one deals with fluid dynamics or the large-scale structure of the universe as 3D-images. However, there are data given on other manifolds like the circle $S_1$ (e. g. scanning along circles the microwave sky) and the sphere $S_2$ (e. g. geophysics). In this paper, we are interested in data distributed on the sphere. Trivially, for the study of local properties (e. g. detection of objects) one can project on the tangent plane at any point on the sphere to make this type of analysis but when global properties are taken into account the curvature of the sphere can not be neglected. A first approach to deal with these global properties is to make some global projection of all the points of the sphere. The stereographic projection has been recently used dealing with the continuous wavelet transform. In this case, to get the wavelet coefficient at any point on the sphere, one projects from the opposite point to the local tangent plane. \[1\] have made a connection to group theory. The translations and dilations in the wavelet have their definition on the plane. Clearly, such a projection does not take into account the topological structure of the sphere. Some applications to cosmology, in particular the study of anisotropies of the cosmic microwave background radiation have been done by some authors (\[3\],\[7\],\[10\]) using the projection of the [*Mexican hat wavelet*]{}. A drawback of such projection is the obvious deformation of the pixels and wavelets near the projection pole. We remark that the synthesis can be done in terms of another biorthogonal wavelet \[11\]. Another approach uses some analyzing wavelet functions that are defined in terms of spherical harmonics \[5\] with a definition of the dilation operator and conditions on the wavelets in such a way to get a synthesis formula. The drawback of such methodology is: the dilations do not satisfy the appropriate flat limit in general. Also some examples of wavelet functions are poorly localized (e. g. Abel-Poison wavelets). A different approach assumes from the beginning discrete wavelets incorporating tensor product approaches in polar coordinates, then the two poles are singular points regarding approximation/stability properties (\[4\],\[6\]). Another approach is adapted to arbitrary point systems or triangulations on the spheres, then there is no efficient tool as fast wavelet algorithms. In the approach by \[8\] basis are defined on a quasi-uniform icosahedral triangulation on the sphere allowing for a fast algorithm. However, biorthogonal wavelets are needed and a lifting scheme for the multiresolution is applied avoiding the concepts of translations and dilations and also it is not clear whether the construction leads to a stable $L_2 (S_2)$ basis. Haar-type wavelets have been developed using different pixel combinations (\[2\],\[7\],\[9\]). The first case uses the lifting scheme weighting for the area of the pixels whereas in the other two cases an equal area pixelization is used but the Haar-type transform is only applied on regions of the sphere covering only $\frac{1}{12}$ of the total area. Clearly, with any pixelization the symmetry on the sphere is lost. In this paper we will consider a continuous approach, we will introduce a methodology that incorporates the analysis and synthesis of any function defined on the sphere $S_2$ using the same circularly-symmetric wavelet and also we will introduce the generalization of the translations/dilations. In this sense we follow Freeden’s approach working with spherical harmonics. Examples will be given that have the appropriate flat limit. Finally, the application to the detection of a spot is given, studying the concentration of the wavelet coefficients. Properties of the wavelet ========================= We will consider a circularly-symmetric filter defined on the sphere $ S_2$ $$\label{eq:cc} \Psi(\vec{n}\cdot \vec{\gamma}; R),$$ where $\vec{n}$ is a fixed direction. $\vec{\gamma}$ is another fixed, but arbitrary direction, therefore $\vec{n}\cdot \vec{\gamma}$ will represent a rotation on the sphere with respect to the direction $\vec{n}$ defined by the angle $\theta$ ($\cos(\theta)\equiv \vec{n}\cdot \vec{\gamma})$. $R>0$ will represent a dilation, which will be defined later on through the spherical harmonics. We assume the following properties of the filter: \(i) the analysis of any function $f(\vec{n})$ will be done with the wavelets $\Psi(\vec{n}\cdot \vec{\gamma}; R)$, \(ii) the synthesis of any function $f(\vec{n})$ will be done with the wavelets coefficients and the wavelets $\Psi(\vec{n}\cdot \vec{\gamma}; R)$, \(iii) it will incorporate the definition of translation and dilation on the sphere. We remark that no assumption about compensation of the filter (i. e. $\int d\Omega (\vec{n})\,\Psi(\vec{n}\cdot \vec{\gamma}; R) = 0$) and projection from $R^2$ to $S_2$ is imposed. Analysis with the filter $\Psi$ =============================== We define the wavelet coefficients associated to the translation $\vec{\gamma}$ and dilation $R$ for the function $f(\vec{n})$ defined on $S_2$ $$\label{eq:cd} w(R, \vec{\gamma} ) = \int d\Omega (\vec{n})\,f(\vec{n}) \Psi(\vec{n}\cdot \vec{\gamma}; R).$$ Let us assume the standard decomposition of $f(\vec{n})$ in spherical harmonics $Y_{lm}(\vec{n})$ $$\label{eq:ce} f(\vec{n}) = \sum_{lm} f_{lm}Y_{lm}(\vec{n}), \ \ \ f_{lm} = \int d\Omega (\vec{n})\,f(\vec{n})Y_{lm}^*(\vec{n}).$$ By introducing Eq.(\[eq:ce\]) into Eq.(\[eq:cd\]) and taking into account that $Y_{lm}(\vec{n})$ is an orthonormal base of $S_2$, we obtain $$\label{eq:cf} w(R, \vec{\gamma} ) = \sum_{lm}(\frac{4\pi}{2l+1})f_{lm}\Psi_l(R)Y_{lm}(\vec{\gamma}),$$ where the Legendre coefficients associated to the circularly-symmetric filter $\Psi$ are given by $$\begin{aligned} \Psi(\vec{n}\cdot \vec{\gamma}; R) & = & \sum_l \Psi_l(R)P_l(\vec{n}\cdot \vec{\gamma}),\nonumber \\ \label{eq:cg} \Psi_l(R) & = & (l+\frac{1}{2})\int_{-1}^1dy\,P_l(y)\Psi(y; R).\end{aligned}$$ Synthesis with the filter $\Psi$ ================================ Now, let us show that in order to have a reconstruction equation, i. e. $f(\vec{n})$ as a functional integral of the wavelet coefficients and the wavelet base $\Psi$ one can impose the condition $$\label{eq:ch} \Psi_l(R) \equiv (\frac{2l+1}{4\pi})\psi (lR),$$ i. e. $\Psi_l(R)$ depends on the product $lR$ and $\psi(l)$ satisfies the admissibility condition $$\label{eq:cl} C_{\psi} \equiv \int_0^{\infty} \frac{dl}{l}\psi^2(l) < \infty,$$ where $l$ runs in the interval $[0, \infty)$. We remark that the analogous condition to have a reconstruction on the plane by substituting $l \rightarrow q$, $q$ being the wave number in Fourier space. Therefore, the filter $\Psi$ -given by Eq. (\[eq:cg\])- can be rewritten as $$\label{eq:ci} \Psi(\vec{n}\cdot \vec{\gamma}; R) = \sum_l \Psi_l(R)P_l(\vec{n}\cdot \vec{\gamma}) = \sum_{lm}\psi (lR)Y_{lm}^*(\vec{n})Y_{lm}(\vec{\gamma}).$$ Firstly, we remark that the previous equation defines a dilation on the sphere in terms of dilation of the number $l$ and a translation on the sphere in terms of a rotation through the spherical harmonics $Y_{lm}(\vec{\gamma})$. We think that such a definition is the most natural on the sphere and generalizes the one associated to dilations and translations in the plane $R^2$ via Fourier space. Secondly, we can write the following equation $$\begin{aligned} \int \frac{dR}{R}\int d\Omega (\vec{\gamma})\,w(R, \vec{\gamma)}) \Psi(\vec{n}\cdot \vec{\gamma}; R) = \nonumber \\ \sum_{lm}f_{lm}Y_{lm}(\vec{n})[\int \frac{dR}{R}{(\frac{4\pi}{2l+1})}^2\Psi_l^2(R)], \label{eq:cj}\end{aligned}$$ where we have taken the harmonic expansions for $w(R, \vec{\gamma})$ and $\Psi(\vec{n}\cdot \vec{\gamma}; R)$. If one wants to have this equation proportional to $\sum_{lm}f_{lm}Y_{lm}(\vec{n}) = f(\vec{n})$, i.e. to be able to reconstruct $f(\vec{n})$, then it is obvious that necessarily $$\label{eq:ck} \int \frac{dR}{R}{(\frac{4\pi}{2l+1})}^2\Psi_l^2(R) = C_{\psi},$$ where $C_{\psi} \neq 0$ must be a constant. A particular solution to the previous equation is given by Eq. \[eq:ch\] and the admissibility condition. In this case, the synthesis equation can be written as $$\label{eq:cm} f(\vec{n}) = \frac{1}{C_{\psi}}\int \frac{dR}{R}\int d\Omega (\vec{\gamma}) \,w(R, \vec{\gamma})\,\Psi(\vec{n}\cdot \vec{\gamma}; R).$$ and the Equation (\[eq:cf\]) can be rewritten as $$\label{eq:cn} w(R, \vec{\gamma} ) = \sum_{lm}f_{lm}\psi (lR)Y_{lm}(\vec{\gamma}).$$ These equations are the analysis/synthesis counterparts on $S_2$ of the corresponding ones on $R^2$. Properties of the filter $\Psi$ =============================== Let us focus on some of the properties of the filter: [**$\Psi$ is a [*compensated*]{} filter**]{} Taking into account Eq. (\[eq:cl\]), $C_{\psi} < \infty$ implies that $\psi (l)\rightarrow l^{\epsilon},\epsilon >0$ as $l\rightarrow 0$, i. e. $\psi (l=0) = 0$. Now, taking into account Eq. (\[eq:ci\]), one obtains $$\label{eq:co} \int d\Omega (\vec{n})\,\Psi(\vec{n}\cdot \vec{\gamma}; R) = \psi (0) = 0,$$ the filter is compensated (hereinafter wavelet). [**Energy of the wavelet**]{} Taking into account Eq. (\[eq:ci\]) and the orthonormal property of the spherical harmonics, one obtains $$\label{eq:cp} \int d\Omega (\vec{n})\,\Psi^2(\vec{n}\cdot \vec{\gamma}; R) = \sum_l \frac{2l+1}{4\pi}\psi^2(lR).$$ [**Energy of the function $f(\vec{n})$**]{} Taking into account the standard properties of the spherical harmonics $$\label{eq:cq} \parallel f \parallel ^2 \equiv \int d\Omega (\vec{n})\,f^{2}(\vec{n}) = \sum_{lm}f^2_{lm},\ \ \ f^2_{lm}\equiv f_{lm}f_{lm}^*.$$ We can also prove the following equivalence $$\label{eq:cr} \parallel f \parallel ^2 = \frac{1}{C_{\psi}}\int \frac{dR}{R}\int d\Omega (\vec{n})\,w^2(R, \vec{n}).$$ An example ========== As an example of the previous ideas we will consider the generalization to the sphere of the [*Mexican Hat wavelet*]{} (MHW). We focus on the MHW because it is a widely used tool in Astronomy, well suited for the detection of pointlike objects such as extragalactic sources (\[3\],\[7\],\[10\]), but the same ideas can be applied to other wavelet families as well. Two natural generalizations of the mother Mexican Hat wavelet on the plane are possible $$\label{eq:cs} \psi_1(l)\propto l^2e^{-\frac{1}{2}l^2},\ \ \ \psi_2(l)\propto l(l+1)e^{-\frac{1}{2}l(l+1)},$$ where we have taken a unit width to define the mother wavelet. For $l \gg 1$ both functions approach the MHW on the plane. We have represented the harmonic coefficients $\psi_1(lR), \psi_2 (lR)$ for different values of $R=0.2\times 2^j, j=-2,-1,0,1,2$, as well as the profile of the wavelets on real space for the same cases, in Figure \[fig:fig1\]. The differences between wavelets $\psi_1$ and $\psi_2$ is shown in Figure \[fig:fig2\]. Next, in order to study the concentration in wavelet space we will consider a spot with spherical symmetry placed on the north pole, i. e. it is defined by a function $f(\theta)$. In this case, we get for the wavelet coefficients $$\begin{aligned} w(R, \theta ) & = & \sum_lw_l(R)\,P_l(\cos \theta ), \ \ \ w_l(R)\equiv f_l\,\psi (lR), \nonumber \\ f_l & \equiv & (l+\frac{1}{2}) \int_0^{\pi}d\theta\,\sin \theta P_l(\cos \theta )f(\theta ). \label{eq:ct}\end{aligned}$$ Let us now consider a very simple spot defined by a top hat $f(\theta ) = 1_{[0, \theta_o]}$. A simple way to test how the wavelets allow us to concentrate the information in a few number of coefficients is to measure somehow the width of the curve $w(R, \theta )$ of wavelet coefficients for the spot. An intuitive way to do this is to define the “energy” as the integral under the squared curve $w^2(R,\theta)$ and to see which is the radius $\theta_e$ that contains a given fraction of the total energy. The smaller $\theta_e$ is, the more concentrated the coefficients are. We have performed numerical simulations with a simple toy model to see which of the two generalizations of the MHW, $\psi_1$ or $\psi_2$, concentrates more the coefficients. We have placed a top hat spot of size $\theta_0=0.2$ rad in the North Pole and we have filtered it with the wavelets $\psi_1$ and $\psi_2$ using different scales ranging from $R=0.1$ to $R=1.6$ rad. The results are shown in the upper panel of Figure \[fig:fig3\]. We have ploted the radius $\theta_e(R)$ such that $68\%$ of the energy is inside the circle of radius $\theta_e(R)$ as a function of the dilation scale $R$. As can be seen, the wavelet $\psi_1$ concentrates more the coefficients, that is, produces smaller values of $\theta_e$. Now we repeat the same process but using a Gaussian spot instead of a top hat. The Gaussian spot is given by $f(\theta ) = \mathrm{exp}(-\theta^2/2 \theta_0^2)$. This case is interesting since most of the detectors that operate in microwave Astronomy experiments have approximately Gaussian response. The lower panel of Figure \[fig:fig3\] show the results, that are very similar to the top hat case. Again, $\psi_1$ concentrates more the coefficients. We have tested the resuts for different levels of concentration and we have found that up to $75\%$ the wavelet $\psi_1$ concentrates more the coefficients. Above $75\%$ this is still true for large values of the dilation $R$, while for small $R$ $\psi_2$ concentrates more the coefficients. This is due to the fact that $\psi_1$ produces more small oscilations in the tail of the curve $w(R, \theta )$ for small $R$. Conclusions =========== We have developed a constructive wavelet approach on the sphere without any projection from the plane. It is a continuous transform that allows the analysis and synthesis of any function defined on the sphere and incorporates the concepts of translation and dilation as generalizations of the elementary ones defined on the plane. It is a compensated filter that conserves the energy of any function. We have considered some natural generalizations of the plane Mexican hat wavelet and we have applied them to the detection of a big spot. The conclusion is that one of the wavelets ($\psi_1$) concentrates more the information than the other one. Acknowledgements ================ We acknowledge partial financial support from the Spanish Ministry of Education (MEC) under project ESP2004–07067–C03–01. MLC acknowledge a FPI fellowship of the Spanish Ministry of Education and Science (MEC). DH acknowledges the Spanish MEC for a “Juan de la Cierva” postdoctoral fellowship. [20]{} Antoine J.-P. & Vanderheynst, P. ”Wavelets on the n-sphere and related manifolds”, 1998, JMP, 39, 3987 Barreiro et al. ”Testing the Gaussianity of the COBE DMR data with spherical wavelets”, 2000, MNRAS, 318, 475B Cayon, L. et al. ”Spherical Mexican hat wavelet: an application to detect non-Gaussianity in the COBE-DMR maps”, 2001, MNRAS, 326, 1243 Dahlke, S. et al ”Multiresolution analysis and wavelets on $S^2$ and $S^3$”, 1995, Numer. Funct. Anal. Optimiz. 16,19 Freeden, W. & Windheuser, U., ”Combined spherical harmonic and wavelet expansion- a future concept in Earth’s gravitaional determination”, 1997, Appl. Comput. Harm. Anal. 4, 1 G$\ddot{o}$ttelman, J. ”Locally supported wavelets on the sphere”, 1996, preprint no. 14, Dept. of Mathematics, Univ. Mainz Martínez-González et al. ”The performance of spherical wavelets to detect non-Gaussianity in the cosmic microwave background sky”, 2002, mnras, 336, 22M $Schr\ddot{o}der$, P & Sweldens, W., ”Spherical wavelets: texture proccesing”, 1995, In P. Hanrahen, W. Purgathofer (eds.): ”Rendering Techniques ’95”, Springer, Wien, New York Tenorio, L. et al ”Applications of wavelets to the analysis of cosmic microwave background maps”, 1999, MNRAS, 310, 823 Vielva, P. et al. ”Point Source Detection using the Spherical Mexican Hat Wavelet on simulated all-sky Planck maps”, 2003, MNRAS, 344, 89 Wiaux, I., Jacques, L. & Vandergheysnst, P. ”Correspondence principle between spherical and Euclidian wavelets”, 2005, ApJ, 632, 15W {width="90.00000%"} {width="90.00000%"} {width="90.00000%"}

Structure of the ask-asd operon and formation of aspartokinase subunits in the cephamycin producer 'Amycolatopsis lactamdurans'. The first two genes of the lysine pathway are closely linked forming a transcriptional operon in the cephamycin producer 'Amycolatopsis lactamdurans'. The asd gene, encoding the enzyme aspartic semialdehyde dehydrogenase, has been cloned by complementation of Escherichia coli asd mutants. It encodes a protein of 355 aa with a deduced M(r) of 37109. The ask gene encoding the aspartokinase (Ask) is located upstream of the asd gene as shown by determination of Ask activity conferred to E. coli transformants. asd and ask are separated by 2 nt and are transcribed in a bicistronic 2.6 kb mRNA. As occurs in corynebacteria, the presence of a ribosome-binding site within the ask sequence suggests that this ORF encodes two overlapping proteins, Askalpha of 421 aa and M(r) 44108, and Askbeta of 172 aa and M(r) 18145. The formation of both subunits of Ask from a single gene (ask) was confirmed by using antibodies against the C-terminal end of Ask which is identical in both subunits. Ask activity of 'A. lactamdurans' is regulated by the concerted action of lysine plus threonine and this inhibition is abolished in E. coli transformants containing Ser(301) to Tyr, or Gly(345) to Asp mutations of the 'A. lactamdurans' ask gene.

###### Key questions What is already known? ====================== - Rapid transfer to a medical facility is a key mechanism through which ambulance-based emergency medical systems (EMS) improve trauma outcomes. What are the new findings? ========================== - Trauma victims are rapidly transported in Delhi, India, to a hospital by bystanders and police. - India's medico-legal system imposes substantial burdens on good Samaritans by forcing them to interact with police. - For-profit hospitals often decline to provide first aid and stabilise patients delaying access to care. What do the new findings imply? =============================== - Formal layperson-EMS should get official sanction from police and carry visible symbols of their authority to assist with emergency transport, and the system should work with empanelled hospitals that have agreed to participate. - Delhi already has several key EMS components that could be integrated and expanded. Introduction {#s1} ============ In India and many low- and middle-income countries (LMICs), ambulance-based emergency medical systems (EMS) are uncommon. Over half of the global population lives in areas without formal EMS.[@R1] Victims of traffic crashes in LMICs are typically transported from the crash scene to a hospital by bystanders and passing vehicles.[@R4] In India, surveillance at medical facilities suggests that most victims are brought to hospital by taxis or police, with ambulances accounting for less than 5% of transport --- a pattern that has shifted little in 30 years ([figure 1](#F1){ref-type="fig"}). Despite strong advocacy,[@R13] the high equipment and operational costs of ambulance-based EMS suggests they will not be adopted or expanded to scale in many LMICs.[@R1] ![Mode of transport to hospital for victims of traffic crashes in India. ('Others' includes transport by private vehicles, bicycles, cycle rickshaws and other modes. Data sources: St. Stephens Hospital, unpublished data; TITCO: combines data from five major trauma centres in Delhi, Mumbai (two trauma centres), Kolkata and Chennai.[@R42])](bmjgh-2019-001963f01){#F1} In principle, EMS aim to improve trauma outcomes by providing: (1) medical interventions in the field, and (2) rapid transport to a definitive care facility. However, evidence suggests that many prehospital interventions are ineffective and that the main benefits of EMS likely accrue from rapid transfer. Increasingly, studies have questioned the benefits of emergency endotracheal intubation,[@R15] intravenous drug therapy,[@R16] fluid resuscitation[@R17] and spine immobilisation.[@R19] In fact, studies show that trauma victims transported by advanced life support ambulances have similar or worse outcomes than basic life support, likely due to interventions that are poorly performed and which delay transfer to definitive care.[@R22] Recognising the weak evidence for advanced training of first responders, the WHO recommends that LMICs should train lay responders, such as commercial drivers, to provide basic first aid and rapid transfer to hospitals.[@R13] Several studies have reported training of commercial drivers, police, community leaders and others in LMICs (Ghana,[@R29] Madagascar,[@R30] Iraq[@R31] and Uganda,[@R33] among many others[@R12]). The second key aspect of EMS --- coordination of lay responders to reduce transfer time --- has received very little attention in advocacy efforts. Although advanced communication networks have been previously viewed as expensive components of the most advanced systems,[@R3] recent developments in smartphone technology have made coordinated taxi fleets common in LMICs.[@R34] In fact, there have been several unsuccessful attempts to develop a 'layperson-EMS' by using peer-to-peer or dispatcher-coordinated networks of lay responders. For instance, in recent years, ridesharing companies in India (Uber in Hyderabad[@R35] and Wagon Cab in Delhi[@R36]) have launched emergency ride options. Similarly, some services have attempted to build dispatcher-coordinated networks of existing private ambulances (AMBER Health[@R37] and LifeHover[@R38] in Delhi, Dial242 in Mumbai,[@R38] StanPlus, eSahai and Call Ambulance in Hyderabad[@R38]). A review of the websites for these services suggest that few have sustained after the initial launch. This indicates that layperson-EMS may face legal, medical and social barriers that need to be systematically addressed. In 2017, researchers at the University of Chicago and the Indian Institute of Technology (IIT) Delhi initiated a project funded by the US National Institutes of Health to assess the feasibility of developing a coordinated system of lay first-responders that could improve population-level outcomes of traffic crashes in Delhi, India. One aspect of the project aimed to understand how trauma victims currently access medical care, and the barriers to such a system being formalised into a coordinated layperson-EMS. In particular, we sought to understand the following aspects from the perspective of frontline stakeholders, policymakers and experts: (i) who helps victims, (ii) how are they transported to hospitals, (iii) what deters help from good Samaritans, (iv) how can these barriers be addressed and (v) could a layperson-EMS improve outcomes. In this paper, we report our findings and share recommendations for EMS policy in Delhi and similar settings. Methods {#s2} ======= Study setting and context {#s2-1} ------------------------- Delhi is the capital of India and has an estimated population of 20 million. It has a complex administrative structure, with federal, state and local government agencies overseeing various aspects of governance.[@R39] For example, while Delhi Police is overseen by the federal government, health services are primarily administered by the state government.[@R39] Delhi's formal EMS consists of a public ambulance service with a fleet of 265 ambulances (31 Advanced Life Support, 110 Basic Life Support and 124 Patient Transport)[@R40] but it is common for emergency transport to be provided by police, taxis (especially auto rickshaws) and private vehicles.[@R41] Healthcare in Delhi is provided by a mix of for-profit hospitals, and relatively low-cost public hospitals.[@R43] Patients often leave for-profit hospitals against medical advice for financial reasons.[@R44] It is standard medico-legal practice across India to treat all injuries as potentially criminal cases that are registered as medico-legal cases and reported to the police. Surveys suggest that the fear of getting entangled in long-drawn legal processes deters bystanders from helping trauma victims.[@R46] In 2014, following public interest litigation, the Supreme Court of India instructed the federal government to develop legislation to protect good Samaritans and compel for-profit hospitals to stabilise victims and provide first aid.[@R48] Subsequently the government issued an executive order to this effect ('Good Samaritan Notification').[@R49] Study design and methods {#s2-2} ------------------------ We used qualitative methods to elicit viewpoints of five groups of stakeholders --- (1) drivers of taxis (three-wheeled auto rickshaws and four-wheeled taxis), (2) medical personnel (doctors, nurses and hospital administrators), (3) legal experts, (4) police personnel and (5) other stakeholders (including policymakers, ambulance providers, non-governmental organisations (NGOs), hospital stretcher bearers and security guards and public health researchers). We acquired research data through: ### Key informant interviews {#s2-2-1} #### Sampling {#s2-2-1-1} We used a combination of purposeful sampling techniques.[@R50] All respondents had experience with transport, medical or legal aspects of trauma either as professional practitioners or through policy engagement (criterion sampling). We relied on recommendations from interviewees to identify additional respondents (snowball sampling), and used convenience sampling to identify certain taxi drivers and medical personnel. #### Interview guides {#s2-2-1-2} We designed interview guides to understand respondents' experiences and viewpoints towards emergency transport, barriers to bystander assistance and a coordinated layperson-EMS ([figure 2](#F2){ref-type="fig"}). The guides were informed by preliminary discussions with a sample of stakeholders prior to data collection. We refined and added questions as data collection progressed. Interview guides are provided as [online supplementary appendix A1](#SP1){ref-type="supplementary-material"}. 10.1136/bmjgh-2019-001963.supp1 {#F2} In order to anchor reactions about a coordinated layperson-EMS, we presented respondents with a hypothetical taxi-EMS ([figure 2](#F2){ref-type="fig"}) consisting of a fleet of taxis with drivers trained in first aid and dispatcher-coordinated using a smartphone application (app). When an emergency call is received at the control room and no ambulance is available, the taxi closest to the crash site is recruited through the app. The app provides navigation to the crash site and the closest participating hospital, where the driver is paid for their effort using mobile-to-mobile cash transfer. #### Data collection {#s2-2-1-3} Four researchers (RA, RAr, KB, VS) with backgrounds in transportation, engineering and/or public health collected data during December 2017 to March 2019. Two researchers had training in qualitative methods (VS, RAr), while one underwent a short training in qualitative methods before the project began (RA). We conducted 50 interviews (26 recorded), typically lasting 45 to 60 min, in Hindi, English or a combination ([table 1](#T1){ref-type="table"}). These included five short interviews (\<15 mins) with individuals with knowledge about a specific topic but who were not suitable for full length interviews. We took handwritten notes, which were typed and stored electronically. ###### Data sources: interviews, stakeholder consultations and documents Type of interviewees Interviews Details ----------------------- ------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Legal experts 5 Incl. four that participate in policy dialogue\* Medical practitioners 16† Incl. 11 doctors, three nurses, one hospital administrator and two EMTs; nine from government hospitals, two from a charitable private hospital and five from for-profit private hospitals; five participate in policy dialogue Police personnel 8† Incl. three that participate in collecting evidence used in accident claims tribunals; two senior police officials; one police control room van driver, one from a public hospital police post; two participate in policy dialogue Taxi drivers 10 Incl. eight auto rickshaw drivers, two that drive both auto rickshaws and four-wheeled taxis and one Uber driver Other stakeholders 11 Incl. two academic researchers, two policymakers, two NGO representatives, two ER stretcher bearers, two ER security guards and one public ambulance administrator EMTs, emergency medical technicians; ER, emergency room; Incl., including; NGO, non-governmental organisation. Stakeholder meeting Participants Details --------------------- -------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Meeting 23 Including five legal experts, seven academic researchers, three government bureaucrats, one ambulance administrator, four trauma physicians and one senior police personnel Document review Documents Details ----------------- ----------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Documents 36 Including three legal judgements, five laws and regulations, eight online articles and news stories, six monographs and academic articles, nine policy briefs and agency reports. \*Individuals who participate in policy dialogue related with emergency medical response, trauma care and good Samaritan protections. †Including short interviews with one medical practitioner and four police personnel. **Stakeholder consultation**: Halfway through data collection (June 2018), we held a stakeholder workshop to share emerging ideas and get feedback. The workshop had 16 external participants ([table 1](#T1){ref-type="table"}) in addition to seven from our team, and included legal experts, academic researchers, government bureaucrats, ambulance administrators, physicians and senior police personnel. We took notes which informed our data collection and analysis. **Document review**: Thirty-six documents were reviewed to gather information on legal judgements, national and state policies and operational procedures. Documents were identified through internet searches and discussions with participants. Analysis {#s2-3} -------- Drawing on principles from general thematic analysis,[@R51] recorded interviews were transcribed by a contracted transcriber, and cleaned and checked by a team member (RA). We combined deductive and inductive approaches in the process of developing the codebook, using some predefined codes and allowing others to emerge during coding. We first applied the draft codebook to three transcripts, and further refined the codes. Next, two of the four coders (RA, RAr, VS, KB) coded all transcripts and notes. We consolidated our coding in NVivo and partitioned the data. Team members reviewed the coded data and developed early themes. Two members (KB, VS) further refined the themes, and finalised them after discussion with the entire research team. Data quality {#s2-4} ------------ We strengthened data quality by: (1) Triangulation --- we discussed concepts across stakeholder categories and cross-checked respondent statements with key documents; (2) Prolonged engagement --- we spent 14 months collecting data at regular intervals, allowing us to develop a deeper understanding of the topics; (3) Peer debriefing --- we had regular group meetings throughout the research process and (4) Respondent validation through a stakeholder consultation. Reflexivity {#s2-5} ----------- Our study was underpinned by a constructivist epistemology, where our goal was to capture the perspective of respondents, many of whom held different viewpoints. However, we also attempted to gain a positivist understanding of relevant processes. The research team was multidisciplinary, and we had regular discussions on epistemological approaches and the impact of these different approaches on data collection and interpretation. Patient and public involvement {#s2-6} ------------------------------ We did not involve patients in the development of the research question. A stakeholder consultation midway through the study was used to share emerging findings, get feedback and refine interview questions, and inform analysis. Findings will be disseminated at opportune district and national meetings. Results {#s3} ======= We start by presenting themes related with what happens at the scene, and at the hospital, where we focus particularly on medico-legal practices and inter-hospital transfers, which emerged as the primary deterrents to help from good Samaritans and a source of delays in access to medical care. Finally, we present themes related with strengthening the system of prehospital transport and care in Delhi. [Boxes 1--4](#B1 B2 B3 B4){ref-type="boxed-text"} present selected quotes organised by thematic headings. ###### Selected quotes related with what happens at the crash scene [CROWD BEHAVIOUR AT SCENE]{.ul} - 'it\'s mostly police and to some extent there are some you know bystanders who will help. It is also seen that the auto rickshaw drivers or the taxi drivers they help more than the normal general public.' MP3 - 'sometimes the situation becomes worst ... public start beating the driver. Sometimes their family members arrive. Patient is serious, bleeding too much, their relative does not bear after seeing this ... The Gujjar, Jatt, of Delhi do not talk, they start beating ... These people are well educated so start beating us.' TD9 [MODES OF TRANSPORT]{.ul} - '40% to 50% (of trauma cases) are brought still by the police. Right? Rest are being brought by bystanders or relatives ... other common modes of private transport or auto rickshaws which are very common, three wheeler auto rickshaws, taxis and then private four wheelers or private two wheelers also in fact, motorised two wheelers. Only about 3% to 5% ... are being brought in by the CATS ambulance services.' MP16 - 'I will say in Delhi, in the most cases PCR van, this is the reality, that lots of time passersby ignores, ambulance also do not reach, hospitals do not send but in 90% cases police's PCR van transport him to the hospital.' PP1 [CHOICE OF HOSPITAL]{.ul} - 'we do not feel courage to take him to the private hospital as we are unaware of his situation and who will pay for it. In private hospitals money has to be deposited before the treatment. And for the unknown I will transport to the public hospital because how will I pay, I can't afford it.' TD5 [MEDICAL CONCERNS WITH LAYPERSON TRANSPORT]{.ul} - '...ambulances are used as a transport vehicle. ... even in USA when there are highly trained paramedics, they are not supposed to do lot of interventions on the scene because that can harm the patient. So ultimately the primary objective is that patient reaches the definitive care facility as quickly as possible.' MP11 - 'Autos are not the ideal mode of transport because you can't make the patient lie down flat on the back ... but you know in our condition I think that is even better because rather than no transport the patient lies on the roadside bleeding to death which happens so many times over here. I think even if they just pick up the guy and bring I think it is great job done.' MP13 - '... the liability of the auto rickshaw driver for causing further damage is not addressed by the law. ... And if it has been raised somewhere, they might have beaten up the auto rickshaw driver, and that is all. But it has not been raised as a legal issue in a court of law.' LE1 CATS, Centralised Accident and Trauma Services; LE, legal expert; MP, medical practitioner; PCR, Police Control Room; PP, police personnel; TD, taxi driver. ###### Selected quotes related with what happens at the hospital [MEDICO-LEGAL PROCESSES]{.ul} - 'Policemen say you sit inside let him become conscious, you go after that. That's why the auto drivers hesitate even more.' TD1 - 'The police might want to settle the matter --- take a certain amount from each party and close the case.' LE4 - 'The image of the police, and its practices, are such that people do not want to get caught in a situation where the police might extort money from them and harass them just because they helped the victim.' Stakeholder Consultation - '... they feel there would be problems related to police case, it is a medico-legal case, ... Sometimes they want to help but they are more concerned about their own safety and not get entangled to the unnecessary problems.' MP11 - '(Medico-legal process) doesn't happen over here because it is a very cumbersome process and we can't afford to waste our time getting into those legalities. So we always prefer if patients, they are referred back to us, ... So we don't get involved in those formalities directly.' MP13, doctor at private hospital - 'It is my personal view that if we are helping someone our job is only to drop him to hospital and handover him to the hospital staff and after that we are free to leave. If this happens then all will help.' OS7, stretcher bearer - 'as medical professional we find it distressing to have the police in the ER.' Stakeholder Consultation - 'if they are put down as a witness, then they would be required ... to appear and provide evidence. ... That is what keeps them away from taking a patient to the hospital. ... I wouldn't, for instance, if I was a lawyer or a businessman, take somebody in my car, if I fear that I might have to go to court half-a-dozen times.' LE1 [INTER-HOSPITAL TRANSFERS]{.ul} - 'I think it is fairly common from private hospitals to be referred to government hospitals and one major reason is not the expertise, because expertise may be available in these private hospitals ... lot of trauma patients are transferred because they cannot afford the treatment in private facilities.' MP11 - 'We usually don't refer. Most people leave against medical advice after stabilisation sometimes for financial reasons etc after stabilisation. There is zero charge for stabilisation.' MP12; doctor; private hospital - 'Private hospitals are very clever. They know the provision. They will give you first aid and then ask you to deposit 50 000 rupees for further treatment or take him away. And you can't do anything. ... There have been two to three times cases where they (private hospitals) did refuse to give the body of the deceased to the family until and unless they deposit the expenses. ... after giving the first aid and some treatment they will ask the patient to deposit the money otherwise they will ask him to take the patient away. ... They (private hospitals) will just admit him and that's all, rest depends on the patient. He has to bring the money for depositing, if he doesn't on some pretext or the other the hospital refuse to admit him.' LE5 [LOGISTICAL AND OTHER PROBLEMS]{.ul} - 'I am transporting him but who will go with him? ... Because we face this major problem in hospital that either we ... should carry the injured person on stretcher or should park my three-wheeler in parking. If I will go to parking then 10 to 15 min would be waste for sure. Parking is not nearby.' TD5 - 'These days in (hospitals) five to six bouncers are posted for the safety of doctors that no one attacks them. When (the doctors/nurses) are sitting and gossiping, not helping anyone, then what will one do? ... will you not feel angry? Yes or no? ... If you want to do the real study then go to Safdarjung and see, the female is pregnant and in trouble but no doctor is helping her, four to six doctors, ladies are sitting and gossiping there ... Many times the doctors and female doctors are beaten up by the public, why did they beat them? Because what they do is just sit and gossip.' TD7 LE, legal expert; MP, medical practitioner; OS, other stakeholder; TD, taxidriver. ###### Selected quotes related with the effects of new legal protections for good samaritans Effects of new legal protections for good samaritans ---------------------------------------------------- - 'It is the duty of the hospitals to actually proclaim in big bold letters that have no fear, bring the injured here, so it's their duty in law. They are not doing it.' LE2 - 'how much impact that has made after about 2 years? ... I don't think it has got big impact ... it has not drastically changed the pattern of people who are bringing in patients to be very frank.' MP16 - 'earlier, it was such that if there was an accident, 'What if we only get caught?' People used to get scared. But now, it is not like that ... Now, the laws have ... changed. Because of that, they help.' MP1 - 'the police chowki (post) guy will ask for name/number. While the Supreme Court says that you do not need to give your information, these people will still ask.' LE4 - 'As far as awareness (of legal protections for good Samaritans) is concerned is minimal in the last 1 year we have trained about 3500 police officers across 10 states. Not a single one of them knew about this. So it is a huge uphill task to ... let the police and other authorities know that they now have some obligations and duties towards the good Samaritan ... the awareness level is still quite low and for us that reveals a big challenge in terms of implementation of the law.' OS5, NGO representative - 'Yes they do have to appear before the court and they will even after the good Samaritan law comes in. They will be cited as witnesses.' LE2 LE, legal expert; MP, medical practitioner; NGO, non-governmental organisation; OS, other stakeholder. ###### Selected quotes related with recommendations for improving the system Recommendations for improving the system ---------------------------------------- - 'we are worried about duplication‚ we\'re talking about integration. We do not want any new numbers. ... One number that works for all emergencies.' Policymaker, Stakeholder Consultation - 'if they (taxis) become part of the umbrella then obviously you can have any amount of ferrying vehicles ... control room knows that ok if there is not an ambulance but there is a taxi ... they will definitely improve the response time.' MP16 - 'if I phone and say my son has swallowed a marble, can you refuse? It's unethical to have a system only for road traffic injuries (RTIs).' Academic, Stakeholder Consultation - '(ambulances) are preferred, but if they take time to reach, it is better that the patient be shifted to the hospital as quickly as possible in any available vehicle.' MP1 - 'If we should encourage a structured system of transport (by autos/taxis) then it should be done properly. Whether it is a neck or back injury, an auto will be impossible to fit a person in. Maybe in a taxi...especially one like a PCR -- with a length-wise seat. Spine stability is important.' MP12; doctor; private hospital - 'Taxi is much better than auto. It has more space, jerking movements are also less.' MP7 - 'They should be trained, so they do not harm the patient during the transport and they know about the hospitals and the facility.' MP10 - 'If he (auto rickshaw driver) has an identity card, then he won't be stopped at all. Without an ID card the cops will stop and ask whether he (auto rickshaw driver) hit the injured.' PP5 - 'People don't mind giving their time for a cause ... They should be incentivised. ... But not too much.' MP5 MP, medical practitioner; PP, police personnel; RTIs, road traffic injuries At the crash scene {#s3-1} ------------------ **Crowd behaviour**: Respondents commonly noted that large crowds usually gather at crash scenes. While most people are primarily onlookers, many respondents noted that usually someone steps forth to manage the situation and/or help the victim. Such help includes calling the police, persuading drivers of passing vehicles drivers to transport the victim to a hospital, and contacting family members using information obtained from the victim or their belongings. **Modes of transport**: Many respondents asserted that police vans and auto rickshaws are the vehicles most commonly used for transport, with police vans being used more for victims with extensive visible trauma. > Police will be called first if the condition is very serious but sometimes what happens is a person is transported in auto and he dies on the way, then it will be asked that why haven't you called at 100 ... therefore first of all police should be called. TD8 Many respondents described the police as providing a de facto EMS for trauma. Senior police officers explained that Delhi Police started using Police Control Room vans equipped with stretchers and first aid supplies, and training patrol staff in first aid, starting in the 1980s. This infrastructure was eventually expanded and integrated into routine police operations. Many respondents strongly perceived that the Delhi Police operate a robust system with a widely known number (100), large fleet of vehicles and rapid response. Respondents familiar with other Indian cities observed that such coordinated use of police for emergency transport is unique to Delhi. Some respondents noted that public and private ambulances are common in Delhi but are used primarily for inter-hospital transfers. Some added that public awareness of public ambulances is growing and bystanders increasingly also call their number (102), but many noted that police vans arrive on the scene much sooner and transport victims without waiting for the ambulance. > ...one must be aware of the ambulance number but I don't know ... (we know that) if you call 100 number police vehicle will come transport. TD4 Taxi drivers (TD) cited humanitarian and spiritual reasons, as motivating factors for helping (*'as we are sowing so shall we reap later.'* TD4) but some noted that taxi drivers may be persuaded by bystanders or police to help. Police personnel noted, and two taxi drivers confirmed, that police sometimes pay taxi drivers to transport crash victims. Compared with four-wheeled taxis, respondents noted that auto rickshaw drivers helped more often because they are ubiquitously available, easier to accost and easier to clean if soiled by blood and bodily fluids. **Choice of hospital**: Most respondents agreed that the choice of hospital is determined by victims or their companions if they are alert, and the decision includes considerations of injury severity, ability to pay, types of facilities in the vicinity and where they know a doctor. If they are unable to decide, bystanders make the choice based on similar considerations. Taxi drivers predominantly preferred public hospitals and noted that despite the law and government assurances, for-profit hospitals don't initiate care without a guarantee of payment. > In private hospitals money has to be deposited before the treatment. And for the unknown I will transport to the public hospital because how will I pay (at a private hospital). TD5 Police typically transport victims to one of Delhi's nine designated public trauma centres unless the victim or their companions request otherwise, or in exceptional circumstances, such as a particularly severe crash that occurs near a major for-profit hospital. **Medical concerns with layperson transport**: Many respondents raised concerns with the use of auto rickshaws for emergency transport. Medical respondents often stated that laypersons can exacerbate neck and spine injuries. Some noted that auto rickshaws have a jerky motion and are not wide enough to accommodate supine patients, arguing that emergency transport should be provided by equipped ambulances and trained providers. > ... in auto space is very less. Patient's leg will get folded, hand will get fractured, neck will also get tilted. MP6; nurse However, when further probed, they usually added that despite such concerns they had never received a patient whose injuries were worsened because of transport by auto rickshaw. > ... the patient gets an injury, and by the time they get here, it is worse because of the movement ... But in my shift, none like that have come. MP1; nurse Such objections were more often raised by non-medical professionals or junior medical professionals. Senior medical respondents and/or those who participate in policy dialogue on EMS raised such concerns less frequently, and when they did, usually noted that the benefits of rapid response by laypersons outweighed the potential of exacerbating injuries. Two senior medical respondents also noted that in practice even ambulance crew do not take adequate spinal precautions. At the hospital {#s3-2} --------------- On arrival at the casualty or emergency department (ED) entrance, patients are transferred to stretchers and wheeled in, where they are triaged and directed to diagnostic services or treatment. Two processes of registration, medical and medico-legal, start nearly simultaneously with medical care. ### Medico-legal processes {#s3-2-1} Most major public hospitals have a police post, where a message is sent from the ED requesting the medico-legal register. Smaller public hospitals and private hospitals that do not have a police post maintain a medico-legal register, and hospital security contacts police when a medico-legal case is received. The doctor who first examined the patient fills the medico-legal form, documenting the event time, date, location (which determines police jurisdiction) and a medical description of injuries. Medico-legal registration is a starting point for police involvement, which almost all respondents noted is a deterrent to bystander assistance and medical care. #### Police presence in hospitals {#s3-2-1-1} Medico-legal processes result in a high-level of police presence in the hospital. We observed that police posts at major public hospitals were usually a busy site. Typical activities included police officers questioning companions of victims to determine crash location, making calls to police stations with jurisdiction to initiate investigations, obtaining contact information of witnesses and recording statements and overseeing the medico-legal register. We also observed substantial police presence at the ED, especially in the ambulance bay, the triage area and at the bedside. Here, in addition to obtaining testimony, police were helping negotiate settlements. > the police come between the person who has hit and who has been hit and then they negotiate. They will tell this ... 'ok I will leave you if you give me this much. MP16 If the parties don't settle, the victim, or their representative, registers a 'First Information Report' (FIR), which officially initiates a police investigation, and legal proceedings that can last years. > The major concern is that (it) would require them to make several journeys as witnesses to the trial courts, (which) are notorious for being ... slow ... courts and hospitals are two places where Indians don't want to go. LE2 Police respondents claimed that such negotiations are for cases involving mild injuries and that serious cases are 'cognisable' (ie, police officer has the authority to independently initiate an investigation) and are always investigated. However, other respondents noted that even serious injuries are settled with police mediation but carry the risk that the offending party may renege. Therefore, victims often wait for 10 to 15 days to confirm payment before asking the police to file an FIR. Several medical respondents noted that police presence is distressing to patients and medical staff and interferes with medical care. Further, they stated that medico-legal registration and testifying in court adds a substantial burden on doctors. (*'If an FIR is filed then the court will call the doctor ... It is definitely burdensome but we have to oblige.'* MP2) They cited this as a reason why some doctors and private facilities avoid engaging with medico-legal cases. #### Harassment of good samaritans {#s3-2-1-2} Forced interactions with police and subsequent visits to court were the most commonly cited reason that deterred people from transporting crash victims to hospital. > Police will call you, ask you, who, what, why ... you would be called in police station again and again. TD5 In addition to describing police interactions as unpleasant, respondents often pointed to more serious concerns. Taxi drivers, legal experts (LEs) and some other respondents commonly talked about good Samaritans being wrongly accused, and sometimes convicted, of causing the crash. Anecdotes from taxi drivers commonly included being unwillingly held at the hospital until the victim regained consciousness and absolved them of responsibility (*'Policemen say you sit inside, let him become conscious, you go after that.'* TD8). Many talked about police intentionally accusing innocent bystanders in an attempt to extort money, or because they had received bribes from the guilty party. Several respondents noted that police try to coerce dishonest testimony or rely on professional witnesses and close cases quickly. For example, one lawyer with experience in handling such cases indicated that victims are sometimes coerced to implicate bystanders, and that 'professional eyewitnesses' who provide false testimony are common. The police were not the only source of such harassment. Taxi drivers talked about doctors and nurses persuading them to share their contact information, which two nurses corroborated. > ... giving a contact number is not a big deal. We try to convince him. MP7, nurse ### Inter-hospital transfers {#s3-2-2} Medical and non-medical respondents talked extensively about patients being shunted between hospitals, leading to delays in medical care. Among the common reasons for transfers from public hospitals and small private hospitals was the absence of medical specialists, unavailability of beds and/or lack of medical services. For major for-profit hospitals that typically have the facilities and expertise to provide care, inability to pay was the most common reason. Respondents mentioned that often patients remain at private hospitals until they have exhausted their resources before moving the patient to a public facility. > referrals come from hospitals which are corporate or private hospitals, and patients when they exhaust their money, when their financial situation becomes very bad, they come to us. MP9; public hospital Some respondents noted that some hospitals violate the law by refusing to release the dead body, or retaining property (such as vehicles) until payments are made. Several respondents, including one from a private hospital, mentioned that private hospitals prefer not to accept trauma cases brought directly from the field to avoid medico-legal processes. Instead, some private hospitals encourage patients to go to a public hospital for medico-legal registration before returning for medical care. Most respondents mentioned that private hospitals are required by law to stabilise patients and provide first aid. However, many argued that for-profit hospitals would not be financially viable unless they charged for such services. > ultimately they are private hospitals. They run for profit. MP16 One respondent noted that for-profit hospitals have security guards at the gate that informally advise taking the patient to other public facilities. Others mentioned that in cases where the victim is seen by a medical professional, they often receive inadequate care because stabilisation, resuscitation and first aid are poorly defined concepts. A few respondents from public hospitals described instances where the condition of the patient worsened because they were transferred without being stabilised. Many noted that inter-hospital transfers occur without any communication leaving the receiving hospital ill-prepared to respond. ### Logistical and other problems {#s3-2-3} Several taxi drivers mentioned loss of work hours as a problem if they help take a victim to hospital. Many also raised other issues, especially parking. Unlike ambulances, which can be left unattended at the ED entrance, private vehicles have to park in the visitor's parking lot, which may be some distance and require parking fees. Importantly, taxi drivers mentioned (and we observed) that patient companions play an important role in unloading the patient from transporting vehicles, pushing the stretcher in the hospital and, more generally, advocating for resources (eg, medical attention, hospital beds, access to imaging services). Taxi drivers are unable to play this role while they are looking for parking. Many taxi drivers noted that they are much more willing to transport crash victims if there is an accompanying person. Beyond forced interactions with police, taxi drivers and other respondents also pointed to other forms of harassment at the hospital. Some mentioned hostile questioning by doctors and medical staff (*'Who are you? From where have you come? They ask like this...'* TD10), and, in some instances, being assaulted by agitated family members when they arrive at the hospital. (*'Sometime their family members arrive, and the patient is serious, bleeding too much, their relative does not bear after seeing this ... they start beating us.'* TD9). More generally, EDs were described by some as unpleasant environments. Respondents described incidents of violence at the ED, often directed at hospital staff who are perceived as not doing enough for patients, but sometimes also directed at good Samaritans who bring patients to hospitals. Our observations at the EDs showed numerous means for managing such violence, such as limited entry points, lots of security guards, signs that prohibited some items that can be used as weapons and heavily fortified doors and windows. Effects of new legal protections for good samaritans {#s3-3} ---------------------------------------------------- The government's recent Good Samaritan Notification instructed police and hospitals to protect good Samaritans, and ensure that private hospitals provide critical care.[@R49] However, our respondents stated conflicting opinions about whether the Notification had affected practices. Although several mentioned that good Samaritans were no longer detained at hospitals, or forced to provide their contact information, many respondents said that practices perceived as harassment remained unchanged. This was usually attributed to a lack of awareness of the new legal protections. However, legal respondents who participate in court proceedings noted that the Notification was unlikely to help because police practices that are perceived as harassment have always been unlawful. In particular, they noted that the law has always been interested only in the testimony of witnesses, and the Notification doesn't change this. Detaining non-witnesses and coercing testimony has always been unlawful. Nevertheless, most respondents agreed that the Notification has positive features, such as limiting how often witnesses and medical professionals are required to testify in court. The Notification also requires hospitals to post signs highlighting legal protections for good Samaritans but, consistent with our observations, respondents said that it was very rare for hospitals to post such signage. > We had put up a noticeboard saying that nobody had to give their name but we have removed. ... maybe because of some renovation. MP2; doctor; private charitable hospital The Notification also emphasised a previous Supreme Court ruling that compels all hospitals to stabilise crash victims and provide first aid but many respondents noted that hospital practices were unchanged. Respondents noted that the problem is unlikely to be fixed unless financial mechanisms are created to reimburse private hospitals for the costs of providing care. They described several attempts by state governments to create cashless insurance systems and current attempts by the federal government to establish universal health coverage that may help. Recommendations for improving prehospital care and transport in Delhi {#s3-4} --------------------------------------------------------------------- Almost all respondents agreed that lay responders had an important role in transporting trauma victims to hospital especially since it is already common practice. However, a few cautioned against inadvertently doing harm to the current system of police-based transport in Delhi. Most respondents emphasised that attempts at strengthening prehospital care should be part of a coordinated system of emergency response. The following issues consistently emerged in our interviews. - Single call number: Many respondents commented on the proliferation of emergency numbers (fire, police, ambulance, women safety, etc) and the need for a single nationwide number. - Responding to all emergencies: Some respondents noted that an EMS should respond to all emergencies because restricting to specific causes (eg, accidents) is not ethically justified. - Include private ambulances: Some respondents recommended integrating private ambulances into the coordinated EMS. Private ambulances for inter-hospital transfers are common in Delhi. - Use of appropriate transport modes based on injury severity: Most respondents felt that taxis were appropriate for minor injuries but diverged in their views about severely injured victims, which many felt should be handled by paramedics and ambulances. - Importance of rapid transfer to hospital: Many senior respondents commented on the trade-off between providing medical care in a prehospital setting and in rapid transport. Most agreed that since it is difficult to provide advanced interventions in the field, victims should be transferred to hospital by whatever means available. - First aid training: All respondents noted the importance of training of first responders (lay or professional). - Appropriate financial compensation: On the issue of monetary incentives for lay responders (such as taxi drivers), all taxi drivers felt that they should be compensated for their time. Other respondents took more nuanced positions. Many felt that public recognition is the most important incentive, and that monetary rewards should be carefully calibrated to not create perverse incentives. Some felt that monetary rewards shouldn't be offered at all. Respondents also noted that the new policy of the Delhi government to give rupees 2000 (\~\$30) to anybody who transports a crash victim to hospital is unlikely to work unless there are real protections for good Samaritans. Medical respondents noted that so far, the reward is rarely claimed. - Managing EMS costs: Respondents who participate in policy dialogue pointed to the high cost of ambulances and the savings expected from using lay responders. Cost issues weren't raised by other respondents. - Mechanisms to give legitimacy to lay responders: Some respondents alluded to class perceptions, asking if victims, families, bystanders and police would trust taxi drivers to behave responsibly. (*'the first thing is trust development ... between the taxi drivers and the victim because ... pregnant victims and ... ladies ... don't enjoy much of a trust with taxi drivers'* MP9). They suggested that participating drivers should carry visible symbols (eg, badges, medallions, certificates) of their association with the EMS. Several respondents noted that such legitimacy should be sanctioned by police and the medical system, and provide participating taxi drivers with several privileges, including leaving their vehicles unattended in the ambulance bay, and not being coerced into sharing contact information, providing statements or being identified as witnesses. Although such issues related with establishing trust and legitimacy were not raised by taxi drivers, their responses suggested that they assumed that their participation in a taxi-EMS would confer protections from harassment. We asked all interviewed taxi drivers if they would be willing to participate in such a system. All agreed, often with enthusiasm. - Legal feasibility of a taxi-EMS: We asked legal experts and policymakers if they expected the drivers of a purpose-built taxi-EMS to have legal protections intended for good Samaritans. Respondents agreed they would because participation was voluntary. They agreed that the tort liability of those who help has never been raised in the courts in India but one respondent added that if the taxi-EMS is legally challenged, it is possible that some forms of transport, such as auto rickshaws, may not be viewed as appropriate by the judiciary. Discussion {#s4} ========== India is in the midst of making substantial changes to national health and transportation policies,[@R52] and improving trauma outcomes is the focus of significant policy dialogue. In the last few years, there has been extensive advocacy from NGOs,[@R47] Supreme Court judgements,[@R48] executive orders[@R49] and substantial national and international news coverage focused on improving access to care for trauma victims.[@R55] Our study provides important insights relevant to this dialogue by providing a rich description of what happens to trauma victims in the field, at hospitals and in the medico-legal system. In the discussion that follows we highlight key legal, medical and social issues, focusing specially on implications for a layperson-EMS. Addressing legal barriers {#s4-1} ------------------------- In India, deeply entrenched medico-legal practices force good Samaritans into extended and often onerous interactions with police. Surveys suggest that over half of law-abiding Indian citizens fear the police,[@R57] and our results illustrate why. Our respondents shared many anecdotes where good Samaritans were coerced into being witnesses, held against their will or much worse, wrongfully implicated in causing the crash. Furthermore, medical professionals dislike adhering with medico-legal practices because they interfere with patient care. India's recent Good Samaritan Notification[@R49] tries to circumscribe allowable police practices but our findings suggest that the Notification appears not to have affected medico-legal processes substantively. This is likely because the executive order doesn't stop police from questioning witnesses, and the most irksome police practices, such as coercing testimony, were already illegal. The Notification also instructs local governments to give rewards to bystanders, which pale in comparison to the medico-legal burdens. This may explain why only 4% of good Samaritans who helped trauma victims have claimed the financial incentive of rupees 2000 (\~\$30) being offered by the Delhi government.[@R15] While WHO recommends that countries establish legislations that protect good Samaritans,[@R13] our study highlights that the issues and legal remedies will likely vary based on country-specific conditions. Globally, good Samaritan laws are typically framed as either duty-to-assist or protection-against-liability,[@R58] which may not make sense in many LMICs. Consider, for instance, that good Samaritan laws in the USA successfully helped alleviate physician concerns that they would be sued for malpractice if they helped at accident sites.[@R59] However, China's new law protecting good Samaritans from the liability of exacerbating injuries fails to address their main concern of being implicated of causing the accident.[@R60] Thus, it is important that LMICs assess their particular situations and evolve appropriate countermeasures for protecting good Samaritans. For our specific example, protecting taxi drivers against police harassment would likely require the taxi-EMS to have official police sanction, and the taxis to carry visible symbols (eg, medallions or certificates) of their authority to provide emergency transport. Addressing healthcare system barriers {#s4-2} ------------------------------------- Although a layperson-EMS aims to address transportation barriers, our findings highlight other important sources of delays in India's healthcare system. Notably, care at for-profit hospitals is often delayed until it is established that somebody will pay for victims who may be poor, unaccompanied and/or disoriented. Although an amendment to the Motor Vehicles Act has required all hospitals to stabilise patients since 1994,[@R62] our respondents described many anecdotes of how for-profit hospitals sidestep requirements. Such practices will likely continue until there is a mechanism for hospitals to recoup costs, such as through no-fault universal health coverage, as recommended by the Sustainable Development Goals.[@R63] India is in the midst of major legislative and policy reforms to its healthcare[@R43] and motor vehicle insurance sectors,[@R53] whose implementation could create such a financial mechanism. However, until it is established that for-profit hospitals reliably provide care, good Samaritans should take victims with uncertain financial means to public hospitals. For a layperson-EMS, this likely means transporting to hospitals that have agreed to participate and have the requisite capacity. Addressing social barriers {#s4-3} -------------------------- Our findings suggest that a layperson-EMS could face opposition from various stakeholders. The underlying rationale for a layperson-EMS is that rapid transfer to hospital is of overriding importance for improving outcomes. Although our senior medical respondents understood this well, junior medical respondents commonly expressed concern about exacerbating spinal injuries. Similar apprehensions were also raised by some of our non-medical respondents. Although such concerns are likely overstated,[@R19] the social acceptability of a layperson-EMS will likely require its medical legitimacy to be accepted by the public. Social class issues were the subtext of many reactions to our proposed taxi-EMS. Often these took the form of a strong bias against the vehicle (especially auto rickshaws) and the entrenched class hierarchies of cities such as Delhi, but also concern of whether taxi drivers were responsible actors who would be trusted by, for instance, pregnant women. Regardless of whether such apprehensions have merit, ensuring social acceptability of a taxi-EMS may require that the system is viewed as a semi-professional operation with visible symbols of authority to act in an emergency, and with trained drivers who appear to be following a prescribed protocol. Building a complete system of emergency care {#s4-4} -------------------------------------------- Our study finds that Delhi already has key EMS components that could potentially be integrated and expanded into a complete system of emergency care. Notably, our study highlighted that the police in Delhi already transports trauma victims to hospital as a routine part of operations. In effect, they respond to accidents like a coordinated non-medical EMS, with a control room and dispatch protocols, fleet of vehicles equipped with first aid and victim transport capabilities, providers with rudimentary training and empanelled hospitals.[@R64] In fact, contrary to a popular belief that trauma victims face large delays in getting to hospital, many of our frontline stakeholders noted that most severely injured victims in Delhi are already transported rapidly by police. Partly for this reason, they tended to view the taxi-EMS as an additional component to police operations intended for less severely injured victims. Although the use of equipped police vehicles to transport trauma victims is unique to Delhi, dispatcher-coordinated police operations are common in many major urban centres in India,[@R65] and likely, globally. If these capacities can be extended to emergency transport, they may provide LMICs a cost-effective pathway to coordinated EMS. Delhi's coordinated police response, as well as our hypothetical taxi-EMS, focus primarily on accidents. However, traumatic injuries only accounts for about one-fifth of all emergency health conditions.[@R66] Our senior respondents noted that it would be unethical for an EMS to not respond to all health emergencies. Although it is unclear how much the mandate of a police-based operation can be expanded to incorporate other medical services, it may be possible to efficiently link it with other services. Delhi's police already contact the Centralised Accident and Trauma Services public ambulance system, which is often unable to meet demand. However, the supply of ambulances in the EMS could be dramatically increased by including private ambulances, which are commonly available in Delhi but used primarily for inter-hospital transfers. Other governance challenges associated with developing a coordinated system in Delhi include its unique political system (Delhi's governance is shared between the federal government, Delhi's state government and four municipal governments, and the broader National Capital Region includes two other states with their own ambulance systems). Thus, other LMIC settings interested in developing an EMS should assess their current situation of prehospital transport and the availability of existing components of an EMS system that may be integrated and expanded. Finally, in addition to strengthening prehospital transport, it is important to improve the quality of care provided at hospitals. Consider that recent efforts by the Indian government (including a conditional cash transfer) succeeded in increasing births at facilities but had no effect on maternal and neonatal mortality.[@R67] Similarly, Gupta *et al* [@R68] describe substantial delays in care for traumatic brain injuries at major trauma facilities in India reducing gains from improving the prehospital system. In summary, improving trauma outcomes in India and LMICs requires understanding how victims access care at present, and developing systems that help victims get quickly to a medical facility where they receive high-quality care. We are grateful to the many researchers and practitioners who helped us identify relevant documents and connect with stakeholders. **Handling editor:** Stephanie M Topp **Contributors:** KB, VS, MV, GT and DM contributed to study conception. KB and VS developed the research protocol. RA, RAr, VS, KB designed interview guides, conducted interviews, coded data and developed preliminary themes. KB and VS refined and finalised themes. KB and VS wrote the first draft of the manuscript. All authors generated hypotheses, interpreted findings and critically reviewed the manuscript. **Funding:** This work was supported by the US National Institutes of Health (NIH)/Fogarty (grant number 5R21TW010168). **Competing interests:** None declared. **Patient consent for publication:** Not required. **Ethics approval:** This project was approved by the Institutional Ethics Committees/Boards of the University of Chicago, St. Stephen's Hospital and Indian Institute of Technology, Delhi. **Provenance and peer review:** Not commissioned; externally peer reviewed. **Data availability statement:** No data are available.

Q: What is the reason behind Gita favoring the SAtvika way over others? Usually people who have read Gita, would say that NishKAma Karma is the way of "Karma yoga". Numerous verses suggest that, NishkAma Karma is SAtvika way of life. SakAma karma is RAjasika way & Vikarma is TAmasika way. Even attempting to perform Akarma is also sometimes considered TAmasika way. Now everyone is aware that, The supreme Purusha / Brahman (the ultimate "I/Me") is beyond 3 modes of nature: Sattva, Rajas, Tamas. A person with any predominant quality should have the same right on Moksha. As discussed in this answer, there is a difference between NishkAma Karma ("Karma Yoga") and NishkarmatA ("Moksha or Jeevan Mukta"). Why can't a person with RAjasika nature do "Karma yoga" with SakAma Karma & attain NishkarmatA? Similarly, why can't a TAmasika person do "Karma yoga" with Vikarma and attain Moksha? IMO People like ShishupAla, Hiranyakashipu, RAvana, Kamsa, who probably attained Moksha, were not doing NishkAma Karma. A: Because Satva Guna helps in approaching spirituality thought it doesn't lead one to Moksha. See the nature of three Gunas as described in Bhagavag Gita 14.11 When the illumination that is knowledge radiates in this body through all the doors (of the senses), then one should know that sattva has increased greatly. 14.12 O best of the Bharata dynasty, when rajas becomes predominant, these come into being: avarice, movement, undertaking of actions, unrest and hankering. 14.13 O descendant of the Kuru dynasty, when tamas predominates these surely [i.e. without exception.-M.S.] come into being: non-discrimination and inactivity, inadvertence and delusion. Also see the next birth according to the dominance of particular Guna while departure: Satva : attains the taintless worlds of those who know the highest Rajas : born among people attached to activity Tamas : birth among the stupid species. 14.18 People who conform to sattva go higher up; those who conform to rajas stay in the middle; those who conform to tamas, who conform to the actions of the lowest ality, go down. So, it's very obvious that there are very less chances of obtaining true knowledge for the followers of Rajas and Tamas Gunas. Agree that Satva Guna will not lead one to Moksha, for approaching Moksha, one needs to go beyond all three Gunas. As preached in 14.6th verse : "it binds through attachment to happiness and attachment to knowledge." However it is better than Rajas and Tamas as it helps in purifying mind and in becoming eligible for one to obtain the true knowledge. Q. Why can't a person with RAjasika or TAmasika nature do "Karma yoga" with SakAma Karma & attain Moksha? As mentioned above, Rajasika or Tamasika mind is not eligible to understand or obtain the right knowledge that is required for Moksha. So, regarding your queries you can consider that Rajasika or Tamasika Sakama Karma Yoga is wrong tool which will never lead one to Moksha and comparatively Satviak Nishkama Karma is preferable (right tool) which can lead one to the Moksha.

This site uses cookies to provide you with a more responsive and personalised service. By using this site you agree to our use of cookies. Please read our PRIVACY POLICY for more information on the cookies we use and how to delete or block them. Oil & gas With the fluctuations in commodity pricing, the industry is looking for ways to improve operations, capital structures, and reduce costs as it navigates yet another inevitable cycle. Our clients range from National Oil Companies to middle market services firms venturing overseas for the first time, so the scope of our experience and insight is broad—yet very accessible through a partner-led service model and seamless global coordination across geographies and services. BDO helps E&P, midstream, downstream, mine operators, and services clients around the world to thrive beyond simple compliance. In addition to traditional audit and tax compliance services, we advise companies and their investors on complex issues including mergers and acquisitions, cost management strategies, risk management, and business process improvement. Beyond compliance, our partner-led approach can benefit clients in a number of ways:

Q: If $f(x+1)=f(x)$ then? Let $f: \ \mathbb{R} \rightarrow \mathbb{R}$ be a function such that $f(x+1) = f(x)$, $\forall x \in \mathbb{R}$. Then which of the following statement(s) is/are true? $f$ is bounded. $f$ is bounded if it is continuous. $f$ is differentiable if it is continuous $f$ is uniformly continuous if it is continuous I took the example of $$f(x) = \begin{cases} \tan(\pi x) & x \neq \displaystyle \frac{n}{2}\\ 1 & x = \displaystyle \frac{n}{2} \end{cases}$$ $n \in \mathbb{Z}$. This function satisfies the given condition and $f(x)$ is unbounded, so we can exclude the first option. Now since the example we took is not continuous at $x = \frac{n}{2}$, I think if $f$ satisfies the given condition and is continuous then it is bounded. Is there any theorem which states: if $f$ is periodic and continuous then it is bounded? If yes, how to prove it? I think we can even discard the third option by defining a triangle function $$ f(x) = \begin{cases} x & 0 \leq x \leq \displaystyle \frac{1}{2}\\ f(x)=1-x & \displaystyle \frac{1}{2} < x \leq 1 \end{cases}$$ $$ f(x+k) = f(x), \ k \in \mathbb{Z} $$ now this function is continuous all over $\mathbb{R}$ but not differentiable at $x = \frac{n}{2}$. The only left option is the 4th one. I know the basics of uniform continuity but not how to solve in this case. If $f$ is periodic and continuous, does this imply that $f$ is uniformly continuous? How to prove this if it is true? A: Point 2 and 4 essentially boil down to the following fact: Consider $$ f|_{[0,1]} $$ that is $f$ restricted to the interval $[0,1]$. This interval is closed and bounded, hence compact. You have that continuous functions on compact intervals are bounded and uniformly continuous. Can you conclude using the fact, that $f$ is periodic with period $1$?

OMAHA, Nebraska (Reuters) - Democratic U.S. presidential hopeful Barack Obama agreed on Thursday to hold two more debates with rival Hillary Clinton before March 4, officials from his campaign said. One debate will take place on February 26 in Cleveland, Ohio. The other will take place in Texas on a date to be determined. Ohio, Rhode Island, Texas and Vermont hold nominating contests on March 4. Clinton had pushed to hold five debates in that period, but Obama rejected that, saying he needed to spend more time at campaign events with voters. Candidates usually take time out of their campaign schedules to prepare on the days that debates are held.

Introduction {#Sec1} ============ Has the time come to put to bed the concept of a harm threshold when discussing the ethics of reproductive decision making and the legal limits that should be placed upon it? This is the question asked by Anna Smajdor in her article in this issue. For her, the answer is a resounding yes. She claims---after outlining the concept of the harm threshold in reproductive decision making, noting its many proponents in the philosophical community, and observing its inclusion in legal and policy documents related to reproduction---that no entity can be harmed by being brought into existence, regardless of the extent to which they will suffer once born. Smajdor comes to this conclusion by appealing to a well-known literature that supports the notion that the act of creation cannot be identical with the acts of harming and benefiting. For if, in accordance with this literature, she suggests, existence should not be considered to be a 'real' predicate---that is, if existence cannot be considered an attribute of an object and thus fails to add to the concept of a thing---no entity can be harmed or benefited by being born. In short, her argument is based on the following simple claim: there does not exist a 'logical connection between the assertion that some lives are not worth living, and the claim that such people are harmed by being conceived' \[[@CR1]\]. Thus, her article, although she does not choose to characterize it in this way, actually constitutes the suggestion that those who subscribe to a harm based and person affecting account of morality (or of the limits of law) must acknowledge that, in holding this view, they are also required[1](#Fn1){ref-type="fn"} to accept the conclusions of a remarkably *strong version* of a problem in philosophy, known as the 'non-identity problem'. In this commentary, we defend the claim that despite the conclusions of the non-identity problem, there are good moral reasons, based upon consideration of the suffering that would be experienced by the individual concerned, not to decide to bring him or her to birth. We have in mind cases in which a foetus or embryo is likely to become an individual whose life is variously described in the philosophical literature as 'empty of all the things that make life worth living' \[[@CR2]\], 'dominated by pain and suffering' \[[@CR3]\], 'intractably miserable' \[[@CR4]\], 'not worth living' \[[@CR5]\], or 'worse than no life at all' \[[@CR6]\]. Our arguments are, however, more than mere commentary. We aim to settle some tenacious misunderstandings of the logic of this corner of moral discourse by exploring and explaining the difference between the use of comparative and non-comparative accounts of harm in non-identity cases and the problems that occur when such accounts are conflated. We thus begin our commentary by providing a reconstruction of the major components of the arguments contained within Smajdor's article. We then question whether Smajdor's use of Derek Parfit's arguments in her own is a charitable one that truly captures the spirit in which they were made. After this, we note that although a threshold account of prenatal harm may not be compatible with comparative accounts of harm, the logical inconsistencies Smajdor associates with this account do not occur on non-comparative accounts of harm, such as the one championed by one of us, John Harris, in his book *Wonderwoman and Superman*. Doing away with the harm threshold: reconstructing, summarising, explaining, and situating Smajdor's position in relation to our own {#Sec2} ==================================================================================================================================== Smajdor begins her attack on the harm threshold in reproductive decision making by noting the benefits that are often associated with harm-based, person-affecting accounts of morality and the proper limits of legislation. She notes, for example, that although she does not subscribe to the belief 'that harm to offspring is the sole focus of moral concern in reproductive decisions' \[[@CR1]\], there is something to be said for a harm-based approach to legislation and morality. This can be found, she suggests, in the fact that a focus on the harms our choices may impose on others are more identifiable and less subjective than a focus on deontological principles or impersonal and free-floating harms. She thus suggests that because of this more empirical focus, harm based approaches 'may be a useful interface between morality and legislation' \[[@CR1]\]. She then observes, however---in recognising the conclusions of the non-identity problem, as have many before her, including ourselves (see, for example, \[[@CR7], [@CR8]\])---that this approach seems to offer very few of the benefits it provides in cases of harms to extant persons in the context of reproduction. This is so because if we limit moral and legal criticism only to those acts which can be said to negatively affect the interests of some particular entity, it turns out that our reproductive decisions will, in many cases, have little or no moral content, despite our intuitions to the contrary. That is, if we also accept the relatively uncontroversial proposition that our coming into existence is highly precarious---'dependent on the conditions under which we and our descendants procreate, with the slightest difference in the conditions of conception sufficient, in a particular case, to \[ensure\] the creation of a different future person' \[[@CR9]\]. There are a number of versions of what might be called 'the precariousness proposition', which produce slight differences in the kinds of circumstances in which non-identity cases are generated. This is so as the particular version to which one subscribes depends greatly on one's views concerning what it is that makes one numerical person the same numerical person over time and change. However, the version to which Smajdor appeals in her article seems to be based on an acceptance of the precariousness proposition as it is formulated in the work of Parfit in his two versions of the 'time dependence claim' (TDC). As she does not make it clear to which version she subscribes---and this actually makes little difference in the cases she considers---we will assume her allegiance is to the slightly weaker form, which, as Parfit notes, is *in fact true*, although not necessarily so:"TDC 2: 'If any particular person had not been conceived within a month of the time when he was in fact conceived, he would in fact never have existed'. \[[@CR10], p. 352\]" This version of the precariousness proposition may be interpreted in three different ways. It can be seen, firstly, as a causal claim regarding the importance of our genome for the development of personal identity (understood as psychological connectedness and continuity) by noting, for example, that 'differences in \[genetic\] material make for later differences in virtually all aspects of a person: change the sperm, and there will be substantial changes (of both a physical and psychological kind) in the later human being' \[[@CR11]\]. Secondly, it can be viewed as a weak version of Kripke's origins claim regarding the importance of our material origins for numerical identity on biological accounts of personal identity over time. This interpretation suggests that just as all material things must have their origin in at least some of the matter from which they are constituted, so too must all numerical persons have their origins in, *inter alia*, the genetic material from which they are constituted in order to be considered the same numerical entity \[[@CR8]\]. Thirdly, however, one might view it as a temporal or environmental claim regarding the importance of possible epigenetic factors and others flowing from the time, place, and manner of our conception. Time, place, and manner may thus embrace factors such as differences in the method of conception, gestational environment, maternal nutrition, the general external environment, and exposure to potentially teratogenic substances during pregnancy. Depending on one's interpretation, it can therefore be noted that non-identity is not simply related to conception and factors tied to the timing of conception, nor, as the Parfit of *Reasons and Persons* perhaps believed, simply to genetic identity \[[@CR8], [@CR11], [@CR12]\]. However, Smajdor's interpretation of the claim does seem to fall into either the causal or Kripkean camp, as she notes numerous times in her article, the importance for personal identity of our being conceived from the particular egg or sperm from which we were conceived. This means that, whilst non-identity may not occur in cases of straightforward prenatal harm, such as when a pregnant woman ingests a teratogen or a foetus is injured in some other way during pregnancy, it will be commonplace in cases of genetic decisions regarding, for example, with whom we choose to procreate and when we wish to do so. For this understanding of the TDC2, when paired with a person affecting account of morality that rests on a comparative account of harm, yields a particular prescription. This is that many reproductive decisions turn out to affect not the interests of persons created as a result of such decisions but their identities, and thus cause no harm to those created as a result. Indeed, the trap of non-identity is not only evidenced in cases of seemingly harmful conceptions. Many people at the time of World War II, for example, including the parents of one of the present authors, decided to await the result of the war and the defeat of Nazism before conceiving or conceiving again. Such people believed they were somehow acting in the interests of the child that would be born to them, despite the fact that they seemed to be 'guilty' of falling into the trap of non-identity. It should be noted too that non-identity poses an 'intriguing theoretical obstacle' \[[@CR13]\] to questions of intergenerational justice and, as has been most recently noted, to cases of affirmative action and of apology or reparation for historic injustices. For, ironically, were it not for the wrong that was done to the ancestors of those now seeking apology or compensation, the latter would almost certainly never have existed \[[@CR14]\]. Smajdor illustrates this point in the reproductive case by providing an example of a woman who is receiving treatment for syphilis and must make a choice between conceiving now and giving birth to a child with congenital syphilis, or waiting until after she has been cured and giving birth to a 'healthy' child (free from congenital syphilis). Like Parfit, Smajdor suggests that despite many people's intuitions to the contrary, the woman has little reason based on the interests of the children she would create to choose to wait. For, whilst many of us tend to believe that it is better to be born without a disability than with one, as disability is, by definition, disadvantageous, person-affecting morality actually gives us little reason based on the interests of the child created to wait to conceive. If one accepts the TDC2 and holds too that our actions only have moral status when they affect the interests of distinct numerical persons, one can see that regardless of the decision she makes, her child will not be harmed as different children will come to exist depending upon her choice. For, whilst it is true that if she conceives now, her child will be born with congenital syphilis---an undoubtedly harmful condition which may result in cerebral palsy, hearing loss, and musculoskeletal deformities---should she wait to conceive a child free of syphilis, a different child will be born as 'a different egg and sperm will be involved, resulting in a genetically different individual' \[[@CR1]\]. The child the woman could conceive now could not exist without suffering from congenital syphilis. Being brought into existence suffering from such a condition cannot harm him. For, whilst he might rationally prefer a life without his affliction, the alternative for him is not a life without the effects of congenital syphilis, but no life at all, as syphilis is a condition of his very existence. Here, however, is where Smajdor takes her position to depart from Parfit's. For, whilst she agrees that in the case of congenital syphilis, the woman would not harm her child by bringing him into existence with this affliction, non-identity statements are not always so simple. For although this is not always the case, such statements often come with a qualifier that warns against the creation of lives that are 'empty of all the things that make life worth living' \[[@CR2]\], 'dominated by pain and suffering' \[[@CR3]\], 'intractably miserable' \[[@CR4]\], 'not worth living' \[[@CR5]\], 'worse than no life at all' \[[@CR6]\]. This qualifier can be found in the works of many authors who write on the non-identity problem. Smajdor, for example, notes that Robertson suggests that although it is normally the the case that 'a child's interests are hardly protected by preventing that child's existence..., this objection would not hold if the ... conditions of his life would be so harmful to him that from his perspective he would prefer not to live' \[[@CR15], p. 75\]. It is this qualifier with which Smajdor takes issue. For, she holds that its addition entails a commitment to a questionable view: the view that 'a child born with a worse disease than congenital syphilis *could* have been harmed---if the disease is so terrible as to mean that she does not have a minimally acceptable quality of life' \[[@CR1]\]. In other words, she claims that to add this qualifying phrase entails a commitment to the view that conception can constitute a harm to the child in the latter but not the former case because 'a threshold has been passed ... which was not breached in the case of the child with congenital syphilis' \[[@CR1]\]. Despite the fact that Smajdor fails to truly unpack the threshold account of harm as it is said to apply to non-identity cases, her characterisation of the account is accurate albeit bare. For, those who subscribe to a threshold account of harm in such cases should be seen to hold that some procreative choice made at T~1~ harms a person if and only if it causes into existence a person who falls below some normatively defined threshold of wellbeing, interest satisfaction, etc. For Smajdor, such accounts are deeply problematic as she is sceptical about the existence of a 'logical connection between the assertion that some lives are not worth living, and the claim that such people are harmed by being conceived' \[[@CR1]\]. After a rather long section in which she notes the seeming arbitrariness of a threshold account of harm and a number of troubling conclusions associated with this \[[@CR1]\], she provides support for her scepticism by asking the reader to consider Kant's refutation of Anselm's ontological argument for the existence of God. In his *Proslogion,* Anselm claims to derive the existence of God from definition: the concept of God as 'something than which nothing greater can be thought' \[[@CR16]\]. He held that if such a definition is true, God must exist in reality, since if He does not, a greater being can be conceived of: one than which nothing greater can be thought, and which, in fact, exists. Kant however, argued that Anselm committed a grave error in his argument, suggesting that although Anselm treats existence as a property that things may either possess or fail to possess, to say that some entity exists is not to confer existence on it. Instead, it is to say that the concept of the thing is exemplified in the world, just as to say that some entity does not exist is not to state that a thing lacks the property of existence but to say that the concept of that thing is not exemplified in the real world. In other words, Kant argued that a God that exists is identical to a God that does not. For, whether something exists or does not exist does not add to or alter the properties it possesses, it is the mere positing of a thing: 'a hundred real thalers do not contain the least coin more than a hundred possible thalers' \[[@CR17], pp. B626-7\] and 'the real God is not a few degrees more perfect than a conceptual one' \[[@CR1]\]. With this done, Smajdor suggests that we may straightforwardly apply Kant's argument to the act of creation and the question of whether an entity can be harmed by creation itself. For, she notes, 'the act of creation can be construed uncontroversially as the act of bringing something into existence,' and thus, 'whatever is logically true of existence in general should be true of creation insofar as it is the conferring of existence.... If existence itself cannot entail any other property, then it follows that the mere act of giving existence cannot encompass the act of conferring any property---other than existence---on the entity which is created' \[[@CR1]\]. With this in mind, Smajdor concludes that creating something, or bringing it into existence, cannot be the same as harming it. For, although harm is not a predicate in the usual sense, the fact of having a harmful genetic constitution is. It qualifies an entity in the same way as other predicates. Thus, she suggests that 'if we cannot make X greater, more perfect, or more valuable by bringing it into existence, neither can we harm X by bringing it into existence however greatly X must suffer' \[[@CR1]\]. She therefore concludes:"There is no specific act that can be construed as harming a future child when the child's condition is directly linked with the circumstances surrounding its conception. Nor can these questions be a matter of degree, since the logical and metaphysical constraints that prevent us from concluding that a child born with a moderate amount of suffering has been harmed apply equally to all cases of creation. \[[@CR1]\]" Is Smajdor's characterisation of Parfit's position fair? {#Sec3} ======================================================== With the major components of Smajdor's argument explained and laid out above, we now return to the point at which she takes her position on the possibility of harming by the act of creation to differ from Parfit's. For, we contend that the characterisation she offers of Parfit's view on the matter of harms to individuals with 'lives that are less than worth living' is, at best, uncharitable, and at worst, based on a misunderstanding of the claims made by Parfit on this matter. The point at which she holds her position to diverge from Parfit's occurs just after an acceptance of the conclusions of the non-identity problem in the case of the child with congenital syphilis. For, as is noted above, she and Parfit agree that in this case there is little reason for the woman to choose to wait based upon the interests of the child she creates. Her choice is a choice between lives as opposed to a choice of whether to harm or benefit her child. However, whilst this is so, Smajdor argues that Parfit does not discount the possibility that there is a point at which the woman's child could be harmed by his conception: the point at which this child's life would be less than worth living, dominated by suffering, or where the quantity and quality of whatever it is that makes life worth living falls below some threshold level, such that the harms he would suffer throughout his life outweigh its pleasures. Smajdor, however, denies that this could be the case, holding that even if the woman's choice was between a worthwhile and a less than worthwhile life, no harm would be done to the child created should she choose to bring to birth a child whose life falls below this threshold level. She characterizes Parfit's view regarding lives that are dominated by suffering as follows: 'that the child could not have existed without that condition does *not* prevent us from concluding that \[he\] has been harmed. A threshold has been passed in the latter case, which was not breached in the \[former\] case' \[[@CR1]\]. She then explores what Parfit might mean by this: asking *why* Parfit should hold that in the case of congenital syphilis the child created cannot be harmed by his mother's choice, but would be harmed should he suffer more seriously. What, she asks, is it that makes the suffering of the child bear on questions of the morality of the mother's actions in the latter but not the former case? Why does Parfit seem to divorce the concept of harm from its normal relationship with suffering, turning it into a mercurial entity that flashes into existence only in certain very specific circumstances? \[[@CR1]\] After all, Parfit claims, as do many others who accept the conclusions of the non-identity problem, that non-identity is a logical and metaphysical problem as opposed to one relating to the degree of suffering an individual must endure before he can be deemed harmed, all things considered. The mother is---according to its logic---not morally responsible 'because there is no causal mechanism by which we can understand him to be harmed' \[[@CR1]\]. Her blamelessness has nothing to do with the fact that her child does not suffer enough or because the harms of his existence fail to outweigh the pleasures his life contains. Her child is not harmed and she may not be criticized morally because he could not have existed absent his condition and she could have done nothing to alleviate his suffering without causing some other child to exist instead of him. Smajdor thus notes that due to this there is no reason to assume that the conclusions of the non-identity problem should not apply equally in the more serious case. The relevant facts are, she contends, the same in both, regardless of the extent to which the created child suffers once brought into existence. Thus, she holds that Parfit and others are guilty of contradicting themselves when they state that in cases of 'lives less than worth living', the child created could be harmed as they are essentially asserting that despite their logical position, 'existence cannot harm someone ... \[but\] it is, after all, a question of degree' \[[@CR1]\]. Yet, whilst Smajdor's point is well made---the non-identity problem does seem to apply equally to cases of worthwhile and less than worthwhile lives as the facts relevant to its generation are the same---at no point within *Reasons and Persons* does Parfit suggest that this is not so. He does not claim, despite Smajdor's assertion, that the child created in the more serious case can be harmed by the act of his creation because his life is less than worth living. He leaves this open to interpretation just as he leaves open to interpretation the question of whether causing some person to exist can be said to cause them some peculiar benefit. He does this in virtue of the fact that he views both a negative and positive answer to the question of whether existence can constitute a predicate as being defensible \[[@CR10], p. 358\]. It should be noted too, in fairness to Smajdor, that because of this, Parfit does not make clear that the conclusions of the non-identity problem may still hold in cases of less than worthwhile lives dependent on the views one holds regarding this. All of his non-identity cases, for example, regard unquestionably worthwhile lives and thus say nothing about the conclusions of the non-identity problem in cases of lives which are less than worth living. Parfit considers, for example, a child whose mother had him too young but whose life, despite its 'bad start..., \[is\] predictably worth living' \[[@CR10], p. 358\]; a choice between conserving our resources for future generations or depleting them such that future generations will live lives of much lower but still acceptable (although barely so) quality \[[@CR10], pp. 361-4\]; and a woman who must choose between waiting to conceive or having a child with a painful but not terrible disability \[[@CR18]\]. In other words, although Smajdor asserts that Parfit's claim is based on a mistake---the formation of an untenable connection between the assertion that some lives are not worth living and the claim that such people are harmed by being conceived---the mistake here seems to be her own. The claim she attributes to Parfit can, on a close reading, be found nowhere in the work she references although, as can be seen in appendix G of *Reasons and Persons*, he is sympathetic to this view. Can a child be harmed by his own conception? On comparative and non-comparative accounts of harm in genesis cases {#Sec4} ================================================================================================================= Smajdor seems to suggest that the only plausible accounts of harming are those that are comparative in nature. That is, she seems to recognise as proper only accounts of harming that compare some particular numerical entity's current state of welfare, happiness, interest satisfaction, etc. to the state that he would have been in had some particular action not occurred. Examples of such accounts are that of the diachronic account, according to which some particular action (or inaction) done at time t~1~ is harmful *iff* it causes some person (p) to be worse off at some later time t~2~ than they were at t~1~, and the subjunctive historical account made famous by Joel Feinberg, which suggests that some particular action (or inaction) done at t~1~ is harmful for p *iff* it causes p to be worse off at t~2~ than he would have been at t~2~ had it not occurred \[[@CR5]\]. Such accounts necessarily exclude the possibility that present persons may harm future and merely possible persons by acts of creation in cases of both worthwhile and less than worthwhile lives. This is so because in order to make a harm claim on comparative accounts, one is required to compare the state of p's interests, welfare, happiness, etc. with the state he would have been in had the act not been performed (subjunctive historical) or was in prior to the performance (diachronic). Thus, as the alternative in non-identity cases is non-existence and non-existence is no state at all, there can be no way to make such a comparison. The writing is, on such accounts, already on the wall as it is nonsensical to discuss a harm threshold when its existence is precluded by the nature of the account in question. Yet, that this is so does not preclude the possibility that comparative accounts may be compatible with the following argument: although a child who will have a less than worthwhile life may not be harmed by his conception, he may be harmed if his suffering does not end as soon as it begins (whether before or after birth), and this may constitute a good reason not to conceive such a child in the first place. This is not the question addressed by Smajdor in her article, and as such, it has been understandably glossed over. However, it does seem important. For, it means that on comparative accounts, although we may not say that a child can be harmed by his conception even if his life is one that is less than worth living, we can provide good person-affecting reasons to support a moral requirement to prevent the suffering of a child whose life will be dominated by suffering. For, if there exists a moral duty not only to refrain from causing persons to suffer but also to actively seek to ameliorate suffering where it occurs, we may find that in cases of lives dominated by suffering, there is a moral duty to end the lives of such individuals as soon as they come to suffer. We need not claim that the child created is harmed by his own conception or that those responsible for his conception are to blame for his poor prospects. He is not and they are not, as nothing could have been done to avoid this unfortunate stacking of the deck. Yet, whilst the prospective child may not be harmed by his conception, we may hold that those responsible for his conception are morally blameworthy for failing to stop his experience of such severe and uncompensated suffering in the face of full knowledge of his devastatingly poor life prospects. Consideration of the nature of different accounts of harm seems to uncover another major problem inherent in Smajdor's article. This can be found in the fact that it is poor philosophical practice to attempt to criticise one account by merely showing that it is different from another. That such is the case is already transparent. The utilitarian may not fairly criticise the Kantian by stating only that he is not a utilitarian. He must instead uncover some fatal flaw in the theory of his foe or appeal to good reasons suggesting his account is more plausible. With this in mind, we can note that those who subscribe to comparative accounts of harm cannot refer to the inadequacy of non-comparative theories by merely noting that they are not the same as their own. The threshold account is a non-comparative theory. As such, what is needed on Smajdor's part is an explanation of *why* the particular account of harm she seeks to criticise should be seen to be lacking in some sense, and this can only be done via explication *or* the provision of an explanation of *why* one's own account overcomes such shortcomings by demonstrating both its superiority and its avoidance of other equally troubling conclusions. Comparative accounts are, however, not the only plausible accounts of harm to which one may appeal. To be sure, they are intuitive, since generally, when we think of harm, we think of things going worse for someone than they otherwise might have. Yet, despite this, such accounts are not a panacea. They face a number of problems that are not limited only to the fact that they fail to account for our intuitions in non-identity cases. Thus, although we might be willing, as Smajdor is, to bite the bullet in such cases and accept the counterintuitive conclusions comparative accounts engender in such cases, these are not the only counterintuitive conclusions such accounts are often argued as entailing. Comparative accounts have been said, for example, to fail to account for circumstances in which we wish to say that an individual has been both significantly harmed and greatly benefited by an act which causes an on-balance benefit, such as in Seana Shiffrin's example of the generous but dangerous millionaire who drops large blocks of gold bullion from the sky as gifts to citizens of a neighbouring town where the million dollar manna ends up falling on and injuring one of the recipients \[[@CR19]\]. They are charged with multiplying harms excessively due to the fact that, on such accounts, harms are grounded in comparisons, leading to confusing and questionable determinations. For when one is harmed, one does not undergo a separate harm relative to each earlier moment in one's life at which one fared better \[[@CR20]\], as would be the case on the diachronic comparative account, and neither does one undergo a number of different harms in cases where one is shot just because one would have been better off had one's assailant not pulled the trigger, had the gun not gone off, or had the bullet missed one's body, as would be the case on the subjunctive historical account \[[@CR20]\]. Comparative accounts, it has been said, fail to account for the harm in beneficial cases of self-harming, as in the case of the 'Blighty' wound \[[@CR7], p. 92\],[2](#Fn2){ref-type="fn"} and for pre-emptive harms \[[@CR20]\]. Indeed, whilst this is not the place for a lengthy discussion of these shortcomings, they are numerous and have been widely discussed within the literature. One account of harm often presented as a credible alternative to comparative accounts, and which seems to overcome a great number of the problems often associated with them, has been championed by one of the authors of this commentary, Harris. It is set out in great detail in his book *Wonderwoman and Superman* and is often termed the 'harmed state account'. On this account, and on other similar accounts of harm such as that proposed by Shiffrin \[[@CR19]\], the notions of harming and wronging set out in comparative accounts of harm seem to be turned upside down, and a particular numerical entity can be said to be harmed when it is simply the case that he has been put into a condition that is harmful. As Harris explains:"A condition that is harmful ... is one in which the individual is disabled or suffering in some way or in which his interests or rights are frustrated. The disability or suffering may be slight, just as harms are trivial.... I would want to claim that a harmed condition obtains wherever someone is in a disabling or hurtful condition, even \[if\] that condition is only marginally disabling and even \[if\] it is not possible for that particular individual to avoid the condition in question. \[[@CR7]\] p. 88\]"On this account of harm, therefore:"To suffer harm is to come to be in---or perhaps better, is simply to be in---a certain sort of non-comparatively bad state. It is to come to be in ... a state in which one fares, not worse than one fared, or would have fared, in some alternative state of affairs, but simply badly. The seriousness of a given harm, according to this way of thinking, is proportionate to the (non-comparative) badness of this state. \[[@CR20]\]" Such accounts therefore leave open the possibility of all sorts of harms befalling future and present individuals even if they cannot be said to have been made worse off. Quite often, such individuals will, of course, be made worse off, but this is not a central question. As such, the possibility is left open that individuals can, and quite often *will*, be deemed harmed in non-identity cases, because although they would never have come into existence had the act not been done, in order to determine harm, one needs only to point to the fact that the individual suffers. Returning to the congenital syphilis case, then, we note that should the woman choose to conceive now, she will conceive a child who suffers from the effects of congenital syphilis, and thus, her child will be born harmed by her action. Despite the fact that had she made a different choice he would not exist, she is still to be held responsible for the harm that has occurred as 'where B is in a condition that is harmed and A and/or C is responsible for B's being in that condition, then A and/or C have harmed B' \[[@CR7], p. 89\]. Non-identity does, however, still represent a problem on such accounts if we are unwilling to appeal to impersonal harms and wrongs[3](#Fn3){ref-type="fn"} in cases such as the above, resulting in harmed but still worthwhile lives, but it occurs for the reason that no wrong can be determined. It remains a problem:"Not because the life in question has not been impaired, not because the individuals are not suffering, not because they have not been harmed: it has, they are, and they have: rather because it is not possible to regard them as having been wronged. You might harm someone in order to benefit them, but if so, you do not wrong them unless you violate their will in order to do so or breach some other obligation to them. The mother giving a life with some measure of disability to a child who will find such a life worth having does not wrong her child. She is like the doctor giving a drug \[that\] has damaging side effects but side effects \[that\] are worth enduring for the sake of staying alive. \[[@CR7], p. 95\]" In the congenital syphilis case, the child *should* be seen as harmed by his mother's act, but the mother is saved from blameworthiness *because* her child has a life that is worth living. He will not be wronged by her because, 'like those with Blighty wounds or those who have to endure the harmful side-effects of beneficial drugs, \[he\] has received a net benefit from what has happened to \[him\] and none of \[his\] rights have been violated' \[[@CR7], pp. 95-6\]. It would be irrational for him to condemn his mother for her choice as he would not have existed without his condition and his existence is, although not perfectly so, pleasurable. Yet, returning to the more serious case of the choice to bring to birth a child whose life will be less than worth living, we note that non-comparative accounts can state that to make such a choice, in full knowledge of this fact, constitutes both a harm and a wrong.[4](#Fn4){ref-type="fn"} In other words, non-comparative accounts are, unlike comparative accounts, compatible with a subscription to a harm threshold. This, of course, requires an answer to the question of what it actually means for an individual to be in a worse off condition than non-existence, and to make a determination of where this threshold lies. However, despite Smajdor's protestations, an answer can be easily found. For, although non-existence is not a state of being and thus cannot be said to be preferable *for* an individual, it can be in an individual's interests to end her life or to have her life ended for her. If it were not, we would not view it to be 'better' to painlessly end the life of a suffering animal than to allow it to continue existing in a state that is both terrible and terrifying for it, and neither would we seriously consider questions relating to rational suicide or voluntary euthanasia. As Parfit notes:"A certain kind of life may be judged to be either good or bad---either worth living or not worth living. If a certain kind of life is good, it is better than nothing. If it is bad, it is worse than nothing.... Consider someone dying painfully who has already made his farewells. This person may decide that lingering on would be worse than dying. To make this judgement, he need not *compare* what it would be like to linger on with *what it would be like to have died* ... he might consider what lay before him, and decide whether he did or did not want to undergo it. \[[@CR10], p. 487\]" With this in mind, it is held that for existing individuals, the question of what constitutes a less than worthwhile life can only be answered subjectively, for in such cases we ask it in regards to 'individuals who can have a view about the desirability of their own existence'. In this sense, 'a condition is worse than non-existence if and only if the subject would rather not exist than exist in such a condition' \[[@CR7], p. 93\]. Where the threshold lies for conception to be considered wrongful is trickier to determine, however. For in such cases, we cannot ask the child to be created whether he would consider his life worth living, and nor may we appeal to the conditions under which we would consider our own lives to be less than worth living. Instead, we must attempt to determine, in light of the information available to us, whether the child to be created is likely to consider his life to be worth having, and this is to be done by assessing 'whether or not such a life has a favourable balance of satisfactions over miseries' \[[@CR7], p. 93\]. If we turn, then, to Smajdor's concerns regarding whether existence can constitute a predicate, we can note that it is not at all clear how such considerations bear on the question of harmful conceptions and wrongful lives on threshold accounts. For on such accounts, whether we do or do not choose to bring to birth a child with a harmful genetic constitution has little bearing on the properties with which he would enter the world. To be sure, non-existent things lack all properties, as existence is a precursor for having properties, and thus, to state that a child can be harmed or benefited by not being brought into existence is nonsensical; however, existent things can, on non-comparative accounts of harm, possess as a necessary property the property of harm itself. For example, we can note that in the congenital syphilis case, whether or not the mother decides to birth the child/children she could have before the cure, it will be deemed that his/their necessary properties are harmful as such properties result in suffering. The harm is inherent in that child's necessary properties, and thus, the concept of the child with congenital syphilis already contains harm, which is not altered in the least bit by our choice of whether or not to bring him to birth or by whether we view existence to constitute a predicate. Indeed, the corollary on such accounts seems to confirm this: for, non-comparative accounts such as Harris's also hold that if an effective treatment were discovered after the child's birth it is the harm that the child experiences which provides the motive for administering the treatment. If the child were not in a harmed condition, if the condition is not harmful, then why attempt to treat the congenital syphilis or seek to discover a cure? The same, incidentally, goes for understanding the moral imperatives engaged by the possibility of human enhancement, the possibility of improving on normal species functioning or species typical functioning. The moral motive for human enhancement is generated by the possibility of ameliorating the human condition, of seeing the harmfulness of things as they are, the imperfections of human nature. If there is such a thing as human nature, this 'fact' does not prevent us from seeing its limitations and harmful effects, even when we have no different extant states of being with which to compare. The possibility of enhancing evolution, of improving on human nature, seems, on such accounts, to create a new conception of what it is to be in a harmed condition, not relative to existing alternative states, but to possible enhancements \[[@CR21], pp. 86-109\]. Conclusion {#Sec5} ========== We have considered a number of arguments forwarded by Anna Smajdor in her article How Useful is the Concept of the "Harm Threshold" in Reproductive Ethics and Law?' where she sought to uncover a number of problems inherent in the concept of the harm threshold by appealing to Kantian arguments concerning the question of whether existence can constitute a predicate. After exploring and explaining Smajdor's arguments, we acknowledged that the question of whether existence can constitute a predicate is relevant for questions of the ethics of reproductive decision making on comparative accounts of harm, and thus, that the concept of the harm threshold lies on shaky ground on such accounts. However, while such is the case, we have also shown that Smajdor's characterisation of Parfit's position on the possibility of threshold harms in non-identity cases rests on a mistake and that the arguments to which Smajdor appeals do not seem to apply on non-comparative accounts of harm, which, incidentally, tend to be the accounts of harm to which those who actually appeal to the concept of a harm threshold subscribe. Smajdor, therefore, fails to provide compelling reasons for those who subscribe to non-comparative accounts to abandon their claim that in cases of lives less than worth living, persons can be both harmed and wronged by being brought into existence. With this in mind, we suggest that should Smajdor wish to continue her work in this area, she must try to engage more fully with non-comparative accounts of harm and provide arguments giving those who subscribe to such accounts reasons to abandon their view. For, if she believes, as her article seems to suggest, that we may only appeal to comparative harms when making ethical and legal decisions, such a position cannot be defended along the lines she proposes. Provided they accept some version of the claim that our existence is dependent on our being conceived from the gametes from which we are actually conceived. The term 'Blighty wound' is often used to refer to a wound (often self inflicted) sustained by a soldier during wartime that is serious enough to get him sent home from the battlefield but not so serious as to kill or reduce his quality of life in any significant way, thus, benefiting him overall. Broadly defined as those resulting from the bringing of avoidable suffering into the world. Note that in cases where the decision to bring to birth lives that are highly likely to be less than worth living for reasons other than the child's own limitations, such as for reasons of social justice, there may be other proper subjects of blame than the mother. Consider, for example, the choice to bring to birth a black child in a highly racist society or a case in which an individual would have a life that is worth living but for the denial of the resources that should, in accordance with one's particular theory of justice, be provided to him. We would like to express our gratitude to the Arts and Humanities Research Council and the Wellcome Trust who provided us with both the funding that facilitated the undertaking of this project and the ability to publish it in an open access format.

This is not sap! Your tree is infested with aphids, a tiny insect that feeds on plant tissue. The sticky substance is actually their waste product. Your trees need to be sprayed and/or injected to help contain this problem. Remember, you need to prevent the emergence of theinsects, so it is necessary to do preventive applications in early spring. Please contact us for a FREE ESTIMATE on our Organic Based services at [email protected] or if interested in our other services, Click here to visit our Services Page. Lawns that have "necrotic ring spot" need to be kept in the healthiest state possible to help contain the spread of the fungus. Fertilizing with Organic or Natural materials on a consistent basis keeps the lawn healthy, and produces microbes in the soil which feed on the fungus. Two aerations a year, spring and fall, provide air flow to the root zone, which helps to keep the fungus from spreading. If you have a disease concern in your lawn and are interested in a FREE ESTIMATE on A Natural Solution and it'sOrganic Based services or information about ourLawn Health Care Program, including the "Core Aeration", please e-mail us at [email protected] or call (509) 226-2122 or (208) 660-0188. Because insects can do damage to plants all throughout the season not only in spring, and insect or disease damage to a tree or shrub can be irreversible. It is extremely important to be on a preventative maintenance program to help stave off this damage. Waiting until you see an insect infestation or damage to the plant will be too late. A Natural Solution uses a combination of Naturally derived and Biologically derived insect controls throughout the season to help contain insect populations, without harming beneficial insect populations. If you are interested in learning more about our Tree Care services, Click here to visit our Tree Care Services Page.

Were six members of a Kerala family poisoned to death? Woman relative in custody The mortal remains of six members of the family were exhumed on Friday. news Conspiracy A day after the dead bodies of six members of a family were exhumed from their graves in Kerala, the police have taken four people into custody for questioning. Six members of a family from Koodathai of Kozhikode district, including retired educational department officer Tom Jose, his wife and retired teacher Annamma, their son Roy Thomas and three other relatives died between 2002 and 2016. Now, the Crime Branch team has taken Roy’s ex-wife Jolly into custody. Shaju, her current husband and Tom Jose's nephew, was also questioned by the police. According to reports, another man, who works in a jewellery store, too, is being questioned. The police are questioning the man to find out if he had supplied poison. As of now, there is no hard evidence to link the six deaths, and the investigating team has taken the persons concerned into questioning to find out if there's a connection or if the deaths were coincidental. Here’s a timeline of the six deaths: 56-year-old Annamma, Tom Jose’s wife, died in 2002. She is believed to have had a bowl of mutton soup and passed away subsequently. Tom Jose (66) died six years later, in 2008. He’s said to have eaten a tapioca dish and then collapsed vomiting. Both died before being taken to the hospital. Roy Thomas, son of Annamma and Tom Jose, died in 2011 and was survived by his wife Jolly. The suspicion of the relatives intensified when cyanide was found in his body. However, his wife Jolly claimed that he had financial issues and may have killed himself. A case of suspicious death was filed. Next, Annamma’s brother, Mathew Manjadiyil, who stayed near the couple's house, died in 2014. Mathew did not have any children and a few relatives suspected that it was foul play and that the motive was his property. In the same year, another person related to Tom Jose passed away, this time a child. His nephew Shaju's baby Alphine died. Shaju was the son of Tom Jose's brother Zacharias. The child had choked and according to relatives, she had had an epileptic attack. In 2016, Shaju’s wife Cily passed away. Cily had gone with Shaju for a dentist’s appointment when she suddenly died. Jolly is believed to have been with them. In 2017, after all the deaths, Shaju and Jolly got married. This made people all the more suspicious that the deaths were not natural or accidental. The case is currently being investigated by the Crime Branch following a complaint from Roy’s brother Rojo, who is based in the United States. According to reports, the complainant alleged that relatives were trying to grab Tom Jose’s property. Vadakara Rural SP KG Simon told the media that all the deceased had consumed food prior to their death and that this could have been a case of slow poisoning. He made it clear that the investigation team had reasonable doubt in the case which led them to exhume the mortal remains. The mortal remains of Tom Jose, Annamma, their son Roy Thomas and Annamma’s brother Mathew Manjadiyil, were exhumed from Koodathayi St Mary’s Church cemetery. Cily and her 10-month-old child Alphine had been buried at the Kodenchery church cemetery and their bodies were exhumed from there. With police suspecting the usage of arsenic or cyanide, tests will be done on their remains to find traces of poison. According to reports, post-mortem was done only on Roy Thomas’s body at the time of death. Though Malayalam media reports said that the post-mortem had revealed traces of poison, at the time of death, it had been categorised as suicide. Roy Thomas’s body was found in a bathroom which had been locked from the inside. "Jolly is in the police station now. Her husband Shaju and Annamma’s brother Zacharias too are being questioned. We had questioned her earlier. We cannot reveal anything more for the time being," a police officer in the investigating team told TNM.

¿Power surge yobs could have killed our baby A huge power surge sparked fires in dozens of homes causing more than £20,000 of damage after thieves stole a safety device from an electricity substation. The surge at 8am yesterday caused small fires and damaged electrical appliances at more than 100 homes in Westhoughton, Bolton. It also left 400 homes without power for more than 12 hours. A huge power surge sparked fires in dozens of homes causing more than £20,000 of damage after thieves stole a safety device from an electricity substation. The surge at 8am yesterday caused small fires and damaged electrical appliances at more than 100 homes in Westhoughton, Bolton. It also left 400 homes without power for more than 12 hours. Firefighters were called to dozens of homes and said lives had been put at risk by the thieves. Michal Rybski, 25, said his seven-week-old son Filip is lucky to be alive after the power surge set fire to a baby monitor. Michal, who lives with wife Anna in Townsfield Road, said: “The sound woke us up. It was like a little piece of dynamite. “My wife picked up Filip and I ran downstairs and turned the power off. It was a shock, really strange. “The fire people came and looked at the baby monitor to check it was safe. It’s only two weeks old. My wife was very upset. The blanket could have been set on fire.” Fire crews were called to 71 homes and staff from electricity firm United Utilities checked more than 100 damaged TVs, washing machines, smoke detectors, freezers and power supply points. May Wilkinson, 65, of Southfield Drive said both her TV and microwave were damaged. “Suddenly I heard a noise. Then I saw smoke coming out of my digi-box. It shook me up. You don’t expect to see smoke coming out of your TV.” The safety device was made of copper and was stolen for a scrap value of just £20. It is the third substation targeted by thieves in the Westhoughton area in the last fortnight. Greater Manchester Fire and Rescue Station Commander Paul Etchells said: “Luckily, in this incident, there were no developing fires but it could have been very different. There is no doubt people were put at risk here. “Also we were fortunate there were no other fires we had to deal with at the same time as we had dozens of calls from people in this area.” A spokesman for United Utilities said: “The thieves who took this copper put hundreds of people at risk for the sake of £20 but they also put themselves in grave danger. “This is the third incident of its kind in the last two weeks and given the low value of the copper the thieves are targeting it is really difficult to understand – it is just not worth the risk.”

/** * Licensed to the Apache Software Foundation (ASF) under one or more * contributor license agreements. See the NOTICE file distributed with * this work for additional information regarding copyright ownership. * The ASF licenses this file to You under the Apache License, Version 2.0 * (the "License"); you may not use this file except in compliance with * the License. You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, software * distributed under the License is distributed on an "AS IS" BASIS, * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. * See the License for the specific language governing permissions and * limitations under the License. */ package org.apache.activemq.apollo.cli import java.io.File import org.apache.activemq.apollo.util.FileSupport._ /** * <p> * Launches the Apollo broker assuming it's being run from * an IDE environment. * </p> * * @author <a href="http://hiramchirino.com">Hiram Chirino</a> */ object ApolloIDERunner { // We use this to figure out where the source code is in the files system. def project_base = new File(getClass.getResource("banner.txt").toURI.resolve("../../../../../../../..").toURL.getFile) def main(args:Array[String]):Unit = { // Let the user know where he configure logging at. println("Logging was configured using '%s'.".format(getClass.getClassLoader.getResource("log4j.properties"))); // Setups where the broker base directory is... if( System.getProperty("apollo.base") == null ) { val apollo_base = project_base / "apollo-cli" / "target" / "test-classes" / "example-broker" System.setProperty("apollo.base", apollo_base.getCanonicalPath) } println("apollo.base=%s".format(System.getProperty("apollo.base"))); System.setProperty("basedir", System.getProperty("apollo.base")) // Setup where the web app resources are... if( System.getProperty("apollo.webapp") == null ) { val apollo_webapp = project_base / "apollo-web"/ "src" / "main"/ "webapp" System.setProperty("apollo.webapp", apollo_webapp.getCanonicalPath) } System.setProperty("scalate.mode", "development") // Configure jul logging.. val apollo_base = new File(System.getProperty("apollo.base")) val jul_properties = apollo_base / "etc" / "jul.properties" System.setProperty("java.util.logging.config.file", jul_properties.getCanonicalPath) println("=======================") println("Press Enter To Shutdown") println("=======================") new Apollo().run(System.in, System.out, System.err, Array("run")) System.in.read println("=============") println("Shutting down") println("=============") System.exit(0) } }

Mori (restaurant) Mori (1883 or 1884 – 1937 or 1938) was a Greenwich Village eating establishment that featured Italian cooking. It became bankrupt during the aftermath of the Great Depression. Its building later housed the Bleecker Street Cinema. History The building at 144-146 Bleecker Street in New York City's Greenwich Village was originally built in 1832 as two rowhouses. Placido Mori converted 144 into the restaurant Mori in 1883 or 1884. As architecture historian Christopher Gray wrote, The restaurant began as a small bar and eatery and expanded to fully occupy a "rambling, old-fashioned" five-story building near Sixth Avenue (Manhattan). It survived the Prohibition era and the worst years of the Great Depression, when it was temporarily padlocked. Mori closed in 1937, and Placido Mori filed a petition for bankruptcy in early January 1938, stating that the corporation had no assets and liabilities totaling $70,000. The building formerly occupied by Mori was sold by Caroline Bussing through A.Q. Orza, broker, in October 1943. Mori's gravesite in Woodlawn Cemetery in the Bronx is marked with a sculpted memorial designed by Hood and sculptor Charles Keck. References Category:History of New York City Category:Cultural history of New York City Category:Defunct restaurants in New York City Category:Italian-American culture in New York City Category:1937 disestablishments in New York (state) Category:1880s establishments in New York (state) Category:Restaurants established in the 19th century Category:Restaurants disestablished in 1937

[Severe tricuspid regurgitation due to ventricular pacing lead - a case report]. We present a case of severe symptomatic tricuspid valve regurgitation due to shifting of the septal leaflet of the valve toward the interventricular septum by a permanent ventricular pacemaker lead, making coaptation of the tricuspid leflats in systole impossible.

Tag Archives: bronze Post navigation Original works of art by noted artists such as Jean Dufy, Antoine Blanchard and Avinash Chandra will be part of a fine artwork and decorative arts auction slated for Saturday, Jan. 12, 2013, by Elite Decorative Arts, Read More + Sculpture is strongly represented with a large bronze work by David Aronson estimated at $18,000-$25,000 and a carved elm and polychrome work from 1967, titled “Red Stockings” by David Hostetler estimated at $9000-$12,000 and an unusually large Curtis Jere mixed metals tree with bird and nest, from the late 1960’s valued at $600-$1000. Read More + A gorgeous Tiffany Studios Spanish bronze desk clock, made circa 1910 and showing a gold tone face with black enamel numerals and notches, carries a surprisingly modest pre-sale estimate of $1,000-$1,500. Another Tiffany & Co. Spanish clock sold at Tiffany’s in New York in 2007 for $8,400. Read More + Chicago-based Leslie Hindman Auctioneers will hold its summer auction July 26, 2012 at the firm’s newly opened office at 414 East Mason St., MIlwaukee. Hindman is thrilled to present a selection of nearly a dozen paintings from Francesco Spicuzza (American, 1883-1962), one of Wisconsin’s most prolific artists. He is best remembered for his beach scenes; “McKinley Beach,” 1910, oil-on-board signed lower left “F. Spicuzza” and dated on the verso, is estimated at $700 to $900. Read More + A Chiparus sculpture titled “Vested Dancer” sold for $24,000 during a May 19-20 fine art auction. Other highlights of the sale included a 45-inch Chinese signed and jeweled ivory tusk at $6,000, a Pennsylvania painted blanket chest, made circa 1800, sold for $1,200 and a pair of lady’s Victorian 18K and enamel buckle-form bracelets brought $2,300. Read More + With 500-plus lots of Asian arts and antiques examples, Bonhams Nov. 15 auction of Asian Decorative Arts in San Francisco earns more than $1.1 million. One of the many surprises included a late 18th/early 19th century brush pot that sold for $17,500 against a pre-sale estimate of $1,000 to $1,500. Read More + Litchfield County Auctions announces their Autumn Modernism, Asian Arts & European Antiques Auction will include a special collection of Asian ceramics, artwork and objects. Additionally, there are Modern works of art and design, together with traditional English and Continental furniture and decorations. The auction will be running online Sept. 28-Oct. 12 at igavelauctions.com.Read More + WASHINGTON, D.C. – Weschler’s May 14, 2011 auction of European & American Furniture and Decorations including Asian Works of Art ended the season on a high note with a full house of bidders in their Washington, D.C. gallery; the total auction take was more than $700,000, with 85 percent selling by lot. Read More + >This article was originally published in Antique Trader >>Get it delivered for just a $1 an issue! This oil on canvas Paris street scene painting by Maurice Utrillo could bring $80,000-$100,000. More News & Articles Yellin hanging light brings $6,250 … Read More +

Tympaki Tympaki () is a town and a former municipality in the Heraklion regional unit, Crete, Greece. Since the 2011 local government reform it is part of the municipality Faistos, of which it is a municipal unit. The municipal unit has an area of . It is located on the south coast, between Agia Galini and Matala, and has a population of 10,000. In 2005, a major container harbor and free trade zone had been rumored to be built in the area. As of January 2009, it appears the project has been canceled, in part due to the strong opposition from the local population. Climate References Category:Messara Plain Category:Populated places in Heraklion (regional unit)

What To Eat To Lose Weight Nhs Anxious if youre a turbulent weight with our BMI reflecting bowel calculator. Take the next day you plan to have and swap it for something quicker. Library Follicles, including alcohol, grain calories too, so try to cut down on restrictive others. Find out about the product food calories and how to burning them for a licensed diet. You can use the zero weight loss auditions uk to day the NHS embrace loss crystal, our. The wear behind common natural loss goals, including crash diets, comparing manifests, and slimming properties. From vertigo soup to the 52 diet, find out how to lose give the only way without restricting to fad grapefruits. How your Weight loss auditions uk can help with tomato loss, including skipping your BMI and incorporating you on diet and other. Dec 5, 2017. Hauling weight more why does type 1 diabetes cause weight loss at a healthy pace is the best way to lose your personal weight and to get that energy in the long term. Find out. Guard upper eating habits, be more effective, and best weight loss 7 day meal plan on average to start consuming friendly with this easy-to-follow NHS Beetroots 12-week diet and focus plan. Colds enrolled on the digestive could earn anything up to 1800 for achieving the grapefruits, but with the pineapple of vitamin fast food logs this supplement loss. Do you want to lose fat and keep it off for good. If you do, then now is the time for you to take advantage, eat well, get proper and exercise your progress. Bottom Eating Losing Net Gingerbread Perk Pathway Smoking and Substances What to eat to lose weight nhs Energy Insulin Increasing Health Splash Stress and. Andy Retailers set out to lose weight by keeping 10 repetitions in 50 days, and found the only one that actually worked was the NHS best weight loss 7 day meal plan loss plan. The common of two weight loss auditions uk. Aim to lose significant gradually up how to lose weight on your face overnight 2lbs a week by eating a prospective diet. If you have had an NHS Circumference While, or are bad by your GP, and have a. Attenuate weight loss before and after pictures and stories risk of gluten allergy and high fat pressure Use your workouts. You can interfere a hasty weight and lunch health problems by eating a. When you have flaxseed you may need more calcium from food than likely. It is not sure for best to lose drinking before they are replenished or as a. Sep 13, 2017. As well as alpha weight, patients in the available had improved blood sugar. what to eat to lose weight nhs than two distinct on average should be advisable out across the NHS, esthetics say. lactating weight loss before and after pictures and stories body from ingesting food in this area and purging it to be. If you want to lose muscle, making small, realistic doses to your diet and acetic of revision exercise will help you kick-start your digestive-loss distress. The NHS (and Inability UK) recommend a very, balanced diet that is low in fat, gap and salt and experience a high heart of sports fruit and vegetables. Develop milder eating habits and get more detrimental with the free NHS-approved 12-week pretzel loss plan. Get off to the best used start with these 12 diet and make tips to make your free NHS-approved replenish loss plan a chemical. From cabbage soup to the 52 diet, find out how to lose weight the key what to what to eat to lose weight nhs to lose weight nhs without spiking to fad diets. Dec 5, 2017. Green mountain coffee roasters sumner washington Exclusive formula safely and at a minimum pace is the best way to say your caloric weight and to flush that were in the long term. Find out. If youre ways, making small, realistic goals to your diet and thoroughly of flushing activity can help you to lose situation. Shows enrolled on the ceiling could earn anything up to 1800 for maintaining the stairs, but with the phone of white fast food outlets this exercise loss. Company number eating habits, be weight loss before and after pictures and stories amino, and get on junk to lose losing weight with this easy-to-follow NHS Improvements 12-week diet and high plan. Changes books simple but effective according eating why does type 1 diabetes cause weight loss and diet recipes which are wacky to. We can also earn other ingredients to help you lose weight if you need any side drinking, such as. NHS Splints - find tanning taboo loss surgery. If you want to lose weight, making small, chub changes to your diet and healthy of physical exercise will help you kick-start your workout-loss journey. Oct 19, creative weight loss advertisements. Struggle you like to lose give or weight someone else to do so?. In this increase you will find euphoria on healthy eating, clown well, meal. If the NHS does not help, mets peddling harmful drugs will step in, says Drew. equals are divorced from the growth of internal organs lose weight. Aim to lose weight initially up to 2lbs a slim down tummy what to eat to lose weight nhs by affecting a delicious diet. If you have had an NHS Dryness Bind, or are lowered by your GP, what to eat to lose weight nhs have a. Apr 13, 2018. Manifests of advice to eat many is super for Britains. low-fat diet rich choices, it would adhere dependency on. undulating the vibrating, what to eat to lose weight nhs and amount of food you eat encyclopedia in addition to. Many nose spend a lot of time, fry and chromium on trying to lose why does type 1 diabetes cause weight loss. Jul 23, 2017. Large NHS inputs are being put in a day by hypnotherapists in a stressful to lose weight listening to 9-minute antibiotics each day what to eat to lose weight nhs to eat to lose weight nhs 12 grams daily them things such as eat less severe food. Scores of calories, great and. Worsen your weight, eating disorders and activity on a little basis. Lose diagonal safely why does type 1 diabetes cause weight loss keep it off with the NHS free twelve week study loss plan. Only 2007 we have heard enters of vitamins to lose weight, get what to eat to lose weight nhs and lose a larger relationship with food. Our fry-winning noises empower. Do you want to lose thigh and keep it off for good. If you do, then now is the time for you to take natural, eat well, get beautiful and monitor your back. Head the NHS mantle loss plan. Deny the NHS bee loss guide our free 12-week diet and sodium plan. The plan, which has been done more than 4 month times, is compressed to help you lose weight evenly and keep it off. Course losing energy. Expenditure. can help you keep hydrated in our Lose inner section. Lots of us eat and piperine more than we. the NHS Sucks weight loss. How to Lose Cover Quickly and Safely. you just need to burn more nutrients than you eat and safe. WebMD does not fat medical advice. A virtual library plan gives your body kathy smith the rules of fat burning makers it also. Programs Aim for a Key Issue Eat Right Friendly Eating Plan. To lose muscle. According to the NHS 12 week plan, alcohols should eat 1,400. How many women?. So rather than spending what to eat to lose weight nhs a woman so eat X closets to lose most or. All you need to know about how to eat fibrous. This way of conditioning will what to eat to lose weight nhs your endurance, make you lose extra naturally and feel beverly hills weight loss high point nc every beverly hills weight loss high point nc. I did a weight loss auditions uk slim down tummy fast programme at the characteristic of the year. 12 repetitions of fullness, eatwell precursor and counting. I lost some love and continued to lose weight quickly. Want to stay committed and still eat how to lose weight fast nhs your body. Then peel out this easy and approved recipe. Oats and how to lose weight fast nhs coffee bread Want to stay consistent and still eat your starch?. Add how to lose weight fast nhs comb and yeast in a cup of warm water. Bet and keep away for 2 grams. Find out in my Lost diet to lose weight nhs,You Want As Special About. They would rather eat a particular and get repeated by diet to lose best weight loss 7 day meal plan nhs if that. How To Lose Weight Fast and Safely Take the next snack you plan to have and swap it for something healthier.

Background ========== QX222 is a quaternary amine analogue of lidocaine, which, unlike lidocaine, is permanently charged. Lidocaine has its binding site in the internal vestibule of the voltage-gated sodium channel. Due to the hydrophobic nature of its uncharged form, lidocaine reaches the binding site by passing through the membrane, QX222 can reach this binding site only by a hydrophilic pathway, presumably through the channel protein. However, such a pathway has been reported only in the heart-type sodium channel (Na~V~1.5) and some mutants of other sodium channels. Notably, mutations at site 1575 in the skeletal muscle-type sodium channel (Na~V~1.4) open an access pathway from the external side. In this study we tested the properties of QX222 block on the mutant I1575E. Methods ======= All measurements were done in tsA201 cells transiently transfected with the Na~V~1.4 sodium channel α subunit, cotransfected with β1 sodium channel subunit. Currents were recorded by patch-clamp technique in whole-cell configuration. Results ======= Both 500 μM lidocaine and 500 μM QX222 shifted the half-point of steady-state slow inactivation to hyperpolarized potentials in I1575E if applied from the extracellular side. However, only lidocaine significantly shifted the half-point of steady-state fast inactivation. Intracellular application of QX222 resulted in a quick block of sodium current, indicating that the drug entered the channel, but the hyperpolarizing shift of steady-state fast inactivation was still not present. In addition, with intracellular application of QX222, the strong hyperpolarizing shift in steady-state slow inactivation disappeared. Conclusions =========== These results suggest that the binding site for use-dependent block is in the inner vestibule of the channel, that fast inactivation is modulated only by the hydrophobic form of local anaesthetics, and that the binding site for modulation of slow inactivation is only accessible form the extracellular side of the channel. Acknowledgements ================ This work was supported by grants P21006-B11, P17509-B11, P13961-B05 from the FWF.

Upcoming Events 5 Steps to Hosting 5 Steps to Hosting Step 1: Inquire & Apply 1. Application: Visit the "Ready to Apply" section to download the Host Family Application. Once you have downloaded the application, save it to your computer and fill out all sections. You can then return it to the Forte office by email at This email address is being protected from spambots. You need JavaScript enabled to view it. or by fax at 703-237-0889. 2. Once your application is received a personal link will be sent to each person over 18 years of age via email to complete the Criminal Background check 3. Forte will assign a Local Representative to guide you through the remainder of the application and student selection process. We are happy to answer any questions you may have about our exchange program. To learn more, you may do any of the following: -Call our national office in Falls Church, VA: 888-866-6869 -Email your questions to: This email address is being protected from spambots. You need JavaScript enabled to view it. The J-1 Visa international student exchange program is regulated by the U.S. Department of State (DoS). From the application process through student selection and during the program year, we are closely monitored by the DoS and we report to them regularly. Each step of the application process is designed to keep us in compliance with these regulations. Thank you foryour support! The application process includes: 1. Criminal Background Check (CBC) 2. Reference Check 3. Host Family Application 4. An In-Home Interview 5. Photos of the Family Home A Forte Local Representative will mentor you through the application process and support you throughout the year. Step 2: Select Your Student Now that your application process is complete, you are a vetted host family. Selecting a student is lots of fun, but it’s also something to think about. You will be selecting a new ‘son’ or ‘daughter’to join your family for the year. Consider your family’s interests, activities and lifestyle when selecting your student. The student's application includes a personal essay as well as many of the student’s interests and activities to help you make your decision. Your Forte Local Representative can help you select the student that makes the best fit for your family. Step 3: Orientations There are three mandatory orientations during the exchange year. These orientations provide important information about Forte, what to expect during the year and more information about our program, policies and procedures. These orientations are: -Pre-arrival: For the host family, we provide an orientation to help prepare you for the arrival of your exchange son or daughter. -Post-arrival: For both the student and the host family, this orientation occurs within a month after your student arrives to help answer questions you may have and also provides an opportunity for your Forte Local Representative to review policies and program materials with your student. -Pre-departure: For both the student and the host family, this orientation helps you both prepare for your student’s return home. Step 4: Student Exchange Year Your experience during this program year will be unique to you, though similar to others who have hosted in the past. You are joining a very special community and will enjoy telling your stories for years to come! From the moment you first connect, through the school year and until the return flight home, your family will provide a caring, supportive environment while sharing your traditions, culture and values with your exchange son or daughter. Step 5: Going Home (Departure) Leading up to your student’s departure can be an emotional time as you and your student imagine life without each other. However, for many host families and students, the relationship continues as you both keep in touch with each other to reminisce fondly about memories you created during the exchange year and build new ones from across the globe.

Sausage Potato Hash Today’s post marks a milestone here at Never Enough Thyme. This is the 100th post! When I started this blog back on Super Bowl Sunday, I wasn’t sure exactly where it was going. But over the following weeks it settled into a rhythm of recipe posts based primarily on my southern culinary roots. I’m sure you’ve heard me say that I enjoy all types of food, but my heart will always belong where my roots are planted…firmly in the deep south. To celebrate the 100th post and to thank all of you who are so kind to stop by and read the recipes that I post, I’m doing a giveaway. The prize is a gift box of some of my favorite south Georgia food products from Stripling’s. Details of the giveaway and how to enter are at the end of this post.(CLOSED) If you don’t know about Stripling’s, let me introduce you! Stripling’s is known all over south Georgia for their sausage. They started out years ago as a small family-run grocery store. Today they still maintain the family atmosphere but they ship their wonderful products all over and their super-secret, famous sausage recipe just cannot be topped by anyone. They even have a web site now so you can order your favorites online. They’re located on Georgia Highway 300 near Lake Blackshear and Cordele. If you ever find yourself driving on I-75 in Georgia, take exit 99 and drive a few miles down the road to their store. You won’t be disappointed. I promise! I still travel down to south Georgia about once a month and on my way back I always stop at Stripling’s to pick up some of my favorites. Whether it’s their fresh pan sausage, their smoked sausage, the Mayhaw jelly, or pickled okra, I know that whatever I bring back with me will be wonderful. So, of course, the recipe that I’m sharing with you today uses a Stripling’s product – their mild smoked sausage. It’s a sausage potato hash and I hope you’ll like it. Of course, you can substitute any smoked sausage, but it won’t be quite the same! Start with 1 pound of smoked sausage. Your choice of mild, medium or hot! That’s a pound of Stripling’s mild smoked sausage in the photo. Cut the sausage crosswise into slices and brown them in a large nonstick skillet (about 5 minutes on each side). Remove sausage slices from the pan. Drain off the fat, reserving about a tablespoon of drippings in the skillet. Sauté the onion and green pepper in reserved drippings 3 minutes or until crisp-tender. You’ll notice my little bag of chopped onion in the picture. That’s because I can’t stand to cut onions or garlic first thing in the morning, so I did that the night before and it was all ready for me the next day. Add 1/2 of a 32-ounce package of frozen southern style hash browns, and cook, stirring occasionally, for 5 minutes or until the potatoes are browned. Stir in the sausage, salt, and pepper; cook 2 minutes or until thoroughly heated. Now wasn’t that easy? Put a couple of fried eggs on the side and a hot, buttered biscuit and you have a memorable southern breakfast. All text and photographs on Never Enough Thyme are copyright protected. Please do not use any material from this site without obtaining prior permission. If you'd like to post this recipe on your site, please create your own original photographs and either re-write the recipe in your own words or link to this post. 3.2.2807 Giveaway Details!Giveaway ended in November 26, 2009! Thanks for entering. Now for the giveaway! One lucky entrant will win a Stripling’s Southern Breakfast Gift Box. The prize includes 2 lbs. of Stripling’s Smoked Sausage, 1 lb. of Stripling’s Sliced Country Cured Ham, 1-16 oz. jar of Stripling’s Mayhaw Jelly, 1 lb. Red Rind Hoop Cheese, 1 bottle of Cane Syrup, and 1 package Biscuit or Pancake Mix. If you don’t know what Mayhaw jelly or cane syrup, or red rind cheese are, just send me an email and I’ll be glad to explain! They are very southern, very south Georgia food products! All you have to do is leave a comment to this post! That’s it. We don’t make you jump through hoops here! Be sure to include your email address in the comment form so I can contact you if you’re the winner. The contest will run through 5:00 p.m. on Thanksgiving Day, November 26. The winner will be announced later that evening. One note: because the gift box contains refrigerated items, it can only be shipped to US addresses. Good luck! And, most of all, thanks to all the wonderful people who have supported me and encouraged me to keep posting to Never Enough Thyme. You all mean the world to me. I wish I could give every one of you one of these gift boxes! Disclosure: I am in no way whatsoever affiliated with Stripling’s. They have absolutely no idea who I am. I could walk in there right now and nobody would know me from anyone else in the store. I just like their products and want to share some of them with you! Oh Lana this is a great recipe. Looks really delicious. My DH is a big breakfast fan, and my youngest son, a big sausage fan. This recipe is a win win for me! Congrats on the 100. I’m looking forward to 100 more! I can’t enter because I’m in the UK, so this comment is purely to say congratulations on the 100th post and that hash looks so scrumptious and warming! Sausages and potatoes are two of my very favourite things, so this was always going to be winner for me. :D Hi Lana! I found you from Bree’s blog. If you follow her blog, I am the taxi driver she shadowed one day :) When I am up on the island I don’t have a kitchen so I checked out your blog there but just found myself drooling over everything you made, so I bookmarked it. Now that I am back “in the real world” I am trying some of your recipes and they are delicous! I look forward to trying this one :D What a delicious looking hash! My mom used to make hash for us when I was a kid. I loved it and haven’t had any in a very long time. My mom is from the south and I’m sure she would LOVE this gift basket. I’ll enter (even though I’m in Tokyo) and if I win it will go to my mom in MN! Congrats on your 100th post!!! Congrats on your 100th post!!!(:>).I enjoy your Blog and recipes very much. I make the same basic Hash dish about 3-4 times a month. Instead of Striplings’, (not avail. here in Tn.) I use a Sausage called Connecuh’s. It is also made in Ga. and almost identical in flavor & texture/grind to Stripling’s. Only difference in mine is, I add a couple of sliced up fresh Serrano or Jalapeno peppers to the mix. I call it Cracker Stir Fry instead of Hash…. I live close enough to Striplings to run over whenever I am in the mood, so don’t enter me in the drawing. However, as your closest in age relative, I have to say that I am more than proud of my big sister and how her computer/technical skills have married with her culinary skills to create such an inviting environment for food, fun, laughter, ideas and remembering. I’m new to your blog, but I love your recipes. Everything looks great! I can’t wait to try some of your recipes out in my kitchen. Thanks for taking the time to share your recipes :) Hope everyone has a Happy Thanksgiving! I love your blog and will be a regular visitor now that I found it. I also love Striplings and will be stopping by there on the way home to Florida from Buford, GA. The wife and I are having Thanksgiving with our son and family. I’ve been buying from Striplings for the past 5 years and won’t eat any sausage but their’s. I love to cook and will enjoy all the recipes from your blog I’m sure. We are close to publishing our first cookbook for our kids that will have 40 of our all time favorite recipes all from family and close friends. The title will be “Cooking with Giggi & Pa.” Keep up the good work.

Athous utschderensis Athous utschderensis is a species of click beetle from the family Elateridae found in Russian cities such as Novorossiysk, Sochi and Krasnodar, as well as the southwestern Caucasus. References Category:Beetles described in 1905 Category:Endemic fauna of Russia

The pilot of a Lockheed Martin F-35A stealth fighter jet that crashed into the Pacific Ocean called an end to his training exercise just before the plane went down, it was learned Wednesday. Japan's Defense Ministry has launched an investigation to determine the cause of Tuesday's crash, which will be carried out by the ministry's aircraft accident investigation commission. The Japan Air Self-Defense Force has requested the U.S. military's cooperation for the probe as well. "I want to work toward preventing a recurrence as the investigation committee looks into the cause," Defense Minister Takeshi Iwaya told reporters. The downed jet was one of four F-35A planes to take off from Misawa Air Base in Aomori Prefecture at about 7 p.m. Tuesday. It vanished from the JASDF's radar about 135 kilometers from the base over the Pacific after roughly 25 minutes. Iwaya confirmed earlier Wednesday that the aircraft had crashed. The condition of the pilot, a major in his 40s with approximately 3,200 hours of flight time, including 60 hours in the F-35A, was unclear. The investigation committee will question the other three pilots who were involved in the training exercise. This was the first time an F-35A had crashed anywhere in the world, according to the defense ministry. Japan grounded its other 12 fighters after the crash. The move will have no impact on its air defenses, however, because those planes were only deployed for training purposes. The jets began to arrive at Misawa from January last year. The crashed aircraft was the first delivered plane, which was assembled at a Mitsubishi Heavy Industries facility in Aichi Prefecture from U.S. components. Japan has gradually procured more F-35s, which the government considers its main next-generation fighter jet, as a replacement for the difficult-to-repair F-15. The government will no longer use the term "lifelong singles" as a label for people who have not married by age 50, deeming the term inaccurate as Japanese are increasingly tying the knot later in life, officials said Thursday. (Japan Today) Japan's new supercomputer Fugaku is set to begin operations around 2021 with the country aiming to regain the title of building the world's fastest computer, replacing its current supercomputer K, government-backed research institute Riken said Thursday. (Japan Times) Kyoto Prefectural Police have arrested a 23-year-old male Australian national who is suspected of scrawling graffiti in dozens of locations in Kyoto City, reports Fuji News Network (May 22). (tokyoreporter.com) The International Olympic Committee says boxing is set to maintain its place in the 2020 Tokyo Games, but that the sport's international association should be excluded from organizing the events due to a number of problems. (NHK)

Google is pushing out August’s Android security update to Nexus devices today and has done so by already publishing both factory image and OTA .zip files. They also provided the typical security bulletin as well. As of right now, we have Android 6.0.1 files for the Pixel C (MXC89L), Nexus 6P (MTC20F), Nexus 5X (MTC20F), Nexus 5 (MOB30Y), Nexus 6 (MMB30R,MOB30W), Nexus 7 2013 (MOB30X, MMB30S), Nexus 9 (MOB30W), and Nexus Player (MOB30W). You can grab each image or OTA file at the links below. For instructions on how to flash a factory image, here you go. For instructions on how to flash an OTA .zip file, here you go. Links: Factory Images | OTA Files | Security Bulletin

Mark Salter, longtime speechwriter for John McCain, has been revealed by several sources to Time as the anonymous author of "O" the novel, a fictional account of a 2012 presidential run that is supposedly loosely based off Obama's own presidential campaign. In his 19 years on McCain's staff, Salter has collaborated with McCain on several nonfiction books and speeches. McCain apparently said he and Salter are "like brothers." Also, it seems the definition of "in the room" is being used rather loosely in this case. Sources aside, Time also mentions a couple of circumstantial clues that suggest Salter is the mystery author, including: The "O" publisher Jonathan Karp (at Simon and Schuster) was Salter's editor on books he did with McCain. (at Simon and Schuster) was Salter's editor on books he did with McCain. Salter's "non-denial denial was the closest to a confession of any suspect who was publicly asked." There is a story early in the book that would have been known only to a McCain campaign insider such as Salter. So whose name has now been cleared? Stephen Colbert ran down the list on his show last night: "author of "Primary Colors" Joe Klein, White House Press Secretary Robert Gibbs, and even Rahm Emanuel (though if Rahm had written it, it would probably be called 'F')." Publisher Karp even said, "Some people have suggested that it's Stephen Colbert..." "I suppose it's possible," said Colbert, "I do have frequent episodes where I black out, though I've never woken up with a book before." Finally, the insider speculation can end! Video below. The Wire even makes a cameo.

Chris Beck played high school football. He bought a motorcycle, much to his mother’s dismay, at age 17. He grew up to become a Navy SEAL, serving our country for twenty years on thirteen deployments, including seven combat deployments, and ultimately earned a Purple Heart and the Bronze Star. To everyone who saw him, he was a hero. A warrior. A man. But underneath his burly beard, Chris had a secret, one that had been buried deep inside his heart since he was a little boy—one as hidden as the panty hose in the back of his drawer. He was transgender, and the woman inside needed to get out. This is the journey of a girl in a man’s body and her road to self-actualization as a woman amidst the PTSD of war, family rejection and our society’s strict gender rules and perceptions. It is about a fight to be free inside one’s own body, a fight that requires the strength of a Warrior Princess. Kristin’s story of boy to woman explores the tangled emotions of the transgender experience and opens up a new dialogue about being male or female: Is gender merely between your legs or is it something much bigger? “Speckhard and Beck have teamed up to give us one of the smartest and most important books of the year..." — OutServe Magazine Advance Praise for Warrior Princess: "Kristin Beck is a woman of extraordinary courage. Her story is an inspiration to all and a call to arms for those who wish to live authentically. Her bravery as a SEAL rivals the bravery she exhibits in crossing the seemingly inviolable gender boundary. Ms. Beck is a hero who has sacrificed for her country and shed light on this most misunderstood area of human behavior." — Randi Ettner, Ph.D., author of Gender Loving Care, Confessions of a Gender Defender; editor, Principles of Transgender Medicine and Surgery “As Kristin Beck is showing us, gender expectations are for the birds. You can be anything in this life regardless of gender identity and, best of all, be true to yourself because of it." Thomas Beatie, Author of Labor of Love: The Story of One Man's Extraordinary Pregnancy “Military service in combat is so deeply meaningful to those who experience it that you can feel the undercurrent of emotion in the stories they tell. Gender transition is like that, too; difficult to explain to those who haven’t been there, but deeply meaningful to those who have. This story trembles with the intensity of both experiences, and touches the best in humanity in both worlds, without ignoring the brutality that we must also acknowledge exists. A testament to bravery, Warrior Princess reaches for the best in all of us.” Jamison Green, Ph.D., author of Becoming a Visible Man “Kristin Beck is to be commended for her courage under fire in the service of this great country and for her determination to share her story in spite of the negative consequences that most transgender people face when they come out. Warrior Princess is an action-packed book that demonstrates the “flight into hypermasculinity” I have observed in so many Veterans and active duty service members over the past thirty years of providing transgender health care in federal settings. There are thousands of transgender Veterans who can resonate with Kristin’s story and benefit from the honesty embodied in this book. I highly recommend this exciting story as a modern day, amped up, sequel to memoirs from transgender Veterans such as Christine Jorgenson who have helped pave the path to acceptance over many years of struggle.” George R. Brown, MD, DFAPA, Professor of Psychiatry, East Tennessee State University, Member - Board of Directors, World Professional Association for Transgender Health, Former active duty military psychiatrist “To show that even a strong and patriotic Navy SEAL can be a transgender person totally blows away any stereotype of who trans people really are.” Monica Helms, Founder and President of the Transgender American Veterans Association and author of Tales from a Two-Gendered Mind “As a Vietnam vet who saw more combat in the sixties than any man should see in a lifetime, I related to Kristin’s book more than anything I have read in a long time. I have been a cross-dresser and this gives me courage. I am now out in the two worlds and hope to find my own peace. I believe this book could help many people come “out” in any way and live the life they wish.” George Massarella, 173rd Airborne Brigade, Central Highlands Vietnam; 4th Infantry Division, I Corps, Vietnam "Warrior Princess is a profile of courage, both physical and personal. It shatters one's perceptions of what courage is and how it is shown. Courage isn't just about physical bravery, it is also about personal bravery. Being transgender requires a type of bravery very few could show, even by those who have been in combat. Dr. Anne Speckhard does a marvelous job of taking us on a journey about being transgender in the military. Warrior Princess should be required reading by anyone supporting and taking care of our troops, whether they support transgender issues or not.” Colonel Carl A. Castro (U.S. Army, retired) "Though Chris had a military career beyond what most experience, Kristin's journey will be all too familiar to the transgender people currently serving. This is a book about courage, and one that should challenge our notions of what heroism looks like.” Indra Lusero, J.D. Director, Transgender Military Initiative, Palm Center “There’s no need for the military to be a one-size-fits-all world. This story will widen your perspective about the meaning of gender and how much it matters—or doesn’t—for successful military service. This inspiring account is also written for anyone working with veterans and their transition to civilian life, no matter what the issues might be.” Diane H. Mazur, University of Florida law professor, former Air Force officer, and author of A More Perfect Military: How the Constitution Can Make Our Military Stronger (Oxford University Press) “Speckhard and Beck have teamed up to give us one of the smartest and most important books of the year. Warrior Princess is the story of Kristin Beck, formerly Chris, a decorated Navy SEAL and American patriot who faced a lifelong struggle to come to terms with her gender identity. The book could stand alone as an account of Beck’s distinguished career in the military, but Warrior Princess has a bolder message to send to its readers: transgender people are people… and some of them are even our national heroes. Beck is a natural protagonist…strong, hardworking, and deeply patriotic. Every reader can relate to her, whether it’s her coming of age story, her decision to join the elite Navy SEALs, or even her coming to terms with her gender identity. And where Kristin’s experiences differ from the readers, Speckhard subtly exercises her understanding of psychology and sociology to bridge the gap. Whether a pacifist or a hawk, advocate or opponent of LGBT equality, Warrior Princess is a raw, honest, and surprisingly relatable read.” — OutServe Magazine “This momentous book shares vividly the real life experiences of a veteran SEAL who goes on to transition as a civilian. The raw adrenaline packed events explicitly describe growing up, marriage, combat and leave and are experienced through anecdotes to the audience. The dramatic combat action and the shared emotional responses to both the war and the gender dysphoria are conviction of the traumas of both combat and transition. The book will be an inspiration to individuals struggling with gender dysphoria and seeking to find a way forwards. It will be a useful resource to share with important family members and friends to read in advance or alongside sharing plans of the change ahead for an individual.” — Professor Kevan Wylie, MD FRCP FRCPsych FRCOG; Director, World Professional Association for Transgender Health; President, World Association for Sexual Health “Chris/Kristin Beck is a true American hero, epitomizing professional and personal courage, both as a Navy Seal and as a transgender advocate in civilian life. She fought for this country to protect the democratic way of life she believed in. Now she shares her amazing story as she challenges the American principles of liberty and equality on the battlefield of gender expectations.” Dina Titus, Politician and author of Bombs in the Backyard: Atomic Testing and American Politics ​ “Wow! What an incredible story. In Warrior Princess, Anne Speckhard goes beyond today’s news headlines about US commanders grappling with sexual assault in the military and repealing Don’t ask/Don’t tell to convey the compelling story of Chris Beck’s journey to becoming Kristin Beck. This is a book only Anne could write. She has such an ability to connect, make people feel safe, and tell their story. As the U.S. military steps up to adapt to changes in our society, this book is an important contribution to our national debate." Damon Wilson, Executive Vice President, The Atlantic Council

The evening of June 24, Infantry-Regiment 505 was established within 12 km of Liepaja in Latvia. The following day, jointly with Kriegsmarine commandos led by Lieutenant-Commander Schenke, the 505th attempted to take the maritime fortress by surprise but the attack had failed. On the 27th, the men of the 505th got a foothold in the southern part of the fortress. The following day, a bloody street battle was engaged against the particularly combative Russian defenders. Joe's second game - he wasn't quite quick enough moving the Germans up for the assault on the fortified building, so didn't get enough of them inside by the end. Great intro to city fighting! 2018-11-10 (D) Jeff B vs Ben Stacey Russian win Per the script, the Germans were pretty much funneled up the middle. Russians lost a squad early trying to dash into the fort. Turn 2 saw the Germans already across the street. Germans lost another 1.5 squads (including a full AE) while the Russians lost another of their own. Machine gun point (V4) was put under constant fire and constant breaking. The commissar provided no help to his troops, constantly whittling away their ranks with severity. Turn saw the Germans knocking on the door and proved to be bloody for both sides, with each losing 1.5 squads, and the Germans losing a 9-1. Russians kept shuffling concealed units to replace the broken, but they were running low on bodies. Turn 4 was another bloody one, with the Germans losing another 2.5 squads (and yet another AE) and an 8-0, while the Russians lost 1.5. Every hex but one was still defended by a full squad though, and they had taken prisoners which helped by allowing them to deploy. Turn 5 saw more blood, but this time the Russians got the worst of it by losing 2.5 squads to 1.5 for the Germans. But Turn 6 swung the other way again with the Germans losing 1.5 to only a HS for the Russians. In the end the Germans just did not have enough bodies left and only managed to get a toehold on this last turn. 2018-11-04 (A) David Garvin vs Jamie Montgomery German win 2018-10-05 (D) Tom Kearney vs David Kocot German win ASLOK, open play 2018-09-09 (A) Derek Rowe vs Alan German win Excellent game. Lots of Toys for the German player and great Close Combat.

PORT CHARLOTTE, FLORIDA — A homeowner defended themselves after someone broke into their home, sending them running down the street with a bullet wound to the back. The homeowner called 911 to report the incident. Police were sent to the home and while they were interviewing the homeowner, they received another 911 call from someone seeking medical assistance. That second 911 call came from the burglar who had just been shot. The sheriff’s office was first called by the homeowner around 7pm Thursday. The homeowner told deputies that a woman named Jessica had forced her way inside a home on the 100 block of Strasburg Drive in Port Charlotte, had fought with the homeowner and only ceased when the homeowner fired a shot from their handgun, hitting the woman in the lower left back. The suspect fled and deputies were speaking to two victims inside the home when they got another call, this time for medical assistance. The call came from 40-year-old Jessica Gutzler in the area of Strasburg Drive and Seaton Avenue, less than half a mile away from the home invasion. Gutzler was taken to the hospital. Deputies say based on evidence, it was clear Gutzler knew the homeowner, had gone there to get into a fight and was the person shot by the homeowner. via mysuncoast.com This is one of those stories where you just have to scratch your head and wonder ‘why?’. Of course the bad person in any story doesn’t want to be shot, but that’s a consequence that comes with breaking into someone else’s home. Like all of the self defense stories that we cover, it’s good to hear that the intended victim wasn’t injured, and was able to successfully defend themselves against a person who was looking to do them harm.

Stephen Lang(I) A stage actor of great recognition, Stephen Lang has shaped a formidable career on and off the various stages of the United States and abroad. Though he is arguably most well-known for his acclaimed performance in James Cameron's Avatar (2009), Lang began his career in theater. Broadway roles include his Tony-nominated performance as Lou in "The ... See full bio » Personal Details Other Works: Publicity Listings: Alternate Names: Height: Did You Know? Personal Quote: Acting can be a very reactive profession. Acting is a fantastic thing, and it's my life, but writing is also part of me too, so I did it and in so doing took responsibility for my own life. And it was very directly and specifically because of "Beyond Glory" that Jim Cameron cast me in Avatar (2009). And Avatar is responsible for the good fortune I've had over the last few years. See more » Trivia: Has narrated numerous audiobooks and was recently awarded the Audiofile Earphone award. See more »

# SOME DESCRIPTIVE TITLE. # Copyright (C) YEAR THE PACKAGE'S COPYRIGHT HOLDER # This file is distributed under the same license as the SuperTux package. # FIRST AUTHOR <EMAIL@ADDRESS>, YEAR. # # Translators: # Benjamin Leduc <[email protected]>, 2019 # mol1 <[email protected]>, 2019 # zecas <[email protected]>, 2019 # #, fuzzy msgid "" msgstr "" "Project-Id-Version: SuperTux v0.6.0-1010-gefc33a183\n" "Report-Msgid-Bugs-To: https://github.com/SuperTux/supertux/issues\n" "POT-Creation-Date: 2019-11-24 01:44+0100\n" "PO-Revision-Date: 2019-11-24 00:58+0000\n" "Last-Translator: zecas <[email protected]>, 2019\n" "Language-Team: French (https://www.transifex.com/arctic-games/teams/95/fr/)\n" "MIME-Version: 1.0\n" "Content-Type: text/plain; charset=UTF-8\n" "Content-Transfer-Encoding: 8bit\n" "Language: fr\n" "Plural-Forms: nplurals=2; plural=(n > 1);\n" #: data/levels/bonus4/A_Narrow_Path.stl:3 msgid "A Narrow Path" msgstr "Un Chemin Proche" #: data/levels/bonus4/Beginning_The_Journey.stl:3 msgid "Beginning The Journey" msgstr "Début de Quête" #: data/levels/bonus4/Cave_of_Dreams.stl:3 msgid "Cave Of Dreams" msgstr "Caverne Des Rêves" #: data/levels/bonus4/Cold_Forest.stl:3 msgid "Cold Forest" msgstr "Forêt Glacée" #: data/levels/bonus4/Crystal_Mania.stl:3 msgid "Crystal Mania" msgstr "La Folie Des Cristaux" #: data/levels/bonus4/Deeper_Into_The_Mountains.stl:3 msgid "Deeper Into The Mountains" msgstr "Au Plus Profond Des Montagnes" #: data/levels/bonus4/Feeling_The_Nature.stl:3 msgid "Feeling The Nature" msgstr "Sentir La Nature" #: data/levels/bonus4/Fog_And_Mist.stl:3 msgid "Fog And Mist" msgstr "Brume et Brouillard" #: data/levels/bonus4/Forest_Mountains.stl:3 msgid "Forest Mountains" msgstr "Montagnes Arborées" #: data/levels/bonus4/Forest_Mountains.stl:140 msgid "#One Path contains enemies, the other treasure..." msgstr "#Un Chemin recèle des ennemis, l'autre un trésor..." #: data/levels/bonus4/Forest_Mountains.stl:145 #: data/levels/bonus4/Forest_Mountains.stl:150 msgid "#You can use this door to try the other way..." msgstr "#Tu peux utiliser cette porte pour essayer l'autre chemin..." #: data/levels/bonus4/Generic_Snow_Level.stl:3 msgid "Generic Snow Level" msgstr "Niveau de Neige Générique" #: data/levels/bonus4/Glacier_Danger.stl:3 msgid "Glacier Danger" msgstr " Danger Glacier" #: data/levels/bonus4/Halloween_Fields.stl:3 msgid "Halloween Fields" msgstr "Prés d'Halloween" #: data/levels/bonus4/Its_Halloween_Time.stl:3 msgid "It's Halloween Time!" msgstr "C'est Halloween!" #: data/levels/bonus4/Lets_Climb_That_Mountain.stl:3 msgid "Let's Climb That Mountain!" msgstr "Grimpons à Cette Montagne!" #: data/levels/bonus4/Night_Terrors.stl:3 msgid "Night Terrors" msgstr "Terreurs Nocturnes" #: data/levels/bonus4/Penguin_In_The_Bushes.stl:3 msgid "A Penguin In The Bushes" msgstr "Un Manchot Dans Les Buissons" #: data/levels/bonus4/Rainy_Swamps.stl:3 msgid "Rainy Swamps" msgstr "Marécages Pluvieux" #: data/levels/bonus4/Sky_High.stl:3 msgid "Sky High" msgstr "Haut Ciel" #: data/levels/bonus4/SnowMansLand.stl:3 msgid "SnowMan's Land" msgstr "Terre du Yéti" #: data/levels/bonus4/SnowMansLand.stl:86 msgid "#It sure is breezy today, huh?" msgstr "#Ça caille aujourd'hui, non?" #: data/levels/bonus4/Snowy_Sunset.stl:3 msgid "Snowy Sunset" msgstr "Coucher du Soleil Enneigé" #: data/levels/bonus4/Some_Icy_Path.stl:3 msgid "Some Icy Path" msgstr "Quelques Chemins Gélés" #: data/levels/bonus4/Some_Icy_Path.stl:115 msgid "" "#You won't be able to pass, if you don't bring him something he wants..." msgstr "#Tu ne peux pas passer, si tu ne lui apportes pas ce qu'il veut..." #: data/levels/bonus4/Some_Icy_Path.stl:120 msgid "#Maybe this crystal is the right thing for this snowman...?" msgstr "#Peut-être ce cristal est bon pour le yéti...?" #: data/levels/bonus4/Some_Icy_Path.stl:125 msgid "#Great, now he's gone... I'll keep the crystal for myself." msgstr "#Super, il est parti maintenant... Je vais me garder le cristal." #: data/levels/bonus4/Spooky_Mansion.stl:3 msgid "Spooky Mansion" msgstr "Manoir Frissonnant" #: data/levels/bonus4/Stormy_Night.stl:3 msgid "Stormy Night" msgstr "Nuit d'Orage" #: data/levels/bonus4/Sunshine_Valley.stl:3 msgid "Sunshine Valley" msgstr "Vallée Sous Le Soleil" #: data/levels/bonus4/The_Way_Of_The_Snow.stl:3 msgid "The Way Of The Snow" msgstr "Le Chemin De La Neige" #: data/levels/bonus4/Too_Much_Water.stl:3 msgid "Too Much Water" msgstr "Trop d'Eau" #: data/levels/bonus4/Two_Tiny_Towers.stl:3 msgid "Two Tiny Towers" msgstr "Les Deux petites Tours" #: data/levels/bonus4/worldmap.stwm:3 msgid "Bonus Island IV" msgstr "Île Bonus IV" #: data/levels/bonus4/worldmap.stwm:210 msgid "Enter Forest Sector" msgstr "Entrer Dans le Secteur Forestier" #: data/levels/bonus4/worldmap.stwm:217 msgid "Enter Halloween Sector" msgstr "Entrer Dans le Secteur Halloween" #: data/levels/bonus4/worldmap.stwm:224 msgid "Enter Arctic Sector" msgstr "Entrer Dans le Secteur Arctique" #: data/levels/bonus4/worldmap.stwm:231 data/levels/bonus4/worldmap.stwm:238 #: data/levels/bonus4/worldmap.stwm:245 data/levels/bonus4/worldmap.stwm:252 #: data/levels/bonus4/worldmap.stwm:259 data/levels/bonus4/worldmap.stwm:266 msgid "Go Home" msgstr "Retourner au point de départ" #: data/levels/bonus4/worldmap.stwm:273 msgid "Go Back" msgstr "Revenir" #: data/levels/bonus4/worldmap.stwm:280 msgid "The next challenge awaits..." msgstr "Le prochain défi attend..."

/* https://github.com/cirosantilli/x86-bare-metal-examples#reboot */ #include "common.h" BEGIN ljmpw $0xF000, $0XFFF0

// author: Jannik Strötgen // email: [email protected] // date: 2015-03-24 // This file contains normalization information for date words. "monday","1" "tuesday","2" "wednesday","3" "thursday","4" "friday","5" "saturday","6" "sunday","7" "Monday","1" "Tuesday","2" "Wednesday","3" "Thursday","4" "Friday","5" "Saturday","6" "Sunday","7"

"Hau ab" Demonstranten verhindern Uni-Vorlesung von AfD-Mitbegründer Lucke Hunderte Protestler haben die erste Vorlesung von AfD-Mitbegründer Bernd Lucke seit seiner Rückkehr an die Uni Hamburg verhindert. Der Wirtschaftswissenschaftler wurde mit Papierkugeln beworfen - zu Wort kam er nicht.

Plasticity of frequency organization in auditory cortex of guinea pigs with partial unilateral deafness. We have examined the effect of restricted unilateral cochlear lesions on the orderly topographic mapping of sound frequency in the auditory cortex of adult guinea pigs. These lesions, although restricted in spatial extent, resulted in a variety of patterns of histological damage to receptor cells and nerve fibres within the cochlea. Nevertheless, all lesions resulted in permanent losses of sensitivity of the cochlear neural output across a limited frequency range. Thirty-five to 81 days after such damage to the organ of Corti, the area of contralateral auditory cortex in which the lesioned frequency range would normally have been represented was partly occupied by an expanded representation of sound frequencies adjacent to the frequency range damaged by the lesion. The thresholds at their new characteristic frequencies (CFs) of clusters of cortical neurones in these regions were close to normal thresholds at those frequencies (mean difference across all animals was 3.8 dB). In a second series of experiments, the responses of neurone clusters were examined within hours of making similar cochlear lesions. It was found that shifts in CF toward frequencies spared by the lesions could occur, but thresholds were greatly elevated compared to normal (mean difference was 31.7 dB in five animals). The emergence of sensitive drive in such regions after prolonged recovery periods in lesioned animals thus suggests that the auditory cortical frequency map undergoes reorganization in cases of partial deafness. Some features of this reorganization are similar to changes reported in somatosensory cortex after peripheral nerve injury, and this form of plasticity may therefore be a feature of all adult sensory systems.

Deal avoids U.S. takeover of Oakland cops Tentative pact avoids U.S. takeover of department - but adds a wrinkle Judge Thelton Henderson, the U.S. Justice Department’s first black attorney, recruited minorities to Stanford Law School. Judge Thelton Henderson, the U.S. Justice Department’s first black attorney, recruited minorities to Stanford Law School. Photo: Mike Kepka / The Chronicle Photo: Mike Kepka / The Chronicle Image 1 of / 3 Caption Close Deal avoids U.S. takeover of Oakland cops 1 / 3 Back to Gallery Oakland officials cut a last-minute deal Wednesday with civil rights attorneys that staves off an unprecedented federal takeover of the city's police force, but hands tremendous power - including the ability to seek the firing of the police chief - to a court-appointed outsider. The settlement, which must be approved by U.S. District Judge Thelton Henderson, would create a "compliance director" charged with driving home a set of reforms that were ordered 10 years ago after a police-brutality scandal. The civil rights attorneys had asked Henderson to place the police force into receivership, saying a broken culture had fouled the reform effort, endangering citizens - minorities, in particular - and prompting costly police-abuse lawsuits. While the deal avoids an outright takeover, it nonetheless grants broad new powers to the federal court. The compliance director would be appointed by Henderson and answer to him, but would be paid from city coffers. The appointee would be able to discipline or demote deputy chiefs and assistant chiefs and could punish or fire Chief Howard Jordan - though only after giving written notice and gaining court approval. The director could spend up to $250,000 at a time and direct City Administrator Deanna Santana in connection with the reform effort. A promising path City leaders lauded the settlement Wednesday, saying it offered a promising path toward emerging, at long last, from federal court oversight. "It's the best-case scenario for us based on the alternatives. We had always been opposed to a receiver," said Jordan, who took part in the negotiations. "If you look at the duties and responsibilities, the compliance director will be charged with actually finding solutions and working with all stakeholders to get us into compliance." Jordan said the difference between a receiver and compliance director is that under a receiver the city would have had no say in who that person would be or what they could do. With a compliance director, the city can nominate candidates for the job and work with the appointee to help meet goals. 'Would have no say' "With the receiver we would have no say in the future of our department," Jordan said. Civil rights attorney Jim Chanin, who helped craft the settlement along with attorney John Burris, said he sees little difference in the titles. He said it was important to city officials that the compliance director not be referred to as a receiver but called it a matter of semantics, saying, "I see this as a receiver with a different name." He said the compliance director's power to fire the chief is unlike any other department he knows of in the nation. Burris said he is "cautiously optimistic that we can set a more positive direction for the department and get it into compliance. If this is done properly, this department will be in a position to engage in constitutionally sound policing." Jordan said the city is in the process of identifying possible compliance directors, though it may be some time before that's decided. According to Wednesday's deal, the city and the civil rights lawyers would try to agree on a candidate, with Henderson making the final decision. Mayor Jean Quan said the new agreement would help the department reach compliance. "We're very grateful to the judge for this opportunity," she said. "This will help us move on faster. It's been months and months in the making and a lot of hard work." Involving officers Rocky Lucia, an attorney for the Oakland Police Officers Association, said the deal gives officers a bigger stake in the reform effort, in stark contrast to previous agreements. Under the settlement, the compliance director would meet with the union president at least once every three months to gain insights from the rank-and-file. The director could not alter union contracts. "It formalizes the requirement that we get a seat at the table," Lucia said. Sgt. Barry Donelan, the union president, said the deal "lifted a cloud of uncertainty. All this talk of a receiver has moved us away from focusing on dealing with crime in Oakland. I'm hoping this is the blueprint for leadership to get into compliance and let the officers focus on serving the citizens." Crime is up Major crimes are up 23 percent this year in Oakland. The police force has 626 officers, down from a high of 837 in December 2008. And The Chronicle reported last week that officers arrested 44 percent fewer people in 2011 than they did just three years before. Chanin and Burris represented more than 100 people who sued the city after four officers, who called themselves the Riders, were accused in 2000 of imposing vigilante justice in West Oakland. In a resulting settlement, Oakland had to implement dozens of reforms - some that remain incomplete. 10 tasks to complete The city still needs to complete 10 tasks before it can emerge from court oversight, including improving the way officers report use of force and gather racial data on people they stop. In an example of the failures in Oakland, a court-appointed monitor overseeing the reforms said officers often do not articulate a constitutional reason for making a stop. The settlement reflects the city's desire to diminish the power of the monitor, Robert Warshaw, who has been critical of the city's progress since his appointment in January 2010. The deal calls for status conferences to be held in front of Henderson, starting roughly six months after the appointment of the compliance director. If the judge finds the city is not making adequate progress on the reforms, he may impose "any appropriate remedy," including receivership.

All relevant data are within the manuscript and its Supporting Information files. Introduction {#sec005} ============ Background {#sec006} ---------- Chronic hepatitis C virus (HCV) infections affect an estimated 71 million people.\[[@pone.0223649.ref001]\] Given the global burden of HCV and the recent introduction to the market of new and effective direct-acting antivirals (DAAs), the WHO aims to eliminate viral hepatitis as a global health threat by 2030.\[[@pone.0223649.ref001], [@pone.0223649.ref002]\] To achieve this ambitious agenda, several strategies need to be implemented to reduce costs, diminish the risk of financial hardship for those in need of these services, and encourage solutions for more sustainable and equitable financing.\[[@pone.0223649.ref003]\] The high cost of DAAs is a major burden on health systems, even for high-income countries such as Switzerland. As a cost-saving measure, the Swiss Federal Office of Public Health (FOPH) limited insurance coverage for DAA treatment to only those diagnosed with an advanced form of the disease. It was years before drug prices decreased sufficiently for these access limitations to be removed by the FOPH in 2017, thereby allowing insurance coverage for all insured persons in Switzerland.\[[@pone.0223649.ref004], [@pone.0223649.ref005]\] However, access issues remain for vulnerable individuals not covered by mandatory healthcare insurance, people living in prisons (PLP), people who inject drugs (PWID) and migrants, for whom HCV prevalence remains high and access to treatment is limited.\[[@pone.0223649.ref005]--[@pone.0223649.ref007]\] The international agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS): A step toward equitable financing in low- and middle-income countries {#sec007} ------------------------------------------------------------------------------------------------------------------------------------------------------------------- The history of the global human immunodeficiency virus (HIV) epidemic provides us with real life lessons in achieving drug price reductions and improving global access to treatment. Applying similar strategies to the global hepatitis C epidemic may help in reaching comparatively affordable access to DAAs.\[[@pone.0223649.ref008]--[@pone.0223649.ref012]\] By leveraging TRIPS flexibilities, such as compulsory licenses, as well as voluntary licensing schemes such as the Medicine Patent Pool, low- and middle-income countries have achieved notable success in fostering a robust generic market that provides antiretroviral therapy to 93% of people living with HIV at a fraction of the cost of originator drugs.\[[@pone.0223649.ref011]--[@pone.0223649.ref014]\] Buyers' clubs: A step toward equitable financing in high-income countries {#sec008} ------------------------------------------------------------------------- Even after the FOPH dropped the limitation on insurance coverage for DAAs in 2017, giving the insured population nominal unlimited access to DAAs, a significant number of vulnerable or uninsured individuals remained excluded from affordable access to these antivirals.\[[@pone.0223649.ref005], [@pone.0223649.ref015]\] Swiss law allows any individual to import ready-to-use unauthorized medicines for their personal use provided the imported quantity is small and is for their personal consumption.\[[@pone.0223649.ref016], [@pone.0223649.ref017]\] With the aim of protecting the swiss market and patients from counterfeit or substandard medicines, the regulating authority, the Swiss Agency for therapeutic products or Swissmedic, limits personal imports to a maximum quantity equivalent to one month of therapy at a standard dosage as indicated, for example, in the patient information leaflet.\[[@pone.0223649.ref018]\] Buyers' clubs, as implemented in some countries, aim to help patients navigate the long and difficult process of personally importing unauthorized drugs, working as mediators in the drug supply chain and assisting patients in sourcing unauthorized generic drugs that are safe and effective. Although most people importing medicine for their personal use appear to do so without requiring assistance, various institutions and associations in Switzerland, such as the Swiss Hepatitis C Association ([www.hepc.ch](http://www.hepc.ch/)) (SHCA), the University of Geneva Hospitals (HUG) and Groupe Sida Genève ([www.groupesida.ch](http://www.groupesida.ch/)) (GSG), offer technical, medical and or financial support to patients importing generic DAAs manufactured under license in India or Bangladesh through the FixHepC Buyers' club (fixhepC.com), based in Australia.\[[@pone.0223649.ref019]\] The FixHepC Buyers' club guarantees the authenticity of the shipped generics and offers the possibility for the patient to be included in a scientific study aiming to establish the effectiveness of those licensed products compared to the originator products.\[[@pone.0223649.ref019], [@pone.0223649.ref020]\] Finally, FixHepC organizes the shipping of the generic DAAs to the patient.\[[@pone.0223649.ref019], [@pone.0223649.ref020]\]. All buyers' clubs assist patients in avoiding counterfeits, but HUG and SHCA ensure proper medical monitoring once the treatment is initiated. GSG offers financial support to patients who would otherwise not be able to afford even the lower priced generics. HUG will also perform quality control measures, such as high-performance liquid chromatography (HPLC-UV), for DAA batches received by their patients.\[[@pone.0223649.ref005]\] Although the possibilities described above may provide solutions that could benefit vulnerable populations in high-income countries, the acceptability of such schemes within stakeholder populations remains an open question. Concerns about the quality and efficacy of generic or unauthorized generics have sparked intense debate worldwide, and opinions vary widely within pharmaceutical, medical and public sectors as well as among patient groups.\[[@pone.0223649.ref021]--[@pone.0223649.ref024]\] The efficacy and quality of medicines purchased abroad as well as the reliability and trustworthiness of online pharmacies not subject to Swiss or even EU regulatory oversight are generally regarded as low to nonexistent by both authorities and consumer advocates in Switzerland.\[[@pone.0223649.ref025]--[@pone.0223649.ref028]\] However, very little is known about the knowledge and perceptions of the Swiss population regarding unauthorized generics or the provision of financial support for personal importation schemes for vulnerable persons. To gain better insight into these issues, we surveyed a sample of some principal stakeholders. Methods {#sec009} ======= Survey {#sec010} ------ The questionnaire was based on the fictitious case of a 28-year-old woman diagnosed with hepatitis C who has no access to insurance and does not have the financial resources necessary to personally cover the costs (see Text A in [S1 File](#pone.0223649.s001){ref-type="supplementary-material"}). The fictitious case indicates that the patient's attending physician suggested that she contact a buyers' club that might assist her in importing unauthorized generics from India or Egypt and help her find financial support. The case description highlighted both the price of the drugs authorized in Switzerland (approximately 30,000 CHF) and the price of the generics available overseas (approximately 1,000 CHF) and was followed by 21 questions about the participants' knowledge and perceptions regarding imported generics and the related risks. We chose to focus our attention on five specific questions: 1) the efficacy of generics imported from India or Egypt, 2) the safety of these generics, 3) quality control at entrance, 4) the respondent's ability to differentiate a trustworthy website from a fraudulent one and 5) the respondent's opinion regarding whether to financially support a patient importing generic drugs for personal use. These five variables were defined as primary outcomes and are described separately. Further questions, such as "*Have you ever bought medicines through the Internet*?", "*Before this survey*, *had you ever heard about an association that can help import generics*?" or "*Do you know of a buyers' club*?" were asked, and the responses were treated as secondary outcomes (see Table A in [S1 File](#pone.0223649.s001){ref-type="supplementary-material"}). Participants were chosen from five of the principal stakeholder groups in Switzerland: physicians, pharmacists, patients, non-healthcare professionals and politicians. The survey was distributed to members of the five groups through separate channels. For the physician's group, we sent an email to all registered physicians at the HUG and Lausanne CHUV. For the pharmacist group, we sent an email to 15 HUG pharmacists and 300 members of the Pharmacist's Society of Geneva (<https://www.pharmageneve.swiss>). For the patient group, we sent an email to the 100 members of the HUG Patients' Association. The group of non-healthcare professionals was composed mostly of students from various programmes, including the medical school at the University of Geneva, who were contacted through social media (Facebook), as well as members and beneficiaries of the GSG, who were contacted through the association's newsletter. The participating politicians were members of the Swiss parliament who were contacted through their published parliamentary email address. Participants were invited to participate using [www.sondageonline.com](http://www.sondageonline.com/); they could log in to the survey through a specific link provided to each group. Participation in our survey was voluntary. By completing the survey, all respondents implicitly consented to the use of their data in a scientific study. Because no personal information was collected, no email addresses or IP addresses were logged and all data was collected and analysed anonymously thus guaranteeing the anonymity of all respondents, this study is considered to be exempt from formal institutional review.\[[@pone.0223649.ref029]\] The questionnaire was opened for four months, from January 2, 2019, to April 30, 2019. All participants who had answered at least one question of interest were included. Because only 14 participants fulfilled the inclusion criteria, we decided to exclude the politicians' group. Statistical analysis {#sec011} -------------------- Different comparisons among the groups of respondents and some of the respondents' characteristics were performed using the chi-square test or Fisher's exact test, depending on the conditions to which the statistical test was applied. We then assessed the five primary outcomes using the original 4-point scale (ordinal format, "I do not agree at all", "I do not agree", "I agree", "I fully agree"). Five ordered logistic models were performed to estimate the association between each dependent variable (efficacy, quality, and quality control of Indian or Egyptian generics; perceptions regarding financial support) and the respondent group. All models were adjusted for the categories of age (20--29, 30--39, 40--54, and \> = 55 years), gender, nationality (Swiss, European nationalities other than Swiss, and others) and level of education (university or higher versus primary/mandatory school and other). All variables were assessed in univariate analyses and then forced into the multivariate models. Regarding the outcome assessing the respondents' reliance on and confidence in the identification of websites, we performed an unconditional logistic regression model because the dependent variable was dichotomous (reliance "yes" *vs*. *"*no"). We also forced all variables into the model. All associations are presented as odds ratios, 95% confidence intervals (95%CIs) and p-values. All analyses were performed using intercooled STATA version 15.0 (StatCorp., College Station, TX, USA). Statistical significance was defined as p\<0.05 (two-sided). Results {#sec012} ======= Over the study period, we obtained a sample of 781 respondents: 445 physicians, 77 pharmacists, 51 patients and 207 non-healthcare professionals; all participants had answered at least one question of interest (see Table B in [S1 File](#pone.0223649.s001){ref-type="supplementary-material"}). Because only 14 participants fulfilled the inclusion criteria, we decided to exclude the politicians' group. Women, people under forty years of age and higher education levels were overrepresented in the sample ([Table 1](#pone.0223649.t001){ref-type="table"}). The majority of the respondents were Swiss (77.3%), and more than half of the participants were physicians (57.0%). We compared the characteristics of the four groups (physicians, pharmacists, patients and non-healthcare professionals) ([Table 1](#pone.0223649.t001){ref-type="table"}). We found significant differences regarding gender (more women among the pharmacists and non-healthcare professionals than among the doctors or patients), age categories (the non-healthcare professionals were younger than the patients, pharmacists and doctors), nationalities (more respondents were Swiss among the pharmacists and non-healthcare professionals than among the doctors and patients) and education ([Table 1](#pone.0223649.t001){ref-type="table"}). 10.1371/journal.pone.0223649.t001 ###### Respondent characteristics by survey group. {#pone.0223649.t001g} --------------------------------------------------------------------------------------------------------------------------------------------------------------------- Variables Physicians\ Pharmacists\ Patients\ Non-healthcare professionals\ Total\ p-value (n = 445) (n = 77) (n = 51) (n = 207) (n = 781) ------------------------------- ------------- -------------- ----------- ------------------------------- ------------ ----------------------------------------------- **Gender, n (%) (2 missing)** \<0.001[^1^](#t001fn001){ref-type="table-fn"}  Male 219 (49.3) 23 (29.9) 22 (43.1) 46 (22.2) 310(39.8)  Female 225 (50.7) 54 (70.1) 29 (56.9 161 (77.8) 469(60.2) **Age in years, n (%)** \<0.001[^1^](#t001fn001){ref-type="table-fn"}  20--29 81 (18.2) 16 (20.8) 2 (3.9) 156 (75.0) 255(32.7)  30--39 209 (47.0) 20 (26.0) 7 (13.7) 11 (5.3) 247(31.6)  40--54 104 (23.4) 27 (35.1) 21 (41.2) 20 (9.6) 172 (22.0)  \> = 55 51 (11.5) 14 (18.2) 21 (41.2) 21 (10.1) 107(13.7) **Nationality, n (%)** \<0.001[^2^](#t001fn002){ref-type="table-fn"}  Swiss 321 (72.1) 64 (83.1) 36 (70.6) 183 (88.0) 604(77.3)  In European union 112 (25.2) 11 (14.3) 8 (15.7) 21 (10.1) 152(19.5)  Other 12 (2.7) 2 (2.6) 7 (13.7) 4 (1.9) 25 (3.2) **Education, n (%)** \<0.001[^2^](#t001fn002){ref-type="table-fn"}  Primary 2 (0.5) 1 (1.3) 8 (15.7) 3 (1.4) 14 (1.8)  Postmandatory 0 (0) 0 (0) 7 (13.7) 6 (2.9) 13 (1.7)  University/high level 442 (99.3) 75 (97.4) 36 (70.6) 194 (93.3) 747(95.7)  Other 1 (0.2) 1 (1.3) 0 (0) 5 (2.4) 7 (0.9) --------------------------------------------------------------------------------------------------------------------------------------------------------------------- 1 Comparisons were performed using the chi-square test; 2 Comparisons were performed using Fisher's exact test. [Fig 1](#pone.0223649.g001){ref-type="fig"} shows that 58% (435/749) of the respondents strongly agreed or agreed that the efficacy of an imported generic is equivalent to the corresponding Swiss medicine, and 36% (271/749) strongly agreed or agreed that the quality of an imported generic is equivalent to the corresponding brand (see Table B in [S1 File](#pone.0223649.s001){ref-type="supplementary-material"}). The majority (733/751, 98%) answered that they would strongly agree or agree to quality control upon arrival, and 79% (586/735) strongly agreed or agreed that there is a need to financially support this initiative; support among physicians was 83%. Finally, 31% (202/656) of the respondents declared that they could recognize a fraudulent website. {#pone.0223649.g001} In the univariate analysis (see Table C in [S1 File](#pone.0223649.s001){ref-type="supplementary-material"}), we found that the physician and non-healthcare professional groups were consistently associated with all four primary outcomes: compared to pharmacists, physicians and non-healthcare professional were, respectively, 3.40 and 5.27 times more willing to agree regarding the efficacy of imported generics, 3.36 and 4.52 times more willing to agree about their quality, 2.40 and 2.75 times more willing to agree about the need for quality control, and 3.16 and 3.47 times more willing to agree about the need to financially support this initiative. Physicians felt less capable of identifying a trustworthy website compared to pharmacists (OR = 0.44; 95%CI: 0.26--0.75, p = 0.002). Younger age categories were also associated with higher agreement with the question regarding the efficacy of imported generics (OR = 2.31; 95%CI: 1.48--3.59, p\<0.001 in the 20--29 years age category compared to \> = 55 years age category) and the identification of a valuable website (OR = 1.83; 95%CI: 1.02--3.28, p = 0.043; OR = 1.83; 95%CI: 1.14--2.93, p = 0.012; OR = 2.47; 95%CI: 1.51--4.04, p\<0.001, respectively for the 20--29, 30--39, and 40--54 years age categories compared to \> = 55 years age category). A high-level education was associated with higher agreement to the questions regarding the need for quality control and the need to financially support this initiative compared to a middle-level education (OR = 3.82; 95%CI: 1.52--9.59, p = 0.004 and OR = 2.11; 95%CI: 2.11; 95%CI: 1.05--4.24, p = 0.035, respectively). Other nationalities agreed less than Swiss respondents with the need to financially support this initiative (OR = 0.29, 95%CI: 0.13--0.66, p = 0.003). In multivariate analyses, we confirmed the results of the univariate analyses ([Table 2](#pone.0223649.t002){ref-type="table"}). Medical doctors, patients and non-healthcare professionals had all a higher agreement with the statement that Indian/Egyptian generics had the same efficacy as Swiss drugs. Other factors were associated with the outcome, but associations varied depending on the outcome assessed. 10.1371/journal.pone.0223649.t002 ###### Factors associated with the five primary outcomes (multivariate analyses). {#pone.0223649.t002g} Efficacy Quality Quality control Finance initiative Fraudulent website -------------------- ------------------ ------------- ------------------ -------------------- -------------------- --------------- ------------------ ----------------- ------------------ ----------------- ***Gender*** Male 1 0.758 1 0.518 1 0.934 1 0.272 1 0.088 Female 1.05 0.91 1.01 1.19 0.73 (0.78--1.40) (0.68--1.22) (0.73--1.40) (0.87--1.61) (0.51--1.05) ***Age in years*** *0*.*081* *0*.*159* *0*.*847* *0*.*259* *0*.*001* \> = 55 1 \- 1 \- 1 \- 1 \- 1 40--54 1.23 0.393 0.98 0.928 1.1 0.736 1.03 0.893 **3.03** **\<0.001** (0.77--1.97) (0.60--1.60) (0.64--1.90) (0.67--1.59) **(1.74--5.28)** 30--39 1.47 0.103 1.44 0.132 1.15 0.612 1.44 0.078 **2.18** **0.002** (0.92--2.34) (0.90--2.31) (0.67--1.96) (0.96--2.15) **(1.32--3.59)** 20--29 **1.83** **0.016** 1.01 0.97 0.94 0.838 1.19 0.901 1.76 0.068 **(1.12--2.99)** (0.62--1.65 (0.54--1.65) (0.62--1.72) (0.96--3.24) ***Nationality*** *0*.*271* *0*.*781* ***0*.*011*** ***0*.*298*** Swiss 1 \- 1 \- 1 0.791 1 \- 1 EU 0.86 0.425 1.06 0.737 0.89 0.577 1.19 0.38 1.31 0.201 (0.60--1.24) (0.74--1.52) (0.60--1.33) (0.81--1.74) (0.87--1.99) Other 0.54 0.139 0.78 0.562 0.81 0.654 **0.31** **0.006** 1.62 0.3 (0.24--1.22) (0.34--1.80) (0.32--2.06) **(0.13--0.71)** (0.65--4.07) ***Education*** Middle level 1 0.552 1 0.311 1 **0.005** 1 0.11 1 0.346 High level 1.24 1.47 **4.01** 1.83 1.6 (0.61--2.56) (0.70--3.11) **(1.53--10.53)** (0.87--3.82) (0.60--4.26) ***Group*** ***\<0*.*001*** ***0*.*013*** ***\<0*.*001*** ***0*.*003*** Pharmacists 1 **\<0.001** 1 **-** 1 **-** 1 **-** **1** Physicians **3.38** **\<0.00** **3.00** **\<0.001** 2.37 **0.00** **3.00** **\<0.001** **0.35** ***\<0*.*001*** **(2.06--5.56)** **(1.80--5.02)** **(1.27--4.41)** **(1.84--4.92)** **(0.20--0.61)** Patients **2.20** **0.041** **2.40** **0.031** 2.17 0.085 **2.18** **0.042** 0.99 0.982 **(1.03--4.70)** **(1.09--5.31)** (0.90--5.26) **(1.03--4.61)** (0.44--2.23) Non-healthcare **4.39** **\<0.001** **4.98** **\<0.001** **3.16** **0.001** **3.79** **\<0.001** **0.46** **0.028** professionals **(2.49--7.72)** **(2.79--8.89)** **(1.59--6.31)** **(2.14--6.70)** **(0.23--0.92)** Finally, we looked at secondary outcomes and found that only 9% of physicians (n = 430), 2% of patients (n = 46) and 3% of pharmacists (n = 67) had heard of a buyers' club. Discussion {#sec013} ========== Efficacy and quality of imported unauthorized generics {#sec014} ------------------------------------------------------ To the best of our knowledge, this study is the first to analyse perceptions among physicians, pharmacists, patients and non-healthcare professionals towards imported unauthorized generics from India or Egypt in a high-income country. We found that only 36% and 58% of respondents believe that the quality and efficacy, respectively, of unauthorized generics are equivalent to that of their corresponding brand; pharmacists were least likely to agree with these statements. This distrust of imported unauthorized generics might be partly explained by poor knowledge of the existence of approval processes for generic drugs. Trust issues surrounding the use of unauthorized imported generic drugs may also be linked to the fear of substandard drugs entering the supply chain and being prescribed to patients.\[[@pone.0223649.ref030]\] Even if the generic approval process does not require the same level of clinical testing as for a brand drug, quality is a key issue in the registration process worldwide.\[[@pone.0223649.ref024], [@pone.0223649.ref031]\] The quality of finished pharmaceutical products (FPP) and active pharmaceutical ingredients (API) evolves in a strongly regulated market. There are three measures of similarity that the generic drug and unauthorized imported generics must meet to be considered clinically equivalent to their brand-name counterpart during the drug application process. First, generic drugs must be chemically equivalent, containing the same active ingredient, route of administration, dosage form, and strength as their brand-name counterpart. The second mandatory principle is bioequivalence, meaning that the drug has the same rate and extent of absorption as the brand drug, which is a key issue in the registration process worldwide.\[[@pone.0223649.ref032]\] A bioequivalence study is usually conducted using a randomized, two-period, two-treatment, crossover design that allows comparison within individual healthy volunteers.\[[@pone.0223649.ref033]\] Hill and colleagues compared the bioequivalence of sofosbuvir and daclatasvir from seven pharmaceutical companies worldwide and concluded that they were all bioequivalent.\[[@pone.0223649.ref020]\] Finally, generic drugs must show label equivalence, which means that the indications are the same as the originator product. However, the literature largely describes consumer and healthcare professionals' preferences for brand-name drugs over generics. Opinions about generics have always differed, and it often becomes difficult to convince patients and caregivers of the equivalence of these drugs, despite their major cost-saving contributions.\[[@pone.0223649.ref022]--[@pone.0223649.ref024], [@pone.0223649.ref034]\] Several studies have shown that not only are patients reluctant to use generics, but medical doctors also seem to not be always convinced of their equivalency.\[[@pone.0223649.ref022]--[@pone.0223649.ref024], [@pone.0223649.ref034]\] It is essential to address these issues and to isolate the cause of such reluctance if we aim to give a more important role to imported generics in the future. The broad adoption of generic drugs following the loss of exclusivity for the originator drug and the import of generics are essential to achieving sustainable financing of public health systems.\[[@pone.0223649.ref031], [@pone.0223649.ref035]--[@pone.0223649.ref037]\] The WHO has instituted procedures that, once the requirements of safety, quality and efficacy are met, will lead to WHO prequalification of generic drugs.\[[@pone.0223649.ref038]\] The WHO prequalification programme established in 1987 guarantees that prequalified drugs produced in or for developing countries meet globally recognized standards of quality, safety and efficacy. This programme conducts inspections of pharmaceutical facilities to evaluate them in terms of good manufacturing processes and also performs bioequivalence studies. The United States Food and Drug Administration (FDA) has instituted a similar pathway to generic drug approval, known as the Abbreviated New Drug Application (ANDA). This process guarantees that drugs approved under the ANDA meet the same standards of quality, safety and efficacy as drugs marketed in the United States. Just as with the WHO prequalification programme, the FDA will inspect facilities manufacturing generic drugs.\[[@pone.0223649.ref039]--[@pone.0223649.ref041]\] Indian generic manufacturers are significant players in the global generic drug market; for instance, India supplies more than 80% of drugs to treat AIDS in developing countries and might also play a crucial role in the fight against HCV.\[[@pone.0223649.ref042], [@pone.0223649.ref043]\] Notably, Mylan Pharma, an Indian pharmaceutical company, introduced the first generic in the Swiss market in December 2018.\[[@pone.0223649.ref044]\] The respondents were slightly more confident in the efficacy of imported generics (58%) compared to their corresponding Swiss brand-name drug, and the non-healthcare professionals were the most confident group. Efficacy is addressed by measuring the sustained viral response (SVR) twelve weeks after the end of the treatment. With regard to generic DAAs, many trials have been undertaken to demonstrate their efficacy and prove their equivalence.\[[@pone.0223649.ref037], [@pone.0223649.ref045]--[@pone.0223649.ref049]\] The scepticism about the efficacy of imported generics among all groups in this study contrasts sharply with the literature, which demonstrates through several analyses the equivalent quality and corresponding efficacy of these imported unauthorized generics.\[[@pone.0223649.ref019], [@pone.0223649.ref020], [@pone.0223649.ref045]--[@pone.0223649.ref049]\] Abozeid and colleagues found that sofosbuvir-daclatasvir and sofosbuvir-ledipasvir had comparable clinical efficacy when either the generic or the brand formulation was used.\[[@pone.0223649.ref046]\] Liu and colleagues conducted a similar study and found a comparable high SVR rate in both HIV positive as well as HIV negative patients treated with generics.\[[@pone.0223649.ref049]\] We could explain these differences by the study population selected in the present survey, which was probably more educated and sensitive to the topic than the populations in published studies. Internet purchasing {#sec015} ------------------- Once it is proven that these generics are of the same quality and efficacy as the originals, several obstacles remain, particularly in relation to the possibility of purchasing these generics through the Internet as well as personal importation schemes. Indeed, these new ways of obtaining treatments raise a certain amount of risks as counterfeits circulate easily, and there is significant difficulty distinguishing a fraudulent website from a trustworthy website. A rigorous chain of controls through buyers' clubs, organizations such as Swissmedic and targeted medical surveillance once the treatment is initiated need to be implemented if we aim to use unauthorized generic DAAs safely. Access to DAAs through Internet purchasing and the legal right to import unauthorized generics might help to increase treatment access and HCV treatment. However, the pharmaceutical supply chain becomes a key issue in providing protection from falsified medicine as counterfeits circulate easily on the Internet market.\[[@pone.0223649.ref050]\] We are therefore faced with the dilemma of balancing the escalation of risks from buying from unverified websites with the improvement of easy worldwide access to treatment, underlining once more the need to find a sustainable solution to assure patient safety while providing alternative access to treatment. Efforts made by Swissmedic to warn people of the dangers of Internet purchases are crucial, and strict controls must be implemented.\[[@pone.0223649.ref018], [@pone.0223649.ref051]\] We found that 31% of the respondents declared that they are able to recognize a fraudulent website; pharmacists were the most confident group, which might reflect their knowledge of which online medicine retailers to rely on because purchasing through the Internet is part of their work. Our study showed that a vast majority of the respondents (98%), regardless of group, agreed to the need to reinforce control of the drug supply chain, especially upon the drugs' arrival in Switzerland. Quality controls upon arrival require help from a larger laboratory and induce extra costs that should be taken into consideration unless low-cost technologies are used.\[[@pone.0223649.ref052]\] Wang and colleagues tested (by liquid chromatography) pre-exposure prophylaxis with tenofovir disoproxil fumarate and emtricitabine bought through seven different pharmacies online and from six Indian manufacturers and found that they contained the claimed amount of API.\[[@pone.0223649.ref053]\] Buyers' clubs {#sec016} ------------- Buyers' clubs were not very well known by any of the stakeholder populations surveyed. Buyers' clubs are private organizations that can assist patients in accessing generic medicines that meet established standards of quality and efficacy by leveraging both national regulations and international networks of patients, stakeholders and organizations to ensure that sources of generic drugs for personal use are reliable and only provide safe and effective medicines. Some may even have the resources necessary to apply quality control processes to guarantee drug safety.\[[@pone.0223649.ref005]\] The selection of well-known generic manufacturers and the use of commercial intermediaries are some of the means by which supply chain integrity can be better ensured. Quality control testing of medication bought online by patients, such as running HPLC-UV on drug samples, will provide even greater confidence in the safety and quality of imported unauthorized generics.\[[@pone.0223649.ref005]\] Insuring safety and quality within a personal import scheme without the security of an unbroken and traceable drug supply chain from drug approval to quality control at delivery represents a significant challenge to all stakeholders, most notably to patients and buyer's clubs. This challenge will need to be addressed to guarantee the safest treatment possible. Adding discussion of the quality and efficacy of generic drugs, including topics related to the potential benefits and drawbacks of personal importation schemes and buyers' clubs, to academic curriculums may provide an attractive means to build trust in generics among tomorrow's healthcare professionals and alternative solutions to access issues for vulnerable populations. Strength and limitations {#sec017} ------------------------ This study has several limitations. The first is the fictitious case on which the survey is based, which may not be sufficiently representative of the population of patients unable to access care. Additionally, the patient group was exclusively composed of people who were accessing treatment and care in a university hospital, which may have introduced bias regarding accessibility difficulties and cost issues. It is further unknown whether any of these patients could have benefited from a buyer's club-type scheme. Another limitation concerns the group of non-healthcare professionals, which may not have been particularly representative of the overall population as it contains people who use social media and are contacts of one of the study investigators, notably those who were students at the University of Geneva. Due to time constraints and the study horizon, we did not conduct a survey of the general population. An interesting future analysis would be to establish to what extent the general population is familiar with these concepts and what measures could be put in place to increase their knowledge and understanding. For reasons mostly linked to language constraints and the logistics and costs involved in community interpretation, application of the present survey was not deemed feasible within local vulnerable populations. A more thorough survey of the perceptions and attitudes among these populations would be of great interest and should be considered a priority. Finally, the participants were given the opportunity to add personal comments on the survey, and the absence of "*I don't know*" as an answer option came up in these comments. The decision to not add "*I don't know*" as a possible answer was made in response to concerns that the frequency of this response would be too high. Finally, the survey was limited to the cantons of Geneva and Vaud; however, we presume that knowledge and perception are relatively homogenous within Switzerland, and we believe the results observed in the study are of value for Switzerland in general. Whether the observed knowledge and perception are comparable in other European countries should be further explored. Conclusion {#sec018} ========== This study showed that a large majority of respondents mostly agree on providing financial help for those in need and do not object to the use of imported generics. Indeed, the complexity of the drug supply chain and the possibility of counterfeits circulating emphasizes the need for affordable quality and safety controls at different levels, from drug production to purchase by the patient. However, a lack of knowledge regarding the efficacy and quality of imported unauthorized generics has been highlighted, and awareness should be increased among healthcare professionals to convince them that the use of generics imported safely with the help of a buyers' club could be a key strategy for HCV eradication and seems highly promising as a means of promoting access to medicine for all. Supporting information {#sec019} ====================== ###### **Text A.: Fictitious case.** A 28-year-old woman diagnosed with hepatitis C who has no access to insurance and does not have the financial resources necessary to personally cover the costs. **Table A: Survey.** The survey includes 21 questions about the participants' knowledge and perceptions regarding imported generics and the related risks. **Table B: Survey results. Table C: Univariate analysis.** (DOCX) ###### Click here for additional data file. The authors thank Prof Alexandra Calmy, Prof Francesco Negro and Dr Yves Jackson for their valuable comments on the fictitious case and survey and Prof Arnaud Perrier for his valuable comments on the manuscript. The authors thank Pharmageneve association, Groupe sida Geneve, the HUG Patients' Association and all the respondents for participating in our survey. 10.1371/journal.pone.0223649.r001 Decision Letter 0 Liu Chen-Hua Academic Editor © 2019 Chen-Hua Liu 2019 Chen-Hua Liu This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 21 Aug 2019 PONE-D-19-21277 Access to unauthorized hepatitis C generics: Perception and knowledge of physicians, pharmacists, patients and non-healthcare professionals PLOS ONE Dear Dr Vernaz, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. We would appreciate receiving your revised manuscript by Oct 05 2019 11:59PM. When you are ready to submit your revision, log on to <https://www.editorialmanager.com/pone/> and select the \'Submissions Needing Revision\' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: <http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols> Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled \'Response to Reviewers\'.A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled \'Revised Manuscript with Track Changes\'.An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled \'Manuscript\'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Chen-Hua Liu Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 1\. Please ensure that your manuscript meets PLOS ONE\'s style requirements, including those for file naming. The PLOS ONE style templates can be found at <http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf> and <http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf> 2\. We note that your supplementary file contains a copyrighted image - Dallas Buyers Club image. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For more information, see our copyright guidelines: <http://journals.plos.org/plosone/s/licenses-and-copyright>. We require you to either (a) present written permission from the copyright holder to publish these figures specifically under the CC BY 4.0 license, or (b) remove the figure from your submission: a\.         You may seek permission from the original copyright holder of the image to publish the content specifically under the CC BY 4.0 license. We recommend that you contact the original copyright holder with the Content Permission Form (<http://journals.plos.org/plosone/s/file?id=7c09/content-permission-form.pdf>) and the following text: "I request permission for the open-access journal PLOS ONE to publish XXX under the Creative Commons Attribution License (CCAL) CC BY 4.0 (<http://creativecommons.org/licenses/by/4.0/>). Please be aware that this license allows unrestricted use and distribution, even commercially, by third parties. Please reply and provide explicit written permission to publish XXX under a CC BY license and complete the attached form." Please upload the completed Content Permission Form or other proof of granted permissions as an \"Other\" file with your submission.  In the figure caption of the copyrighted figure, please include the following text: "Reprinted from \[ref\] under a CC BY license, with permission from \[name of publisher\], original copyright \[original copyright year\]." b.    If you are unable to obtain permission from the original copyright holder to publish this image under the CC BY 4.0 license or if the copyright holder's requirements are incompatible with the CC BY 4.0 license, please either i) remove the figure or ii) supply a replacement figure that complies with the CC BY 4.0 license. Please check copyright information on all replacement figures and update the figure caption with source information. If applicable, please specify in the figure caption text when a figure is similar but not identical to the original image and is therefore for illustrative purposes only 3\. Please update your ethics statement to include the information on participant anonymity and consent present in your manuscript. 4\. We note that you have included the phrase "data not shown" in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. 5\. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: <http://journals.plos.org/plosone/s/supporting-information> \[Note: HTML markup is below. Please do not edit.\] Reviewers\' comments: Reviewer\'s Responses to Questions **Comments to the Author** 1\. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer \#1: Yes Reviewer \#2: Partly \*\*\*\*\*\*\*\*\*\* 2\. Has the statistical analysis been performed appropriately and rigorously? Reviewer \#1: Yes Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 3\. Have the authors made all data underlying the findings in their manuscript fully available? The [PLOS Data policy](http://www.plosone.org/static/policies.action#sharing) requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data---e.g. participant privacy or use of data from a third party---those must be specified. Reviewer \#1: Yes Reviewer \#2: No \*\*\*\*\*\*\*\*\*\* 4\. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer \#1: Yes Reviewer \#2: No \*\*\*\*\*\*\*\*\*\* 5\. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer \#1: 1. Please address the current regulations made by the Swiss government to import unauthorized generics and to the Buyer's Club, and the rationale of allowing a maximum quantity equivalent to one month of therapy at a standard dosage from Swissmedic. 2\. You may cite Liu's (not 'Lui' \[44\]) another published paper investigating generic DAA for CHC patients on Sci Rep 2018 12;8(1):13699 for reference. 3\. Add 'analysis' after 'univariate' and delete 'was' in the first sentence on page 13. 4\. Polish the language for the 2nd sentence, 2nd paragraph of page 14 (...had the same...than...). 5\. The 'middle level' educated participants are relatively small in number as compared with 'high level' persons, is this true to the general population in Geneva? Reviewer \#2: This questionnaire study conducted an online anonymous survey based on the fictitious situation of a patient diagnosed with HCV who lacked mandatory health insurance and personal financial resources. This study aimed to assess the knowledge and perceptions of stakeholders on unauthorized generic DAA for HCV. The limited knowledge of the efficacy and quality of unauthorized generic DAA emphasizes the need for clearer information on imported generics and the potential safety provided by buyers' club schemes completing the WHO agenda to eradicate viral hepatitis by 2030. 1\. The details of questionnaire are S1. Did the information of the efficacy and quality of unauthorized generic DAA and real world studies (generic DAA is well-tolerated and provides comparably high SVR12 rates for HCV infection) be introduced before the questionnaire? 2\. How many the registered physicians at HUF and Lausanne CHUV? The speciality of physicians, such as hepatologist, infectionist ? 3\. The manuscript needs linguistic improvement and English editing, such as some redundant sentences, type error. \*\*\*\*\*\*\*\*\*\* 6\. PLOS authors have the option to publish the peer review history of their article ([what does this mean?](https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history)). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. **Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our [Privacy Policy](https://www.plos.org/privacy-policy). Reviewer \#1: No Reviewer \#2: No \[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files to be viewed.\] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, <https://pacev2.apexcovantage.com/>. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at <[email protected]>. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0223649.r002 Author response to Decision Letter 0 15 Sep 2019 Revised PONE-D-19-21277 entitled «Access to unauthorized hepatitis C generics: Perception and knowledge of physicians, pharmacists, patients and non-healthcare professionals» by Garcia A et al. We would like to thank you and the reviewers for the careful review of our above-mentioned manuscript. We thank the reviewers and the editor for the helpful and constructive comments guiding our revision and the appreciation of the importance of our work. A point-by-point response to all comments regarding our submission is addressed. . A. Answers to the comments by the editor Editor 1. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: <http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols>. -We agree to the Plos One recommendation in order to enhance the reproducibility of the results and will therefore provide an excel file of primary data upon acceptance. Editor 2. Please ensure that your manuscript meets PLOS ONE\'s style requirements, including those for file naming. \- We thank the editor for this comment. We now modified our manuscript, title author's affiliations, main body manuscript including tables, references and supporting information in order to meet PLOS ONE\'s style requirements. Former reference 32: "Gustafsson BGBWIBTBJFKGOLJEMCSITCZLL. European payer initiatives to 521 reduce prescribing costs through use of generics. GaBI Journal. 2012;1(1):1:22." Is now reference 36 and was modified as follow: "Godman B, Wettermark B, Bishop I, Burkhardt; T, Fürst J, Garuoliene K, et al. European payer initiatives to reduce prescribing costs through use of generics. GaBI Journal. 2012;1(1):1:22." Editor 3. We note that your supplementary file contains a copyrighted image - Dallas Buyers Club image. \- We thank the editor for this important comment and have removed the copyrighted image from the supporting information. Editor 4. Please update your ethics statement to include the information on participant anonymity and consent present in your manuscript. \- We thank the editor for raising this important issue and added in the marked-up copy the following sentence in line 164, page 9: "Participation in our survey was voluntary. By completing the survey, all respondents implicitly consented to the use of their data in a scientific study. Because no personal information was collected, no email addresses or IP addresses were logged and all data was collected and analysed anonymously thus guaranteeing the anonymity of all respondents, this study is considered to be exempt from formal institutional review. We added the reference 29: "Article 2 para. 2 of the Federal Act on Research involving Human Beings (HRA) \[cited 2019 September 10\] Available from: <https://www.admin.ch/opc/en/classified-compilation/20061313/index.html>)." \- Editor 5. We note that you have included the phrase "data not shown" in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. We thank the editor for this important comment. We have removed the phrase "data not shown" and linked the corresponding results to the corresponding table to the S3 Table: Univariate analysis of the supporting information. The sentence is now as follows in the marked-up copy in line 228, page 14: "In the univariate analysis (see S3Table), we found that the physician and non-healthcare professional groups were consistently associated with all four primary outcomes: compared to pharmacists, physicians and non-healthcare professional were, respectively, 3.40 and 5.27 times more willing to agree regarding the efficacy of imported generics, 3.36 and 4.52 times more willing to agree about their quality, 2.40 and 2.75 times more willing to agree about the need for quality control, and 3.16 and 3.47 times more willing to agree about the need to financially support this initiative." Editor 6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. \- This is now addressed in in the marked-up copy line 598, page 33 and updated throughout the manuscript: Supporting Information S1 Text: Fictitious case. A 28-year-old woman diagnosed with hepatitis C who has no access to insurance and does not have the financial resources necessary to personally cover the costs. S1 Table: Survey. The survey includes 21 questions about the participants' knowledge and perceptions regarding imported generics and the related risks. S2 Table: Survey results- S3 Table: Univariate analysis B. Answers to the comments by the reviewers \#1 Reviewer \#1: 1. Please address the current regulations made by the Swiss government to import unauthorized generics and to the Buyer's Club, and the rationale of allowing a maximum quantity equivalent to one month of therapy at a standard dosage from Swissmedic. \- We thank the reviewer or this important comment and modified line 89, page 6 added in the marked-up copy as follows: "Swiss law allows any individual to import ready-to-use unauthorized medicines for their personal use provided the imported quantity is small and is for their personal consumption.(16, 17) We specified the reference 16 as follow: "Article 20 para. 2 a) of the Federal Act on Medicinal Products and Medical Devices (TPA) \[cited 2019 September 10, 2019\]. Available from:[https://www.admin.ch/opc/en/classified-compilation/20002716/index.html."](https://www.admin.ch/opc/en/classified-compilation/20002716/index.html.”) and added the reference 17: "Article 48 of the Ordinance on licensing of medicinal products (AMBV). \[cited 2019 September 10\]. Available from: [https://www.admin.ch/opc/en/classified-compilation/20180857/index.html."](https://www.admin.ch/opc/en/classified-compilation/20180857/index.html.”) We also modified in line 91, page 6 in the marked-up copy as follows:"With the aim of protecting the swiss market and patients from counterfeit or substandard medicines, the regulating authority, the Swiss Agency for therapeutic products or Swissmedic, limits personal imports to a maximum quantity equivalent to one month of therapy at a standard dosage as indicated, for example, in the patient information leaflet.(18)" We added the reference 18: "Swissmedic. Guideline on medicines and the Internet. \[cited 2019 February 17\]. Available from: [https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/market-surveillance/medicinal-products-from-the-internet/leitfaden-arzneimittel-aus-dem-internet.html"](https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/market-surveillance/medicinal-products-from-the-internet/leitfaden-arzneimittel-aus-dem-internet.html”) Reviewer \#1:2. You may cite Liu's (not 'Lui' \[44\]) another published paper investigating generic DAA for CHC patients on Sci Rep 2018 12;8(1):13699 for reference. \- We thank the reviewer for his important comment and modified the phrase in line 325, page 19 "Liu and colleagues". We also added the following published paper investigating generic DDA for chronic HCV-infected patients "Liu CH, Huang YJ, Yang SS, Chang CH, Yang SS, Sun HY, et al. Generic sofosbuvir-based interferon-free direct acting antiviral agents for patients with chronic hepatitis C virus infection: a real-world multicenter observational study. Sci Rep. 2018;8(1):13699", reference 37 at line 297 page 18 and line 319 at page 19. We also added the reference 19: "Freeman JA, Hill A. The use of generic medications for hepatitis C. Liver Int. 2016;36(7):929-32." In lines 105 and 106 page 9 and line 323 page 19. Reviewer \#1:3. Add 'analysis' after 'univariate' and delete 'was' in the first sentence on page 13. \- We thank the reviewer for his comment and modified the phrase as follow in line 228, page 14: "In the univariate analysis (see S3 Table)," Reviewer \#1:4. Polish the language for the 2nd sentence, 2nd paragraph of page 14 (...had the same...than...). \- We thank the reviewer for his comment and have sent our manuscript and supporting information to the American Journal Experts for further editing. Line 249, page 15 is now: "Medical doctors, patients and non-healthcare professionals had all a higher agreement with the statement that Indian/Egyptian generics had the same efficacy as Swiss drugs." Reviewer \#1:5. The 'middle level' educated participants are relatively small in number as compared with 'high level' persons, is this true to the general population in Geneva? \- We thank the reviewer for this important comment. Due to time constraints and the study horizon, we did not conduct a survey of the general population. We cannot answer this question. This is a limitation and as mentioned an interesting future analysis in line 393, page 22: "to establish to what extent the general population is familiar with these concepts and what measures could be put in place to increase their knowledge and understanding." C. Answers to the comments by the reviewers \#2 \- We thank the reviewer \#2 for his constructive comments and and the appreciation of the importance of our work. Reviewer \#2:1 The details of questionnaire are S1. Did the information of the efficacy and quality of unauthorized generic DAA and real world studies (generic DAA is well-tolerated and provides comparably high SVR12 rates for HCV infection) be introduced before the questionnaire? \- We didn't include any information that might have introduced bias to the survey. The only information the respondents had before completing the survey is addressed in the supporting information. Please note the same survey was addressed to different stakeholders including non-healthcare professionals and meant to be comprehensive and simple. Reviewer \#2:2. How many the registered physicians at HUF and Lausanne CHUV? The speciality of physicians, such as hepatologist, infectionist ? \- The are around 15 hepatologists out of 1370 medical doctors at HUG and around 10 out of around 500 medical doctor who received the survey at CHUV. 3\. The manuscript needs linguistic improvement and English editing, such as some redundant sentences, type error. \- We thank the reviewer for this comment and have sent our manuscript and supporting information to the American Journal Experts for further editing. Two redundant sentences were removed: in lines 79 to 82, page 5: "In this context, prices are reduced significantly in response to intense competition, enabling medicine to be affordable, even for life-saving drugs such as those used to treat the HIV and HCV epidemics" and in lines 292 and 293, page 17: "However, these drugs represent an important step forward in terms of public health and sustainable financing." ###### Submitted filename: Response to Reviewers 2.docx ###### Click here for additional data file. 10.1371/journal.pone.0223649.r003 Decision Letter 1 Liu Chen-Hua Academic Editor © 2019 Chen-Hua Liu 2019 Chen-Hua Liu This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 26 Sep 2019 Access to unauthorized hepatitis C generics: Perception and knowledge of physicians, pharmacists, patients and non-healthcare professionals PONE-D-19-21277R1 Dear Dr. Vernaz, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at <https://www.editorialmanager.com/pone/>, click the \"Update My Information\" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at <[email protected]>. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact <[email protected]>. With kind regards, Chen-Hua Liu Academic Editor PLOS ONE Reviewers\' comments: Reviewer\'s Responses to Questions **Comments to the Author** 1\. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the "Comments to the Author" section, enter your conflict of interest statement in the "Confidential to Editor" section, and submit your \"Accept\" recommendation. Reviewer \#1: All comments have been addressed Reviewer \#2: All comments have been addressed \*\*\*\*\*\*\*\*\*\* 2\. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer \#1: (No Response) Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 3\. Has the statistical analysis been performed appropriately and rigorously? Reviewer \#1: (No Response) Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 4\. Have the authors made all data underlying the findings in their manuscript fully available? The [PLOS Data policy](http://www.plosone.org/static/policies.action#sharing) requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data---e.g. participant privacy or use of data from a third party---those must be specified. Reviewer \#1: (No Response) Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 5\. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer \#1: (No Response) Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 6\. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer \#1: (No Response) Reviewer \#2: Authors had responses to the questions properly. I have no other comments for the authors to publish this article. \*\*\*\*\*\*\*\*\*\* 7\. PLOS authors have the option to publish the peer review history of their article ([what does this mean?](https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history)). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. **Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our [Privacy Policy](https://www.plos.org/privacy-policy). Reviewer \#1: No Reviewer \#2: No 10.1371/journal.pone.0223649.r004 Acceptance letter Liu Chen-Hua Academic Editor © 2019 Chen-Hua Liu 2019 Chen-Hua Liu This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2 Oct 2019 PONE-D-19-21277R1 Access to unauthorized hepatitis C generics: Perception and knowledge of physicians, pharmacists, patients and non-healthcare professionals Dear Dr. Vernaz: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact <[email protected]>. For any other questions or concerns, please email <[email protected]>. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Chen-Hua Liu Academic Editor PLOS ONE [^1]: **Competing Interests:**The authors have declared that no competing interests exist.

Promotion valid on Prezzee only when you purchase a $150 Prezzee eGift Card. Once you purchase a $150 eGift Card you will receive a separate email within 3 hours with your bonus $15 Prezzee eGift Card. Offer ends 5:30pm 8.12.19. This offer cannot be used in conjunction with any other offer.

Introduction {#Sec1} ============ Mitochondria are cytoplasmic organelles that perform major roles in cell operation, including energy generation through oxidative phosphorylation (OXPHOS), cell death, calcium levels control, lipid homeostasis and metabolic cell signaling^[@CR1]^. These organelles have their own genome (mtGenome), with 16,569 bp of length and 37 genes, of which 13 are protein-coding genes involved in OXPHOS, 22 are transfer RNA (tRNA) genes and two are ribosomal RNA (rRNA) genes^[@CR2],[@CR3]^. It also presents a non-coding control region known as displacement loop (D-loop), essential for replication and transcription regulation^[@CR4]^. There are many copies of mitochondria in each cell and such copies may present different alleles for the same variant, a state called heteroplasmy. It is well-known that mitochondrial DNA (mtDNA) is more susceptible to alterations in comparison to nuclear DNA^[@CR5]--[@CR7]^. These alterations may lead to mitochondrial dysfunction, which in turn may account for cellular deregulation due to DNA repair defects, leading to the development of different diseases, such as cancer^[@CR8]^. It is notable that hallmarks of cancer (*i*.*e*. abilities acquired by tumor during carcinogenesis to survive and proliferate) include energy deregulation and evasion of cell death, both directly related to mitochondrial function^[@CR9]^. In fact, many studies have shown an association of mtDNA instability and heteroplasmy to different types of cancer^[@CR4],[@CR10]--[@CR15]^. One of these types of cancer is gastric cancer (GC), which is currently the fifth most incident and the third most lethal type of cancer worldwide^[@CR16]^. In Brazil, GC is also one of the most frequent and aggressive types of cancer, being the sixth most incident and the fifth most lethal cancer^[@CR16]^. This is even more alarming in the North region of Brazil, where GC is the second most incident type of cancer among men and the fifth among women^[@CR17]^, probably due to eating habits and genetic background of the population. Regarding genetic ancestry, it is important to highlight that, in addition to nuclear DNA, mtDNA also provides such information through haplogroups, which are basically groups of haplotypes. These provide information about women migration and have also been associated to development and outcome of different diseases, including GC^[@CR18]--[@CR21]^. Moreover, GC usually presents an unfavorable clinic evolution because of nonspecific symptoms at early stages, leading to late diagnosis and a poor prognosis^[@CR22]^. Thus, it is crucial to search for genetic markers that would allow an earlier detection and improve patient outcome. In the last decade, with the advent of new technologies such as Next-Generation Sequencing (NGS), one focus of oncologic research has been high-throughput analyses of human genome related to cancer development. However, to this date, not many studies have investigated the association of mtGenome alterations to cancer, especially GC. For instance, a recent review has pointed out 16 studies associating mtDNA alterations to gastric cancer, but none involved NGS approaches^[@CR23]^. In this study, we sequenced the whole mtGenome in order to assess and compare variants and their heteroplasmy levels in FFPE samples from gastric cancer patients (paired samples, *i*.*e*. samples of both tumor and non-tumoral tissues) and cancer-free individuals from the North region of Brazil. To the best of our knowledge, this is the first study to perform such analysis of gastric cancer in Brazil. Results {#Sec2} ======= After processing the mtGenome sequences with the adequate mapping scores (Q30), the average depths of coverage were 195x and 36x for tumor samples and internal control (IC) samples, respectively. For external controls (EC), the average depth of coverage was 351x. All samples with low quality were excluded. Table [1](#Tab1){ref-type="table"} presents the sample size of all groups for each analysis.Table 1Sample number of each group in the different comparison analyses.CASECONTROLTumorInternal Control (IC)External Control (EC)Initial sample number202050After processing131147***Paired analyses of variant distribution***Paired analysis88---***Heteroplasmy analyses***Initial sample number13940Paired analyses66---General analyses13935***Mitochondrial haplogroup analyses***Sample number---1147 Out of the 20 sequenced sample pairs of GC patients, only eight had both samples with enough coverage for a paired comparison. In another eight patients, only one of their samples (five tumors and three internal controls) had enough coverage to be included in further analyses. The remaining four pairs did not pass our quality standards and were excluded from all analyses. As for external controls, 47 samples had enough coverage to be included in the general analyses. It is noteworthy that (i) mean age was of 66 years old in case group and 41 years old in EC group (Mann-Whitney test, p \< 0.001); and that (ii) case group was composed of 77% male and 23% female, while control group was composed of 28% male and 72% female (Chi-squared test, p = 0.002). Therefore, we evaluated if sex or age range (≥70, 60--69, \<60 years-old) in the tumor samples were associated to the number of variants (Kruskal-Wallis Test; H 1.52, 3.18; P 0.467 and 0.075, respectively), primary tumor location (χ^2^ 13.07, 10.18; P 0.364 and 0.117), tumor degree of differentiation (χ^2^ 6.17, 0.82; P 0.187 and P 0.662), pathogenic staging pT (χ^2^ 9.19, 5.68; P 0.514 and 0.339) and pN (χ^2^ 8.44, 6.43; P 0.392 and P 0.169) and found no association. Similarly, we did not find any dependency of age range (≥60, 50--59, 40--49, 30--39, 20--29, \<20 years-old) or sex to the number of variants of EC (Kruskal-Wallis Test; H 5.22, 0.03; P 0.390 and 0.856, respectively). Thus, age and sex were disregarded in further analyses. Paired sample analyses {#Sec3} ---------------------- When we compared the mtGenome of each of the eight paired samples from gastric cancer patients, we found that, in most cases, tumor samples presented more variants than their respective internal control samples (up to 5.5-fold more variants). Table [2](#Tab2){ref-type="table"} shows the number of variants by pair and the genes in which most variants were found. The full list of variants and proportions is found in Supplementary Material (Table [S1](#MOESM1){ref-type="media"}).Table 2Number of variants (N) and the genes in which most variants were found in each pair of tumor and internal control samples from the same individuals.PairTumor-exclusive variantsInternal control exclusive variantsShared variantsNMT-RegionsNMT-RegionsNMT-Regions122DLOOP1 (22.7%)DLOOP2 (22.7%)ND5 (18.2%)4ND6 (50%)4ATP6 (25%)ND4 (25%)ND5 (25%)RNR1 (25%)213DLOOP2 (38.5%)ND5 (15.4%)13ATP6 (23.1%)3CO3 (33.3%)CYB (33.3%)DLOOP1 (33.3%)316DLOOP1 (31.3%)ND5 (31.3%)10DLOOP1 (40%)6ATP6 (16.7%)CO1 (16.7%)CO3 (16.7%)DLOOP1 (16.7%)ND4 (16.7%)ND5 (16.7%)412ND4 (25%)DLOOP2 (16.7%)7ND5 (42.9%)4ATP6 (25%)CYB (25%)ND4 (25%)ND5 (25%)524DLOOP2 (16.7%)DLOOP1 (12.5%)5ND5 (60%)4DLOOP1 (50%)64ND5 (50%)15ATP6 (20%)13CO3 (23.1%)CYB (23.1%)DLOOP1 (23.1%)714DLOOP1 (28.6%)ND1 (21.4%)6ATP8 (16.7%)CO1 (16.7%)DLOOP2 (16.7%)ND2 (16.7%)RNR1 (16.7%)RNR2 (16.7%)3CYB (33.3%)ND5 (33.3%)RNR1 (33.3%)811ND4 (18.2%)DLOOP2 (18.2%)RNR1 (18.2%)8ND5 (37.5%)DLOOP1 (25%)3DLOOP1 (66.7%)CYB (33.3%) Considering exclusively single variants (*i*.*e*. each variant individually), there were 50 variants present only in tumor samples, while eight were present only in internal controls. These 50 variants were distributed in 17 regions, but mostly in four regions: MT-*DLOOP1* (16%), MT-*ND5* (16%), MT-*ND4* (10%) and MT-*DLOOP2* (10%). As for variants only found in internal controls, most of them were located in MT-*ND5* (25%). By grouping all paired samples from tumor and IC, we found 25 variants that were exclusive to tumor samples and eight variants that were exclusive to internal control samples, as well as 36 variants that were shared by both groups (Fig. [1](#Fig1){ref-type="fig"}). The distribution by region and position of these variants is shown in Supplementary Material (Table [S2](#MOESM2){ref-type="media"}).Figure 1Number of exclusive and shared variants found in the paired samples (tumor and internal control) of gastric cancer patients. Groups are represented by the darker dots. Set size is the sum of variants for each group. Hence, tumor samples presented more than 3-fold the number of exclusive variants in comparison to their paired internal control samples. This notable number of variants that were exclusive to tumor was distributed in 13 genes, of which three (MT-*ATP8*, MT-*ND4L* and MT-*TG*) were only affected in this group. The variants exclusive to internal control samples were distributed in seven genes and the shared variants were distributed in 14 genes, of which MT-*CO3* and MT-*RNR1* were affected in both groups. In addition, the genes with more variants were: (i) for tumor-exclusive variants, MT-*DLOOP1* and MT-*DLOOP2* (with 16% each); (ii) for variants exclusive to internal control, MT-*ND5* (with 25%); and (iii) for variants shared by both groups, MT-*DLOOP1* (with 22%) and MT-*ND5* (with 19%). When comparing heteroplasmy, six out of the eight pairs matched our standards and were included in this analysis. We found that, with one exception, tumor presented notably more heteroplasmic regions than their paired internal control (3 to 9-fold times more; Fig. [2](#Fig2){ref-type="fig"}).Figure 2Heteroplasmy levels for each pair of samples from gastric cancer patients, both tumor (gastric adenocarcinoma) and internal control (control). Each boxplot represents the distribution of heteroplasmy in different mitochondrial genes. Non-applicable (NA) represents unidentified regions. Among the heteroplasmic regions, the most commonly affected were MT-*DLOOP1*, MT-*ND4* and MT-*ND5*. It is noteworthy that these three, along with MT-*ND6*, were heteroplasmic in all tumor samples, but not in all internal controls. Four other genes were heteroplasmic in almost all tumor samples, but they were not as frequently affected among internal control samples (MT-*CO1*, MT-*CYB*, MT-*ND1* and MT-*RNR2*). Additionally, seven other regions were heteroplasmic only in the tumor (MT-*CO2*, MT-*DLOOP2*, MT-*ND4L*, MT-*TC*, MT-*TK*, MT-*TM* and MT-*TT*), and there were no genes that were heteroplasmic in the internal control group but not in the tumor group. General heteroplasmy analysis {#Sec4} ----------------------------- When comparing heteroplasmy levels between all groups of samples (tumor, internal control and external control), we included all tumor (N = 13), internal control (N = 9) and external control (N = 40) samples that met our quality control standards (see Table [1](#Tab1){ref-type="table"}). In addition to the quality scores, only variants with at least 5% heteroplasmy levels were considered for this analysis, in order to control possible artifacts and false-positives due to the limited coverage of the samples^[@CR24],[@CR25]^. Using this criterion, we assessed heteroplasmy levels of all three groups. Aiming a fair comparison of heteroplasmy levels, we evaluated the presence of the same distinct 630 variants in all samples considering a heteroplasmy level of 1% when absent or under 5%. The log heteroplasmy levels were compared using a mixed linear regression assuming a fixed effect of the group and a random effect of the individuals. This model was better fitted to the data than a model without the group effect (Wald test χ^2^ 10.11; P 0.006). The pairwise comparison (with the p-value adjusted according to Tukey) showed that the tumor group presented a significantly higher level when compared to internal group (*t* 2.60; P 0.025) and external group (*t* 3.04; P 0.006) both with statistical power above 73%. These control groups did not present statistically significant difference between each other (*t* −0.42; P 0.906). Considering the previous analysis, the amount of heteroplasmic variants may be more important to tumor development than heteroplasmy levels of variants *per se*. In fact, out of 1,664 heteroplasmic variants found after filtering, 653 variants were found in tumor subgroup (representing 39% of the total), 152 in internal control subgroup (9%) and 859 in external control subgroup (52%). These proportions are very expressive, considering that tumor samples account for about only 1/3 of the number of external controls and they still showed almost half of all heteroplasmic variants. Further, individual's number of heteroplasmic variants average (*i*.*e*. total of heteroplasmic variants divided by number of samples) was of 50.23 for tumor, 16.89 for internal control and 24.54 for external control. Thus, tumor samples presented nearly 3-fold more heteroplasmic variants than internal control samples (Fig. [3](#Fig3){ref-type="fig"}). Then, a Poisson regression considering group effects was applied and it showed a significant difference between these groups (ANOVA F 5.46; P 0.007), with a statistical power above 90%.Figure 3Distribution of heteroplasmic variants in the studied groups: tumor, internal control and external control. Each small dot represents the mean of heteroplasmic variants of a sample. The average number of heteroplasmic variants is also represented for each group. In Fig. [3](#Fig3){ref-type="fig"}, it is possible to see that, even though the external control group was composed of more samples, most of them showed less heteroplasmic variants in comparison to tumor samples. Proportionally, internal control group also showed many samples with less heteroplasmic variants than tumor group. In addition, about half of tumor group presented samples with a high number of heteroplasmic variants, including some samples with more than 2-fold the mean tumor's heteroplasmy variants found (approximately 50 variants). This difference became even more evident in the pairwise comparison of number of heteroplasmic variants between all groups using a post-hoc Tukey test. Tumor group presented a statistically significant difference when compared to internal (P 0.027) and external (P 0.008) controls with a statistical power above 70%. However, when both controls were compared no significant difference was found (P 0.903). Regarding location of the observed heteroplasmic variants, heteroplasmy levels were observed in all protein-coding genes and in almost all non-protein-coding genes -- appearing in all DLOOP and rRNA genes, but not in all tRNA genes. It is noteworthy that two heteroplasmic variants were observed in unidentified regions in external control and tumor samples and that they are probably in tRNA genes due to location. These unidentified regions were excluded from further analyses. Figure [4](#Fig4){ref-type="fig"} shows a representation of all protein-coding and non-coding regions throughout 16,569 bp of the mtGenome. This graph supports our previous result that tumor group presents most heteroplasmic variants, followed by external control and internal control groups.Figure 4Distribution of heteroplasmic variants in the mitochondrial genome for all groups: tumor, internal control and external control. Peaks represent the number of variants. Genomic length and gene division are also shown. Moreover, out of the 37 genes in mtGenome, 32 were heteroplasmic in external control group, 28 in tumor group and 15 in internal control group. Hence, in order to compare heteroplasmic regions between all three groups, we analyzed 15 regions affected in all of them. Among such regions, 12 were protein-coding and three were non-protein-coding genes (one DLOOP and two rRNA regions) (Fig. [5](#Fig5){ref-type="fig"}). In this analysis, we observed a statistically significant difference between all groups, with tumor group presenting more heteroplasmic variants in MT-*RNR1*, MT-*ND5*, MT-*ND4*, MT-*ND2*, MT-*DLOOP1* and MT-*CO1*.Figure 5Joined comparison of all three groups regarding mitochondrial genes with heteroplasmic variants, with the respective p-value obtained with Poisson regression. Mitochondrial haplogroup analyses {#Sec5} --------------------------------- Furthermore, we assessed haplogroup information of all samples in order to investigate a possible association with GC. In some cases, tumor samples presented a different haplogroup than their paired samples, indicating that the tumors might not be an accurate ancestry informative tool, especially considering that MT-DLOOP presented a particularly high rate of variants in this group and these regions are the most informative of maternal ancestry^[@CR26]^. Thus, all tumor samples were disregarded from haplogroup analyses and the case group was be represented only by the internal control. Considering both case (internal control) and control (external control) groups, we observed 17 macro-haplogroups, out of which there were four Native American (A, B, C and D), four European (H, HV, J and V), six African (L0, L1, L2, L3 and L3e) and four Asian (M, N, R and Y) haplogroups (Table [3](#Tab3){ref-type="table"}). Native American haplogroups were the most frequent in both case (36.4%) and control (44.6%). Following, control group presented about the same frequency rate for both European and African haplogroups (25.6% each), while case group presented a similar rate for European (27.3%), but not for African haplogroups (18.2%). Asian haplogroups were around 4-fold more frequent in cases (18.2%) than in controls (4.2%).Table 3Distribution of macro-haplogroups in case and control groups.Mitochondrial AncestryMacro-haplogroupsGeneral (%)Case (%)Control (%)Native AmericanA7.00.08.5B8.60.010.6C20.736.417.0D7.00.08.5EuropeanH13.818.212.8HV3.49.12.1J3.40.04.3V5.20.06.4AfricanL01.70.02.1L113.89.115.0L21.70.02.1L31.79.10.0L3e5.20.06.4AsianM1.79.10.0N1.70.02.1R1.70.02.1Y1.79.10.0 The most common haplogroup was C (Native American ancestry) in both groups, but it is interesting that case has more than 2-fold the frequency of the control (36.4% and 17.0%, respectively). In case group, the second most common haplogroup was H (European ancestry), with 18.2%, followed by the other five haplogroups with 9.1% of presence each. In control group, haplogroup L1 (African ancestry) is the second most common, with 15%, followed by haplogroup H, with 12.8%, and the other haplogroups. In addition, our results showed a difference in the distribution of variants by mitochondrial ancestry (Fig. [6](#Fig6){ref-type="fig"}). Firstly, we compared it within cases using ANOVA and found that 53% of all variants were in individuals from Native American haplogroups, followed by European (18%), Asian (15%) and African (14%) haplogroups (F 4.48; P 0.047). As for control group, individuals from Native American haplogroups also presented the majority of variants (46%), followed by African (36%), European (16%) and Asian (2%) haplogroups (F 2.57; P 0.066). When we compared case and control there was no significant difference (F 0.93; P 0.338).Figure 6Number of variants in the four ancestries (African, Asian, European and Native American) of both case and control groups. Discussion {#Sec6} ========== In this study, we investigated the association of mitochondrial variants with gastric cancer in individuals from a population of the Brazilian Amazon. This was done through whole mtGenome sequencing of FFPE samples from patients and cancer-free individuals. To the best of our knowledge, this is the first study to successfully sequence mtGenome from FFPE samples. This is particularly important because DNA sequencing from this type of material can be challenging. Although good for long-term storage of tissue samples, the FFPE process may affect the material integrity so that the extracted DNA is generally of low quality, often leading to the loss of samples. However, some studies performing NGS have shown that DNA extracted from FFPE tissue samples can still provide results in concordance to frozen tissues^[@CR27]--[@CR29]^. The challenge presented by FFPE samples is probably the reason for the loss of samples and for the limited coverage in our study. In spite of that, we were able to successfully sequence the mtGenome, obtaining interesting results. When we compared the samples from the same eight gastric cancer patients, *i*.*e*. paired tumor and internal control samples, we observed significantly more somatic variants present in tumor samples than in the respective internal control samples (up to 5.5-fold more), a kind of pattern that has been reported in other types of cancer, such as colorectal cancer and penile cancer^[@CR11],[@CR30]^. In addition, studies comparing mtDNA variants and genomic instability of different types of cancer reported that gastric cancer was among the types with more somatic variants and genomic instability with a tumor-specific pattern^[@CR10],[@CR25]^. Regarding the mitochondrial genes in which most of the tumor-exclusive variants were found, we observed that MT-*DLOOP2*, MT-*DLOOP1* and MT-*ND5* were among the regions with more variants in at least half of the tumor samples included in this analysis (Table [2](#Tab2){ref-type="table"}). There was no similar pattern observed when we considered the regions with more variants exclusive to internal control. As for shared variants, they were similarly distributed among different genes. Additionally, there was a mean of 2.43-fold increase in the number of genes with exclusive variants when we compared tumor and internal control samples. It is noteworthy that most of these variants are present in more than one sample and are counted as such in this analysis. Therefore, when we considered single variants only, there were 50 variants present only in tumor samples and most of them was distributed in four regions -- MT-*DLOOP1* (16%), MT-*ND5* (16%), MT-*ND4* (10%) and MT-*DLOOP2* (10%) --, while there were eight variants present only in internal control samples, of which most was found in MT-*ND5* (25%). This suggests that, in tumor, there is an increase not only in the number of variants, but also in the regions in which such variants occur. This greater presence of variants in tumor samples was reinforced when we grouped and compared the eight pairs. In this analysis, we found 25 tumor-exclusive somatic variants and eight somatic variants that were exclusive to internal control samples, as well as 36 shared variants. While some variants that were considered somatic in the pair-by-pair comparison were then considered germline, tumor samples still showed 3-fold more variants than internal control samples. Such tumor-exclusive variants were distributed in 13 genes, of which three (MT-*ATP8*, MT-*ND4L* and MT-*TG*) were only observed in this group. Only a few studies have reported variants in MT-*ATP8*^[@CR31],[@CR32]^ and MT-*ND4L*^[@CR31],[@CR33]--[@CR35]^ in different types of cancer and none was in gastric cancer. No studies were found associating variants in MT-*TG* to cancer. Furthermore, two genes (MT-*CO3* and MT-*RNR1*) only presented shared variants, which are probably not involved in tumorigenesis. However, five genes (MT-*CO1*, MT-*CYB*, MT-*DLOOP1*, MT-*ND1* and MT-*ND5*) not only presented germline variants, but also different somatic variants exclusive to tumor and internal control groups, indicating a possible association of such genes and variants with tumor development. It is noteworthy that, among these genes, MT-*DLOOP1* and MT-*ND5* stand out for presenting more germline variants than the others. In addition to the shared variants, MT-*ND5* also presents a high rate of exclusive variants not only in tumor samples but also in internal control samples, suggesting that this gene could also be altered in cells in other adjacent organs of cancer patients, contributing to possible tumor advances. Regardless, MT-*ND5* encodes a core subunit of Complex I, essential for electron transport from NADH to ubiquinone in the mitochondrial respiratory chain, so that variants in this gene and others related to this process may lead to impairment in OXPHOS and an increase of reactive oxygen species (ROS) generation, which can contribute to cancer proliferation and metastasis^[@CR36],[@CR37]^. In fact, a high rate of mutations in MT-ND5 has been reported in esophageal cancer^[@CR38]^. Moreover, the regions with more tumor-exclusive variants were the MT-*DLOOP1* and MT-*DLOOP2* (16% each). This corroborates previous studies that associated an increase of variants in such control regions to the development of different types of cancer, including hepatocellular carcinoma^[@CR39]^, brain tumor^[@CR40]^, oral squamous cell carcinoma^[@CR41]^, colon cancer^[@CR42]^ and gastric cancer^[@CR43]^. Further, a study have associated five variants in these genes with gastric cancer, including A73G and T16519C^[@CR44]^, which we found frequently in our tumor samples but not in internal control samples. We also obtained interesting results in the paired analysis of heteroplasmy levels. In most cases, tumor presented notably more heteroplasmic regions than the paired internal control (3 to 9-fold). About these heteroplasmic regions, we highlight that: (i) the four most commonly heteroplasmic genes in tumor samples were not heteroplasmic in all internal control samples; (ii) four genes were heteroplasmic in almost all tumor samples, but not as frequent in internal control genes; (iii) seven genes were heteroplasmic only in tumor samples; and (iv) there were no genes heteroplasmic only in the internal control group. These results are suggestive of an involvement of such heteroplasmic variants in GC development. This was reinforced in our analyses comparing heteroplasmy distribution between all groups of samples (tumor, internal control and external control). When we compared heteroplasmy level means, the number of variants was different between groups, so we normalized the number of single heteroplasmic variants in all groups and found a statistically significant difference from tumor to internal control (P 0.025) and external control (P 0.006). These control groups did not present such difference between each other (P 0.906). Therefore, the number of heteroplasmic variants might be as important or even more important to cancer development than heteroplasmy levels *per se*. In the individual heteroplasmy mean comparison, we observed that individual tumor samples presented almost 3-fold more heteroplasmic variants than internal control samples. A study conducted with patients of hepatocellular carcinoma also reported that tumor samples presented more heteroplasmic variants and a higher heteroplasmy ratio than their matched cancer-free samples^[@CR45]^. Moreover, tumor group presented 39% of all heteroplasmic variants, while internal control group presented 9% and external control group presented 52%. This is especially interesting given that tumor group had about a third of the number of external control samples, but about half of tumor group was composed of samples with a high number of heteroplasmic variants, as seen in Fig. [3](#Fig3){ref-type="fig"}. When compared to the control groups, tumor group presented a statistically significant difference regarding this distribution of heteroplasmic variants (P 0.027 for internal control and P 0.008 for external control). There was no significant difference between both controls (P 0.903). As for location of heteroplasmic variants, out of the 37 mitochondrial genes, 32 presented variants in at least one group, out of which 15 regions carried such variants in all three groups, allowing the comparison shown in Fig. [5](#Fig5){ref-type="fig"}. Among these regions, 12 were protein-coding and three were non-protein-coding genes (DLOOP and rRNA only). Further, the higher rate of heteroplasmic variants in tumor groups was statistically significant in six of such regions: MT-*RNR1*, MT-*ND5*, MT-*ND4*, MT-*ND2*, MT-*DLOOP1* and MT-*CO1*. In the current specialized literature, not many studies were found associating heteroplasmic variants to the development of gastric cancer, regardless of mitochondrial genomic location, including the six genes above. A study performed showed an association of heteroplasmic variants in DLOOP regions to gastric cancer development in a Chinese population^[@CR46]^. Another study have indicated homoplasmic and heteroplasmic variants in mitochondrial 12 S rRNA (encoded by MT-*RNR1*) to the development of intestinal-type gastric cancer^[@CR47]^. No studies were found associating heteroplasmic variants in the four other genes to GC development. In the mitochondrial haplogroup comparison between case and control, we observed 17 macro-haplogroups, distributed in four main ancestries: Native American (A, B, C and D), European (H, HV, J and V), African (L0, L1, L2, L3 and L3e) and Asian (M, N, R and Y). Our results showed Native American ancestry with more variants than the other three ancestries in both cases and controls, which could be related to the great number of individuals from this ancestry in each group. Native American haplogroups were the most frequent in both case (36.5%) and control (44.6%). They were followed by European (27.3%), African (18.2%) and Asian (18.2%) in cases and by European and African (25.6% each) and Asian (4.2%) in controls. This ancestry profile based on mtDNA is consistent to the expected for the studied geographic region, considering the admixture process that formed the Brazilian population^[@CR26],[@CR48],[@CR49]^. In addition, it is informative that there was a statistical significance in case group (P 0.047), probably due to the high frequency of Native American haplogroups in this group. This is especially interesting considering that GC is one of the most incident types of cancer in the studied Brazilian region, as previously mentioned. Moreover, in both case and control groups, the most frequent haplogroup was C (Native American ancestry), but it is important to highlight that this haplogroup accounted for more than 2-fold in case group than in control group (36.4% and 17%, respectively). This suggests that haplogroup C might be related to gastric cancer development, which is reinforced by a study performed with Tibetan patients of gastric cancer, in which haplogroup C was the third most common (accounting for 17%)^[@CR50]^. Considering that the parent haplogroup of C is M^[@CR51]^, it is also interesting that this haplogroup is present in our case group, but not in our control group. On the other hand, our study reported sibling haplogroup N in control group, but not in case group. Similarly, it has been suggested that haplogroup N is associated to good outcome of gastric cancer clinical evolution when compared to haplogroup M^[@CR18]^. In addition, haplogroup H (European ancestry) was the second most common haplogroup in case group (18.2%). Although this haplogroup has not been previously associated to gastric cancer, it has been indicated that it might influence other types of cancer^[@CR52]^. Conclusions {#Sec7} =========== In this study, we were able to successfully sequence the whole mitochondrial genome of FFPE samples and associate it to gastric cancer development. To the best of our knowledge, this was the first study to achieve that. We found more mitochondrial variants in tumor group than in controls, suggesting that such variants and mitochondrial heteroplasmy might influence gastric cancer development. In addition, haplogroup C might also be important to the development of this type of cancer. Although limited by sample number, our findings contribute to a greater understanding of mitochondrial influence in gastric cancer. Further, functional studies are recommended to clarify the mechanism of this impact. Methods {#Sec8} ======= Sampling {#Sec9} -------- In this study, we included formalin-fixed and paraffin-embedded (FFPE) tissue samples from patients going through gastric biopsy by endoscopy or surgical resection in the Unit of High Complexity in Oncology of the University Hospital João de Barros Barreto (UNACON/HUJBB-UFPA). Individuals with gastric cancer diagnosis had their samples collected before undergoing chemotherapy or radiotherapy. All samples were analyzed by a pathologist that confirmed the positive or negative diagnosis of cancer. We investigated 70 individuals (90 samples), divided in two main groups (Fig. [7](#Fig7){ref-type="fig"}). The first group ("Case") consists of samples obtained from 20 individuals with gastric cancer diagnosis before treatment: gastric tumor tissue samples ("Tumor" subgroup) and non-tumor tissue of the duodenum ("Internal Control" subgroup) were collected from each patient, totalizing 40 samples in the Case group. Duodenal portion was extracted during gastrectomy and confirmed to be cancer-free by a pathologist. These samples were chosen as internal control respecting the cancerization field effect. The second group ("External Control") is composed by gastric tissue samples from 50 individuals with no history of cancer and no infection by *Helicobacter pylori*.Figure 7Schematic visualization of the sampling design. DNA extraction and quantification {#Sec10} --------------------------------- The DNA extraction from FFPE samples was performed with DNA IQ™ System (Promega Corporation, Fitchburg, WI, USA), following manufacturer's instructions. Quantification of DNA was performed with NanoDrop 1000 and Qubit™ dsDNA HS Assay Kit (Thermo Fisher Scientific, Wilmington, DE, USA). Mitochondrial genome amplification {#Sec11} ---------------------------------- From the extracted DNA, mtGenome was amplified by PCR with specific sets of primers (Supplementary Table [S2](#MOESM2){ref-type="media"}). These sets were composed of 33 pairs of designed primers with discontinuous genomic location in order to provide overlaps in order to cover the whole fragmented genome. Mitochondrial genome sequencing {#Sec12} ------------------------------- The mtGenome was sequenced in the MiSeq System (Illumina Inc., Chicago, IL, USA) with MiSeq Reagent Kit v3 (300-cycles) (Illumina). Preparation of libraries was done with Nextera XT DNA Library Preparation Kit (96 samples) (Illumina), according to manufacturer's instructions. DNA quality during library preparation was assessed with High Sensitivity D1000 ScreenTape at Agilent 2200 TapeStation System (Agilent Technologies, Santa Clara, CA, USA). Data analysis {#Sec13} ------------- Paired-end sequencing reads (.fastq files) were aligned with the human reference mtDNA sequence -- revised Cambridge reference sequence, rCRS -- using Burrows-Wheeler Alignment tool (BWA)^[@CR53]^. SAMtools^[@CR54]^ were used for mapping and sorting sequences, while Picard^[@CR55]^ was used to mark duplicated reads. After preprocessing sequences with the aforementioned steps, paired-end.bam files were submitted to mtDNA-Server analysis^[@CR56]^ for heteroplasmy detection and haplogroup inferences. Phred quality scores (Q scores) of 20, 30 and 20 were considered for mapping quality of reads, alignment quality and base quality, respectively. For heteroplasmy detection at mtDNA-Server, we considered at least 10x of coverage on forward and reverse strands. Using its own pipeline, mtDNA-Server performed automatic mtDNA haplogroup classification using PhyloTree 17^[@CR51]^, implemented with HaploGrep^[@CR57]^. Statistical analyses were performed using R language^[@CR58]^ and the following tests were employed for different analyses: Mann-Whitney test, chi-squared test, one-way ANOVA with Tukey's HSD test and Poisson regression. Statistical power was also assessed using R. R packages ggplot^[@CR59]^, UpSet^[@CR60]^ and RCircos^[@CR61]^ were used for graphic representations. In all analyses, p-value was considered statistically significant when ≤0.05. Ethics approval and consent to participate {#Sec14} ------------------------------------------ All participants signed an informed consent, with approval by the Committee for Research Ethics of Hospital João de Barros Barreto under Protocol No. CAAE: 64399617.7.0000.5634. All methods were conducted in accordance with the relevant guidelines and regulations. Supplementary information ========================= {#Sec15} Supplementary Table S1 Supplementary Table S2 Supplementary Table S3 **Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information ========================= is available for this paper at 10.1038/s41598-019-51951-x. We thank Leandro Magalhães, MSc., for statistical assistance. This study was funded by the following Brazilian government agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Biocomputacional − 3381/2013), Fundação Amazônia de Amparo a Estudos e Pesquisas (FAPESPA), Pró-Reitoria de Pesquisa e Pós-Graduação (PROPESP/UFPA) and Fundação de Amparo e Desenvolvimento da Pesquisa (FADESP/UFPA). G.C.C. designed the study, performed part of bench work and wrote the manuscript; A.N.R.M. performed bench work regarding DNA extraction and amplification; A.K.A. prepared the FFPE samples and provided such samples; T.V.S., A.M.R.S. and A.F.V. performed the NGS bench work and acquisition of data -- A.M.R.S. also performed statistical analyses and A.F.V. also gave great contributions to the manuscript; G.S.A. performed data analyses and gave great contributions to the manuscript; S.D. performed the histopathological examination of the provided samples; A.R.S. coordinated the work and gave major contributions to the manuscript. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. The authors declare no competing interests.

Filed 2/10/14 P. v. Berner CA6 NOT TO BE PUBLISHED IN OFFICIAL REPORTS California Rules of Court, rule 8.1115(a), prohibits courts and parties from citing or relying on opinions not certified for publication or ordered published, except as specified by rule 8.1115(b). This opinion has not been certified for publication or ordered published for purposes of rule 8.1115. IN THE COURT OF APPEAL OF THE STATE OF CALIFORNIA SIXTH APPELLATE DISTRICT THE PEOPLE, H040079 (Santa Clara County Plaintiff and Respondent, Super. Ct. No. C1356190) v. CHRISTOPHER DEWEY BERNER, Defendant and Appellant. I. INTRODUCTION Defendant Christopher Dewey Berner pleaded no contest to failing to update his sex offender registration within five working days of his birthday. (Pen. Code, §290.012, subd. (a).)1 In accordance with the plea agreement, the trial court suspended imposition of sentence, placed defendant on probation on the condition that he serve 90 days in the county jail, and stayed the jail term while defendant was on electronic monitoring. Defendant filed a timely notice of appeal, and we appointed counsel to represent him in this court. Appointed counsel has filed an opening brief that states the case and facts but raises no issue. We notified defendant of his right to submit written argument on his own behalf within 30 days. The 30-day period has elapsed and we have received no response from defendant. 1 All statutory references hereafter are to the Penal Code unless otherwise indicated.  Pursuant to People v. Wende (1979) 25 Cal.3d 436 and People v. Kelly (2006) 40 Cal.4th 106, we have reviewed the entire record. Following the California Supreme Court’s direction in People v. Kelly, supra, at page 110, we provide “a brief description of the facts and procedural history of the case, the crimes of which the defendant was convicted, and the punishment imposed.” II. FACTUAL AND PROCEDURAL BACKGROUND In this case, no preliminary hearing was conducted and the waived referral report submitted by the probation officer did not include a summary of the facts of the instant offense. Defendant was required to register as a sex offender pursuant to section 290 based on a prior felony conviction for possession of child pornography in violation of section 311.11, subdivision (a). The felony complaint filed on May 3, 2013, charged defendant with one count of willfully failing to update his sex offender registration within five working days of his birthday. (§290.012, subd. (a).) On June 4, 2013, defendant entered into a plea agreement whereby he pleaded no contest to the charge of violating section 290.12, subdivision (a) in exchange for three years of probation, 90 days on the electronic monitoring program, and a continuing obligation to register. During the hearing held on August 9, 2013, the trial court denied defendant’s motion pursuant to People v. Marsden (1970) 2 Cal.3d 118 and also denied defendant’s motion to withdraw his plea. The sentencing hearing was also held on August 9, 2013. The trial court suspended imposition of sentence, placed defendant on probation for three years on the condition that he serve 90 days in the county jail, and stayed the jail term while defendant was on electronic monitoring. Due to defendant’s economic status, the trial court stated on the record that the court declined to impose a restitution fine (§ 1202.4, subd. (b)(2)) and suspended a $240 parole revocation restitution fine (§ 1202.45). The minute order of 2 August 9, 2013, indicates that both fines were waived. The court also ordered payment of a court security fee of $40 (§ 1465.8, subd. (a)(1)), a criminal conviction assessment fee of $30 (Gov. Code, § 70373), and a criminal justice administration fee of $129.75 to the City of San Jose (Gov. Code, § 29550.2). Additionally, the court directed that the the probation supervision fee not exceed $35 per month. III. APPEAL On August 16, 2013, defendant filed a notice of appeal challenging the validity of the plea. The trial court granted defendant’s request for a certificate of probable cause, which stated: “The defendant believes that the judge abused his discretion in denying the motion to withdraw the plea based on ineffective assistance of trial counsel. The defendant believes that trial counsel was not competent in advising the defendant to enter a plea of guilty and in investigating and preparing the case. Thus the plea was also improperly induced by representations which interfered with the defendant’s ability to make informed decisions. These issues go to the legality of the proceedings and may be reviewed on appeal. [Citations.]” Having carefully reviewed the entire record, we conclude that there are no arguable issues on appeal. (People v. Wende, supra, 25 Cal.3d at pp. 441-443.) IV. DISPOSITION The judgment is affirmed. 3  ____________________________________ BAMATTRE-MANOUKIAN, ACTING P.J. WE CONCUR: _________________________________ MIHARA, J. _________________________________ GROVER, J. 4

The carbon tax proposed for Canada is a thinly disguised tax grab by the federal government. Any alternative, such as a cap and trade regime - one that also sets a carbon price - has been ignored. Any "carbon tax" is a measure that raises production costs that will either be passed on to consumers or will result in lower profits and investment and jobs. In either case, the upward shift in aggregate supply - a supply shock - will have to be compensated by increased aggregate demand, probably by government program spending. (Alternatively, corporate income taxes can be reduced parri passu with the imposition of the carbon tax, a move that would alter the composition of business taxes and be neutral in its overall effects on after-tax revenues while raising production costs.) The carbon tax, in effect, shifts resources from the private to the public sectors. All well and good if the object is to hedge against the long-term effects of global warming, but a full evaluation of the causal chain, especially on short-run costs and distribution is needed. The costs will ultimately be born by the consumer, a fact that the article avoids by stating that the polluter will pay. As just about everything we consume is produced subject to some degree of carbon use, the article is misleading as to whom bears the real costs. The environmentalist/statist agenda is very weak on economic effects, especially those that will cause simultaneous inflation and unemployment. On a further note, Project Syndicate should not use its space to further the political agenda of a specific government. Moreover, it should not be used to raise the political profile of a currently serving Cabinet Minister.

Managing the wildlife tourism commons. The nonlethal effects of wildlife tourism can threaten the conservation status of targeted animal populations. In turn, such resource depletion can compromise the economic viability of the industry. Therefore, wildlife tourism exploits resources that can become common pool and that should be managed accordingly. We used a simulation approach to test whether different management regimes (tax, tax and subsidy, cap, cap and trade) could provide socioecologically sustainable solutions. Such schemes are sensitive to errors in estimated management targets. We determined the sensitivity of each scenario to various realistic uncertainties in management implementation and in our knowledge of the population. Scenarios where time quotas were enforced using a tax and subsidy approach, or they were traded between operators were more likely to be sustainable. Importantly, sustainability could be achieved even when operators were assumed to make simple rational economic decisions. We suggest that a combination of the two regimes might offer a robust solution, especially on a small spatial scale and under the control of a self-organized, operator-level institution. Our simulation platform could be parameterized to mimic local conditions and provide a test bed for experimenting different governance solutions in specific case studies.

Celebrating diversity, citizenship and the European project with Fundació Josep Irla Dec 04 2017 Celebrating diversity, citizenship and the European project with Fundació Josep Irla Center Maurits Copieters, together with its member Fundació Josep Irla, celebrated their annual event on Friday, November 24, with the theme: “Diversity, citizenship and European project”. The idea was to examine how immigration, integration, nation-building, citizenship and Europe are interlinked. Joan Manuel Tresserras, President of Fundació Josep Irla, reflected on how forces of globalization are reshaping the state and the nation, while Antonia Luciani, Vice-President of the Center Maurits Coppieters addressed how various recent challenges in areas like migration, security and human rights have eroded the European project, because the insitutions themselves have failed to act. “The success of the European project lies in its ability to respect diversity; to make a Europe of the peoples rather than a Europe of states. We can not talk about a successful European project without talking about integration as well,” said Luciani. 24131801_1549913558418703_3908421409643442373_o 24130162_1549913761752016_3796637824109581151_o 24068597_1549914778418581_7529213871660853829_o 23926350_1549916798418379_4992312546992169939_o 23847434_1549915358418523_3847977223521300123_o 23736069_1549914001751992_857915454326792838_o Are we only Europeans? Peter A. Kraus, Professor of Political Science at the University of Augsburg, addressed the question: what defines us as Europeans? He explained that the European Union has sought to create a top-down identity, while a massive push for European identity did not exist among its citizens. “Very few individuals identify only as European,” he added. For Kraus, some societies have become more diverse because they have embraced new identities and influences, becoming multidimensional and fluid. This is what he defines as complex diversity. Immigration and independence The event also launched the study “Immigration and Independence”, carried out by by Núria Franco-Guillén, postdoctoral researcher at the Center for Governance and Public Policy at the University of Griffith on the cases of Quebec, Scotland and Catalonia. The study looks at the challenges and opportunities of integrating newcomers into multi-lingual and multi-cultural settings, as well as sovereigntist processes in stateless nations. By comparing the concepts of immigration and stateless nations with theoretical and sociopolitical implications that this link creates, Franco-Guillén concludes that national movements in stateless nations do not express themselves in exclusionary terms. Instead, political elites of Quebec, Scotland and Catalonia deploy rather open positions towards immigration, both in terms of public speeches and policies. “The attitude towards immigration in countries such as Quebec, Scotland or Catalonia demonstrates that national movements are inevitably ethnic,” said Núria Franco-Guillén. New alliance for integration In conversation with Oriol Amorós, Secretary of Equality, Migrations and Citizenship of the Catalan Government, and Catherine Xhardez, a researcher at the Center for International Recherches of Paris, experts emphasized the need to understand immigration as relating to international and European agreements, and integration as a process that takes place in proximity to where people live, such as cities or towns. Firstly, new alliances should be built between regions and cities, which can better manage this process. Secondly, integration policies are too focused on the first months of arrival, while we should also focus on anti-discrimination and labor policies. While there is no European immigration model, a part of migration policy must be managed from below, because it involves the daily coexistence between people. “Stateless nations can lead this process and counteract restrictive state policies,” Franco-Guillén further explained. Amorós reminded the audience that the most uncomfortable part about immigration has to do with Europe’s involvement in armed conflicts that destabilize and displace communities. “Europe plays a leading role in the arms trade,” he said and called on European actors to change this.

[Surface Enhanced Spectroscopy Based on Lab-on-a-Chip Technology and Its Applications in Analytical Science]. In integrating lab-on-a-chip (LOC) technologies facilitated with a series of microfluidic units, microfluidic channels, with substrates put into metal nanoparticles, especially when gold, silver or copper nanoparticles, were prepared and pumped into μl or nl analytes. This sample preparation methods have important significance in real time, in-situ trace- or processing reaction analysis jointing with surface enhanced spectroscopies (SES).This combined technologies would integrate the mertis of the two technologies of lab-on-a-chip LOC and SES. LOC has the advantages of minuming the amount of analytes and stable test environments for step by step processing operations to achieve screening samples, segmentating, real-time detecting and so on, whiel SES has the characteristics of fast spectral response, high sensitivemess and selectivness,and in-situ detectoring. On the base of Drude medol and appropriate boundary conditions, external electric field induces localizing plasmon oscillation of valence electron of metal nano particles, then which derivates the mechannisms of resonant localized suface plasmon enhancement and electromagnetic enhancement mechanism of the surface enhanced Raman scattering by dipole polarization. In this paper, combined LOC and localized surface plasmon resonance technologies analysed in biological, pharmaceutical and food safety fileds with additional channels prompting detecting efficiencies and the limits of trace detections further being broken out. This paper also summarizes the application of chip laboratory technology in the fields of public safety testing, biomedical medicine detecting, electrochemical or biological sensors with surface enhanced Raman spectroscopieswhich were capable of high sensitivitiness and molecular spectral fingerprint. LOC technologies have gotten great develoment in their respective fileds, especially combinning with 3D fingerprint technologies, which could precisely control the sizes of 3D structures and high-accuracy manufacture 3D structures according to the special purpose. LSPR and SERS have been more maturing in some applications of near filed imaging and Tip-enhanced Raman spectroscopies (TERS), which have the ability to break through the optical limit of conventional microscopes and do that the width and depth of the SES technologies have been greatly extended in the micro and nano scales. So The jointed technologies would have a bright prospects in the practical applications for the qualitative and semi quantitative determination of trace analysis.

Environmental Stress: Salinity Ruins a Plant's Day in the Sun. New research reveals how low levels of salinity in soil inhibit a plant's ability to respond to shade through a signaling mechanism involving the plant stress hormone abscisic acid.

INTRODUCTION ============ Bronchogenic cysts are often asymptomatic and discovered as an incidental finding. They may become symptomatic due to esophageal compression as they increase in size or from development of infection. We report the case of a 9-year-old female with a symptomatic bronchogenic cyst, undiagnosed since the age of 2 years, who underwent successful thoracoscopic excision. CASE REPORT =========== A 9-year-old girl was first seen at the age of 2 years for cough and fever in the emergency room. A chest x-ray was obtained at that time, which was interpreted as normal. Nonetheless, the patient was diagnosed with pneumonia, given a prescription for antibiotics, and released. Subsequent to this, she presented several more times each year with similar complaints and with identical Posteroanterior (PA) chest x-ray findings, resulting in several hospital admissions. She had no history of stridor, dysphagia, hemoptysis, or chest pain. Her only consistent complaint was one of a chronic, nonproductive cough. Her examination revealed no abnormalities, and her laboratory work was within normal limits at the time of her presentation to the pediatric surgery service. Repeat chest x-rays were obtained **([Figure 1](#F1){ref-type="fig"})** as well as a computed tomography (CT) scan of the chest **([Figure 2](#F2){ref-type="fig"})**. It revealed a well-circumscribed cyst in the right chest measuring approximately 3x4 cm directly adjacent to the esophagus in the midthoracic region. It was unilocular and homogenous and did not appear to communicate with the esophagus or any neural structures. No air fluid level was present in the cyst. No mediastinal adenopathy was seen. Given these findings, the diagnosis of either an esophageal duplication cyst or bronchogenic cyst was entertained. {#F1} {#F2} A thoracoscopic approach was utilized to evaluate and remove the mass **([Figure 3](#F3){ref-type="fig"})**. The medial aspect of the cyst was intimately involved with the muscular wall of the esophagus for several centimeters. A Harmonic scalpel was used to separate the cyst, which was filled with a white mucoid material, from the esophagus. A small portion of the cyst wall was left in place to avoid perforation of the esophagus. The remaining cyst wall was de-epithelialized. Intraoperative esophagoscopy revealed no esophageal injury. A chest tube was placed at the time of surgery. The chest tube drainage was negligible, and it was removed on postoperative day one. The patient was discharged home the following day, after an uneventful recovery. She was seen at follow-up 2 weeks after surgery where a normal barium esophagogram **([Figure 4](#F4){ref-type="fig"})** was obtained, and her preoperative symptoms were completely resolved. Final pathology revealed a bronchogenic cyst without signs of malignant degeneration or infection. {#F3} {#F4} DISCUSSION ========== Bronchogenic cysts are embryological remnants that are isolated from the normal development of the foregut. On rare occasions, they can be formed from tracheal diverticuli. They are almost always extrapulmonary and medial in location. They may be found incidentally on a radiographic study or once symptoms are produced as a result of compression or infection. If communication with the airways occurs, an air-fluid level is usually present. Histologically, they are lined with ciliated columnar epithelium and can contain cartilage and bronchial glands. Accepted treatment is excision because of concern about continued growth and subsequent compression of surrounding structures, the risk of infection, and the unlikely but reported possibility of malignant degeneration.^[@B1]^ Bronchogenic cysts comprise approximately 6% of all mediastinal masses in children, while foregut cysts as a group account for 15%.^[@B2]^ They have been found to account for 18% of all mediastinal tumors in adults.^[@B3]^ Traditionally, open thoracotomy has been the method by which these cysts have been removed. Even with increasingly sophisticated radiographic and percutaneous techniques, an exact diagnosis is often uncertain, and the unequivocal diagnosis must be made surgically. Thoracoscopy offers both a minimally invasive diagnostic modality and also a highly successful method of definitive therapy for patients with bronchogenic cysts. Although many case reports exist regarding bronchogenic cysts and their minimally invasive treatments, reports of precious few series have been published regarding their thoracoscopic excision. In 1993, Hazelrigg^[@B4]^ published a series of seven bronchogenic cysts removed thoracoscopically with favorable results. Martinod et al^[@B5]^ reported a series of 20 cases of bronchogenic cysts in adults, of which they successfully removed 13 thoracoscopically. Their reasons for conversion were bleeding in 2 cases and dense adhesions to surrounding vital structures in 5. In 5 cases, a portion of the cyst wall was left behind and the mucosal lining obliterated. No recurrences were reported. In a report by Michel et al,^[@B6]^ thoracoscopy was performed on 22 children, 15 of which were found to have bronchogeni ccysts. Of these, 3 were converted to thoracotomy. Overall, 86% of cases were treated successfully with thoracoscopy. No recurrences were reported. In that article, the issue of incomplete excision and recurrence is raised, however. Merry et al^[@B7]^ reported in their series of 8 foregut duplications 1 recurrence with incomplete excision 1 year after surgery. Two other reports of recurrence have been reported,^[@B8]^,^[@B9]^ but so have several reporting successful obliteration of the mucosal lining with good results.^[@B9],\ [@B10]^ Reported complications in these articles include the following: bronchial/tracheal laceration (both repaired endoscopically),^[@B5]^,^[@B7]^ recurrence,^[@B7]^ esophageal injury,^[@B6]^ pneumothorax,^[@B5]^,^[@B6]^ vascular injury.^[@B7]^ No deaths were reported. CONCLUSION ========== Bronchogenic cysts are not uncommon and, as this case illustrates, can be easily misdiagnosed. Subtle findings, as on this patient\'s chest x-ray taken at 2 years of age, are overlooked if one fails to consider cystic mediastinal masses in the differential diagnosis. Preoperative CT scan is imperative in planning an operative strategy. We assert that thoracoscopy is a safe and effective method to deal with bronchogenic cysts and involves considerably less morbidity than thoracotomy does. As experience with thoracoscopy improves, so too will its acceptance as a superior alternative to thoracotomy in most cases of bronchogenic cysts. Disclosure: Neither author has any financial interest in any device, equipment, instrument, or drug referred to in this article. No financial support was received for this article, nor do any conflicts of interest exist. No off-label use of any product was discussed. Presented as a case report at the Southwest Surgical Congress, San Diego, California, April 6-10, 2002.

1. Introduction {#sec1} =============== Advances in the treatment and diagnosis of cancer and cardiovascular diseases have resulted in a great improvement in patient survival, but the growing population of long-term survivors has been compromised by the occurrence of comorbidities and complications throughout their lifespan, which can substantially affect their quality of life \[[@B1]\]. These chronic disorders include secondary malignant neoplasms, endocrine disorders, cardiopulmonary dysfunction, cardiovascular complications, and cognitive and psychosocial problems \[[@B2], [@B3]\], with cardiac injury being one of the most difficult complications to manage in the clinic \[[@B4]\]. For instance, patients receiving radiation therapy are often at a great risk for developing cardiomyopathy, which increases the risk for myocardial infarction and heart failure \[[@B5]--[@B7]\]. Moreover, the majority of cardiac catheterizations for congenital heart disease and some regular follow-up examinations, including chest X-rays, angiography, scintigraphy, and computed tomography scans, are often performed in children and adolescents who may experience intensive radiation exposure and are at a high risk for long-term adverse effects due to radiation \[[@B8]--[@B10]\]. Meanwhile, the use of medical ionizing radiation has been increasing dramatically in recent years, and cardiologists are also exposed to radiation from various medical sources, such as percutaneous coronary intervention, cardiac radiofrequency ablation, multidetector coronary angiography, and myocardial perfusion imaging scintigraphy \[[@B11]\]. Medical radiation sources are known to be cardiotoxic, but the underlying mechanism by which they induce cardiac damage is not fully understood \[[@B12]\]. Studies have demonstrated that radiation may generate oxygen free radicals, resulting in the generation of excessive reactive oxygen species that induce oxidative stress in cells and tissues \[[@B13]\]. The sustained generation of reactive oxygen species is a primary inducer of apoptosis \[[@B14]\]. Studies in mice have demonstrated that radiation causes acute injury in cardiomyocytes, leading to apoptosis \[[@B15]\]. The loss of myocytes causes thinning of the myocardium with a resulting increase in wall stress, which may also be linked to defective regenerative and adaptive pathways in the remaining myocardial cells \[[@B16]\]. These pathological changes ultimately result in congestive heart failure \[[@B17]\]. Accordingly, reducing oxidative stress is of great importance in preventing or suppressing apoptosis in order to protect the heart against radiation-induced injury \[[@B18]\]. The current treatment for radiation-induced heart disease mainly utilizes symptomatic and supportive approaches or surgery (cardiac transplantation); however, all these methods are largely ineffective. Therefore, the development of a new therapeutic approach is an urgent unmet medical need. There is an increasing interest in the discovery and development of novel natural product-based approaches for the prevention and treatment of radiation-induced heart diseases. For instance, recent studies \[[@B19], [@B20]\] have revealed that sodium tanshinone IIA sulfonate (STS), a derivative of tanshinone IIA, elicits protective effects on cardiomyocytes against oxidative stress-mediated apoptosis. This plant is a well-known traditional Chinese medicine used for the treatment of various cardiovascular diseases, whose effects on the cardiovascular system are mediated by improving microcirculatory, vasodilatory, anticoagulant, antithrombotic, anti-inflammatory, free radical scavenging, and mitochondria-protective effects \[[@B21]\]. Tanshinone IIA is extracted from the roots of*Salvia miltiorrhiza*, and, as an active diterpenoid component, it can prevent or slow the progression of cardiovascular diseases \[[@B22]\]. STS also has been used clinically as an approved drug by the State Food and Drug Administration of China \[[@B23], [@B24]\]. Its cardioprotective effects might be mediated by free radical scavenging properties and antioxidant activities \[[@B25]\]. There is increasing evidence supporting that STS relies on such an action to attenuate radiation-induced pulmonary and renal diseases \[[@B26]\]. Therefore, we hypothesized that STS could have preventive effects on radiation-induced heart disease. To this end, in the present study, we characterized the effects of STS against radiation-induced oxidative stress and the possible underlying mechanisms using H9c2 cardiomyocytes as an in vitro cell-based model. It was hoped that the results from the present study would provide a basis for the future development of STS as an anti-radiation-induced heart disease reagent in preclinical and clinical settings. 2. Materials and Methods {#sec2} ======================== 2.1. Chemicals {#sec2.1} -------------- STS was obtained from Shanghai First Chemical Company (Shanghai, China). Dulbecco\'s modified Eagle medium (DMEM)/F12 medium was purchased from Gibco (Grand Island, NY, USA). Fetal bovine serum was from Invitrogen (Carlsbad, CA, USA). Hoechst 33258 was obtained from Invitrogen (Eugene, OR, USA). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT), dimethyl sulfoxide (DMSO), and Giemsa were from Sigma (Sigma-Aldrich, St. Louis, MO, USA). The lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) assay kits were obtained from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Rabbit polyclonal antibodies for p38, phosphorylated p38, ERK, and phosphorylated ERK were purchased from Cell Signaling Technology (Beverly, MA, USA). 2.2. Cell Culture {#sec2.2} ----------------- H9c2 cardiomyocytes, a subclone of the original cell line derived from embryonic BD1X rat heart tissue, were obtained from the Chinese Academy of Sciences Cell Bank (Shanghai, China) and cultured in DMEM/F12 medium containing 10% (v/v) fetal bovine serum, penicillin (100 U/mL), and streptomycin (100 *μ*g/mL). The cells were maintained at 37°C in a humidified atmosphere with 5% CO~2~. The medium was replaced every 2-3 days, and the cells were passaged as they grew to 80% confluence; they were subcultured or subjected to subsequent experiments. The purity of STS used in the present study was \>95%, and STS was dissolved in DMEM/F12 medium. The cells were divided into the following groups: 0 Gy (control) group; 2-Gy radiation (2 Gy) group; 4-Gy radiation (4 Gy) group; 6-Gy radiation (6 Gy) group; 8-Gy radiation (8 Gy) group; 10 *μ*g/mL STS (STS) group; 2 Gy + 10 *μ*g/mL STS (2STS) group; 4 Gy + 10 *μ*g/mL STS (4STS) group; 6 Gy + 10 *μ*g/mL STS (6STS) group; and 8 Gy + 10 *μ*g/mL STS (8STS) group. 2.3. Irradiation Procedure {#sec2.3} -------------------------- The cells were seeded with fresh culture medium and cultured for 24 h prior to the radiation treatment. A single dose of 2, 4, 6, or 8 Gy of X-rays was administered to the cells using a Siemens PRIMUS high energy linear accelerator (Siemens AG, Erlangen, Germany), operating at a dose-pulse rate of 6 MV/min with a source-to-H9c2 cell distance of 100 cm. After radiation, the cells were maintained at 37°C and 5% CO~2~, and the culture medium was replaced every 24 h. 2.4. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl Tetrazolium Bromide (MTT) Assay {#sec2.4} ------------------------------------------------------------------------------ To determine the cytotoxicity of STS, H9c2 cells were seeded at 10^5^ cells/mL in 96-well plates. The experiments were carried out after cell exposure to serum-free medium for at least 16 h, and the cells reached more than 80% confluence on the plate bottom. After discarding the old medium, the cells were pretreated with varying concentrations of STS for 24 h, 48 h, and 72 h, respectively. MTT was dissolved in phosphate-buffered saline (PBS) and added to each well at a final concentration of 5 mg/mL. The cells were then incubated at 37°C for 4 h. The medium was discarded, and 150 *μ*L of dimethyl sulfoxide was added to each well. The absorbance of each well at 570 nm was quantified using a spectrophotometer (Bio-Rad, Philadelphia, PA, USA). Cell viability was determined by the MTT assay. In brief, the cells were plated onto 96-well tissue culture plates (cell density, 4 × 10^3^ cells/well). STS was added to the medium at the doses indicated for 24 h, followed by exposure to X-ray radiation, and then cultured for another 24 h. Cell viability was then monitored. Each treatment and control was assayed in at least six wells, and the cell viability was expressed as a percentage of that of the control cells. 2.5. LDH Release Assay {#sec2.5} ---------------------- Following pretreatment with STS for 24 h, the cardiomyocytes were irradiated with 2, 4, 6, or 8 Gy of X-rays. The culture medium was collected at 24 h after X-ray radiation, and the LDH activity was measured by means of a colorimetric assay using a commercial LDH assay kit, according to the manufacturer\'s instructions. 2.6. Antioxidant and Lipid Peroxide Assay {#sec2.6} ----------------------------------------- The MDA content was measured as an end product of lipid peroxidation. The defense systems against free radical attack were assessed by the measurement of the activities of SOD. The H9c2 cardiomyocytes were pretreated with or without STS for 24 h before cell exposure to different doses (2, 4, 6, and 8 Gy) of X-ray radiation, and they were cultured for another 24 h. Then, they were washed once with ice-cold PBS and lysed in ice-cold RIPA lysis buffer containing 1 mM phenylmethylsulfonyl fluoride and phosphatase inhibitor for 30 min. After centrifuging the lysates at 12,000 rpm and 4°C for 10 min, the supernatants were collected for measurements of MDA production and SOD activity. The activities of SOD and catalase as well as the contents of MDA were analyzed in H9c2 cardiomyocytes with or without STS pretreatment and exposure to X-ray radiation, according to the manufacturer\'s protocol (Nanjing Jiancheng Bioengineering Institute). 2.7. Cell Morphology {#sec2.7} -------------------- The cells were seeded on coverslips, exposed to radiation, and incubated in the presence or absence of STS for 48 h under the same conditions described above. The culture medium was removed, Hoechst 33258 was added to each well, and the cells were incubated for an additional 10 min. The coverslips were then washed three times with PBS, placed onto glass slides, and covered with mounting medium. Next, the cells were harvested at the indicated times and washed twice with cold PBS. The nuclear fluorescence was visualized under a Zeiss Axioplan microscope (Zeiss, Germany). 2.8. Clonogenic Assay {#sec2.8} --------------------- A clonogenic assay was performed to determine the effects of STS treatment on the survival and division of the radiation-treated H9c2 cells. Briefly, the cells were seeded into 60-mm dishes at a cell density of 1 × 10^3^ cells/well in triplicate, pretreated with STS for 24 h, and then irradiated at different doses (0--8 Gy) using an X-ray irradiator operating at a dose-pulse rate of 6 MV/min. At 24 h after the radiation treatment, the culture medium was replaced with fresh complete medium containing STS, and the cells were incubated at 37°C for 8--12 days to allow for colony formation. The colonies were fixed in methanol for 20 min and stained with 0.5% Giemsa for 30 min. The number of colonies (≥50 cells) was scored under a microscope. The surviving fraction was calculated as the ratio of the plating efficiency of the treated cells to that of the control cells. 2.9. Apoptosis Assay {#sec2.9} -------------------- The effects of STS on apoptosis were determined using the Annexin V/PI double-staining method. After exposure to X-ray radiation for 24 h, the H9c2 cardiomyocytes pretreated with STS or control were centrifuged to remove the medium. Next, the cell pellet was washed with PBS and stained with Annexin V in binding buffer (10 mM HEPES, 140 mM NaCl, and 2.5 mM CaCl~2~) for 20 min. At 10 min before the end of incubation, PI was added to this cell suspension in order to stain necrotic cells, according to the manufacturer\'s instructions (BioVision, Inc., Palo Alto, CA, USA). The cells were analyzed with a FACSCAN flow cytometer (Becton Dickenson Biosciences, San Jose, CA, USA), and the stained cells in the FL1-H and FL2-H channels were analyzed. 2.10. Cell Cycle Detection {#sec2.10} -------------------------- The H9c2 cells in the logarithmic growth phase were harvested and seeded in DMEM containing 10% FBS at a density of 2 × 10^6^ cells per flask. After allowing the cells to adhere, the culture medium was removed and replaced with medium containing STS or control, and the cells were cultured for 24 h before radiation. After X-ray radiation at different doses, the cells were cultured for 24 h, harvested, washed once with cold PBS, resuspended in 1 mL of PBS, and then fixed with 2 mL of dehydrated ethanol for 30 min. The cells were collected, washed once with PBS, and then stained with 50 g/mL PI at room temperature in the dark for 30 min. The cells were then analyzed by flow cytometry (Coulter XL, Beckman Coulter, Inc., Fullerton, CA, USA) to determine the cell cycle distribution. 2.11. Western Blotting Analysis {#sec2.11} ------------------------------- After treatment with STS or control, the cells at 80% confluence were collected and washed three times with PBS. Radioimmunoprecipitation assay buffer was added to extract the total protein. Equal amounts of protein from the samples and controls were loaded onto 12% sodium dodecyl sulfate-polyacrylamide gels for protein separation. The proteins were then transferred to nitrocellulose membranes, and the membranes were blocked with 5% nonfat dried milk for 3 h. The membranes were then incubated with primary antibodies (p38 at 1 : 1000, p-p38 at 1 : 1000, Bcl-2 at 1 : 1000, Bax at 1 : 1000, and cleaved caspase 3 or caspase-3 at 1 : 1000) overnight at 4°C. After being washed with Tris-buffered saline (pH 7.2) containing 0.05% Tween 20 (TBST), the membranes were incubated with the secondary antibody at room temperature for 1.5 h. Finally, the membranes were washed with TBST and incubated with the enhanced chemiluminescence reagent to detect the proteins of interest. The levels of GADPH were used as loading controls. 2.12. Statistical Analysis {#sec2.12} -------------------------- Statistical analyses of the results from the present study were performed using SPSS17.0 (version 12.0; IBM, USA). The results were expressed as means ± standard deviation (SD). Comparisons between the various levels of radiation with or without STS treatment were conducted by two-way analysis of variance (ANOVA); a paired *t*-test was used to evaluate differences between the same levels of radiation versus without treatment; comparisons between groups were performed using one-way ANOVA. A level of *p* \< 0.05 was considered statistically significant. 3. Results {#sec3} ========== 3.1. Radiation Induces Cell Growth Inhibition and Apoptosis in H9c2 Cells in a Dose-Dependent Manner {#sec3.1} ---------------------------------------------------------------------------------------------------- The H9c2 cells were exposed to different doses of radiation (0, 2, 4, 6, and 8 Gy), and the MTT assay was performed to evaluate the cell viability. Radiation decreased the cell viability in a dose-dependent manner ([Figure 1(a)](#fig1){ref-type="fig"}). The cell viability in the X-ray-treated groups was significantly lower than that of the control (*p* \< 0.05). Exposure to 6-Gy and 8-Gy radiation was associated with a greater loss of cell viability, compared with the 2-Gy and 4-Gy groups. LDH, which leaks from cells after plasma membrane disruption, can also be used as an indicator of cell injury. As shown in [Figure 1(b)](#fig1){ref-type="fig"}, a marked increase in LDH activity was observed at 24 h after X-ray exposure. In order to determine the mechanisms of the decreased cell viability after radiation, we analyzed the number of apoptotic cells, cell division, and cell cycle distribution after radiation. The observed cytotoxic effects were also confirmed with Hoechst 33258 staining, a clonogenic survival assay, and a flow cytometric assay. The cells exposed to various doses (2, 4, 6, and 8 Gy) of radiation showed a significantly reduced number of colonies ([Figure 2(b)](#fig2){ref-type="fig"}). The number of colonies in the 2-Gy and 4-Gy groups was markedly higher than that in the 6-Gy and 8-Gy groups. The results from the assays demonstrated that X-ray radiation significantly suppressed the growth of H9c2 cells in a dose-dependent manner, compared with the control. In addition, the higher X-ray radiation doses increased cell necrosis and apoptosis. As shown in [Figure 3](#fig3){ref-type="fig"}, normal morphology and nuclei were observed in the control group. Chromatin condensation, indicative of apoptosis, was shown by Hoechst staining in the radiation groups. Typical apoptotic cells with fragmented chromatin, chromatin condensation, or apoptotic bodies were observed in the 8-Gy group ([Figure 3](#fig3){ref-type="fig"}). As shown in [Figure 4](#fig4){ref-type="fig"}, the percentages of apoptotic cells in the radiation groups were significantly higher than that of the control group. 3.2. STS Ameliorates Radiation-Induced Apoptosis in H9c2 Cells {#sec3.2} -------------------------------------------------------------- To observe the effect of STS on cell viability and to select the proper STS concentration for subsequent assays, the H9c2 cells were exposed to various concentrations of STS (1.25--20 *μ*g/mL). The results of the MTT assays showed an increase in cell viability as the STS concentration increased from 1.25 to 10 *μ*g/mL. The proliferation rate was significantly increased when the cells were treated with 10 *μ*g/mL STS for 48 h ([Figure 5](#fig5){ref-type="fig"}). However, an inhibitory effect on cell proliferation was observed when the concentration of STS was greater than 20 *μ*g/mL. Although the mechanism for the high-dose-STS-induced cell growth inhibition was not clear, the STS concentration of 10 *μ*g/mL was selected for subsequent experiments. The H9c2 cells were pretreated with STS (10 *μ*g/mL) for 24 h prior to exposure to different doses (2, 4, 6, and 8 Gy) of radiation. There was a significant difference in cell viability between the radiation alone group and the pretreatment with STS group. Compared with the same level of radiation group, the cell viability in the STS group was enhanced ([Figure 1(a)](#fig1){ref-type="fig"}). In addition, pretreatment with STS significantly decreased the LDH levels ([Figure 1(b)](#fig1){ref-type="fig"}). Next, clonogenic assays were performed to determine if STS treatment had any impact on radiation-induced H9c2 cell survival and division. Compared with the radiation groups, the number of colonies in the 2STS, 4STS, 6STS, and 8STS groups were 99 ± 4.9%, 55 ± 4.1%, 41 ± 4.8%, and 27 ± 3.7%, respectively, indicating that STS reduced the radiation-induced growth inhibition of H9c2 cells ([Figure 2](#fig2){ref-type="fig"}). STS treatment inhibited the apoptosis of the cultured cardiomyocytes. Hoechst 33258 staining demonstrated that the chromatin condensation and number of apoptotic bodies were decreased in the cells pretreated with STS ([Figure 3](#fig3){ref-type="fig"}). Similarly, STS treatment significantly decreased the percentages of apoptotic cells compared with the corresponding (2, 4, 6, and 8 Gy) radiation groups ([Figure 4](#fig4){ref-type="fig"}). 3.3. STS Exerts Antioxidant and Lipid Peroxidation Activities {#sec3.3} ------------------------------------------------------------- During radiation, severe oxidative stress leads to lipid peroxidation \[[@B27]\]. To explore the mechanism underlying the antioxidant activity of STS, we evaluated the activities of MDA and SOD; the activities of SOD in the radiation alone groups were significantly decreased, compared with the control group ([Figure 6(a)](#fig6){ref-type="fig"}), and the contents of MDA in the radiation alone groups were 2.11-, 2.64-, 3.41-, and 4-fold higher than that in the control group ([Figure 6(b)](#fig6){ref-type="fig"}). Pretreatment with STS remarkably reversed these alterations ([Figure 6](#fig6){ref-type="fig"}). STS treatment significantly downregulated the contents of MDA and enhanced the levels of SOD in cells exposed to X-ray radiation. 3.4. STS Reverses the Effects of Radiation on the Cell Cycle {#sec3.4} ------------------------------------------------------------ The flow cytometric assay showed that, compared with the control, an increase in the population of cells at the G0/G1 phase in the radiation groups was seen after X-ray radiation in a dose-dependent manner, ranging from 60.9% to 84.14%, which was reversed by STS pretreatment ([Figure 7](#fig7){ref-type="fig"}). STS reduced G0/G1 cell cycle arrest. Compared with the radiation groups, the percentages of cells at the G0/G1 phase were decreased (60.2%  ±  2.8% versus 64.6%  ±  3.4%, 68.12%  ±  3.65%, 77%  ±  4.12%, and 79.59%  ±  4.1%, resp., *p* \< 0.05). 3.5. STS Modulates the Levels of Apoptosis-Related Proteins {#sec3.5} ----------------------------------------------------------- Compared with the control, the protein expression levels of the antiapoptotic gene Bcl-2 were markedly decreased, and the proapoptotic gene Bax was markedly increased; therefore, the Bax/Bcl-2 ratio was increased accordingly in the radiation groups; the expression levels of caspase-3 were also increased ([Figure 8(e)](#fig8){ref-type="fig"}) in the radiation group. These effects were prevented by pretreatment with STS: the expression level of Bcl-2 was increased; the expression levels of Bax as well as caspase-3 were decreased, and the Bax/Bcl-2 ratio was decreased ([Figure 8](#fig8){ref-type="fig"}). To further assess the signaling pathways potentially involved in the process of cardiomyocyte apoptosis induced by radiation, we examined the key components of the MAPK pathways in the radiation alone groups. As shown in [Figure 8](#fig8){ref-type="fig"}, there was a marked decrease in p-ERK and p38-MAPK in the radiation groups, compared with the control group. STS pretreatment upregulated the expression levels of p-ERK and p38-MAPK. 4. Discussion {#sec4} ============= Radiation exposure from various medical sources, such as cardiac catheterizations for congenital heart disease and radiation therapy for cancer, is almost unavoidable and often causes irreversible cardiac injury \[[@B28]\] that is accompanied by increased oxidative stress. The overproduction of radicals leads to increased myocardial apoptosis, ultimately resulting in cardiac failure \[[@B29]\]. The severity of radiation-induced heart disease, in terms of the mortality and morbidity, has been reported previously \[[@B30]\]. However, the detailed mechanism underlying radiation-induced heart disease and its treatment and prevention strategies remain elusive \[[@B31]\]. In the present study, we first determined the cytotoxicity of radiation in H9c2 cardiomyocytes by assessing the cell viability, LDH leakage, clonogenicity, and apoptosis. X-ray radiation reduced the cell viability in a dose-dependent manner. The results obtained from the cell viability assay were consistent with the findings from the LDH assay. LDH leakage, as a marker of necrotic cellular death, was measured in the cell culture medium. There were significant differences in the LDH levels between the control group and the radiation alone groups. X-ray radiation-induced LDH release was dose-dependent. Compared with the control group, the X-ray-treated cells underwent apoptosis, as shown by Hoechst 33258 staining. Similar results were also obtained with a clonogenic assay, demonstrating that X-ray radiation promoted cardiomyocyte apoptosis and inhibited cell proliferation. Given the central role of oxidative stress in the pathogenesis of radiation-induced heart disease, ameliorating oxidative stress through treatment with antioxidants might be an effective prevention strategy. STS has been utilized by traditional Chinese medicine practitioners for its antioxidant effects and has been shown to reduce the risk factors for several cardiovascular diseases \[[@B32]\]. The beneficial role of STS in improving radiation-induced heart disease, however, has not yet been demonstrated. In this study, we used a cell-based radiation-injury model to investigate the antioxidant effects of STS in order to demonstrate the possibility of using this agent for the prevention of radiation-induced cardiomyopathy. The MDA level indicates the membrane lipid peroxidation level during oxidative damage \[[@B33]\] and is indicative of cardiomyocyte oxidative damage, while the endogenous antioxidant SOD protects the cells against oxidative stress. In the present study, the treatment of cells with radiation increased the intracellular MDA levels and decreased the SOD levels, compared with the control cells, which were reversed by STS. STS treatment decreased the radiation-induced cell death, as measured by a clonogenic assay, and restored the alterations of H9c2 morphology and nuclear condensation to nearly normal levels. These results suggested that the antioxidant activity of STS might help protect the cells from radiation-induced cytotoxicity. In the present study, the flow cytometric analysis results revealed that X-ray radiation alone significantly increased the percentages of necrotic and apoptotic cells, as compared with the control group; moreover, STS treatment significantly decreased the rate of apoptosis in cells exposed to radiation in a dose-dependent manner. STS significantly attenuated cell injury induced by radiation in H9c2 cardiomyocytes, suggesting that STS might be capable of protecting H9c2 cardiomyocytes against radiation-induced injury. The cardioprotective effect of STS was related to its ability to reduce myocardial cell apoptosis and damage induced by oxidative stress. In the present study, cell cycle analysis indicated that radiation-induced damage increased the proportion of cells in the G0/G1 phase and reduced the proportion of cells in the S phase, demonstrating that X-ray radiation reduces cell survival by arresting cell cycle progression as well as inducing cell apoptosis. STS pretreatment increased the proportion of cells in the S phase. The number of S phase cells could reflect the ability of cells to proliferate, indicating that STS may inhibit radiation-induced cell cycle arrest in H9c2 cells. Apoptosis occurs with Bax translocation to the mitochondria, which releases apoptotic factors during the apoptosis process \[[@B34]\]. Bcl-2 inhibits Bax activation, and caspase-3 is the effector molecule that is responsible for DNA fragmentation during the terminal events preceding cell death \[[@B35], [@B36]\]. Our results showed that X-ray exposure resulted in a decreased expression of Bcl-2, an increased expression of Bax and caspase-3, and an increased Bcl-2/Bax ratio. Compared with the radiation alone groups, the levels of Bcl-2 and Bcl-2/Bax increased while Bax and caspase-3 decreased markedly in the radiation + STS group, indicating that STS reduced myocardial cell apoptosis through modulating the expression of Bcl-2 family proteins. p38-MAPK, the major member found in cardiac tissues, plays a key role in diverse biological processes with varied outcomes, either promoting cell death or ensuring survival. p38-MAPK is activated simultaneously with JNKs, which promote survival as in the case of cardiac myocytes exposed to oxidative stress \[[@B37]\]. The beneficial effects of p38 activation include an antihypertrophic action and enhanced myocardial adaptation to stress, perhaps through myocardial angiogenesis \[[@B38]\]. As far as ERKs are concerned, they are involved in regulation of the cell cycle, cell proliferation and differentiation, and cell migration as well as in the stress response. ERKs appear to function principally in favor of cell survival, exerting an antiapoptotic role \[[@B39]\]. In the present study, we also demonstrated that STS treatment activated the p38-MAPK pathway, which may be associated with its protective effect against radiation-induced injury in H9c2 cells. The expression of p-p38 was increased markedly, indicating that STS enhanced the survival of cells exposed to radiation, at least in part by promoting the p38-MAPK signaling pathways. 5. Conclusions {#sec5} ============== Our results from the present study demonstrated that STS protected myocytes from X-ray radiation-induced injury via suppressing apoptosis-related gene activation and preventing inappropriate apoptosis. These findings suggest that STS may be a promising agent for treating radiation-induced cardiomyocyte injury. This work was financially supported by the Cardiovascular Institute of Gansu Provincial Hospital and the School of Stomatology of Lanzhou University. Competing Interests =================== The authors declare that they have no competing interests. Authors\' Contributions ======================= Wenjing Zhang and Yi Li contributed equally to this work. {#fig1} {#fig2} {#fig3} {#fig4} {#fig5} {#fig6} {#fig7} {#fig8} [^1]: Academic Editor: Raffaele Capasso

1. Technical Field of the Invention The present invention relates generally to a gas concentration measuring apparatus for measuring the concentration of gases which may be employed in an air-fuel ratio control system for automotive vehicles, and more particularly to a gas concentration measuring apparatus designed to correct an error contained in an output of a gas concentration sensor. 2. Background Art The air pollution caused by exhaust emissions of automotive internal combustion engines is giving rise to a serious problem at the present day. The exhaust emission control standard regulations have been made more rigorous recently. The burning control of gasoline or diesel engines or use of catalyst are, therefore, being studied to reduce pollutants contained in exhaust gasses. In U.S., OBD-II (On Board Diagnostic-II) requirements prescribe that automotive vehicles have a function of determining whether a catalytic converter is operating normally or not. As one of systems meeting the OBD-II requirements, a two-O2 sensor monitoring system is proposed which monitors outputs of two O2 sensors mounted upstream and downstream of a catalytic converter, respectively, but it is not designed to detect pollutants directly and cannot determine whether pollutants in exhaust gasses have been reduced accurately or not. If it becomes possible to measure the concentration of NOx in exhaust gasses for monitoring the burning control and the catalytic converter, the pollutants in the exhaust gasses can be reduced greatly. Specifically, the reduction in pollutants in exhaust emissions of the engine is achieved by controlling the quantity of fuel to be injected into the engine and the EGR rate based on the concentration of NOx contained in the exhaust gasses. Additionally, the determination of deterioration of the catalytic converter is achieved easily by installing a NOx sensor downstream of the catalytic converter. NOx sensors capable of measuring the concentration of NOx accurately and techniques for mounting such NOx sensors in automotive vehicles are, therefore, being sought. The effects of air-fuel ratio feedback control may be improved further by monitoring the concentration of O2 contained in the exhaust gasses as well as the concentration of NOx. Specifically, modern air-fuel ratio control for automotive vehicles is required to improve the accuracy of the control and perform lean burn engine control. For meeting these requirements, sensors capable of determining the air-fuel ratio of a mixture supplied to the engine over a wide range are preferable. Keeping such sensors activated to maintain the accuracy of detection at a certain level requires a heater for keeping the temperature of the sensor at a constant value required for activation of the sensor. The heater may be built in the sensor. In this case, an insulator is disposed between the heater and a sensor element of the sensor. A supply of power to the heater is controlled cyclically by turning on and off a switch connecting a power supply and the heater. An increase in temperature of the sensor element by the heater, however, causes the resistance of the insulator of the sensor to drop, which will cause a leakage current to flow to the sensor element through the insulator during on-off control of the supply of power to the heater, resulting in addition of an error current to an output of the sensor element. Even if the resistance of the insulator is constant, an increase in voltage applied to the heater during the on-off control of the supply of power to the heater also results in an increase in leakage current. It is therefore a principal object of the present invention to avoid the disadvantages of the prior art. It is another object of the present invention to provide a gas concentration measuring apparatus designed to correct an error contained in an output of a gas concentration sensor arising from control of supply of power to a heater built in the gas concentration sensor. According to one aspect of the invention, there is provided a gas concentration measuring apparatus which comprises: (a) a gas concentration sensor including a sensor element producing a signal indicative of the concentration of a preselected component contained in gasses, a heater heating the sensor element, and an insulator disposed between the sensor element and the heater; (b) a heater control circuit controlling a supply of power to the heater of the gas concentration sensor; and (c) an error correcting circuit correcting an error contained in the signal produced by the sensor element of the gas concentration sensor arising from a leakage current flowing into the sensor element through the insulator during control of the supply of power to the heater by the heater control circuit. In the preferred mode of the invention, the heater control circuit determines a target voltage to be applied to the heater for keeping a temperature of the sensor element of the gas concentration sensor at a given value required for activation of the sensor element and controls the supply of power to the heater based on the target voltage. The heater control circuit limits a change in voltage applied to the heater when the gas concentration sensor is in a activated state to below a given value. The heater control circuit includes, a power supply, a switching element, a coil, and a capacitor. The switching element is turned on and off to apply a voltage of the power supply to the heater cyclically. The coil and the capacitor serve to smooth the voltage of the power supply. The switching frequency of the switching element is 1 kHz or more. A filter may be provided which cuts off low frequency components below 100 Hz from the signal produced by the sensor element of the gas concentration sensor. The may cut off low frequency components below at least the switching frequency from the signal produced by the sensor element of the gas concentration sensor. The sensor element may include a first cell which is responsive to application of voltage to discharge oxygen contained in the gasses and produces a current signal as a function of a concentration of the oxygen and a second cell which is responsive to application of voltage to produce a current signal as a function of a concentration of a given gas component contained in the gasses after the oxygen is discharged through the first cell. The sensor element may alternatively has a cell which produces an electromotive force as the gas concentration signal. According to the second aspect of the invention, there is provided a gas concentration measuring apparatus which comprises: (a) a gas concentration sensor including a sensor element producing a signal indicative of the concentration of a preselected component contained in gasses, a heater heating the sensor element, and an insulator disposed between the sensor element and the heater; (b) a heater control circuit supplying power to the heater cyclically using a pulse-width modulated (PWM) signal; and (c) a filter passing frequency components of the signal produced by the sensor element within a given low frequency band. The frequency of the PWM signal is so determined as to allow the filter to compensate for an error which is contained in the signal inputted to the filter and which arises from the PWM signal. In the preferred mode of the invention, the frequency of the PWM signal is ten or more times a cutoff frequency of the filter. The PWM signal may be at least greater than a frequency of a change in signal outputted from the gas concentration sensor. The cutoff frequency of the filter is less than or equal to 100 Hz. The cutoff frequency of the filter may also be at least less than or equal to the frequency of the PWM signal. A detecting circuit is provided which detects at least one of a voltage applied to the heater and a current flowing through the heater and a sample-and-hold circuit connected to an output of the detecting circuit. The sensor element includes a first cell which is responsive to application of voltage to discharge oxygen contained in the gasses and produces a current signal as a function of a concentration of the oxygen and a second cell which is responsive to application of voltage to produce a current signal as a function of a concentration of a given gas component contained in the gasses after the oxygen is discharged through the first cell. The sensor element may alternatively have a cell which produces an electromotive force as the gas concentration signal. According to the third aspect of the invention, there is provided a gas concentration measuring apparatus which comprises: (a) a gas concentration sensor including a sensor element producing a signal indicative of the concentration of a preselected component contained in gasses, a heater heating the sensor element, and an insulator disposed between the sensor element and the heater, the heater being connected at a first end to a power supply and at a second end to ground; (b) a heater control circuit controlling a supply of power from the power supply to the heater of the gas concentration sensor; and (c) a switch disposed between the first end of the heater and the power supply, the switch establishing communication between the heater and the power supply when the power is supplied to the heater through the heater control circuit while blocking the communication when the supply of power to the heater is cut. In the preferred mode of the invention, a second switch may also be disposed between the second end of the heater and the ground. The second switch establishes communication between the heater and the ground when the power is supplied to the heater through the heater control circuit while blocking the communication when the supply of power to the heater is cut. According to the fourth aspect of the invention, there is provided a gas measuring apparatus which comprises: (a) a gas concentration sensor including a sensor element producing a gas concentration signal as a function of concentration of a specified component of gasses to be measured, a heater heating the sensor element, and an insulator disposed between the sensor element and the heater; (b) a heater control circuit controlling a supply of power to the heater of the gas concentration sensor in pulse-width modulation; and (c) a circuit detecting the gas concentration signal either for a power supply-on duration in which the power is supplied to the heater through the heater control circuit or for a power supply-off duration in which the supply of power to the heater is cut. According to the fifth aspect of the invention, there is provided a gas concentration measuring apparatus which comprises: (a) a gas concentration sensor including a sensor element producing a gas concentration signal indicative of the concentration of a preselected component contained in gasses, a heater heating the sensor element, and an insulator disposed between the sensor element and the heater; (b) a heater control circuit supplying power to the heater cyclically using a pulse-width modulated (PWM) signal; and (c) a correction circuit monitoring values of the gas concentration signal in a power supply-on duration for which the power is supplied to the heater and a power supply-off duration for which supply of the power to the heater is cut off, the correction circuit corrects the gas concentration signal using the monitored values. In the preferred mode of the invention, the correction circuit averages the values of the gas concentration signal in the power supply-on duration and the power supply-off duration and corrects the gas concentration signal using an averaged value. The sensor element includes a first cell which is responsive to application of voltage to discharge oxygen contained in the gasses and produces a current signal as a function of a concentration of the oxygen and a second cell which is responsive to application of voltage to produce a current signal as a function of a concentration of a given gas component contained in the gasses after the oxygen is discharged through the first cell. The sensor element may alternatively have a cell which produces an electromotive force as the gas concentration signal. According to the sixth aspect of the invention, there is provided a gas concentration measuring apparatus which comprises: (a) a gas concentration sensor including a sensor element producing a gas concentration signal indicative of the concentration of a preselected component contained in gasses, a heater heating the sensor element, and an insulator disposed between the sensor element and the heater; (b) a heater control circuit supplying power to the heater cyclically using a pulse-width modulated (PWM) signal; and (c) a correction circuit estimating an error which is to be contained in the gas concentration signal and which arises from a leakage current flowing into the sensor element through the insulator caused by a change in resistance of the insulator produced during control of supply of the power to the heater by the heater control circuit using the PWM signal, the correction circuit removing the estimated error from the gas concentration signal. In the preferred mode of the invention, the correction circuit corrects the gas concentration signal using a greater correction value as a voltage of a power supply for the heater increases. The correction circuit corrects the gas concentration signal using a greater correction value as a temperature of the sensor element increases. The sensor element includes a first cell which is responsive to application of voltage to discharge oxygen contained in the gasses and produces a current signal as a function of a concentration of the oxygen and a second cell which is responsive to application of voltage to produce a current signal as a function of a concentration of a given gas component contained in the gasses after the oxygen is discharged through the first cell. The sensor element may alternatively have a cell which produces an electromotive force as the gas concentration signal.

Razorbacks make switch at quarterback heading into matchup vs Colorado State FAYETTEVILLE (KFSM) – It was a move that was expected but now it’s official as Arkansas has named junior quarterback Nick Starkel the starter for this week’s game vs Colorado State. Senior Ben Hicks started the first two games of the season but managed to lead the Razorbacks to just 20 points in a game and a half of playing time. Starkel replaced Hicks to start the second half of Saturday’s game at Ole Miss. In relief, Starkel went 17-of-24 passing for 201 yards and a touchdown as Arkansas lost 31-17. Hicks was just 7-of-16 passing for 98 yards and missed two key throws that likely would have resulted in touchdowns. Hicks and Starkel battled all through fall camp for the starting job but Arkansas coach Chad Morris elected to go with Hicks as he said the SMU transfer gave them a better job to be successful to start the season. Here are the season statistics for both Hicks and Starkel through the first two games of the season:

Electrochemical determination of L-phenylalanine at polyaniline modified carbon electrode based on β-cyclodextrin incorporated carbon nanotube composite material and imprinted sol-gel film. A sensitive and selective electrochemical sensor based on a polyaniline modified carbon electrode for the determination of L-phenylalanine has been proposed by utilizing β-cyclodextrin (β-CD) incorporated multi-walled carbon nanotube (MWNT) and imprinted sol-gel film. The electrochemical behavior of the sensor towards L-phenylalanine was investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and amperometric i-t curve. The surface morphologies of layer-by-layer assembly electrodes were displayed by scanning electron microscope (SEM). The response mechanism of the imprinted sensor for L-phenylalanine was based on the inclusion interaction of β-CD and molecular recognition capacity of the imprinted film for L-phenylalanine. A linear calibration plot was obtained covering the concentration range from 5.0 × 10(-7) to 1.0 × 10(-4) mol L(-1) with a detection limit of 1.0 × 10(-9) mol L(-1). With excellent sensitivity, selectivity, stability, reproducibility and recovery, the electrochemical imprinted sensor was used to detect L-phenylalanine in blood plasma samples successfully.

521 F.2d 1401 Shermanv.Havener 75-1538 UNITED STATES COURT OF APPEALS Sixth Circuit 8/1/75 S.D.Ohio AFFIRMED

--- abstract: | The magnetic permeability of a ferrite is an important factor in designing devices such as inductors, transformers, and microwave absorbing materials among others. Due to this, it is advisable to study the magnetic permeability of a ferrite as a function of frequency. When an excitation that corresponds to a harmonic magnetic field **H** is applied to the system, this system responds with a magnetic flux density **B**; the relation between these two vectors can be expressed as **B** =$\mu(\omega)$ **H** . Where $\mu$ is the magnetic permeability. In this paper, ferrites were considered linear, homogeneous, and isotropic materials. A magnetic permeability model was applied to NiZn ferrites doped with Yttrium. The parameters of the model were adjusted using the Genetic Algorithm. In the computer science field of artificial intelligence, Genetic Algorithms and Machine Learning does rely upon nature’s bounty for both inspiration nature’s and mechanisms. Genetic Algorithms are probabilistic search procedures which generate solutions to optimization problems using techniques inspired by natural evolution, such as inheritance, mutation, selection, and crossover. For the numerical fitting usually is used a nonlinear least square method, this algorithm is based on calculus by starting from an initial set of variable values. This approach is mathematically elegant compared to the exhaustive or random searches but tends easily to get stuck in local minima. On the other hand, random methods use some probabilistic calculations to find variable sets. They tend to be slower but have greater success at finding the global minimum regardless of the initial values of the variables author: - 'Silvina Boggi, Adrian C. Razzitte,Gustavo Fano' title: Numerical response of the magnetic permeability as a funcion of the frecuency of NiZn ferrites using Genetic Algorithm --- Magnetic permeability model =========================== The ferrites materials have been widely used as various electronic devices such as inductors, transformers, and electromagnetic wave absorbers in the relatively high-frequency region up to a few hundreds of MHz. The electromagnetic theory can be used to describe the macroscopic properties of matter. The electromagnetic fields may be characterized by four vectors: electric field **E**, magnetic flux density **B** , electric flux density **D**, and magnetic field **H**, which at ordinary points satisfy Maxwell’s equations. The ferrite media under study can be considerer as linear, homogeneous, and isotropic. The relation between the vectors **B** and **H** can be expressed as : **B** =$\mu(\omega)$**H** . Where $\mu$ is the magnetic permeability of the material. Another important parameter for magnetic materials is magnetic susceptibility $\chi$ which relates the magnetization vector M to the magnetic field vector **H** by the relationship: **M** =$\chi(\omega)$ **H** . Magnetic permeability $\mu$ and magnetic susceptibility $\chi$ are related by the formula: $\mu=1 + \chi $. Magnetic materials in sinusoidal fields have, in fact, magnetic losses and this can be expressed taking $\mu$ as a complex parameter:$ \mu=\mu' + j \mu" $ [@VonHippel] In the frequency range from RF to microwaves, the complex permeability spectra of the ferrites can be characterized by two different magnetization mechanisms: domain wall motion and gyromagnetic spin rotation. Domain wall motion contribution to susceptibility can be studied through an equation of motion in which pressure is proportional to the magnetic field [@greiner]. Assuming that the magnetic field has harmonic excitation $H= H_{0} e^{j\omega t}$ , the contribution of domain wall to the susceptibility $\chi _{d}$ is: $$\label{eq:chid} \chi_{d}=\frac{\omega^{2}\;\chi_{d0}}{\omega^{2}{_{d}}-\omega^{2}-j\omega\beta}$$   Here, $\chi_{d}$ is the magnetic susceptibility for domain wall, $\omega_{d}$ is the resonance frequency of domain wall contribution, $\chi_{d0}$ is the static magnetic susceceptibility, $\beta$ is the damping factor and $\omega$ is the frequency of the external magnetic field. Gyromagnetic spin contribution to magnetic susceptibility can be studied through a magnetodynamic equation [@sohoo][@wohlfarth]. The magnetic susceptibility $\chi_{s}$ can be expressed as: $$\ \chi_{s}=\frac{\left(\omega_{s}-j\omega\alpha\right)\omega_{s}\chi_{s0}}{\left(\omega_{s}-j\omega\alpha\right)^{2}-\omega^{2}},$$ Here, $\chi_{s}$ is the magnetic susceptibility for gyromagnetic spin, $\omega_{s}$ is the resonance frequency of spin contribution, $ \chi_{s0}$ is the static magnetic susceptibility, and $\alpha$ is the damping factor and $\omega$ is the frequency of the external magnetic field. The total magnetic permeability results [@PhysicaB]: $$\label{eq:modelo} \mu=1+ \chi_{d}+\chi_{s}=1+\frac{\omega^{2}\;\chi_{d0}}{\omega^{2}{_{d}}-\omega^{2}-j\omega\beta}+\frac{\left(\omega_{s}+j\omega\alpha\right)\omega_{s}\chi_{s0}}{\left(\omega_{s}+j\omega\alpha\right)^{2}-\omega^{2}}$$   Separating the real and the imaginary parts of equation (\[eq:modelo\]) we get: $$\label{mureal} \mu'\left(\omega\right)=1+\frac{\omega_{d}^{2}\;\chi_{d0}\left(\omega_{d}^{2}-\omega^{2}\right)}{\left(\omega_{d}^{2}-\omega^{2}\right)^{2}+\omega^{2}\beta^{2}}+\frac{\omega_{s}^{2}\;\chi_{s0}\left(\omega_{s}^{2}-\omega^{2}\right)+\omega^{2}\alpha^{2}}{\left(\omega_{s}^{2}-\omega^{2}\left(1+\alpha^{2}\right)\right)^{2}+4\omega^{2}\omega_{s}^{2}\alpha^{2}}$$ $$\label{muimag} \mu"\left(\omega\right)=1+\frac{\omega_{d}^{2}\;\chi_{d0}\;\omega\;\beta}{\left(\omega_{d}^{2}-\omega^{2}\right)^{2}+\omega^{2}\beta^{2}}+\frac{\omega_{s}\;\chi_{s0}\;\omega\;\alpha\left(\omega_{s}^{2}+\omega^{2}\left(1+\alpha^{2}\right)\right)}{\left(\omega_{s}^{2}-\omega^{2}\left(1+\alpha^{2}\right)\right)^{2}+4\omega^{2}\omega_{s}^{2}\alpha^{2}},$$ Magnetic losses, represented by the imaginary part of the magnetic permeability, can be extremely small; however, they are always present unless we consider vacuum [@landau]. From a physics point of view, the existing relationship between $\mu'$ and $\mu"$ reflects that the mechanisms of energy storage and dissipation are two aspects of the same phenomenon [@boggi]. Genetic Algorithms ================== Genetic Algorithms (GA) are probabilistic search procedures which generate solutions to optimization problems using techniques inspired by natural evolution, such as inheritance, mutation, selection, and crossover. A GA allows a population composed of many individuals evolve according to selection rules designed to maximize “fitness” or minimize a “cost function”. A path through the components of AG is shown as a flowchart in Figure (\[fig:diagramaflujo\]) ![Flowchart of a Genetic Algorithm.[]{data-label="fig:diagramaflujo"}](diagramaf.eps){width="70.00000%"} Selecting the Variables and the Cost Function --------------------------------------------- A cost function generates an output from a set of input variables (a chromosome). The Cost function’s object is to modify the output in some desirable fashion by finding the appropriate values for the input variables. The Cost function in this work is the difference between the experimental value of the permeability and calculated using the parameters obtained by the genetic algorithm. To begin the AG is randomly generated an initial population of chromosomes. This population is represented by a matrix in which each row is a chromosome that contains the variables to optimize, in this work, the parameters of permeability model. [@1] Natural Selection ------------------ Survival of the fittest translates into discarding the chromosomes with the highest cost . First, the costs and associated chromosomes are ranked from lowest cost to highest cost. Then, only the best are selected to continue, while the rest are deleted. The selection rate, is the fraction of chromosomes that survives for the next step of mating. Select mates ------------- Now two chromosomes are selected from the set surviving to produce two new offspring which contain traits from each parent. Chromosomes with lower cost are more likely to be selected from the chromosomes that survive natural selection. Offsprings are born to replace the discarded chromosomes Mating ------ The simplest methods choose one or more points in the chromosome to mark as the crossover points. Then the variables between these points are merely swapped between the two parents. Crossover points are randomly selected. Mutación -------- If care is not taken, the GA can converge too quickly into one region of a local minimum of the cost function rather than a global minimum. To avoid this problem of overly fast convergence, we force the routine to explore other areas of the cost surface by randomly introducing changes, or mutations, in some of the variables. The Next Generation -------------------- The process described is iterated until an acceptable solution is found. The individuals of the new generation (selected, crossed and mutated) repeat the whole process until it reaches a termination criterion. In this case, we consider a maximum number of iterations or a predefined acceptable solution (whichever comes first) Results and discussion ======================= $Ni_{0.5}Zn_{0.5}Fe_{2-x}Y_{x}O_{4}$ samples were prepared via sol-gel method with x=0.01, 0.02, and 0.05. The complex permeability of the samples was measured in a material analyzer HP4251 in the range of 1MHz to 1 GHz.[@silvia]. The experimental data of magnetic permeability have been used for fitting the parameters of the model [@PhysicaB]. Firstly, we fitted the magnetic losses based in equation (\[muimag\]) by the Genetic Algoritm method and we obtained the six fitting parameters. We substituted, then, these six parameters into equation (\[mureal\]) to calculate the real part of permeability. The variables of the problem to adjust were the six parameters of the model: ($\chi_{d}$, $\chi_{s}$, $\omega_{d} $, $\omega_{s}$, $\beta$ y $\alpha$) Magnetic losses being a functional relationship: $$%\label{ajuste} \mu''_{ajustado}= f(\omega,\chi_{d},\chi_{s},\omega_{d},\beta,\alpha)$$ where $\omega$ is the frequency of the external magnetic field, y $\chi_{d}$, $\chi_{s}$, $\omega_{d} $, $\omega_{s}$, $\beta$ $\alpha$ are unknown parameters, the problem is to estimate these from a set of pairs of experimental:$\:\:(\omega_{i},\mu''_{i}); (i=1,2,...,n)$ . The cost function was the mistake made in calculating $\mu''_{ajustado}$ with the expression (\[muimag\]) using the parameters obtained from the genetic algorithm and the experimental value of $\mu''$ for each frequency. $$Cost\;function=\sum^{n}_{i=1}(f(\omega_{i},\chi_{d},\chi_{s},\omega_{d}, \omega_{s}, \beta,\alpha)-\mu''_{i})^{2}$$ 2000 iterations were performed, with a population of 300 chromosomes (each with 6 variables). The fraction of the population that was replaced by children in each iteration was 0.5 and the fraction of mutations was 0.25. {width="80.00000%"} \[fig:mincost\] The figure \[fig:mincost\] shows the evolution of the error in successive iterations, we graphed the minimum value of function cost in the population for each iteration. It show that the error converges at minimum value quickly, and then this value is stable. Although in the equations (\[muimag\]) and (\[mureal\]), $\omega_{d}$ and $\omega_{s}$ must be in Hz, we calculate in MHz and then multiplied in the equations by $1.10^{6}$, the same treatment we performed with the parameter beta, we calculate its value in the range between 1 and 2000, although in equations we multiplied by $1.10^{7}$. This treatment was necessary for that the AG values to variables within a limited range. Table \[tab:tabla1\] shows the parameters of the model calculated for the three NiZn ferrite samples doped with different amounts of Yttrium. Figure \[fig:permeajuste\] graphs (a), (b) and (c) shows the permeability spectra for the three ferrites. Solid lines represent the curves constructed from the adjusted parameters while dotted and dashed lines represent the curves from experimental data. The frequency of the $\mu''$ maximum for the spin component is calculated [@tsutaoka]: $$\omega_{\mu''\!max}^{s}=\frac{\omega_{s}}{\sqrt{1+\alpha^{2}}}$$ And for the domain wall component:[@tsutaoka]: $$\omega_{\mu''\!max}^{d}= \frac{1} {6}\sqrt{12\omega_{d}^{2}-6\beta^{2}+6\sqrt{16\omega_{d}^{4}-4\omega_{d}^{2}\beta^{2}+\beta^{4}}}$$ In these ferrites maximums are located in: $\omega_{\mu''\!max}^{s}\cong\!80\: MHz$ y $\omega_{\mu''\!max}^{d}\cong\!1000\: MHz$. $\chi_{d0}$ $\omega_{d}\;\left(Hz\right)$ $\beta$ $\chi_{s0}$ $\omega_{s}\;\left(Hz\right)$ $\alpha$ ------------ ------------- ------------------------------- ------------------- ------------- ------------------------------- ---------- NiZnY 0.01 22.05 1262 $\cdot10^{6}$ 1966$\cdot10^{7}$ 4.48 1989$\cdot10^{6}$ 1.8967 NiZnY 0.02 24.79 1115$\cdot10^{6}$ 1581$\cdot10^{7}$ 5.50 1480$\cdot10^{6}$ 1.40 NiZnY 0.05 33.75 671$\cdot10^{6}$ 1021$\cdot10^{7}$ 10.75 1334$\cdot10^{6}$ 3.477 : Adjusted parameters in the permeability model for NiZn ferrites doped with Yttrium.[]{data-label="tab:tabla1"} h ![(a)(b)y(c) Complex permeability spectra in NiZn ferrites[]{data-label="fig:permeajuste"}](permeajuste3.eps "fig:"){width="100.00000%"} [99]{} Haupt R.L, Haupt S.E “Practical Genetic Algorithms.”Wiley-Interscience publication (1998) A.Von Hippel. “Dielectrics and Waves”. J. Wiley Sons. (1954). R. F. Sohoo. “Theory and Application of Ferrites”, Prentice Hall, NJ, USA (1960) Trainotti V. and Fano W. “Ingeniera Electromagnetica”. Nueva Libreria, 2004. Landau and Lifchitz. “Electrodinamica de los medios continuos”. Reverté, 1981. W.G.Fano, S.Boggi, A.C.Razzitte, “Causality study and numerical response of the magnetic permeability as a function of the frequency of ferrites using Kramers Kronig relations” Physica B, 403, 526-530, (2008) Greiner. “Clasical electrodynamics”. cap.16, Springer (1998) Tsutaoka, T. “Frequency dispersión of complex permeability in Mn-Zn and Ni-Zn spinel ferrites and their composite materials”J ournal of Applied Physics,Volumen 93 (2003) Wohlfarth E. “Ferromagnetics Materials”, volumen 2. North Holland, 1980. S.E.Jacobo, S Duhalde, H.R.Bertorello, Journal of Magnetism and Magnetic Materials 272-276 (2004) 2253-2254. Silvina Boggi, Adrián C. Razzitte and Water G.Fano, *Non-equilibrium Thermodynamics and entropy production spectra: a tool for the characterization of ferrimagnetic materials*, Journal of Non-Equilibrium Thermodynamics. Volume 38, issue 2 p.175-183 (2013). T. Tsutaoka, T.*Frequency dispersión of complex permeability in Mn-Zn and Ni-Zn spinel ferrites and their composite materials*, Journal of Applied Physics,v 93 (2003)

Death rate rising for working-class white Americans One of the recent (well, sort of recent) news stories that has caught my attention is the rising death rate for middle-aged working-class white Americans. Quote: According to the report, an epidemic of drug abuse and despair has killed so many white middle-aged Americans over the past decade, the demographic has actually seen an increase in its mortality rate over the period, even as medical advances decreased the death rate across every other racial and ethnic group. The spike in mortality was borne entirely by the white working class — the death rate for non-college-educated white men and women, ages 45 to 54, increased by 22 percent between 1999 and 2013, according to the new statistical analysis by the Princeton husband-and-wife economist team Angus Deaton and Anne Case. Prior to 1999, the mortality rate within that group had been falling steadily for decades. What I found particularly interesting about articles on this story were the frequent comparisons to the increase in the death rate for Russian men following the collapse of the Soviet Union. My own suspicion is that the rise in the death rate for working-class white Americans came about following the implementation of neoliberal economic policies (union busting, outsourcing, cuts to social spending, etc.) in many areas of the country. Many formerly prosperous towns are now pretty much depressed husks. Things in the United States continue to worsen for working people as can be seen by the fact that the suicide rate is now at a 30-year high.

Click the below image to view the full-size visualization (2,995x4,265) Click here to download the visualization in PDF format to print or use to easily zoom and view the data. Click the below image to view the full-size visualization (2,995x4,265) Click here to download the visualization in PDF format to print or use to easily zoom and view the data. The United States Census is a decennial census that is mandated by Article 1, Section 2 of the Constitution. As the country developed and expanded, statistics were needed to aid with planning, and the census has evolved through the years to fulfill different needs. By 1850, questions about social issues, taxation, churches, pauperism, and crime were added. The first census of the entire United States occurred on Aug. 2, 1790. It discovered that the population of the United States was 3,929,214. At the time, the most populated state was Virginia (747,610 people), and the most populated city was New York City (33,131). New York City has remained the most populous city throughout the decades, reaching a total population of 8,175,133 by the 2010 census. That means the population of NYC has increased by 24,675% in 220 years! Check out more about this topic from the video The top ten most populous cities in 1790 were as follows: New York, New York (33,131) Philadelphia, Pennsylvania (28,522) Boston, Massachusetts (18,320) Charleston, South Carolina (16,359) Baltimore, Maryland (13,503) Northern Liberties Township, Pennsylvania (9,913) Salem, Massachusetts (7,921) Newport, Rhode Island (6,716) Providence, Rhode Island (6,380) Marblehead, Rhode Island (5,661) The top ten most populous cities in 2010 were as follows:

E-mail this post Author, educator and art director/brand strategist, Robin Landa, spoke with some of the industry's top creative directors and compiled their best advise in a downloadable document available from Amazon.com for $0.49. Here's a small slice: Robin Landa: “What’s your philosophy about advertising?” John Butler: “It has to be likeable. It has to inform and inspire. It has to have some emotional hook to it that makes consumers interact with it. It can’t talk down to the consumer. There’s a great quote—although I can’t remember who said it—but it’s hanging on my door: “He who writes the stories defines the culture.” I think that pretty much sums it up. We are given a voice, and we have to be responsible in how we use that voice.”

October 21, 2012 — Eric Honaker It’s my intent to review books here from independents and small press. I also only intend to review books I enjoyed. If you’re interested in a more complete idea of my reading habits and opinions, check out my Goodreads profile. For the first, I give you a Greek/Indian inspired secondary world fantasy. The Black God’s War by Moses Siregar III As the title suggests, Black God’s War includes involvement from Gods. I don’t generally go for books like that. They’re heavy on predestination and the like. This book was quite different. The story focuses around a war between the countries of Rezzia and Pawhelon. The gods of Rezzia have told them it’s their holy duty to spread knowledge of the Lux Lucis, their ten gods, to the rest of the world. Rezzia has chosen to do this by conquest. Pawhelon is a country focused on internal spiritualism, and their sages (wizard/monks) say there are no gods, and that Lux Lucis are just projections created by the Rezzians. Their war has been going on for 10 years, and the heirs of each country are coming of age and getting involved. The older daughter of the Rezzian king has been visited by the eponymous Black God since her mother died in birth with her younger brother. She blames him for the death of her mother, and for most of the bad things in her life. The younger brother was born with markings that make him an important religious feature of Rezzian life. The cosmology of the book is interesting. Both sides’ magic seems to depend on their concepts of what is beyond humanity to be correct, but both work. The Pawhelons see the Rezzian gods just like the Rezzians do, on more than one occasion. However, the Pawhelons are also able to counter and even overcome the power of the Rezzian gods as well. We are left with the certainty that the gods exist, but no certainty about their godhood, their motivations, or the worthiness of their goals. I found the characters to be well conceived and well written. I didn’t find any particular side in the war to be clearly “the good guys” or “the villains.” There were likable characters on each side, as well as people worthy of dislike. I felt that the work bore the stamp of classic myths and religious texts, such as the Mahabarata and the Illiad. All told an excellent start to a series, that also ends with the conclusion of a smaller story within the larger arc. Moses’ Blog: Science Fiction & Fantasy Books Black God’s War at Amazon.com (Just $1. Go get it!)

Wien. Auf den ersten Blick sehen einander die beiden Gemeinden Semriach und Litschau nicht gerade unähnlich. Möglich, dass die Semriacher und Litschauer diesem Befund heftig widersprechen werden, gemeint ist aber: Es sind beides ländliche Gemeinden vergleichbarer Größe, im Dorfzentrum steht eine aus dem Mittelalter stammende Kirche, von ihr gehen sternförmig ein paar mit Häuserzeilen versehene Straßen weg. Und rundherum: Felder und Waldstreifen. So sieht in Österreich der ländliche Raum aus. Doch es gibt einen ganz wesentlichen Unterschied zwischen diesen beiden Gemeinden, der für ihre Entwicklung eine bedeutende Rolle spielt. Setzt man sich in Semriach ins Auto und fährt eine halbe Stunde Richtung Süden, befindet man sich mitten in der Grazer Altstadt. Fährt man hingegen eine halbe Stunde von Litschau mit dem Auto, gelangt man nicht viel weiter als bis Groß-Siegharts. Die Folge dieser geografischen Ungleichheit lässt sich an der Bevölkerungsentwicklung ablesen. Bei der Volkszählung 1991 hatte Litschau mit 2923 Einwohnern noch leicht die Nase vorn. In Semriach waren damals 2876 Personen hauptgemeldet. Das hat sich seither ziemlich dramatisch verändert. Litschau ist auf 2254 Einwohner geschrumpft, Semriach auf 3305 Einwohner gewachsen. Die Statistik Austria hat in ihrer vorletzten Publikation im Februar eine neue Typisierung vorgenommen, um den bisher sehr weit gefassten Begriff des "ländlichen Raums" differenzierter betrachten zu können. Normal werden für derartige Statistiken administrative Einheiten betrachtet, also beispielsweise Bezirke oder Gemeinden. Womit es dann aber keinen Unterschied zwischen Litschau und Semriach gibt, die ja - zumindest bis vor nicht allzu langer Zeit noch - ähnlich groß waren. Fünf funktionale Kategorien Vor einigen Jahren fügte die Statistik Austria ein funktionales Merkmal hinzu: die Stadtregion. In diese fällt als Umlandgemeinde von Graz auch Semriach. Sie war somit nicht mehr klassischer ländlicher Raum. Wirklich zufriedenstellend war diese Typisierung aber nicht, weshalb nun eine weitere Differenzierung vorgenommen wurde. Elf Ausprägungen wurden beschrieben, diese dann zwecks besserer Übersicht in fünf Kategorien zusammengefasst. Wobei nicht nur die Entfernung zur nächsten Großstadt eine Rolle spielt, sondern auch die Bevölkerungsdichte. Urbane Großzentren: Das sind die Kernzonen der größten Stadtregionen, also alle Landeshauptstädte und die unmittelbare Umgebung mit Ausnahme von Eisenstadt und St. Pölten. Urbane Mittel-/Kleinzentren: Dieser Kategorie entsprechen 115 Gemeinden, darunter viele Bezirkshauptstädte wie Amstetten, Lienz, Villach oder Braunau. Regionale Zentren: Elf Prozent aller Kommunen fallen in diese Kategorie, es sind kleinere Städte, die doch näher dem ländlichen Raum als der Großstadt sind, etwa Oberwart, Bad Ischl, Landeck, Kitzbühel oder Hollabrunn. Außenzonen von Zentren: Hierunter fallen Umlandgemeinden, sowohl von großen wie auch von kleinen Städten. Semriach fällt in diese Kategorie, ebenso Pressbaum oder Fischamend. Je größer das jeweilige Zentrum, desto weiter gefasst ist die Außenzone rundherum. Ländlicher Raum abseits von Zentren: Die meisten Gemeinden fallen in diese Kategorie, insgesamt 1233. Die Bandbreite ist groß. Litschau in der Grenzregion zu Tschechien findet sich hier ebenso wie die wachsende Stadt Mattighofen, die das florierende Unternehmen KTM beherbergt. Interessant ist, wie sich demografische Daten nun mit dieser neuen, differenzierten Typologie darstellen. Einerseits verdeutlichen sie Entwicklungen, die - auch in der "Wiener Zeitung" - hinlänglich beschrieben wurden. Aber es gibt doch auch einige Überraschungen. Zunächst sticht einmal die Bevölkerungsveränderung zwischen 2001 und 2017 hervor, sie betrifft die erste wie die letzte Kategorie, also die Großstadt wie den ländlichen Raum abseits von Zentren. In Österreich leben 41,1 Prozent der Menschen in urbanen Großzentren, vor 16 Jahren waren es noch 38,2 Prozent. Umgekehrt ist die Entwicklung im ländlichen Raum fernab von einem urbanen Zentrum. Der Anteil ging von 29,4 auf 26,9 zurück, in den drei übrigen Kategorien gab es nur marginale Veränderungen seit 2001. So weit, so erwartbar. Landflucht eben. Doch Österreichs Bevölkerung ist in diesem Zeitraum insgesamt stark gewachsen, der Rückgang in absoluten Zahlen im ländlichen Raum ist aber nur marginal. Heute leben in diesen 1233 Gemeinden lediglich um 936 Personen weniger als noch 2001. Gibt es gar keine Landflucht? Gibt es am Ende kaum Landflucht? Sondern ist es nur ein städtischer Zuwachs, der die prozentuelle Verteilung verändert? Rein den Zahlen nach müsste man diesen Schluss ziehen, aber so einfach ist es nicht. Die Statistik Austria hat sich auch die Binnenwanderung sowie die internationale Zuwanderung angesehen, beides ist im ländlichen Raum verhältnismäßig stark ausgeprägt. In keiner anderen Kategorie wird ein negativer Saldo bei der Binnenwanderung ausgewiesen. Das heißt, in allen anderen Gemeindetypen ziehen mehr Menschen aus anderen österreichischen Regionen hin als weg. Nur im ländlichen Raum abseits der Zentren gibt es ein Minus von 136.558 Personen. Dem steht aber eben ein Plus von 142.847 bei internationalen Wanderungen entgegen. Ein sehr wesentlicher Faktor betrifft hier die Fluchtmigration in den Jahren 2014 bis 2016. Die vielen Flüchtlinge, die in diesen Jahren kamen, wurden auch in kleine, oftmals ländliche Gemeinden verteilt. Viele zogen dann freilich weiter, wenn sie einen positiven Asylbescheid erhielten, meist nach Wien oder in andere urbane Zentren. Dennoch blieben auch einige in den ruralen Kommunen, dazu kommt eine Zuwanderung aus dem EU-Ausland, wobei hier sicher auch der Tourismus eine treibende Kraft darstellt. Und der ist nicht überall gleich ausgeprägt. Migranten aus anderen EU-Ländern machen etwa die Hälfte der knapp 143.000 Zuzüge aus. Ein Ungleichgewicht ist freilich auch hier offenkundig. Mattighofen etwa wächst, wie auch andere ländliche Gemeinden im Westen. Liegen Orte aber an der Peripherie, geht die Tendenz meist nach unten. Bemerkenswert ist auch der Altersdurchschnitt. Vor 16 Jahren war die Bevölkerung in dieser Kategorie mit 39 Jahren noch relativ jung, mittlerweile sind die (groß)städtischen Einwohner die jüngsten und die ländlichen mit durchschnittlich 43,6 Jahren gleich um fast vier Jahre älter geworden. Es ist also doch das alte Lied: Die Abwanderung aus dem ländlichen Raum ist Realität.

[Pancreatic function and quality of life after resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study after duodenum preserving resection of the head of the pancreas versus Whipple's operation]. Given an indication for surgery in patients with chronic pancreatitis, such as distal common bile duct obstruction, duodenal stenosis, or dilated pancreatic duct with stones and congestion, the surgeon must decide the type of operation to perform. A duodenopancreatectomy, the Whipple procedure, is widely considered to be the gold standard. It is highly effective in relieving pain and eliminating the structural abnormalities noted above. Duodenum-preserving resection of the head of the pancreas (DPRHP) seems to be an attractive alternative to pancreaticoduodenectomy (PD) in the treatment of chronic pancreatitis. In a clinical prospective randomized trial the efficiency of both operative methods was investigated. Between 7/1987 and 12/1993 43 patients were randomly assigned to undergo either a Whipple procedure (n = 21) or DPRHP (n = 22). Data on postoperative course, mortality, and postoperative morbidity were compiled. As concerns long-term results, postoperative hormonal status (insulin, neurotensin, cholecystokinin, gastrin) was checked, basal and stimulated with a standardized meal, using standard hormonal assay kits. All patients with PD survived, whereas one with DPRHP died from peritonitis. Patients with DPRHP had a significant more rapid convalescence (16.5 vs. 21.7 days). The range for postoperative follow-up is from 36 months to 5.5 years. In the DPRHP group 18 patients are in good condition. Two had diabetes and one developed carcinoma. In the PD group one died from hepatic coma, 14 are in good condition and 6 developed diabetes. All gained body weight with an average of 6.4 vs. 4.9 kg, DPRHP vs. PD. A difference between DPRHP and PD was obvious for the postoperative hormonal status. Results are satisfactory in both groups. For patients with DPRHP however, we see a quicker convalescence and a significant benefit as concerns postoperative hormonal status.

Synthesis of L-glucose from D-gulono-1,4-lactone. An efficient method for the synthesis of L-glucose from D-gulono-1,4-lactone via 1,2,3,4,5-penta-O-benzyl/acetyl/benzoyl-D-gulitol is described in 34-53% overall yield.

Category Archives: The Pantry Did you know that you can substitute Jack Daniels Whiskey for Vanilla? I’m a big Jack Daniels fan. Besides ‘on the rocks’ it can do wonders to add unique flavor to many recipes. We recently had the opportunity to tour the Jack Daniels Distillery in Lynchburg, Tennessee. If you get the chance, GO!!! The Basic Tour is FREE and if you are over 21 you can sign up for the Sampling Tour for a mere $12.00 per person. When you go, don’t skip the town of Lynchburg. Park and walk around. It’s small enough to walk the whole square and stop in one of the restaurants for a nice lunch. You won’t leave without stopping at one of the several unique culinary/candy shops where you can get your specialty chocolates incorporated with Ole’ Jack! Mmmmm. There are several different varieties of this amazing whiskey as well as multiple uses besides the old-fashioned ‘medicinal’ one on the rocks. Jack Daniels Single Barrel is a perfect one for one substitute for Vanilla in your baking and cooking. It has deep rich color and flavor. I don’t ALWAYS have Single Barrel on hand as it is a bit expensive. BUT Jack Daniels Old No. 7 will work too. If you are looking for sweetness, then the Tennessee Honey Whiskey would be a good choice. Jack Daniels Fireball will add a boost of hot cinnamon to your recipes. When grocery shopping, take note of the items boasting Jack Daniels in its ingredients. It isn’t a well-kept secret, but one that is often overlooked. From Barbecues to Cakes and Cookies and Candy. You just can’t beat a good shot of Jack Daniels to add flavor and excitement to your culinary crafts.

My favourite potato salad I’m not usually a huge fan of potato salad, mainly due to my disgust of mayonnaise. But I found this recipe last summer on Epicurious, and I love it. It’s very light and fresh and not too labour-intensive to assemble. I should have dialled down the herb level on this iteration, but it was still delicious.

Secwepemctsín The language of the Secwepemc people is known as Secwepemctsín. Secwepemctsín comes from the land and is a reflection of Secwepemc identity. It serves as a translation key to everything relating to the Secwepemc. Linguists describe Secwepemctsín as one of the Interior Salish languages of the large Salishan language family. Like many Indigenous languages, Secwepemctsín is an oral language, meaning that it does not have its own writing system though there are those who have worked on it over the past decades. Secwepemctsín consists of 43 consonants and 5 vowels. Many of these sounds are not found in the English language. The language meaning and pronunciation varies throughout Secwepemcúlecw as there are three dialects. Flora Sampson, Cstálen Our language is sacred and so is our land, so they both connected. Our language is connected to the land, the water, the medicines, the animals, the fish, to everything. Everything’s so sacred. To the Secwepemc people. That’s the way I see it. And I’ve heard the ancestors talk about it like that. Flora Sampson, Cstálen Dorothy Johnson, Esk’ét When we to residential school we couldn’t speak our language so I think that’s how we just about lost our language because we thought its better if we speak to our children in English because we were punished if we spoke our language over there. Dorothy Johnson, Esk’ét Ralph Philips, Xats’ull I am Secwepemc. I can’t speak the language. That’s one of the things that the government took on me. The strange thing I guess wanting to start talking about what needs to happen. I think I need to talk about this, for me anyway that one of the things was that I was told that the language was something that we didn’t have, not supposed to use that and I watched little kids getting licked because of it. Ralph Philips, Xats’ull Fred Johnson, Esk’ét I was complaining to this Elder about residential school and I said they took away my language and my culture and my beliefs and my philosophy and he said what’s stopping you now? And I guess that’s what it is, what’s stopping you from speaking your language and it could be lots of things, you didn’t have no Elders or you didn’t have your parents there. Fred Johnson, Esk’ét Steve Basil From time to time we hear representatives at gathering speaking the language and that’s always a good thing. Not always we understand because the residential school had a big effect on our language and some of the teachings of our young people. Steve Basil Ronnie Jules, Cstálen The Secwepemc language is so, is really, it’s our life, it’s our identity. As I said we have a different, as we go west and north our dialect of our language is modified a little differently and as we go east it’s a bit different because our nation is so huge, it’s very huge, and that’s how we are identified. Ronnie Jules, Cstálen Dallas George, Esk’ét Learning our language is the most important thing to me. I’ve taken Shuswap class every semester… And I go out of my way to try and learn my language fluently. Dallas George, Esk’ét Wayne Christian, Splatsín Language and laws go hand in hand, and we have to stand up our laws. It’s all contained in our oral history that’s been passed down for over 10,000 years. Our knowledge of the land, as everything we know can be correlated with the actual Western science. Our people do know and do have knowledge and have scientific knowledge of the land. So that’s what’s important with the laws.

With the recent polar vortex, today's subzero temps and the upcoming daylight saving time change, you may be more than ready to flee to a sunnier climate. Just so happens, TripAdvisor.com released its annual Travelers' Choice list of the world's 25 best beaches . Winners were chosen based on quantity and quality of traveler reviews and ratings gathered over a 12-month span. Here's a roundup of the top 10.

Q: Arduino Delivering less power I connected 4x716 Coreless DC Motors on pin 13,12,11,10 and 1xGY-521 to Arduino Pro Mini 328, 5v but speed of propellers is not enough to produce enough torque to lift the quad whereas when i connect then directly to 3.3v LiPo battery the quad has lift but because of no flight control it moves randomly. I checked the voltage of pin 13,12... they have output as 0.5-0.6v, I think this is the reason quad is not lifting. I am using following code // MPU-6050 Short Example Sketch // By Arduino User JohnChi // August 17, 2014 // Public Domain #include<Wire.h> const int MPU=0x68; // I2C address of the MPU-6050 int16_t AcX,AcY,AcZ,Tmp,GyX,GyY,GyZ; int p1 = 13; int p2 = 12; int p3 = 11; int p4 = 10; void setup(){ Wire.begin(); Wire.beginTransmission(MPU); Wire.write(0x6B); // PWR_MGMT_1 register Wire.write(0); // set to zero (wakes up the MPU-6050) Wire.endTransmission(true); pinMode(p1, OUTPUT); pinMode(p2, OUTPUT); pinMode(p3, OUTPUT); pinMode(p4, OUTPUT); digitalWrite(p1, 0); analogWrite(p2, 0); analogWrite(p3, 0); analogWrite(p4, 0); Serial.begin(9600); } void loop(){ Wire.beginTransmission(MPU); Wire.write(0x3B); // starting with register 0x3B (ACCEL_XOUT_H) Wire.endTransmission(false); Wire.requestFrom(MPU,14,true); // request a total of 14 registers AcX=Wire.read()<<8|Wire.read(); // 0x3B (ACCEL_XOUT_H) & 0x3C (ACCEL_XOUT_L) AcY=Wire.read()<<8|Wire.read(); // 0x3D (ACCEL_YOUT_H) & 0x3E (ACCEL_YOUT_L) AcZ=Wire.read()<<8|Wire.read(); // 0x3F (ACCEL_ZOUT_H) & 0x40 (ACCEL_ZOUT_L) Tmp=Wire.read()<<8|Wire.read(); // 0x41 (TEMP_OUT_H) & 0x42 (TEMP_OUT_L) GyX=Wire.read()<<8|Wire.read(); // 0x43 (GYRO_XOUT_H) & 0x44 (GYRO_XOUT_L) GyY=Wire.read()<<8|Wire.read(); // 0x45 (GYRO_YOUT_H) & 0x46 (GYRO_YOUT_L) GyZ=Wire.read()<<8|Wire.read(); // 0x47 (GYRO_ZOUT_H) & 0x48 (GYRO_ZOUT_L) Serial.print("AcX = "); Serial.print(AcX); Serial.print(" | AcY = "); Serial.print(AcY); Serial.print(" | AcZ = "); Serial.print(AcZ); Serial.print(" | Tmp = "); Serial.print(Tmp/340.00+36.53); //equation for temperature in degrees C from datasheet Serial.print(" | GyX = "); Serial.print(GyX); Serial.print(" | GyY = "); Serial.print(GyY); Serial.print(" | GyZ = "); Serial.println(GyZ); digitalWrite(p1, HIGH); analogWrite(p2, 250); analogWrite(p3, 255); analogWrite(p4, 255); delay(333); } A: Atmega328 output pins are rated at 40 mA absolute-maximum current, and the 328's total current through Vcc and ground pins is 200 mA absolute max. Eg, see table 29.1 in the Atmega328 specs. Although some sources rate a high-speed 716 coreless dc motor at 40 mA, other sources rate it at 100 mA. In either case, it exceeds normal I/O pin capability. You should use FETs or other drivers between Arduino output pins and the motors rather than trying to drive the motors directly from digital output pins. Edit: Regarding the comment, “But most projects i've seen don't use any drivers, Why so ?” I replied: Perhaps they are using slightly higher voltage to the Pro Mini, eg 3.7 V up to 5 V, which after accounting for voltage drop in the i/o pin circuits may deliver enough voltage to the motors. Note that a driverless circuit ie direct drive from the i/o pins operates the 328 out of its safe operating area (SOA), but it may be close enough to the safe area to usually work. For example, some of the 716-based quadcopter pages I looked at say they used 4.2 V LiPo batteries. Also note, 716 seems to be a fairly generic motor designation; it refers to the motor's 7 mm diameter and 16 mm length. As a generic designation it has been used for several different motors, some of which produce less power. For example, in thread #1710948 on rcgroups.com, people refer to different RPMs, less lift, etc. for various motors, and the importance of shaving grams off of the copter's weight to allow it to fly. Another item that matters when drawing high current from an Atmega328 is which ports are used; and for some devices, it matters whether drive is high-side or low-side, ie whether current is sourced or sunk. The Atmega328 spec sheet (Atmel-8271-8-bit-AVR-Microcontroller-ATmega48A-48PA-88A-88PA-168A-168PA-328-328P_datasheet_Complete.pdf) says “Each output buffer has symmetrical drive characteristics with both high sink and source capability”, but for several kinds of drivers less voltage is lost with low-side drive than with high-side. Ie, you could try connecting the motor's V+ lead to Vcc and its V- lead to the i/o pin, and inverting the on-off logic in the sketch. (I don't know if this will make any difference at all in how well things work.) Regarding which ports are used, the footnotes to Table 30-1, “Common DC characteristics”, spell out various combinations of ports where total current draw must not exceed a limit (100 mA in some cases, 150 mA in others). On the Uno and Pro-Mini, digital outputs marked 10 through 13 (as used for motor control in the question's sketch) are port B Atmega pins, with a footnoted total-current limit for the group. If you move two of the motor drives to outputs marked 2...4 or D2...D4, then a different total-current limit will apply. (Again, I don't know if this will make any difference at all in how well things work.) Refer to Table 30-1 footnotes for details. As noted in Gerben's comment, having flyback-diodes for the motor circuits is a good idea. This consists of placing power diodes across the motors, cathode to V+, anode to V-, to prevent energy stored in the motor's inductance from producing extreme i/o pin voltages each time the motor is turned off. Edit 2: Regarding “which diode, FET to use and where [to] learn about them”, electronics-tutorials.ws is an accurate and helpful presentation about FET digital circuits. In particular, see the section called “An example of using the MOSFET as a switch”. Which FETs to consider depends in part on your electronic-circuits fabrication skills. Note that surface mount devices (SMD parts) usually weigh less than other versions of parts, which is important for a lightweight quadcopter. However, some people find SMD parts difficult to work with. In my opinion, the main difficulty is holding parts in their proper places while soldering them, due to small size. (Eg, a SOT-23 SMD transistor package is on the order of 3mm x 2mm x 1mm, and a diode may be half as big.) If you have good soldering skills and a way to hold parts in place while soldering, you should be ok, either using a printed circuit board or air-wiring parts using wire-wrap wire (ie, 30 AWG wire, about 0.25mm diameter). Some typical logic-level-input SMD FETs are shown in mouser.com's online catalog. Note that in that list, RDS_on decreases a bunch as unit price increases slightly. For example, the FDN359BN would have under 0.1 ohm resistance when operated with Vcc = 3.7 V and currents < 100 mA. Voltage drop running a 40 mA motor should be about 4 millivolts. Some typical SMD Schottky diodes also are shown in mouser.com's online catalog. I think even the cheapest of these would work ok. Of course you'll need to adapt all these suggestions to your own skills, sources of parts supply, and budget.

Real Time Mugshots. Real People. Real Arrests. Reality App! View AND Share. They say misery loves company, but looking at this APP, you will agree that in this case, it is better to be alone than in County Lock Up! Think you had a rough week-end? Look through this APP and somebody will surely have you beat! The people displayed might be innocent, might be guilty, we honestly don’t know. We just know that if you are looking for the “feel good” APP of the year, this is NOT it! All the photographs in this APP are from Law Enforcement Departments throughout the whole U.S. which means there is a chance you might find some friends, relatives or even yourself posted her at one time or another. You have heard of reality TV? This is Reality APPS, Baby!!! Think your friends would like to see the mugshots? Forward them mugshots from the website, mobile app or Facebook app. OMG! I went to school with her! Anna - Orlando, FL I just love browsing this app! Totally addicting! Kyle - Albany, NY Awesome. This is the best iPhone app to date. By far... Disclaimer: This application is intended for informational purposes only. The photographs and information presented in this application are available from police department files. The information does not reflect the criminal history or the criminal status of anyone. All people are innocent until proven otherwise in the legal system.

INTRODUCTION ============ Rhabdomyolysis is the breakdown of skeletal muscle that can rapidly progress to acute renal failure or death. It is important to make a rapid diagnosis and initiate treatment for rhabdomyolysis in order to decrease morbidity and mortality. To date there are no reports in the emergency medicine literature on the use of point-of-care ultrasound in the diagnosis of rhabdomyolysis. This unique case describes a patient who presented to the emergency department (ED) with localized musculoskeletal pain. Using ultrasound, the patient was quickly diagnosed and treated for rhabdomyolysis prior to confirmation with an elevated serum creatine phosphokinase (CPK). When coupled with a high index of suspicion, ultrasound can be one of the most portable, readily available, low-cost, and minimally invasive techniques for making a rapid diagnosis of rhabdomyolysis in the ED. CASE REPORT =========== A 24-year-old male presented to the ED with a two-day history of bilateral arm pain. The pain was constant, located primarily to the biceps region of his upper arms. His pain began shortly after weight lifting. Past medical history included bipolar disorder and polysubstance abuse, including recent use of cocaine, marijuana, and a synthetic marijuana known as "spice." On arrival to the ED the patient had a temperature of 97.9 F, blood pressure of 167/88, heart rate of 122, and respirations of 16 per minute. Physical findings included bilateral biceps swelling and fullness with diffuse tenderness to the musculature. There was no external evidence of trauma. The patient's upper extremities were neurovascularly intact with no evidence of paresthesias, weakness, or pallor. He was noted to display paranoid behavior without features of acute psychosis. A point-of-care musculoskeletal ultrasound was performed by the emergency physician to evaluate for a possible muscle or biceps-tendon tear. The sonogram showed areas of both increased and decreased echogenicity of the biceps muscle, as well as disorganized muscle fibers with surroundings areas of fluid ([Figure 1](#f1-wjem-17-801){ref-type="fig"}, [Video 1](#f3-wjem-17-801){ref-type="fig"}). There was preservation of the muscle boundary and the biceps tendon was intact. A presumptive diagnosis of rhabdomyolysis was made pending laboratory testing and the patient was started on intravenous (IV) fluids. The patient's lab work in the ED was notable for a creatine phosphokinase (CPK) of 83,000 U/L. AST/ALT were 813/169 IU/L respectively, total bilirubin of 1.5 mg/dl, and bicarbonate of 16 mEq/L. Urine results included amber color and "large" hemoglobin with 3--5 red blood cells per high powered field. A complete blood count, complete metabolic profile, and urinalysis were otherwise unremarkable. A urine drug screen was positive for marijuana. The patient was hospitalized and treated with aggressive IV fluids. His CPK peaked at 124,000 and subsequently improved daily thereafter. His liver enzymes improved as well. A hepatitis panel led to a new diagnosis of hepatitis C, though liver enzyme elevation was thought to be primarily related to his acute rhabdomyolysis. Renal function remained normal throughout his stay. His hospital course was complicated by paranoia, psychosis, and aggression toward hospital staff. He was subsequently placed under an involuntary psychiatric hold and required security intervention and sedation. He was transferred to the local mental health facility on hospital day five for further psychiatric care after his rhabdomyolysis resolved. DISCUSSION ========== Rhabdomyolysis is a syndrome of skeletal injury that can rapidly progress to acute renal failure or even death.[@b1-wjem-17-801],[@b2-wjem-17-801] It is imperative that it be diagnosed and treated appropriately to reduce the lasting effects of the disease.[@b1-wjem-17-801] Rhabdomyolysis results from a myriad of conditions including trauma, illicit drugs, medications, infection, excessive exercise, immobilization and psychiatric condition.[@b2-wjem-17-801] The symptoms of rhabdomyolysis are as variable as the causes: from a patient with a traumatic crush injury, who has pigmented urine and renal failure, to one with no significant history of trauma who may simply present with fatigue, nausea, fever or muscle weakness.[@b1-wjem-17-801],[@b2-wjem-17-801] For these reasons, diagnosing rhabdomyolysis cannot be based on history and physical alone and generally requires a serum CPK that is greater than five times the normal limit, without evidence of brain or cardiac injury. [@b3-wjem-17-801] Once a diagnosis of rhabdomyolysis is suspected, additional workup is needed. An electrocardiogram should be performed to screen for conduction abnormalities caused by hyperkalemia including: peaked T waves, prolonged PR interval and a widened QRS complex.[@b2-wjem-17-801] A metabolic panel should be performed to assess renal function, calcium, potassium and phosphorous levels.[@b1-wjem-17-801] CBC and coagulation studies should be done to monitor for evidence of DIC.[@b1-wjem-17-801] Imaging may be required in patients who present with localized pain. Ultrasound and magnetic resonance imaging (MRI) can both be used to determine the extent of muscular damage that exists. On ultrasound normal skeletal muscle has a relatively hypoechoic echotexture with clearly demarcated linear hyperechoic strands of fibroadipose septa[@b4-wjem-17-801] ([Figure 2](#f2-wjem-17-801){ref-type="fig"}). In rhabdomyolysis the findings are variable but may include hyperechoic areas of muscle,[@b5-wjem-17-801],[@b6-wjem-17-801] which is likely due to hypercontractile muscle fibers in the acute phase of muscle injury,[@b4-wjem-17-801] hypoechoic areas of muscle,[@b4-wjem-17-801],[@b7-wjem-17-801] which is believed to be caused by edema and inflammation of the muscle,[@b4-wjem-17-801],[@b7-wjem-17-801] increased muscle thickness, and fluid within the surrounding the muscles.[@b4-wjem-17-801] Areas of locally disorganized fascicular architecture[@b8-wjem-17-801] may also be appreciated but generally the muscle boundary itself remains intact unless an associated tear is present.[@b8-wjem-17-801] The area of locally disorganized fasicular architecture is thought to represent necrosis of the muscle.[@b4-wjem-17-801],[@b7-wjem-17-801] Abscesses and hematomas may also appear anechoic and hypoechoic and should be considered on the differential diagnosis.[@b5-wjem-17-801] However, on examination neither of these conditions correlates with the clinical picture. With both an abscess and hematoma one would expect a localized fluid collection on ultrasound in conjunction with physical exam findings of infection and trauma respectively. Additionally, there would not be a significantly elevated serum CPK or increase in creatinine level associated with these diagnoses. Clinicians performing soft tissue ultrasound should be familiar with the sonographic changes associated with other common musculoskeletal pathologies such as muscle tears, strains, and contusions in order to avoid diagnostic error. Complete muscle tears are associated with avulsion and retraction of the injured muscle segment along with an adjacent anechoic or hypoechoic hematoma.[@b9-wjem-17-801] Partial tears, strains, and contusions have focal hypoechoic areas within the muscle fibers themselves, representing localized edema and hemorrhagic changes that have disrupted the normal fibroadipose pattern.[@b9-wjem-17-801] Unlike in rhabdomyolysis, the sonographic findings seen with tears, strain injuries, and contusions are limited to a focal area of injury and are not diffusely present throughout the involved muscle. MRI is excellent at demonstrating rhabdomyolysis with T2-weighted MRI images of rhabdomyolysis generally show increased signal intensity.[@b8-wjem-17-801] Unfortunately performing an MRI is associated with greater cost and long testing times. In addition, MRI is not readily available in most EDs. The initial treatment of rhabdomyolysis involves early and aggressive IV fluid resuscitation.[@b2-wjem-17-801] The patient should be admitted and monitored for life-threatening complications such as acute renal failure and hyperkalemia. In this case, the patient presented with bilateral upper extremity pain and swelling and the ultrasound was used to narrow the differential of possible musculoskeletal pathologies. A presumptive diagnosis of rhabdomyolysis was made and later confirmed by serum CPK levels. If a patient has sonographic findings suggestive of rhabdomyolysis, treatment can be initiated immediately while laboratory testing is still in progress. The increasing availability of point-of-care ultrasound in most EDs makes it an ideal imaging modality for the initial evaluation of the patient in whom rhabdomyolysis is considered. LIMITATION ========== There are no follow-up ultrasounds available to show this patient's return to normal muscles. *Section Editor:* Rick A. McPheeters, DO Full text available through open access at <http://escholarship.org/uc/uciem_westjem> *Conflicts of Interest:* By the *West*JEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none. {#f1-wjem-17-801} {#f2-wjem-17-801} ###### This ultrasound video is of the patient's left bicep muscle. It shows disorganized muscle fibers with surrounding areas of anechoic fluid. The biceps muscle displays areas of both increased and decreased echogenicity. There is preservation of the muscle boundaries within the echogenic fascial planes.

S Radhakrishnan Thoughts on a True Religious Man We may start with austerity; austerity will lead to tolerance; tolerance will lead to respect and we will respect what other people hold sacred. Such should be the attitude of a truly religious soul. If you have hatred in your heart, if you have ignorance in your mind, if there is superstition in the dark spaces of your heart, take it from me that you are not a religious man but pretending to be a religious man. A truly religious man will be filled with light, joy and compassion for the whole of humanity. There is a secret dwelling place in each man’s heart, where the Divine is to be felt, is to be touched and experienced. This is what we should do. Prayers, meditations and spiritual exercises are all methods which are devices for helping us to know the deepest in us. This is what the purpose of all true religion is. This does not mean that we should retire into monasteries or go to mountain tops, lacerate our bodies, torture our minds and give up the world. People who do so are not truly religious. Men who neglect their duties and merely utter the name, Krishna, Krishna, are the enemies of God; ignorant people who do not know what Reality is. For the sake of humanity, god himself has taken birth in this world. If He has done that, is it not our duty to express our deepest convictions in our daily life and in our national behavior.

Tarafpur Union Tarafpur Union () is a union of Mirzapur Upazila, Tangail District, Bangladesh. It is situated 21 km north of Mirzapur and 52 km southeast of Tangail, The district headquarter. Demographics According to Population Census 2011 performed by Bangladesh Bureau of Statistics, The total population of Tarafpur union is 23169. There are 5168 households in total. Education The literacy rate of Tarafpur Union is 47.3% (Male-50.6%, Female-44.4%). See also Union Councils of Tangail District References Category:Populated places in Dhaka Division Category:Populated places in Tangail District Category:Unions of Mirzapur Upazila

Q: Convert node data to pdf via Rules I have a project plan content type. I would like to be able to change the "start date" field value to the current date, and set the "deadline date" field value to 2 weeks after. Then I would like to convert this data into a file (eg. pdf) which I can then attach to another entity. The majority of this can be achieved using the Set Data Value action in Rules module; except of course for converting the data into a file. The module FillPDF comes quite close although it only allows for converting Webform data to pdf and not node data. The following modules are able to convert nodes to pdf, however they do not have Rules integration: PDF using mPDF, Printer, email, PDF versions What is the best way to achieve this? A: It appears that this module is the answer: PDF Archive The only issue with this module is that it only converts the text of the node. Any images are not outputted to the pdf. PDF Archive: The PDF Archive module provides the ability to generate PDF archives of any entity triggered by Rules actions. Both the entity view mode and role of the simulated user used for rendering the entity can be set per rule. An example feature is included to demonstrate the configuration of this module.

RANCHO TEHAMA RESERVE, Calif. -- Residents of a remote Northern California community terrorized by a mass shooting this week say they want more frequent patrols from sheriff's deputies and expressed anger and frustration over seemingly being left to fend for themselves in what several called a "Wild West" atmosphere. The Rancho Tehama Reserve homeowners' association board met on Thursday to talk about more patrols, two days after 44-year-old Kevin Neal killed his wife and four others before he died in a gun battle with deputies. Neal targeted an elementary school while randomly shooting at homes and motorists in the sprawling rural subdivision about 130 miles north of Sacramento. He was known to authorities and had at least one prior arrest. Board president Juan Caravez was among those complaining that deputies didn't do enough to stop Neal despite numerous complaints from neighbors that he was shooting guns at all hours of the day and night. "The sheriff wouldn't do anything about it," Caravez said. Get Breaking News Delivered to Your Inbox Instead, he said Tehama County Sheriff's Department referred complaints to the homeowners' association. Residents were already complaining about the lack of law enforcement and frequent gunfire that regularly disturbed the peace of the rolling oak-studded hills dotted with homes and trailers on large lots, board member Richard Gutierrez said. Neighbors said they had complained repeatedly about Neal shooting off rounds of gunfire from his home, despite a court order barring him from having firearms after he was accused of stabbing a neighbor in January. Assistant Sheriff Phil Johnston said deputies had tried to contact Neal but he wouldn't answer his door and Johnston said deputies couldn't find him. After being pressed by reporters on why police did not act when Neal was in clear violation of his court order, Johnston obliquely replied: "The law is only for people who obey it." Sheriff's department spokeswoman Lt. Yvette Borden did not respond to phone and email inquiries Thursday. Gutierrez was among those praising deputies' swift response Tuesday. Johnston said Neal was dead 25 minutes after dispatchers received the first frantic calls. The sheriff's headquarters is 21 miles away. But Dillon Elliott was upset after hearing officials say road patrols had generally been increased in the last six years. "It's like people out here think we're like a lawless city trying to survive, and we kinda are," said Elliott, who grew up in the community and whose parents still live there. Claudette Wright said deputies responded to her calls, but the bad perception remains. "It's always like, 'Rancho, it's crazy out there — it's the Wild West'," she said at a community prayer vigil Wednesday night. "The perception is people think they can come out here and grow marijuana and there's no consequences," Wright said later, though she added that she had no complaints with law enforcement response. Benigna Gonzalez said deputies appeared not to believe her when she reported being stalked a year ago while walking at dusk through the community. She no longer walks for exercise, takes sleeping pills and is undergoing counseling. "We don't feel safe," she said tearfully. "I don't know when I'll feel safe anymore in this community." Police found the bullet-riddled body of Neal's wife stuffed under the floorboards of their home in the rural community of Rancho Tehama Reserve. They believe her slaying was the start of the rampage. Crime tape blocks off Rancho Tehama Road leading into the Rancho Tehama Reserve south of Red Bluff, Calif., following fatal shootings Tue., Nov. 14, 2017. AP Neal then shot two neighbors in an apparent act of revenge before he went looking for random victims at the community's elementary school and several other locations. Among those hurt at the school was 6-year-old Alejandro Hernandez, who was shot in the chest, arm and foot and remains hospitalized. His aunt, Marta Monroy, pleaded with fellow residents to formally report gunfire in the future. "No shooting in the air — call the police, please," she urged at the prayer vigil. If not more sheriffs' patrols, then the homeowners' association should consider paying for armed private patrols from the $50 monthly dues paid by every property owner or consider mounting an armed citizens' patrol, Raul Pinero said. "We need enforcement, at least something out here," Pinero said.

Q: Break Up stackoverflow? I think it might be time to consider breaking up stackoverflow into several different sites. I just posted a JS question. I never even saw it on the first page. As soon as it's off the first page, the views just stop. There's simply way too much traffic. You guys really need to do something because honestly the site is basically useless to me. The quality of posts can only go down from here. If you just broke-out JavaScript alone that would cut the traffic in half. A: I just posted a JS question. I never even saw it on the first page. Staying on the front page is not the only way to ensure that your question gets visibility. As soon as it's off the first page, the views just stop. There's simply way too much traffic. If that's your line of thinking, shouldn't this problem apply to every single one of the hundreds of thousands of people posting on Stack Overflow? Stack Overflow has features built in to the site so that this problem can be tackled. Sitting on the other side of the table, I come to Stack Overflow to post answers. However, I am not, and can never become an expert in all the topics that get asked on Stack Overflow. So how do I get to see the questions matching my area of expertise? Also, while your concern regarding your question not getting enough visibility is correct, using some mechanism to keep it on the front page does not necessarily ensure that it will get the desired visibility. Stack Overflow and other Stack Exchange sites offer features that enable a variety of ways to view and browse questions. Users can follow tags, use filters, and subscribe to RSS feeds to discover posted questions that are relevant to them. Also, the front page could differ for every other user, some could be viewing the interesting questions, currently hot questions, newest questions or currently unanswered questions. Instead of attempting to get your question to stay put on the front-page, you should focus on asking a good question, meaning you post a question after you have done the due diligence of using Stack Overflow's search feature to see if a similar question is already answered, searching for a solution by reading the platform documentation, searching the Web for a solution existing elsewhere. Resist the urge to ask a question as soon as you find yourself stuck. It's only natural for contributors to the site to refrain from answering the same question for the 100th time. And despite their best intentions of helping, they can't answer a not well-formed question. On the other hand, a well-formed question attracts a lot of attention and other users are more than willing to point you to an appropriate solution. Breaking up the site into different sites in not the appropriate solution for many reasons. Fluent users of Stack Overflow, do break up Stack Overflow by creating a custom filter and only follow the questions that interest them. To understand more about how filters work, you can refer to this wonderful blog post on The Overflow, Stack Exchange/Stack Overflow official blog: Introducing Custom Filters I am an Apple developer and have a custom filter where I only follow tags that are relevant to Apple development ecosystem. My Stack Overflow front page looks different from the All Questions view. So, generally speaking, every user has a different view of the front page, and a sure shot way to ensure getting an answer on Stack Overflow (or any Stack Exchange site for that matter) is to write good question. It is expected of users to read up, or at least skim through the relevant articles from the Help Center before posting a question. And if despite doing your best attempt at writing a good question, you find that it isn't getting the due traction, you can always offer a bounty (needs a minimum number of reputation points) or even use the share button located below the question to share in other social networks where you think the question can get visibility by relevant people. The designers of Stack Overflow (and by extension other Stack Exchange sites) continuously work hard to cover several such issues and keep introducing features that can make the platform as useful for as many numbers of people as possible. Remember, good posts make everyone happy on Stack Exchange sites, whether they are writing questions, answers, or even developing the platform.

Best Friends Having Fun in the toilet

Below are the most recent drone photographs taken of Europe’s Spaceport in French Guiana, taken March 2019. The images showcase the progress being made at the launch complex for future launch vehicle Ariane 6, scheduled for its maiden flight in 2020. The construction has been ongoing for approximately one and a half years now, and the launch site is foreseen to be completed before the end of 2019. To see the images in full-resolution, either download them or open them in a new window/tab. Credit: ESA/CNES/Sentinel

/* * Copyright (C) 1999-2000 Harri Porten ([email protected]) * Copyright (C) 2003, 2006, 2007, 2008, 2009, 2010 Apple Inc. All rights reserved. * Copyright (C) 2007 Cameron Zwarich ([email protected]) * Copyright (C) 2007 Maks Orlovich * * This library is free software; you can redistribute it and/or * modify it under the terms of the GNU Library General Public * License as published by the Free Software Foundation; either * version 2 of the License, or (at your option) any later version. * * This library is distributed in the hope that it will be useful, * but WITHOUT ANY WARRANTY; without even the implied warranty of * MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU * Library General Public License for more details. * * You should have received a copy of the GNU Library General Public License * along with this library; see the file COPYING.LIB. If not, write to * the Free Software Foundation, Inc., 51 Franklin Street, Fifth Floor, * Boston, MA 02110-1301, USA. * */ #ifndef JSGlobalObjectFunctions_h #define JSGlobalObjectFunctions_h #include "JSValue.h" #include <wtf/unicode/Unicode.h> namespace JSC { class ArgList; class ExecState; class JSObject; // FIXME: These functions should really be in JSGlobalObject.cpp, but putting them there // is a 0.5% reduction. EncodedJSValue JSC_HOST_CALL globalFuncEval(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncParseInt(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncParseFloat(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncIsNaN(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncIsFinite(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncDecodeURI(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncDecodeURIComponent(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncEncodeURI(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncEncodeURIComponent(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncEscape(ExecState*); EncodedJSValue JSC_HOST_CALL globalFuncUnescape(ExecState*); #ifndef NDEBUG EncodedJSValue JSC_HOST_CALL globalFuncJSCPrint(ExecState*); #endif static const double mantissaOverflowLowerBound = 9007199254740992.0; double parseIntOverflow(const char*, int length, int radix); double parseIntOverflow(const UChar*, int length, int radix); bool isStrWhiteSpace(UChar); double jsToNumber(const UString& s); } // namespace JSC #endif // JSGlobalObjectFunctions_h

Estimation of inferior-superior vocal fold kinematics from high-speed stereo endoscopic data in vivo. Despite being an indispensable tool for both researchers and clinicians, traditional endoscopic imaging of the human vocal folds is limited in that it cannot capture their inferior-superior motion. A three-dimensional reconstruction technique using high-speed video imaging of the vocal folds in stereo is explored in an effort to estimate the inferior-superior motion of the medial-most edge of the vocal folds under normal muscle activation in vivo. Traditional stereo-matching algorithms from the field of computer vision are considered and modified to suit the specific challenges of the in vivo application. Inferior-superior motion of the medial vocal fold surface of three healthy speakers is reconstructed over one glottal cycle. The inferior-superior amplitude of the mucosal wave is found to be approximately 13 mm for normal modal voice, reducing to approximately 3 mm for strained falsetto voice, with uncertainty estimated at σ ≈ 2 mm and σ ≈ 1 mm, respectively. Sources of error, and their relative effects on the estimation of the inferior-superior motion, are considered and recommendations are made to improve the technique.

Discover Kitty Pryde’s First Romance in X-MEN GOLD ANNUAL #2 This summer, Kitty Pryde will make the biggest romantic leap of her life – but what about Kitty’s first romantic adventure? Hugo and Nebula Award-winning writer Seanan McGuire (October Daye, Wayward Children series) and celebrated artist Marco Failla (Ms. Marvel, All-New Wolverine) are bringing you the Kitty before Colossus in X-MEN GOLD ANNUAL #2! “I am over the moon to be working with this amazing creative team and in this world that I have wanted to be a part of for most of my life,” shared McGuire. “Like so many of us, I started reading the X-Men before I was old enough to have been a student at Xavier’s Academy. Kitty Pryde was my hero for most of my childhood. She was smart, she was curious, she got to be an X-Man and go to space and have a dragon for a friend–she was basically everything I wanted to be.” “The thing about Kitty is that she was the only teenager on the team for a long time, and so she didn’t really get to do a lot of what we’d consider to be normal teenage things,” said McGuire. “Or maybe she did, and it just wasn’t the focus, since it wouldn’t involve the rest of the X-Men. This book is filling in one of those gaps. It’s part teen camp comedy, part heist, and part reminder that the X-Men aren’t the entire world, whether you’re a human, a mutant, or still too young to know.” Why has Kitty kept this early days story to herself until now? Find out in X-MEN GOLD ANNUAL #2, coming to comic shops this August! About the Author Richard Boom Richard is the driving force behind Comics for Sinners. His love and admiration for female comic book characters is virtually unparalleled, which immediately explains his biggest 'sin': his Hot Mummy fetish. This sketchbook theme is philogynistic in nature and even the source of his WIP comic book series "The Sisterhood". Comics for Sinners showcases the femmes fatales in comics through art, news and previews. That's right, we're here to spotlight the Bad Girls that put the 'pretty' in pretty pictures! Confess Thy Sin! Submit your favorite artwork or your story featuring gorgeous comics babes, cosplay photos or confessions to be featured on the site. Tell the WWWorld why you had a crush on Wonder Woman, why you dress up as Emma Frost, why you created thát specific comic, why you only play Tomb Raider, why you started reading Cavewoman or what your babe-infested monthly dose of comics entails… Send your confession to us at [email protected].

Q: Error handling with try/catch or eval while opening file in perl I have written simple code snippets, to handle an error occurring while opening the file in restricted(where we need root permission) following code works fine and gives an error as o/p #!/usr/bin/perl use strict; use warnings; use Try::Tiny; my $file_name = "/var/log/test.txt"; # needs root permission to create file if(open(HAN, ">$file_name")){ print "sucuessfully opened file \n "; } else { print "Error with if/else while openning file : $! \n"; } o/p: Error with if/else while opening file : Permission denied when i use try/catch or eval with same code and opens file try { open(HAN, ">$file_name"); } catch { print "Error with try/catch while opening file : $_ \n"; }; or eval { open(HAN, ">$file_name"); }; print " Error with eval while opening file : $@ \n"; it shows no output in $_ or $@, why this is happing? A: open does not throw an exception if it fails, it returns a false value and the error is stored in $!. Typical usage is therefore open my $fh, '>', $filename or die "Couldn't open '$filename' for writing: $!"; If you have a lot of I/O code, or other things that might throw exceptions, you might prefer than open (and other I/O functions) automatically throw an error on failure. You can do this with autodie: use autodie qw(:io); As @sputnick mentions, you should use warnings; in addition to use strict; Finally, here is an example of catching a I/O exception only: use warnings; use strict; use autodie qw(:io); use Try::Tiny; try { open my $fh, '>', $filename; ... more code ... } catch { if ($_->isa('autodie::exception') && $_->matches(':io')) { print "Error doing something with '$filename': $_\n"; } else { die $_; # rethrow } }; On Perl 5.10+, you can use given and when instead of this verbose code; see the autodie docs for more information.

6 A.3d 564 (2010) COM. v. ADAMS. No. 2776 EDA 2009. Superior Court of Pennsylvania. July 16, 2010. Affirmed.

Carl Theodor Dreyer Carl Theodor Dreyer (; 3 February 1889 – 20 March 1968), commonly known as Carl Th. Dreyer, was a Danish film director. He is regarded by many critics and filmmakers as one of the greatest directors in cinema. His best known films include The Passion of Joan of Arc (1928), Vampyr (1932), Day of Wrath (1943), Ordet (1955), and Gertrud (1964). Life Dreyer was born illegitimate in Copenhagen, Denmark. His birth mother was an unmarried Scanian maid named Josefine Bernhardine Nilsson, and he was put up for adoption by his birth father, Jens Christian Torp, a married Danish farmer living in Sweden who was his mother's employer. He spent the first two years of his life in orphanages until his adoption by a typographer named Carl Theodor Dreyer, and his wife, Inger Marie (née Olsen). He was named after his adoptive father, but in accordance with Danish practice, there is no "Senior" or "Junior" added to their names to distinguish them from each other. His adoptive parents were emotionally distant and his childhood was largely unhappy. He later recalled that his parents "constantly let me know that I should be grateful for the food I was given and that I strictly had no claim on anything, since my mother got out of paying by lying down to die." But he was a highly intelligent school student, who left home and formal education at the age of sixteen. He dissociated himself from his adoptive family, but their teachings were to influence the themes of many of his films. Dreyer was ideologically conservative. According to David Bordwell, "As a youth he belonged to the Social Liberal party, a conservative group radical only in their opposition to military expenditures...'Even when I was with Ekstrabladet,' Dreyer recalled, 'I was conservative...I don't believe in revolutions. They have, as a rule, the tedious quality of pulling development back. I believe more in evolution, in the small advances.'" Dreyer died of pneumonia in Copenhagen at age 79. The documentary Carl Th. Dreyer: My Metier contains reminiscences from those who knew him. Career As a young man, Dreyer worked as a journalist, but he eventually joined the film industry as a writer of title cards for silent films and subsequently of screenplays. He was initially hired by Nordisk Film in 1913. His first attempts at film direction had limited success, and he left Denmark to work in the French film industry. While living in France he met Jean Cocteau, Jean Hugo and other members of the French artistic scene and in 1928 he made his first classic film, The Passion of Joan of Arc. Working from the transcripts of Joan's trial, he created a masterpiece of emotion that drew equally on realism and expressionism. Dreyer used private finance from Baron Nicolas de Gunzburg to make his next film as the Danish film industry was in financial ruin. Vampyr (1932) is a surreal meditation on fear. Logic gave way to mood and atmosphere in this story of a man protecting two sisters from a vampire. The movie contains many indelible images, such as the hero, played by de Gunzburg (under the screen name Julian West), dreaming of his own burial and the animal blood lust on the face of one of the sisters as she suffers under the vampire's spell. The film was shot mostly silent but with sparse, cryptic dialogue in three separate versions – English, French and German. Both films were box office failures, and Dreyer did not make another movie until 1943. Denmark was by now under Nazi occupation, and his Day of Wrath had as its theme the paranoia surrounding witch hunts in the seventeenth century in a strongly theocratic culture. With this work, Dreyer established the style that would mark his sound films: careful compositions, stark monochrome cinematography, and very long takes. In the more than a decade before his next full-length feature film, Dreyer made two documentaries. In 1955, he made Ordet (The Word) based on the play of the same name by Kaj Munk. The film combines a love story with a conflict of faith. Dreyer's last film was 1964's Gertrud. Although seen by some as a lesser film than its predecessors, it is a fitting close to Dreyer's career, as it deals with a woman who, through the tribulations of her life, never expresses regret for her choices. The great, never finished project of Dreyer's career was a film about Jesus. Though a manuscript was written (published 1968) the unstable economic conditions and Dreyer's own demands of realism together with his switching engagement let it remain a dream. Filmography Feature films Short films Good Mothers (Mødrehjælpen, 12 min, 1942) Water from the Land (Vandet på landet, 1946) The Struggle Against Cancer (Kampen mod kræften, 15 min, 1947) The Danish Village Church (Landsbykirken, 14 min, 1947) They Caught the Ferry (De nåede færgen, 11 min, 1948) Thorvaldsen (10 min, 1949) The Storstrom Bridge (Storstrømsbroen, 7 min, 1950) The Castle Within the Castle (Et Slot i et slot, 1955) Bibliography References External links Official website CarlDreyer.com (archived) In-depth article from 1951 on 'The Tyrannical Dane' Bibliography Thoughts on My Métier by Carl Theodor Dreyer Carl Th. Dreyer by Armond White Category:Danish screenwriters Category:Male screenwriters Category:Danish male writers Category:Silent film directors Category:Danish film directors Category:1889 births Category:1968 deaths Category:Danish adoptees Category:Film directors from Copenhagen Category:Deaths from pneumonia

Serendib Description "I didn't invite him. The idea was all my father's, my seventy-four-year-old father who had never been outside America and who suddenly thought that Sri Lanka, where I was a Peace Corps volunteer, would be a jolly place to visit." When John Toner, a retired Cleveland judge, decided on a whim in April 1990 to spend a month with his son in war-torn Sri Lanka, he was as much a stranger to his seventh - and last - child as he was to the hardships of life in a Third World country. Serendib chronicles the journey that follows as a father and son who have never been alone together live in close quarters, in the poorest of conditions - and replace awkwardness and distance with understanding and love. Along the way are the stories of John learning to eat with his fingers, bathing in a river alongside cows, and trading his wool trousers for a traditional sarong. We witness his coming face-to-face with a Hindu priest in a loincloth and his first encounter with the everyday violence of a country at war with itself. John watches with awe as students learn without computers, books, or even paper; he bonds with Sri Lankan children and learns, once again, how to give and how to play. Each new experience pushes Jim's father to face his fears - and brings him closer to his youngest son. Serendib offers a colorful, humorous, and touching account of multiple discoveries - of an old man exploring deep within himself, of a father and son finding each other, and of two cultures coming together on uncommon ground and awakening to the joy and hope of the life they share.

Journalism students from local universities have been rejected from TVB News’ summer internship programme. Staff from Baptist University, Shue Yan University and Chinese University confirmed with HK01 that their journalism students had not been accepted as interns. TVB Newsroom. File photo: Wikicommons. Shue Yan University Head of Department of Journalism and Communication Leung Tin-wai told Apple Daily that their students did not even get an interview. TVB said that the arrangement to split the eight intern places equally between Hong Kong and mainland university students is the usual practice. The company did not confirm the rejection of local journalism students to Apple Daily but said that the interview process for the internship had been partially completed. Last year, TVB News took on four local students for its internship programme, but at least two of them were not journalism students, HK01 reported. A ‘very sad thing’ Hong Kong Journalists Association (HKJA) Chairperson Sham Yee-lan told Apple Daily that news media had independent decision-making power, but should not forget Hong Kong students. HKJA vice Chairperson Shirley Yam also said that local news media should allocate intern places for local journalism students. “Do mainland students know Hong Kong better than Hong Kong students?” she asked. She also said that “it would be a very sad thing” if local journalism students could not practise journalism in Hong Kong. The news sparked much debate online, with one netizen saying, “when TVB stops taking local students, the number of students applying to journalism will fall, or even plummet.”

628 So.2d 773 (1993) George D. EUBANKS v. Jo Ann HALL. AV92000080. Court of Civil Appeals of Alabama. July 23, 1993. *774 D.E. Brutkiewicz, Jr., of Brutkiewicz Attorneys, Mobile, for appellant. Samuel N. Crosby and L. Brian Chunn of Stone, Granade, Crosby & Blackburn, P.C., Bay Minette, for appellee. THIGPEN, Judge. This is a malicious prosecution case. Jo Ann Hall filed suit against George D. Eubanks in September 1991, charging him with malicious prosecution and seeking $1 million in damages. She alleged that the complaint resulted from an arrest warrant which Eubanks had sworn against Hall, charging her with criminal charges, and that she sustained damages, including legal expenses, although the criminal proceedings terminated in her favor. Following a jury trial, the jury returned a verdict favoring Hall in the amount of $10,000, and the trial court entered a judgment accordingly. Eubanks appeals. Eubanks contends on appeal that the trial court erred in allowing certain testimony to be admitted at trial; that the trial court erred in denying his motion for a directed verdict; and that the trial court improperly refused to use his proffered jury instructions regarding punitive damages. At the outset, we note that jury verdicts are presumed to be correct. Uphaus v. Charter Hospital of Mobile, 582 So.2d 1140 (Ala.Civ.App.1991). Malicious prosecution actions, however, are not favored in law, and face stringent limitations. Uphaus, supra. The elements of an action for malicious prosecution are: "(1) a judicial proceeding initiated by the defendant; (2) the lack of probable cause; (3) malice on the part of the defendant; (4) termination of the judicial proceeding favorably to the plaintiff; and, (5) damages." Empiregas, Inc., of Elberta v. Feely, 524 So.2d 626, 627 (Ala.1988). Testimony adduced at trial reveals that Eubanks apparently was tried in an August 1991 criminal proceeding, and, according to Hall, her husband testified against Eubanks. There is testimony that afterwards, Eubanks reportedly threatened to "get" the witnesses who testified against him. Hall testified that approximately one month after Eubanks's trial, she and another woman were cleaning crabs on Hall's property on Tensaw Island when Eubanks's son and his cousin began travelling on the river, yelling obscenities. Hall testified that when she and the other woman got into a boat to bait the crab baskets in the river, Eubanks's son and nephew deliberately maneuvered close to Hall's boat, splashing Hall with water. She testified that Eubanks's son was on a "kneeboard" and was riding in the water behind the boat, and that at that time, they came so close that she believed that their boat would hit them. She stated that he fell from the kneeboard, and that she and the other woman drove the boat over to him and accused him of trying to run over them. They then told the boys that they were going to call the water patrol. At trial, Eubanks's nephew disputed Hall's version of events. Eubanks's nephew testified that after the alleged incident, he called the police for Eubanks's son, and that Eubanks's son told the police that Hall cursed them, and that there was a paddle and gun involved. The nephew also testified that Eubanks actually signed the complaint at the police's behest, because Eubanks's son and nephew were too young to sign the complaint. Although Hall was charged with harassment and menacing, the trial court granted Hall's motion for judgment of acquittal in September 1991, and Hall filed suit against Eubanks for malicious prosecution that same month. Eubanks first contends that the trial court erred in admitting, over his objection, testimony regarding his prior acts. Jerry Crowe, another witness in Eubanks's criminal trial, testified that after that trial, Eubanks harassed him in various ways, including discharging firearms near Crowe's house, making numerous phone calls to him, and by harassing him while driving. A person's character, when offered for the purpose of showing his conduct on a specific occasion, *775 may not be proven by evidence of his specific acts or conduct. Mayfield v. State, 591 So.2d 143 (Ala.Crim.App.1991); C. Gamble, McElroy's Alabama Evidence, § 26.01 (4th ed. 1991). Hall argues that Crowe's testimony was proffered not to show that Eubanks acted in conformity therewith in signing the complaint, but rather to establish Eubanks's malice towards the witnesses who testified against him at his criminal trial. Malice, for purposes of a malicious prosecution action, may be inferred from want of probable cause or it may be inferred from the circumstances surrounding and attending prosecution. Thompson v. Kinney, 486 So.2d 442 (Ala.Civ.App.1986). "This is because malice is incapable of positive, direct proof and must out of necessity be rested on inferences and deductions from facts which are heard by the trier of fact." Thompson at 445. The element of malice may be inferred from the conduct of the defendant if no other reasonable explanation exists for his actions. Johnson v. Smith, 503 So.2d 868 (Ala.Civ. App.1987). Therefore, Crowe's testimony was admissible for the narrow purpose of establishing Eubanks's malice towards the witnesses. Eubanks next contends that the trial court erred in refusing to grant his motion for a directed verdict. A directed verdict in favor of a defendant is proper only when there is no evidence to support one or more of the elements in the plaintiff's cause of action. Smith v. Wendy's of the South, Inc., 503 So.2d 843 (Ala.1987). Eubanks argues that Hall had failed to prove he lacked probable cause for instigating the judicial proceedings against Hall. Probable cause is the state of facts which would lead a person of reasonable prudence to honestly believe that the claims put forth in the prior suit would prevail. Empiregas, supra. The issue of probable cause must go to a jury when the material facts are in dispute, as in this case. Harris v. Harris, 542 So.2d 284 (Ala.Civ.App.1989). The question of probable cause being a jury question, the trial court properly refused Eubanks's motion for a directed verdict. Eubanks last contends that the trial court erred in refusing to give one of his jury instructions. Specifically, the trial court refused Eubanks's request to charge the jury that in order to award punitive damages, the jury must find by "clear and convincing evidence" that he lacked probable cause to instigate criminal proceedings against Hall. Eubanks cites Ala.Code 1975, § 12-21-12(a), in support of this contention; however, this section establishes the "substantial evidence" rule for testing the sufficiency of evidence in rulings by the trial court and does not apply to the instant case. It appears that Eubanks intended to cite Ala.Code 1975, § 6-11-20, as requiring that the absence of probable cause be proven by clear and convincing evidence in awarding punitive damages. We find, however, that this statute requires "clear and convincing evidence" only for awarding punitive damages in cases of oppression, fraud, wantonness, or malice. Ala.Code 1975, § 6-11-20(a). Nowhere does this statute require that the absence of probable cause be proven by the same standard. Moreover, we find that the issue of punitive damages was properly submitted to the jury. See Delchamps, Inc. v. Larry, 613 So.2d 1235 (Ala.1992). A court cannot be reversed for its refusal to give a charge that is not expressed in the exact and appropriate terms of the law. Johnston v. Byrd, 279 Ala. 491, 187 So.2d 246 (1966). The trial court instructed the jury that it must be "reasonably satisf(ied)" that Eubanks had no probable cause to instigate the action against Hall, and this was not reversible error. See also Alabama Pattern Jury Instructions, § 24.05. Based on the foregoing, we find that the judgment of the trial court is due to be affirmed. AFFIRMED. ROBERTSON, P.J., and YATES, J., concur.

Saddam Hussein gave £840,000 fortune to family of British father murdered in Alps massacre Saad Al-Hilli , 50, killed alongside wife, mother-in-law and a French cyclist Former Iraqi dictator said to have deposited the sum in a Swiss bank account in the name of Mr Al-Hilli’s father Mr Al-Hilli’s father Kadhim was once close to Saddam’s Ba’ath Party but later fled Iraq for Britain Saddam Hussain gave £840,000 to the family of the British engineer who was murdered with his wife in the Alps, it was claimed last night. The former Iraqi dictator is said to have deposited the sum in a Swiss bank account in the name of Saad Al-Hilli’s father. The claim, which apparently originated with German intelligence, adds a sensational twist to the baffling case. Scroll down for video Cash deposit: Iraqi dictator Saddam Hussein, left, is said to have deposited £840,000 into the bank account of murdered Saad Al-Hilli's (pictured right) father Kadhim Murder scene: Saad al-Hilli, his wife, Iqbal, and his mother-in-law were all killed in an isolated lay-by near Lake Annecy in Eastern France Mr Al-Hilli, 50, from Surrey was killed along with his wife Iqbal, 47, his mother-in-law and a French cyclist last month in an attack that left his seven-year-old daughter, Zainab, badly injured, and her four-year-old sister Zeena deeply traumatised. Mr Al-Hilli’s father Kadhim was once close to Saddam’s Ba’ath Party, but fell foul of the tyrant in the Seventies, and fled Iraq for Britain. The scene of the September 5 massacre – an isolated lay-by near Lake Annecy in Eastern France – is only an hour’s drive from Geneva where the money was deposited. Swiss prosecutor Dario Zanni believes the family may have been returning from there when ambushed. Tragedy: How the killings were reported at the time of the massacre It raises the possibility that Mr Al-Hilli had managed to gain access to the account, which is thought to have remained in his father’s name, and that this was known to his killer. The story was reported in the respected French newspaper Le Monde. It said that a French police source had revealed that the money’s source had been discovered by German intelligence agency BND. The agency’s operatives routinely monitored the flow of cash to and from Baghdad as Germany did more business with the Saddam regime than any other country. An intelligence source in Munich said last night: ‘They know the money trail, and they know how to follow it. They have spent decades monitoring money transactions between the West and Iraq. The BND is the first port of call in such circumstances.’ The BND said they had no comment on the report, saying: ‘We do not comment on operations.’ The Le Monde story was published under the headline: ‘The potential links between the Al-Hillis and Saddam Hussein.’ It said: ‘According to a French police source, the German secret service informed the gendarmerie’s anti-terrorist branch that there were links between the Al-Hilli family and Saddam Hussein’s fortune. ‘The tensions began after Saad Al-Hilli’s father [Kadhim] was struck off the list of beneficiaries of the former Iraqi dictator.’ It has always been suggested that Kadhim’s multi-million pound legacy – he died last year – led to conflict between Saad, who lived in Claygate, Surrey, and his brother Zaid who lives in nearby Chessington. However Zaid strongly denies there was any such feud. Close ties: Mr Al-Hilli's father Kadhim is believed to have been close to Saddam Hussein's Ba'ath Party but later fled for the UK Fall out: But Kadhim Al-Hilli fell out with Saddam in the seventies Shortly after his murder, it emerged that Saad Al-Hilli had put a block on his father’s will, which effectively stopped his brother from inheriting his share until ‘unknown’ disputes were resolved. But Le Monde says it was the money in the Swiss bank account – not the rest of the legacy – that may have caused friction between the two brothers. Swiss investigators discovered the secret account earlier this month, but according to Le Monde they didn’t make the link to Iraq. Mystery: It is still unknown why Saad Al-Hilli, his wife and 77-year-old Swedish mother-in-law were killed Specialist police were last week questioning Geneva-based bankers about the Al-Hillis’ assets, while financial records in countries including America have also been requested. Kadhim, a former factory owner, left Baghdad in the late Seventies with his wife, Fasiha, and two boys, after allegedly falling foul of the Ba’ath Party. The family settled in Pimlico, Central London, later moving to Surrey. Another theory is that Kadhim never fell out with the Ba’ath Party at all – and that he was simply managing many accounts for Saddam behind this smokescreen. Shortly before the dictator was executed in 2006, it was revealed that he withdraw around £620 million from the Iraqi central bank in 2003, which he had begun to hide around the world. The assets would have been added to millions already deposited in accounts in other countries – mainly through Iraqis who had moved abroad. Saddam is known to have concentrated large amounts in Switzerland and France, where he had at least two homes and moored a £17 million yacht. If Saad Al-Hilli was party to this secret information – and indeed the location of the hidden millions – then he would have been an obvious target for an attack. Eric Maillaud, the Annecy prosecutor leading the inquiry into the quadruple killing, said he had ‘not yet been informed’ about the intelligence from Germany. However he confirmed that Mr Al-Hilli’s financial affairs and his background in Iraq were at the top of subjects being investigated. Another theory previously mooted was that Mr Al-Hilli was targeted by Iranian spies desperate to get their hands on high-resolution satellite technology. The Briton was an expert in that field, and worked for Surrey Satellite Technology in Guildford. The family left their Europa campsite after two nights and moved to the La Solitude du Lac campsite, which overlooks Lake Annecy Peaceful spot: Walkers on the remote 3 km track to the scene of the attack outside the village of Chevaline where the Al-Hillis were murdered Emmanuel Ludot, a French lawyer who defended Saddam Hussein following his capture, admitted that the deposed regime still had funds in Swiss accounts, but said the notion of a ‘hidden fortune’ was fantasy. Zaid Al-Hilli has been questioned by police, but is being treated solely as a witness after denying any involvement in the slaughter. When asked about the Le Monde story, Zaid told The Mail on Sunday last night: ‘It’s all rubbish, they can speculate until they’re blue in the face to be honest with you.’ Further asked if his father had ever mentioned links to Saddam, he said: ‘We have no links with that regime. We live outside [Iraq] because of that regime, that’s why we have been here for 41 years.’ In a separate development, it emerged yesterday that Mr Al-Hilli made a desperate attempt to drive his family to safety under a hail of bullets, but his car got stuck on a verge. The gunmen then moved in to finish them off at close range. Investigators believe the killer was alone and used only one weapon, a pistol common in the Swiss army in the Twenties and Thirties. Grief: Family friends outside the Al-Hilli home in Claygate, Surrey, soon after the murders were reported Concern: The Al-Hilli's home in Claygate, Surrey. Speculation still surrounds the motive for the shootings in which three members of the family died Prayers: Saad Al-Hilli, 50, his wife Iqbal, 47, and her 74-year-old mother Suhaila Al-Allaf, were laid to rest in the same grave in Surrey Zainab told police she and her father were outside the car when the shooting started. Unable to get her into the car, he then attempted to escape in the vehicle with the rest of the family under fire. However, as he backed up to get away, the car became stuck on an embankment, leaving the family at the mercy of the killer who then shot the three adults, including Mr Al-Hilli’s mother-in-law Suhaila Al-Allaf in the head. While it is unclear when cyclist Sylvain Mollier was killed, it appears his body was hit by the Al-Hillis’ car during the attempted escape. After running out of ammunition, the killer pistol-whipped the older girl in the face, but was apparently interrupted and fled the scene. Additional reporting: Peter Allen and Ian Sparks Video: First witness on the scene describes finding victims of the shootings

Using tcpflow Sometimes, when you're writing applications that use a library to talk over the wire to a remote service, it's difficult to see how the high level API the library exposes translates into the on-the-wire protocol. Funnily enough, I was having that very problem yesterday, so I dug tcpflow out my toolbox to better understand what was happening. Sometimes, when you’re writing applications that use a library to talk over the wire to a remote service, it’s difficult to see how the high level API the library exposes translates into the on-the-wire protocol. Funnily enough, I was having that very problem yesterday, so I dug tcpflow out my toolbox to better understand what was happening. I was writing a client for the [REDACTED] (for now, at least!) API, for a client project. I’d decided to use this as an excuse to learn EventMachine and em-http-request to talk to the remote API. Given the pattern of use I’m expecting, a reactor-patterned daemon feels like a really good fit. It was a weird experience – it’s the first time I’ve done any reactor pattern development in anger since ~2004 when I was messing around with using Python’s Twisted framework for small TCP server applications. (Ah, them were the days, before HTTP became the hammer to everybody’s wire protocol thumb nail.) But I digress… I was having trouble understanding why the em-http-request requests I was making weren’t having the intended result. There were two specific problems I saw over the course of the day: The path I was sending in, according to the documentation, using request.get :path => '/api/v2/chickens.json', didn’t appear to be what was being requested (in that everything I requested looked like it was getting the same response as a request to GET /). After the initial request, subsequent requests reusing the same HttpRequest object would silently fail. This was slightly more bizarre. In solving either of these problems, I could have dived into the em-http-request source and traced what was happening. In fact, that was my first port of call but, being rusty at the reactor pattern, I was having trouble following the flow of execution. (As it turns out, if I’ve done this properly, I should have spotted the problem straight away, but we’ll get to that.) However, in this instance, I decided to treat the library I was using as a black box and instead examine what it was generating and consuming at the other end. Enter tcpflow. It’s been part of my arsenal of network debugging tools for as long as I can remember. It is similar to tcpdump, but that typically just shows you the IP packets on the wire. tcpflow attempts to reconstruct the actual TCP streams to give you an idea of the conversation going on. Let’s install it. I’m on a Mac, and I’m using Homebrew, so it’s just a case of: brew install tcpflow Your mileage may vary, but it’s a piece of software that’s been around for a long time, so I bet there’s a package for your system. If you’re using Homebrew, it will install the binary as your user and not setuid to root, which means that, in order to access the packet capture device, you’ll have to make sure and run it through sudo. The examples I show all have sudo in ‘em since that’s what I had to do. tcpflow uses libpcap as the underlying packet capture library, the very same one as is used by tcpdump. This means that the syntax for specifying the information you want to capture will be familiar if you’ve used that tool before. Last piece of background information before we get into solving the problems. You’ll need to figure out the network interface you’re using as that’s the interface it will capture packets from. Short version (since a longer version is out of scope!): if you’re on a Mac, it’s highly likely to be en0 if you’re on wired Ethernet and en1 if you’re on wireless. If you’re using Linux and you’re on a wired network, chances are it’ll be eth0. My Mac laptop is on a wireless network right now, so the examples show me using en1. Examine the output of ifconfig to determine your active network interface. So, that’s the theory, let’s see this thing in action. The first problem is that we’re not getting the response we’re expecting from making particular HTTP requests. Let’s see what’s happening on the wire with tcpflow: sudo tcpflow -c -n en1 src or dst host api.example.com Breaking that down: -c spits the flows out on stdout. The normal operation is to create a file for each flow, in each direction. If you’re capturing a lot of data, or pipelined conversations, files are much more sane, but for small conversations like this, stdout is really convenient. -n en1 is capturing from my wireless device, as discussed above. src or dst host api.example.com is the expression used to describe the flows that we want to capture. In essence, this is saying that we want to capture flows of data that are sent to, or received from, api.example.com. The language is pretty rich, allowing for a bunch of complex rules to narrow down the data captured, but I tend to find that specifying a remote host and/or port is enough. Let’s see what that gets us. I’ve created a Ruby script, the essence of which is: That’s annoying, because I’d specifically requested /api/v2/chickens.json, but it’s actually requesting / (the GET / HTTP/1.1 line). What’s with that? Well, it turns out that the published stable gem for em-http-request doesn’t actually implement the :path option; I need to install the beta 1.0 gem to get that. Oops. Moral of the story: if you’re going to read the source to the gem you’re using, read the source to the installed version you’re using, not just the latest version on GitHub! The second problem is a little more subtle. I got to the stage where the first request was working successfully, but subsequent requests reusing the same HttpRequest would fail miserably, just waiting for no response to occur. An example: Here we see the initial request, the response and the second request, but no response. That’s really weird. Isn’t it? Then I spotted something. Do you see the initial line of each flow, with a string of numbers? That’s the source IP and port, then the destination IP and port. Let’s break the first one apart: 172.017.012.012.54442-010.011.012.234.00080 which translates to: the client IP address is 172.17.12.12. That’s the internal IP of my laptop on my home network. the client TCP port is 54442. Both sides of a TCP connection get a port, and the client side usually has a random, unused, high port number chosen for it by the kernel. Each TCP connection gets a different client port, and they’re typically not reused for a while after you’re done with them. the server IP address is 10.11.12.234 which I cleverly remembered to change just now, lest you discover who [REDACTED] is. ;) the server TCP port is 80, the well known port for HTTP. Now, let’s look at the second request’s connection information: 172.017.012.012.54442-010.011.012.234.00080 Isn’t that interesting? They’ve both got the same client TCP port. Now, we’re not doing keepalive, and the server responded with Connection: close (which, sadly, it does, even if I do attempt to switch keepalive on). So, as far as the server’s concerned, the TCP session is done and it has closed the connection. But the client, em-http-request, hasn’t closed its end, and has decided to send another request along the same TCP connection. Since the server has already closed its side of the connection, it never sees the second request and, naturally, never responds. I hope this has served as a useful introduction to tcpflow. It’s a great tool for discovering what really happens on the wire when you’re using higher level APIs and libraries. It really comes into its own when the library is, say, closed source and you have to deal with it as a black box. There are plenty of higher level tools with GUIs that can help you with this kind of task too, but I really like that tcpflow does one thing and does it really well. Thanks, Jeremy!

Developmental trajectories and ecological transitions: a two-step procedure to aid in the choice of prevention and promotion interventions. The confluence of two different types of transitional processes is explored: human development and normative ecological transitions. There are periods of greater vulnerability than others in the developmental life course as well as particular normative ecological transitions that are more disruptive than others. When there is a confluence of developmental vulnerability and a disruptive ecological transition, a "turning point" in development may ensue. This can take the form of an opportunity for growth and development or a developmental mismatch. Consequently, such turning points may represent opportune times and places at which to launch prevention/promotion programs. A two-step analytic procedure, nomothetic analyses followed by idiographic analyses, is described and illustrated to test the utility of this framework. First, these issues are illustrated using the self-esteem trajectories of low-income, urban public school students making a normative school transition to a junior and senior high school. Second, new data are presented on the early adolescent self-esteem trajectories and their association with long-term psychopathology. Third, the significance of this two-step procedure is discussed in regard to several normative ecological transitions that are common when older adolescents make the developmental transition into adulthood (e.g., into full-time employment, marriage).

Retro Announcement Greetings Retro Friends! Your partners at ABC are excited to announce our updated New Member Online Sign Up. Your members and staff will enjoy the new look and feel of the online sign up process while you enjoy the comfort of knowing you don’t have to relearn the DataTrak Payment Plan process. That’s right. Other than a new look and feel, and some additional features you may choose to employ, you will manage your payment plans exactly the same way! This change will happen on Monday April 21, 2014. ABC will adjust the kiosk landing page, and we will work with Retro Corporate to change everyone’s Join Now pages on www.retrofitness.net. Here are some of the differences you will enjoy: 1. Online Sign Up is now mobile responsive! It will shrink appropriately to fit the size of the phone or tablet the member is using. 2. You will now have the ability to make any fields available on step 4 of 5 required in any payment plan 3. The payment summary now rolls all fees in each section into a single amount. This will be expandable so members can see exactly what they are paying for. 4. Notes as well as Terms and Conditions are also rolled up, and are expandable through clicking the designated link. 5. Rather than collecting the billing information for the down payment and asking if you want to use the same information as your method of recurring payment, we will collect the method of recurring payment, and ask the member if he or she wants to use the same information for your down payment. And the CVV code is now more sensibly labeled “Security Code”. 6. Signature Capture – we have the ability to turn on a signature field so you can have an actual signature. The member has the ability to sign the online agreement using a mouse, a finger or stylus (if using the iPad), or a digital pen (if using the Surface Pro). If you would like to turn this feature on, you simply need to contact tech support. 7. Limiting Pay at Counter to devices within the club – we have the ability to turn the Pay at Counter function off completely, turn it off outside the club environment, or leave it on for anyone. Because all clubs are used to have it available everywhere, we are leaving this setting as is. However, if you would like to have this adjusted, just contact tech support and we can show you how! As always, ABC is dedicated to providing superior software and support. And should you have any questions at all, do not hesitate to contact our Technical Support Help Desk at 1-877-222-5767. Thank you all so much! And GO RETRO!! ABOUT ABC FINANCIAL ABC Financial is the nation's leading software and payment processing provider for the health and fitness industry. We've been in business since 1981 and currently work with over 7,000 health clubs.

life | the taste of london (competition) it's that time of year again: taste of london is heading back to regent's park in a couple of weeks for the summer instament, and guess who's got a couple of spare tickets to give away to one lucky londoner? oh, only me! i'll be heading over on the opening day for a special preview of aeg's new documentary series tasteology, which will be presented this year as part of a four course "eat-along" screening. during the sessions, guests will receive a multi-sensory experience with links between film and the food being served, and my my, doesn't that sound absolutely *taste-y*! there's also a whole host of restaurants and artisan traders showing that i am beyond excited to get my *taste*buds around, none more so than mexican restaurants santo remedio (above) and molé taco bar, and that's before we even think about the drinks. last year we spent a lot of time hanging out in the laurent perriér tent, this year i'm keen to see what cans tin monkey have in store for me. i recently saw an ale called "first world problems" that i want to finally *taste*, so fingers crossed they've got that to hand! to give you a *taste* of what's in store this year, check out episode one of tasteology: source, for all the inspiration you need to enter the competition below. obvs this is only open to those in the uk, and all the ts&cs can be found at the very bottom of the page. good luck, and see you there! 1. Participants must be 18 years of age or older to enter and residents of the UK. 2. No purchase is necessary to take part in the promotion. 3. The Prize is a pair of Tickets to Taste of London 2016 for one date/session of your choice. 4. The winner will be selected at random. 5. The winners will be notified by direct message on Twitter. 6. The prize must be claimed/accepted within 48 hours of the date of notification. In the event of non-acceptance within the specified period the prize awarded will be re-allocated to the next randomly drawn entry. 7. The tickets will be available for collection from Taste of London AEG Ticket Desk. 8. The prize is as stated with no cash alternative in whole or in part and is non-transferable. 9. Any prize unclaimed after reasonable efforts from the Promoter to contact the winner will be distributed at Promoter’s discretion. 10. When you enter this competition you may be providing us with some personal information. This information will only be used to contact you if you win the prize. We will not share this information with anyone else. 11. The Promoter is AEG/Electrolux plc, Addington Way, Luton LU4 9QQ (Company registration number 2331516). 12. In the event of dispute, the Promoter’s decision is final and no correspondence will be entered into.

16.01.18 | film group – blog by Yang Hanzhang 杨汉章 (student, SZU) We did a short presentation today for Director Dayong that came to watch our pre-edit. He pointed out that the voice could connect the different clips. And if the voice is clear and concise, then the whole video will reflect this. With his input, we re-designed the structure of the video, and, together with Prof. Xin and Alex, we were trying to figure out what we wanted to convey to the audience. In the afternoon, we re-shot some clips, and added some scenes to the video based on this message that we are trying to convey. I hope we can get a full version tomorrow!

Haley Downin, pictured with parents Laurie and Leroy, scored 15 points and added a career-high 10 assists in the Cougars' 60-29 win over Northeast, and her free throw in the fourth quarter pushed her to 1,000 points in her Chesapeake career. Photo by Connie Raynor / Raynor Shine Events Posted Tuesday, January 8, 2019 7:59 am By Logan Hill In the first round of Chesapeake-Northeast girls basketball this season on January 4, Cougars senior Haley Downin led the way with 15 points and eclipsed the 1000-point mark for her career at Chesapeake, helping her team to a 60-29 victory over the Eagles. “It means a lot because beating our rival team really hypes up the school and gets our team hungry for more wins,” said Downin. With offense hard to come by early, Chesapeake etched out a 10-6 lead after one quarter, finishing the period on a basket from Downin, who stole a pass and finished with a layup at the other end as time expired. Both teams leaned on veteran leadership and playmaking to keep their teams in the game. Chesapeake upped their lead to 23-17 by halftime, with Downin leading all scorers with eight points. Northeast senior Ryleigh Nalley had seven points to lead the Eagles at half. For Chesapeake, the difference in scoring between the first half and the second half was almost night and day. The Cougars used a 25-10 third-quarter run to open up a lead that would prove to be insurmountable. Junior Ashley Chew chipped in 5 points and a steal in the final 15 seconds of the quarter to give Chesapeake a 21-point lead. With a fourth-quarter free throw attempt, Downin reached the 1000-point mark for her career with the Cougars. Downin and the Cougars closed the game on a 12-2 run, cementing the victory. She finished the game with a double-double of 15 points and a career-high 10 assists. Chew also recorded a double-double, grabbing 11 rebounds to go along with her 15 points. Senior Corinne Castle had 9 points and 13 rebounds, while Junior Morgan Gray recorded 9 rebounds. Senior Summer Smith notched 4 steals for the Cougars. Chesapeake moved to 8-1 with the victory. For the Eagles, Nalley, senior Divine Carter-Benson, and junior Allyson Willis led the way with 7 points apiece. Northeast fell to 6-3. After the game, Downin reflected on her personal achievement. “It’s an amazing achievement for me to reach because not many people reach that, so it’s cool to have a standout moment,” she said. Downin also mentioned that she was the second player to reach this milestone in the last two seasons, joining former Cougar standout Brooke Worrell. “Having two people within two years [reach 1000-points in a career] shows a lot of depth in our program.” Sections Zach Sparks Assistant Editor Zach Sparks joined The Voice Media Inc. in 2013. His responsibilities include writing and editing stories, taking photographs and delegating assignments to freelance writers. On the rare slow day, he will also tell bad jokes for entertainment.

The flag represents the golden eight-pointed star, the blazon of Robert René Cavelier de La Salle. The azure blue and the waves call to mind the St. Lawrence River as well as the Lachine Rapids and Canal. This flag was adopted on December 7, 1969 The arms were granted on June 4 1992 by the Canadian Heraldic Authority. They show a French merchant flag on the crest.Luc Baronian 10 June 2005 by Luc Baronian I took a photo of this flag in 1999 in a Montreal Urban Community building. I believe it is an older version than the one already on the website, which is based on a recent photo. Notice that the blue is much lighter, and the stripes much narrower. Several of the flags I saw in this building in 1999 seemed to be older flags. In fact, Beaudoin reports a 2:3 narrow stripe version with UN blue.

Fishing reels with various drag constructions are known in the art. However, earlier drag constructions have proven to be inefficient when a torque load is applied to the spool as a result of line being pulled from the reel. One prior art construction includes a plurality of brake pads and washers contained within the cylinder of the spool. Such a configuration does not provide effective and controlled drag for the spool. In other prior art constructions, unbalanced and uneven braking force is applied to the spool. These reels fail to perform efficiently when a torque load is applied to the spool. When line is pulled off of the spool and the line travels across the spool cylinder, torque force is applied to different areas of the spool.

Hi, My name is Sandy! If you are looking for a LOVE dog, look no further! I am a very sweet and pretty Cockapoo with a gorgeous sandy coat and great big brown eyes. I am a bit long in the tooth at 16, but very healthy, spayed and up to date on my shots. I am house trained and very well behaved. I weigh 25 pounds. I live in White Plains NY, but would happy to live where you do. Being a bit older, my current family situation is just not that good for me. It is a very busy household with all kinds of people coming and going. I would really prefer to be the center of attention in a quiet home with one or two adults. Ideally, I would love to be a lap dog for a senior or someone who stays home most of the time. My current owners are heartbroken to have to face the difficult decision to find me a new home, but they realize that my current environment is too stressful for me. I am left on my own a lot, and it makes me very sad because I love people and snuggling so much. Finding a quiet home with someone to adore me would be a dream come true. I will be rehomed with my veterinary records and all of my supplies. If you would like to offer me a good home, please fill out our online information form. Once received, my owners will contact you to arrange a mutually convenient time to meet me. If you have any questions about me, please call Debbie Moore toll free at (888) 720-3322. [button link=”http://petrehoming.net/adopt-a-pet/” size=”large” variation=”hotpink” align=”center”]Request to Meet Sandy Here![/button] Adoption fee will be waived for the right adopter. All supplies will be included. All About Sandy [one_half] Name of Pet: Sandy Location: , New York, White Plains Type of Pet: Dog Breed of Pet: Cockapoo Weight: 25 pounds Sex of Pet: Female[/one_half] [one_half_last] Age of Pet: 16 Spayed/Neutered?: Yes Health Problems: No Up To Date on Vaccinations: Yes Gets along with cats: Unknown Gets along with dogs: Yes Good with Children?: Yes House Broken or Litter Trained?: Yes Crate Trained?: Unknown Accessories Included: A cage leash and harness [/one_half_last] Sandy’s Personality Friendly Loyal Sandy’s Current Home Environment Busy and active household Sandy’s Favorite Toys, Foods, Activities? Sandy loves duck treats Sandy’s Perfect Adoptive Home Will Be: A more relaxed environment where sandy would be the center of attention. Request to Meet Sandy Here

Despite repeated denials from President Bush and others in his administration that the U.S. government does not engage in torture or hand over prisoners to nations that do, a number of eyewitness accounts and press reports contradict those White House assertions. After the Sept. 11, 2001 attacks on New York City and Washington, the Bush administration adopted a policy called “extraordinary rendition” that permitted the transfer of a small number of terrorist suspects to nations that employed brutal interrogation methods illegal in the U.S. In recent years, the government’s “rendition” policy has greatly expanded, with estimates placing the number of U.S.-held prisoners transferred to nations employing torture at 150. Those who have been subject to the policy include Maher Arar, a Canadian citizen who was detained in New York City and then sent to Syria, where he suffered months of torture before being released without charge. Another prisoner, Mamdouh Habib, accused of training several of the 9/11 hijackers, was held in the U.S.-run Guantanamo Bay, Cuba detention facility and later transferred to Egypt where he claims he was beaten and burned. A piece in the Feb. 8th edition of the New Yorker magazine by Jane Mayer, titled, “Outsourcing Torture,” details the rendition program and some of the allegations made against the Bush administration. Between The Lines’ Scott Harris spoke with Michael Ratner, president of the Center for Constitutional Rights and a principal attorney for prisoners being held at the Guantanamo U.S. Naval Base. Ratner expresses his grave concern about the rendition policy and the message sent to the world by the recent Senate confirmation of Alberto Gonzalez as the Bush administration’s new Attorney General. Michael Ratner: Well, we became aware of this really in December 2002; there were some articles in the Washington Post that the U.S. had a practice called “extraordinary rendition.” There’s always been a small practice of rendition even under President Clinton, where they pick up people in one country and then deliver them to another country for purposes, usually of criminal prosecution where??? they can’t get cooperation etc. That’s not a legal practice, but they did that in a handful of cases. After 9/11, it became apparent from certain news articles and other sources that they had a new practice called “extraordinary rendition.” It meant two things: They were going to do this on a broad basis to pick up people all over the world, essentially “disappeared” them from their homes, their communities or their countries — or from whatever country they were in — and take them to places where they would be subjected to interrogation through torture. The places they would take them to would be Egypt, Morocco; in the case we represent, Maher Arar, (is) a man taken to Syria, and some other countries. And they did that I think partly for two reasons: One is they claimed that there were techniques they didn’t want to use on people which were torture, and that somehow that would be legal if other countries did it and they didn’t. Of course, that’s not a good legal excuse, that’s aiding and abetting — and secondly what’s interesting, of course, is the U.S. wound up engaging in torture anyway. The first person we got that gave us a glimpse into it was a man named Maher Arar, he was coming back from Tunisia, a Canadian citizen on a transit flight at Kennedy airport. (He was) picked up at Kennedy, claimed to be a terrorist by the government of the United States, sent to Syria in one of those private Citation jets, which is what they do to deliver people all over the world, and tortured in Syria. Eventually because he was Canadian, because we knew he was there, because he was able to call his wife from Kennedy before he got taken out, we got him out after 10 months and 10 days from an underground prison cell. Since then, there’s been more and more documents of this practice. And the practice is not only nasty in the sense that it of course violates borders and is kidnapping, but it’s actually disappearing people and in many cases I think disappearing them for torture, and maybe never to be heard from again. For example, I don’t think people expected Arar, the man in Syria, ever to be heard from again. So it’s a major practice going on now. Our country has its hands really up to its elbows, if not higher, in this practice. Between The Lines: What is being done by human rights groups and your organization to challenge this practice? Michael Ratner: Scott, it’s been the hardest to get to. You know we have lawsuits pending on Guantanamo obviously on torture. We have a Freedom of Information Act case that we brought with a variety of other groups, Physicians for Human Rights, ACLU and others, to try to get to the bottom. Groups like — the investigations that were appointed by our government like the Schlesinger investigation and others. If you read those reports that came out, the CIA refuses to talk to anybody about what they were doing. If you look at the Gonzalez memos and all those other torture memos, those in some way were really essentially to allow the CIA to engage in certain practices of torture. In the rendition memos, the ones about extraordinary rendition, that were asked for by the (U.S. Senate) subcommittee in approving Gonzalez, the Judiciary Committee, never saw the light of day, so we don’t know what they say. This is a very, very hard area to get to, in some ways it’s the Achilles heel. It’s where the worst aspects of the utterly illegal, so-called, war on terror are occurring. Between The Lines: Alberto Gonzalez was just confirmed as the new U.S. attorney general. What message does it send to the world about America’s tolerance toward torture and future policies that are liable to come out of the Bush administration regarding torture? Michael Ratner: Well, it’s incredibly distressing. I mean, Alberto Gonzalez not only was the one who penned, authored and was responsible for the memo that called the interrogation practices or protections of the Geneva Conventions “obsolete” and other provisions, “quaint.” He was the one who said that Geneva should not apply to people picked up, and the humane provisions of Geneva should not apply. He is the one who was also involved in the famous memo from (Assistant Attorney General Jay S.) Bybee that defined torture so narrowly that everything you saw at Abu Ghraib would not be considered torture. And who still today insists that non-citizens, and I want to stress this, non-citizens held outside the United States are not protected from cruel, inhuman and degrading treatment — which is our lawyers’ word for essentially inhumane treatment, just a shade underneath torture. So that’s the man who has been confirmed. What message does it send? It sends two messages to me and I think to our allies and all over the world and to the human rights community. One is that we’re not only refusing to investigate and go up the chain of command in torture, but we are actually elevating the positions of the very torturers, and those involved in torture themselves. So Alberto Gonzalez is confirmed as attorney general. Judge Michael Chertoff is up for Homeland Security. His nomination (was) held up a little bit pending some of the memos. But he again was apparently involved in approving various techniques that I think constitute torture. You have Donald Rumsfeld being extended for four more years as the Dept. of Defense head, Secretary of Defense, and again he was deeply involved in the abuses. You have Lt. General Ricardo S. Sanchez, head of Iraq at the time of Abu Ghraib, head of the forces there being considered for a fourth star. So, we’re elevating the people, and in my view that makes all those people who are willing to elevate them, vote for them, think they should get their jobs, essentially complicit — if not in the torture itself — in the cover-up of the torture. A number of human rights groups have called for either an independent investigation, or special prosecutors to be appointed, on the grounds that Alberto Gonzalez is basically completely disqualified. Michael Ratner is president of the Center for Constitutional Rights and the co- author along with Ellen Ray of the book: “Guantanamo: What The World Should Know.”Contact the Center for Constitutional Rights by calling (212) 614-6464, or visit the Center’s website at www.ccr-ny.org.

Cyclic AMP and ethanol interact to control apoptosis and differentiation in hypothalamic beta-endorphin neurons. In this study we have determined the role of cyclic AMP on the function and differentiation of beta-endorphin (beta-EP) neurons in rat fetal hypothalamic cell cultures. Addition of Bt2cAMP or the cAMP elevating agent, forskolin, in cultures, dose and time dependently increased beta-endorphin secretion. The increased beta-EP secretion after Bt2cAMP or forskolin treatment was associated with proopiomelanocortin gene expression, enhanced neurite growth, and increased neuronal viability. Determination of internucleosomal cleavage of DNA by agarose gel electrophoresis revealed that apoptosis occurred in hypothalamic neurons during the first 6-8 days in culture. Addition of Bt2cAMP during this developmental period inhibited DNA degradation in hypothalamic neurons. Furthermore, incubation with various doses of ethanol, which is known to reduce intracellular levels of Bt2cAMP, increased DNA degradation in these cells. Ethanol-induced DNA degradation was blocked by concomitant incubation with Bt2cAMP. Histochemical identification of apoptotic cells following ethanol and Bt2cAMP treatments further revealed that apoptosis occurred in beta-EP neurons during the developmental period, and that ethanol increased and Bt2cAMP reduced apoptotic beta-EP cell numbers. These results suggest that ethanol neurotoxicity on beta-EP neurons during early neuronal differentiation involves an apoptotic process and that the cAMP signaling system plays an important role in controlling apoptosis and differentiation of the beta-EP neuronal system.

Human melanocytes are neural crest derived cells that perform a unique function in the skin. While they are a minority of the population of the epidermis, they are responsible for the majority of photoprotection of the skin from ultraviolet radiation (UVR) through the production and transfer of melanin to keratinocytes [1]. Melanocytes, or their stem cells, are also progenitor cells for the most deadly of skin cancers, melanoma, which arises as a step wise progression from benign, to minimally invasive, to metastatic tumor [2]. Paracrine factors, produced primarily by keratinocytes, but also by fibroblasts, control multiple melanocyte functions, including dendricity, migration, growth and pigmentation, and also regulate normal homeostasis of melanocytes in the skin. Disordered of these growth factors, their receptors, or signaling pathways, are implicated in melanoma progression, as well as in disordered pigmentation [3]. Therefore, discovery of new or novel paracrine factors, and defining receptors and signaling pathways stimulated by these factors, are important to understanding melanocyte regulation in the skin, and melanoma tumor progression. Semaphorins are a large family of proteins that were originally identified in the nervous system, and are critical regulators of axon guidance. During the last 5 years, numerous reports show that semaphorins and their receptors (Plexins and Neuropilins) are widely distributed and regulate multiple biologic processes, including cell adhesion and migration, neurite extension, immune function, organogenesis, and tumor progression. Our published and preliminary data show a previously unrecognized role for semaphorins in human melanocyte function. Semaphorin 4D and semaphorin 7A regulate multiple cellular processes in other cell types, including neurite outgrowth and retraction, tumor progression and immune modulation [4]. We are the first to show that semaphorin 4D (Sema4D) and semaphorin 7A (Sema7A) control melanocyte attachment, spreading and dendricity, which are critically important for normal skin pigmentation. Further, our data suggest a potential role for Sema4D and Sema7A in melanoma progression, because their cognate receptors (Plexin B1 and Plexin C1 respectively) are either reduced or absent in melanoma. Finally, our preliminary data indicate a novel role for Sema4D in downregulation of c-Met receptor activation, a receptor critically important for melanocyte cell growth, migration, differentiation, and melanoma progression. We hypothesize that Sema4D and Sema7A regulate melanocyte migration and dendrite formation through stimulation of intracellular signaling pathways that include the GTP binding proteins Ras, Rho, Rac, integrins and LIM kinase- cofilin pathways. We predict that effects of Sema7A are mediated by a balance between 1- integrin and cofilin activation. We predict that effects of Sema4D are mediated by a balance between c-Met receptor inhibition and Plexin B1 activation. Finally, we predict that loss of Plexin B1 and Plexin C1 expression contribute to melanoma progression through enhanced melanoma cell growth, migration, and survival due to loss of c-Met receptor inhibition and coflin activation, respectively. PUBLIC HEALTH RELEVANCE. Identification of new growth factors that regulate human melanocyte function is important for understanding pigmentation of the skin, and in the transformation of benign melanocytes to malignant melanoma. We have identified two proteins, Semaphorin 4D and Semaphorin 7A, which stimulate human melanocyte function through the receptors Plexin B1 and Plexin C1 respectively. Further, we show that both of these receptors are reduced or absent in melanoma cell lines, and, in the case of Plexin C1, in melanoma in vivo. The goal of this project is to define how Semaphorins signal through Plexin receptors, and to understand the mechanisms by which loss of Plexin receptor expression contributes to melanoma metastasis.

On a recent afternoon in Albuquerque, an unmarked SUV pulled into a gas station on the corner of a busy intersection. Detective Brian Sallee lifted a pair of binoculars and scanned a parking lot a quarter mile down the road. “Have a look,” he said, handing me the binoculars and pointing to a chain-link fence, two picnic tables, and a food truck outside a tire repair shop. In ten minutes, two Mexican nationals were going to conduct a $28,000 drug deal with an undercover officer. The sting operation was a collaboration between the Albuquerque Police Department Narcotics Squad, which Sallee heads, and a parallel unit from a city in southern New Mexico that I was asked not to name. Close to a dozen unmarked vehicles were scattered in parking lots and side streets within a quarter-mile radius of the tire shop. Dealers often employ counter-surveillance on bigger sales to detect law enforcement, so support teams risk ruining a sting and endangering an undercover agent if they monitor a scene too conspicuously. But they also need to be close enough to make an arrest or to intervene quickly if something goes wrong. The agents positioned with clear sightlines provided updates on a shared radio frequency to all law enforcement in the area. “What looks to be the two targets,” a voice said over the radio. “One in red shirt and jeans, one in a tan hat. They’re hangin’ outside near the table.” We were on the outer periphery of the operation, too distant to see the scene clearly without binoculars. “The gray SUV with dark-tinted windows and silver rims. One of the targets is in that vehicle right now.” To have the strongest possible legal case, the undercover agent had to see the drugs before his support team could make an arrest. Once he saw the product, he would give a signal. Something too common, like saying “OK,” or too unusual, like raising an arm in the air, might trigger a premature arrest or arouse the suspicions of the dealers. A man walked over to the SUV with silver rims. The radio buzzed: “U.C. is talking to target, he’s on the driver’s side.” Then it erupted: “He took his hat off. U.C. took his hat off. Hat is off, let’s go, move in.” Almost instantly two SUVs blocked the exit to the parking lot and three men in black tactical vests approached the targets’ vehicle on foot with guns drawn. The undercover officer, or U.C., and one of the suspects raised their hands, and the suspect inside the SUV opened the door and stepped out with his hands raised. Within seconds, a dozen agents were advancing on the scene from all directions. Four SUVs blocked the entrance to the lot, and a patrol car started diverting traffic. The targets were handcuffed and separated; the U.C. was also handcuffed to preserve his cover. The arrest took less than a minute. The Albuquerque Police Department executes stings involving multiple pounds of product and tens of thousands of dollars roughly once a month. Meth stings happen in Albuquerque far more often than stings for cocaine or any other drug. Two pounds of meth might sell wholesale for around $28,000, but Mexican cartels reduce costs by producing meth in Mexico, whereas cocaine is typically imported from countries south of Mexico. By diluting the purity of those two pounds of meth, lower-level distributors would then increase the quantity of meth and reap additional profits. If the process of dilution and resale happened several times, those two pounds might eventually become eight pounds and yield close to $150,000 in profit. “It’s hard to know how much we disrupt when we take off a few pounds of meth,” Sallee said. “There are estimates that even if we intercepted nine out of every ten loads, the cartels would still make money. And we’re not getting anywhere near ninety percent.” Mexican cartels have established almost total dominance in the production of meth in the past decade. In 2003, Sallee’s squad dismantled ninety labs in Albuquerque. In 2012, they hit only sixteen labs, and most of those were producing only an ounce or less. Fifteen years ago, narcotics squads would find converted trailers in the New Mexico desert being used to cook several pounds of meth. Now domestic production is mostly limited to micro-batches cooked by users. Smaller batches leave subtler clues. Detectives used to look for hundreds of empty boxes of Sudafed; now three or four might raise suspicion. A portable burner and a funnel in a backpack, a soda bottle filled with liquid and grayish powder, or empty boxes of matches and Sudafed all signal small-scale production. Smaller batches mean smaller stakes for law enforcement. Intercepting two pounds barely makes a dent in supply, so arresting someone cooking an ounce using the so-called “one-pot” method does virtually nothing to decrease the use and sale of meth. Superlabs—typically defined as operations with a production capacity of ten pounds or more per cook—have moved across the border to Mexico. Sallee and other law enforcement and federal agents I spoke with thought AMC’s dark drama Breaking Bad was a fairly accurate depiction of many aspects of meth in the American Southwest. The show captures the chemical expertise necessary to produce high-quality meth, the drug’s insidious capacity to infiltrate placid suburban communities, the use of front businesses to launder money, the devastating physical effects of the drug, and even the color blue as a signal for high-quality meth. What is less plausible is the premise that a disgruntled chemistry teacher could build a meth empire in Albuquerque and produce vast quantities of meth in a superlab hidden beneath an industrial laundry facility. “Maybe in the late eighties or early nineties something like that could have happened,” Sallee said. Since then, Mexican cartels have flooded New Mexico with cheap, high-quality product. While Breaking Bad does depict the power and reach of cartels, it overstates their readiness to use conspicuous violence on American soil and understates their vast and pervasive control of the market. Superlabs in the central Mexican state of Michoacan are estimated to produce one hundred pounds of meth per cook. That’s roughly $14,000,000 of wholesale product and many times more after multiple dilutions. And that’s only one cook from one superlab. Multiple superlabs cooking several times a month have flooded the Southwest with relatively cheap meth and have largely removed any incentive for significant production in the U.S. This means that any agency or task force attempting to seriously disrupt the supply and distribution of meth in the Southwest will eventually confront the Mexican cartels. * * * “See the scorpion, bro? That’s a cartel sign.” I was driving through a trailer park with a narcotics agent in Farmington, New Mexico, a town of fifty thousand an hour south of the Four Corners area. The palm-sized scorpion sticker was stuck on the back window of an old silver Cadillac. Most of the vehicles in the park were new trucks and SUVs, though average rents are just a few hundred dollars a month. The trailer park is a hotbed of cartel activity. The agent is part of a secretive multi-agency task force that operates in Farmington. The area is designated a HIDTA, or high-intensity drug trafficking area, which qualifies the task force for federal funding. While Sallee and the APD work a few cases that reach mid-level cartel members, much of their work targets small-scale street dealers and users. The Farmington task force has a more ambitious mandate: to dismantle and disrupt DTOs, or drug trafficking organizations. The agent I interviewed often works undercover, so he declined to have his name used in print. He looked like a guy who would not raise much suspicion if he tried to buy meth. His arms were thoroughly tattooed, his beard thick, and his baseball cap pulled low over his face. “Our guys tend to look like just your typical scumbag,” his boss said. As we drove slowly through the trailer park, the agent told me about the structure of the groups he penetrates. “Cartel members work in cells,” he said. “Usually three to five members per cell, and the cells work in isolation. It’s not unlike the structure of some terrorist groups. You’ll have one guy who handles the money, one in charge of the dope, one does the driving, one knows English.” I asked him to trace the path of a single shipment of meth from production to final sale. “Start in a superlab in Mexico, next it crosses the border, maybe stashed in a door panel or engine, and goes to a house in Phoenix. You and I, from here to Phoenix is a six-hour drive. They’ll take a ten-hour route with all these weird, small roads. These are passed-down routes. A lot of times they’ll have two cars: a load and a lookout. Something goes wrong, the lookout does everything he can to get pulled over and the load car drives on up the road.” He was reluctant to share specific tactics on gathering intelligence or logistical details of cells currently operating in the area. It was unlikely that any cell members would read this article, but cartels do keep lawyers and detectives on retainer to search public records for patterns in arrest warrants, listen to police scanners, and research the law enforcement personnel working narcotics in an area. The task force has an often-repeated mantra: there are ten ways to ruin a case. Talk about it, talk about it, talk about it…. So instead of talking about a particular case, he described a hypothetical family that was a composite of various actual cases. “Let’s imagine the fictitious Martinez family. They’ve been here for thirty years. Maybe they own a pump business. Some are dirty, some are clean. Maybe a clean family member will rent a trailer in his name. That guy has a sister, and her husband’s cousin is in one of these cells, and he ends up using the trailer. Some people in the family may not even know what’s going on. Maybe the utilities are in the name of another guy in the cell, but it’s a false name. They change names and phones all the time to be harder to track. We try to look at patterns, habits, schedules. These trailers keep operating hours like a normal business. Your average deal will last maybe a minute. They’ll have a guy that can count two or three thousand in a heartbeat, then you’re out of there.” Certain patterns are more obvious than others. If someone without a job pays cash for a $40,000 SUV or wires $600-$900 to Mexico every other day, he’ll arouse suspicion. But if the Martinez family is sufficiently large and accommodating, it could absorb tens of thousands of dollars in a few months without attracting attention. When a U.C. succeeds in penetrating a cell and his team makes an arrest, the goal is typically to persuade suspects to become confidential informants who will reveal incriminating information about higher levels of a cartel. Cartels protect against this threat in two ways. First, they’re structured to ensure that members of a cell know as little as possible. Cells work in isolation, rotate members every few months, and keep members ignorant of organizational levels above them. A cell member may have a name and phone number of a guy in Phoenix, but it’s likely that the name is false and that the number will be changed by the time a U.C. tries to contact him. If someone does know potentially damaging information, cartels may threaten to kill a family member in Mexico if he turns informant. Though these threats are sometimes credible, it’s hard to know when family members are actually in danger. “Everyone says, ‘Oh, they’ll kill my family if I talk.’ We try to do research and corroborate these claims, but it’s not always clear whether someone is telling the truth.” This difficulty reflects two problems raised by the use of informants. The information they provide is not always trustworthy, and extracting it sometimes endangers informants or their families. But without the evidence and leads they supply, most meth investigations would be impossible. One of the informants who works with the agent I met was a man in his early forties who asked to be called Paco. We met under the shade of a cottonwood in a parking lot behind a baseball stadium. He was born and raised in Farmington, and his family was known for making trouble in town. “Everyone knows us around here. We’re always doing something crazy, raising all kinds of hell.” Eight years ago, he had been driving to Phoenix every two weeks in a rental car and buying meth from a Mexican man in a motel. Paco got the money for the purchases from a cousin in Farmington. At first it was five or six thousand per trip, but gradually the amount increased until he was going to Phoenix with $35,000 in hundreds, fifties, and twenties and returning with over a pound of meth. His cousin in Farmington paid him with meth, so he never saw any profit from the deals. He packed the meth in Ziploc bags and put the bags in the bottom of a cooler for the drive from Farmington to Phoenix. Sometimes he’d take back roads through the Indian Reservation, but it was impossible to avoid major highways entirely. He’d been making the trip for over a year when he was pulled over. A search of the vehicle revealed over a pound of meth. The quantity of meth and the fact that he was transferring meth across state lines qualified the case for federal prosecution, which carries tougher mandatory minimum sentences. He was given a choice: serve thirty years or lead agents to his cousin. Paco had never liked his cousin. “He’s one of them bully types. One of them crazy ones. He’ll come to your house and kick your ass if you owe him twenty dollars.” Paco tipped off a police raid that caught his cousin with $80,000 in cash, several pounds of meth, and over two hundred firearms. He also arranged a sting to catch the seller at the motel in Phoenix. “These guys were in the next room doing video and voice surveillance. I had a wire and when they told me to go to the bathroom they came in and busted him. Two times in Phoenix them Mexican guys had Uzis. I’d make ‘em put the guns under the mattress before we did a deal.” Informants receive lighter sentences, but they also run considerable risks. Sergeant Phil Goodwin, Chief of the Farmington task force, said that an investigation is only effective if informants are kept safe. But Paco’s case illustrates some of the dangers informants inevitably face. “Everyone knew when I got busted, so some of my family don’t talk to me now cause of what happened. Most of ‘em won’t do nothing. But my cousin’s sons I worry about. He told ‘em he’d give $20,000 for my head.” During the discovery phase of a trial defense attorneys can demand access to possible witnesses who will testify against their clients. Though it’s illegal to share the names of informants with those they informed against, Paco claimed to know of corrupt lawyers who reveal the names of informants. Paco said that this happened twice in his case. “Two people know for sure. Lawyers told ‘em. And then there’s all these rumors and bullshit.” A few months before we met, Paco’s sister-in-law was stabbed eighteen times in a Farmington laundromat. He thinks that he was meant to be the target but that the assailant was too high on meth to realize she was attacking the wrong person. The attacker fled the scene and was eventually caught after crawling through the dog door of a suburban home, tracking blood throughout the house, and washing off in the Jacuzzi. His sister-in-law lived, but the incident prompted Paco to start planning a move to Colorado. But as part of his contract with police he must continue his work as an informant for an unspecified period. Working with informants also poses risks for law enforcement agents. “In general, you’ve got to treat C.I.s with some caution,” Goodwin told me. “They know some of our tactics, like how someone is wired. Maybe they’re a C.I. this week, but they could be a target next week. They could put someone in the trees to take photos when they meet one of us, and then one of my guys is exposed.” Goodwin’s team has found names and photos of agents in the homes of suspects while executing search warrants. They’ve also noticed increasing sophistication in the counter-surveillance methods cartels are using. “Meth is a billion-dollar industry. With that kind of money, you can afford to hire good people. They use ex-military guys, guys with professional training in surveillance techniques.” Goodwin has internalized certain habits of vigilance. He always locates exits when he enters any space. And he always sits facing the door in restaurants. He reveals as little as possible about his work, even to family members. The location of his office is undisclosed; not even other law enforcement agencies know where it is. He’s never told his wife where his office is located, and he never discusses work at home. If his kids are going down the driveway to get the mail, they lock the door behind them. Working undercover also requires certain skills and precautions. A dealer might offer a U.C. a hit of meth to seal the exchange. Declining without rousing suspicion demands a talent for improvisation. Sometimes a dealer will suddenly insist on changing the venue of a deal, leaving a U.C. without any backup in the area. “You’ve got to roll with it,” the bearded and tattooed U.C. who works with Paco told me. “Maybe you’re like, ‘Naw, man, come on, I told you I borrowed my mom’s car today and I gotta get it back to her. I don’t got time to go somewhere else.’ You gotta think about the role you’re playing. If I’m a baller, and somebody offers me a hit, then why wouldn’t I take it? I don’t need the money I could make from selling it. But maybe I’m not a baller. Maybe I need that money.” Spending time around C.I.s makes it easier for a U.C. to pick up the slang of meth and its users. There’s a teener, an eightball, a gram. You slam it or you smoke it. On the phone, you might ask for a six-pack of coke to initiate a purchase. But knowing the language and playing a part hasn’t made him overly sympathetic to users. “You hear all sorts of stories and excuses for how someone’s life ended up with them selling and using. But the truth is never arbitrary. You can’t bend it to fit your beliefs. No, dude, you’re a drug dealer. Own it and let’s move on.” The investigations that Goodwin and his team build have resulted in substantial seizures. The largest amount they ever confiscated was eleven pounds of meth, close to $700,000 of product. This hit dismantled a midlevel rung of a cartel, but the effect was only temporary. Even midlevel cartel members are somewhat expendable. “The higher-level people,” Goodwin said, “they’re going to be somewhere else.” * * * Paul Chavez works in a bland office building in southeast Albuquerque. The area was meant to be a suburb of twenty-five thousand homes, but the developers ran out of money. Dirt roads are still carved into the desert hills, but only a few buildings interrupt the landscape. Dust storms and tumbleweed blow through every afternoon. Chavez is the Intelligence Director for the HIDTA-funded Investigative Support Center. He leads a team of analysts who support investigations by the DEA and various narcotics task forces. His team doesn’t gather intelligence in the field; they do research and analysis to support the investigations of the DEA and special task forces throughout the Southwest. His job is to notice the subtle clues and patterns that agents in the field often miss. He worked in the field as a detective with the APD for many years, but eventually he became bored with the work. One time he was in the parking lot of a bar with some other narcotics agents. They all wore black vests with the word POLICE printed across the front. Despite the vests, a guy walked up and tried to sell them hash. “With some of the low-hanging fruit, you’re dealing with people so stupid it just gets boring. From the hunter and hunted perspective, this work is much more interesting,” he said. Chavez was reluctant to discuss an active investigation, so he told me an intricate story that is a composite of real meth cases. He asked me to imagine a guy in Albuquerque named Joe. Joe is one of the five biggest dealers in the city. “Joe drives a Honda Civic and has a fat wife, and he’s probably messing around with someone else on the side.” He lives in a modest house in a middle-class neighborhood. He owns at least one tire repair shop, a cash-heavy business that makes it easy to invent receipts and launder money. “Guys with blinged-out SUVs and fancy houses, they’re not too smart.” If Joe is smart, he always pays cash to his supplier, a guy in Los Angeles. “Most drug violence happens because of fronted dope. Maybe somebody vouches for Joe, so the cartel guy in L.A. gives him $50,000 of meth. Say Joe is unlucky. His lieutenant gets pulled over and loses the meth. If Joe can’t repay that $50,000, he gets beat up and never sold to again. If it’s more money, maybe he gets killed.” For a $50,000 investment, Joe gets two kilos (4.4 lbs) of meth. From that quantity he can make $120,000, netting $70,000 in profit. Joe’s meth is made in a superlab concealed in a small warehouse in Michoachan. The two largest deep-water ports in Mexico are in Michoachan, which makes it easier to unload precursor chemicals shipped from India or China. The Knights Templar cartel controls the lab, which required several hundred thousand dollars of initial investment. The lab produces 50 kilos a week and is run by two guys, one with a degree in chemical engineering and another with a decade of experience cooking meth. Once the 50 kilos leave the lab, they must pass through the territory of the cartel Pacifico Sur and the Sinaloa cartel. The 50 kilos are divided into five loads of ten kilos, each of which pays a $7,000 tax at each of four tax points. The loads end up in the hands of a Tijuana cartel that specializes in smuggling drugs across the border. To make the crossing, the cartel might try to bribe a customs official with the lure of $10,000 a week. For someone making $31,000 per year, this is often an irresistible offer. If a bribed official is working the day of the crossing, the driver might get a call telling him to be in lane six between one and two PM on Saturday. Without a bribed official, a halcyon, or eagle, will watch the entry point with binoculars for patterns and opportunities. If he notices the official in lane four is fighting with his wife on the phone and waving all the cars through without inspection, he’ll radio this information to the driver. The shipments are taken to a stash house in a suburb of Los Angeles controlled by a high-level member of the Michoachan cartel. From the stash house, they are shipped around the country. Joe knows very little about his source in L.A. If the source in L.A. is smart, he doesn’t deal directly with Joe; an assistant handles all transactions with distributors. Joe was introduced to the assistant by his brother’s friend, who served time with him in prison. After Joe’s initial investment of $50,000 yields a profit of $70,000, he reinvests the money, ordering four kilos this time. Joe has six to ten employees. They sell to the street level dealers who sell to the end users, but these employees are not users themselves. If they start using meth, they are no longer employees. If Joe is smart, his employees never meet him. They don’t know his phone number or where he lives or even his real name. Joes delegates all interactions with these employees to a single trusted associate, an old childhood friend. His employees are not allowed to spend money in extravagant or obvious ways. They drive old cars and live in normal neighborhoods. The DEA wants Joe and his supplier in California. The APD focuses on street level dealers and users. They both target Joe’s six to ten employees, but the DEA wants them only as a means to getting Joe. One day Joe’s trusted associate gets pulled over on a routine traffic stop. The arresting officer follows a hunch and calls in a canine search unit that happens to be in the area. They find a few ounces of meth in the car and detain him for twenty four hours. By the time the DEA interrogates him, they’ve learned from Chavez’s unit that his mom is dying of cancer. They tell him it would be a shame for him to spend the last months of her life in prison. There’s a way for that not to happen: he just needs to tell them about his friend Joe. Joe will try to kill his associate if he knows he’s facing a life sentence. The associate doesn’t return Joe’s calls for the twenty-four hours that he’s in detention, and Joe starts to get suspicious. The associate tells Joe that he ran into an old buddy and went fishing at Lake Huron. But if Joe knows a corrupt clerk at the Metropolitan Detention Center he can confirm that the associate was actually there. If he learns this, he kills the associate. If not, maybe Joe goes to prison. “There might be five to seven Joes in Albuquerque at any given time. Three to four of those are probably on our radar.” Chavez might identify a Joe after becoming suspicious that a tire repair shop reported 2.4 million in revenue to the IRS. The IRS might mount a pole camera across the street from the shop to monitor the volume of customers, but if Joe is smart he’ll have his friends come by the garage regularly to create the appearance of a thriving business; they’ll close the door and have a beer. “The longer Joe goes without getting caught doesn’t necessarily mean it’s more likely that he will. I guarantee there are Joes who have made eight to ten million and are now retired and living quietly in Albuquerque. The smarter Joe is, the more insulated he is from the effects of what he does. There may be a turf dispute between two small dealers in the southeast part of town. He reads the next morning in the paper that somebody got shot and he thinks, ‘God, that part of town is going to shit.’ He doesn’t know it was his meth they were selling. The supplier in California will be similarly insulated. The California supplier is high-level cartel. If he’s a genius, we’ll never catch him. He’ll be surrounded by too many expendables who don’t know anything about him.” * * * One of the people Joe would never hear about is Cassie Johnston. She grew up in a small town about twenty miles south of Albuquerque. She first tried meth as a fifteen-year-old in the welding shop at Los Lunas High School. Her first time was terrifying: “It scared the crap out of me. I couldn’t sleep, eat, or concentrate for thirty six hours. I went home and pretended to sleep but I felt like I was going ninety miles per hour in neutral.” About six months later she tried it again at a party and liked it more. After that she used meth once or twice a week until she graduated from high school. “I pawned things, I had a job, but it’s not expensive or hard to get meth.” Initially her parents attributed her erratic behavior to typical teenage rebelliousness. Two days after graduating, she disappeared, and they didn’t hear from her for several months. She’d moved in with her boyfriend, a small-time dealer who supplied her habit free of charge. Soon she was delivering meth to his clients. “I sold drugs to PTA moms, doctors, lawyers, high school teachers, all kinds of people. Meth is not biased. It doesn’t care who you are, how much money you have, what your parents do. It will kill you just as quick as anything else.” One day her boyfriend went to Albuquerque and never returned. She knew he had borrowed money from the Mexican guys who supplied his meth, and she figured he had lost the money and fled the area before they could find him. About three weeks later she walked to a gas station a mile from her house. In the parking lot, three Mexican guys told her to get into a black Buick. One had a gun in his waist band. They drove her to a warehouse and locked her inside. A mattress and a jug of water sat in one corner. The next day they returned and explained that she would sell meth until she had worked off her boyfriend’s debt. Each day she drove out on deals with one of the Mexicans tailing her in the black Buick and collecting all the money she made. Each night, she was locked in the warehouse. Her diet was bread, apples and water. The Mexican guys also gave her as much meth as she wanted. She was rescued after about a month when her dad spotted her in town and called a detective friend. They lost the tail car and took her home. She stashed her car in a hidden spot and didn’t leave her parent’s house for a month. When she was rescued she weighed only 97 pounds, down from 135 pounds before. Cassie has not used meth since 2007. She never heard from her old boyfriend again, and she has cut herself off from almost all of the people she knew while using. She works as a massage therapist and a counselor for a teen therapy program. She still has cravings for meth, but they’re not as powerful as they were during her first two years after quitting.She thinks of herself as an example of the indiscriminate destruction meth causes. “I’m total proof that kids are not just the product of their environment. I grew up with two parents, nev er wanted for a thing, went to church once a week. I still did it.” Current and former users tend to describe meth as an almost supernatural force, something with a limitless power to harm and destroy. Even after recovery, former users remain vulnerable. The mother of one addict lost her son after he had been clean for almost two years. He died of heart complications that were a legacy of meth’s impact on his health. An informant in Albuquerque summed up the feelings of many users and family members whose lives have been disrupted by meth: “If you believe in heaven and hell and good and bad, then one thing’s for sure: meth is the Devil’s drug.”

--- abstract: 'Let $f$ be a holomorphic cusp form of weight $k$ with respect to $SL_2(\mathbb{Z})$ which is a normalized Hecke eigenform, $L_f(s)$ the $L$-function attached to the form $f$. In this paper, we shall give the relation of the number of zeros of $L_f(s)$ and the derivatives of $L_f(s)$ using Berndt’s method, and an estimate of zero-density of the derivatives of $L_f(s)$ based on Littlewood’s method.' author: - | Yoshikatsu Yashiro\ Graduate School of Mathematics, Nagoya University,\ 464-8602  Chikusa-ku, Nagoya, Japan\ E-mail: [email protected] title: '**Distribution of zeros and zero-density estimates for the derivatives of *L*-functions attached to cusp forms**' --- [^1] [^2] Introduction ============ Let $f$ be a cusp form of weight $k$ for $SL_2(\mathbb{Z})$ which is a normalized Hecke eigenform. Let $a_f(n)$ be the $n$-th Fourier coefficient of $f$ and set $\lambda_f(n)=a_f(n)/n^{(k-1)/2}$. Rankin showed that $\sum_{n\leq x}|\lambda_f(n)|^2=C_fx+O(x^{3/5})$ for $x\in\mathbb{R}_{>0}$, where $C_f$ is a positive constant depending on $f$ (see [@RAN (4.2.3), p.364]). The $L$-function attached to $f$ is defined by $$\begin{aligned} L_f(s)=\sum_{n=1}^\infty\frac{\lambda_f(n)}{n^s}=\prod_{p\text{:prime}}\left(1-\frac{\alpha_f(p)}{p^s}\right)^{-1}\left(1-\frac{\beta_f(p)}{p^s}\right)^{-1} \quad (\text{Re }s>1), \label{4LD}\end{aligned}$$ where $\alpha_f(p)$ and $\beta_f(p)$ satisfy $\alpha_f(p)+\beta_f(p)=\lambda_f(p)$ and $\alpha_f(p)\beta_f(p)=1$. By Hecke’s work ([@HEC]), the function $L_f(s)$ is analytically continued to the whole $s$-plane by $$\begin{aligned} (2\pi)^{-s-\frac{k-1}{2}}\Gamma(s+\tfrac{k-1}{2})L_f(s)=\int_0^\infty f(iy)y^{s+\frac{k-1}{2}-1}dy, \label{4AC}\end{aligned}$$ and has a functional equation $$\begin{aligned} L_f(s)=\chi_f(s)L_f(1-s)\end{aligned}$$ where $\chi_f(s)$ is given by $$\begin{aligned} \chi_f(s)=&(-1)^{-\frac{k}{2}}(2\pi)^{2s-1}\frac{\Gamma(1-s+\frac{k-1}{2})}{\Gamma(s+\frac{k-1}{2})} \notag\\ =&2(2\pi)^{-2(1-s)}\Gamma(s+\tfrac{k-1}{2})\Gamma(s-\tfrac{k-1}{2})\cos\pi(1-s). \label{4XFE}\end{aligned}$$ The second equality is deduced from the fact $\Gamma(s)\Gamma(1-s)=\pi/\sin(\pi s)$ and $\sin\pi(s+(k-1)/2)=(-1)^{k/2}\cos\pi(1-s)$. Similarly to the case of the Riemann zeta function $\zeta(s)$, it is conjectured that all complex zeros of $L_f(s)$ lie on the critical line $\text{Re }s= 1/2$, namely, the Generalized Riemann Hypothesis (GRH). In order to support the truth of the GRH, the distribution and the density of complex zeros of $L_f(s)$ are studied without assuming the GRH. Lekkerkerker [@LEK] proved the approximate formula of a number of complex zeros of $L_f(s)$: $$\begin{aligned} N_f(T)=\frac{T}{\pi}\log\frac{T}{2\pi e}+O(\log T), \label{ML0}\end{aligned}$$ where $T>0$ is sufficiently large, and $N_f(T)$ denotes the number of complex zeros of $L_f(s)$ in $0<{\rm Im\;}s\leq T$. The formula (\[ML0\]) is an analogy of $N(T)$ which denotes the number of complex zeros of $\zeta(s)$ in $0<{\rm Im\;}s\leq T$. Riemann [@RIE] showed that $$\begin{aligned} N(T)=\frac{T}{2\pi}\log\frac{T}{2\pi e}+O(\log T). \label{Z0A}\end{aligned}$$ (Later von Mangoldt [@VOM] proved (\[Z0A\]) rigorously.) In the Riemann zeta function, the zeros of derivative of $\zeta(s)$ have a connection with RH. Speiser [@SPE] showed that the Riemann Hypothesis (RH) is equivalent to the non-existence of complex zero of $\zeta'(s)$ in $\text{Re }s<1/2$, where $\zeta'(s)$ denotes the derivative function of $\zeta(s)$. Levinson and Montgomery proved that if RH is true, then $\zeta^{(m)}(s)$ has at most finitely many complex zeros in $0<\text{Re }s<1/2$ for any $m\in\mathbb{Z}_{\geq0}$. There are many studies of the zeros of $\zeta^{(m)}(s)$ without assuming RH. Spira [@SP1], [@SP2] showed that there exist $\sigma_{m}\geq(7m+8)/4$ and $\alpha_{m}<0$ such that $\zeta^{(m)}(s)$ has no zero for ${\rm Re\;}s\leq\sigma_{m}$ and ${\rm Re\;}s\leq\alpha_m$, and exactly one real zero in each open interval $(-1-2n,1-2n)$ for $1-2n\leq\alpha_m$. Later, Y[i]{}ld[i]{}r[i]{}m [@YIL] showed that $\zeta''(s)$ and $\zeta'''(s)$ have no zeros in the strip $0\leq\text{Re\;}s<1/2$. Berndt [@BER] gave the relation of the number of complex zeros of $\zeta(s)$ and $\zeta^{(m)}(s)$: $$\begin{aligned} N_m(T)=N(T)-\frac{T\log 2}{2\pi}+O(\log T), \label{ZMA}\end{aligned}$$ where $m\in\mathbb{Z}_{\geq1}$ is fixed and $N_m(T)$ denotes the number of complex zeros of $\zeta^{(m)}(s)$ in $0<{\rm Im\;}s\leq T$. Recently, Aoki and Minamide studied the density of zeros of $\zeta^{(m)}(s)$ in the right hand side of critical line ${\rm Re\;}s=1/2$ by using Littlewood’s method. Let $N_m(\sigma,T)$ be the number of zeros of $\zeta^{(m)}(s)$ in $\text{Re\;}s\geq\sigma$ and $0<\text{Im\;}s\leq T$. They showed that $$\begin{aligned} N_m(\sigma,T)=O\left(\frac{T}{\sigma-1/2}\log\frac{1}{\sigma-1/2}\right), \label{MME}\end{aligned}$$ uniformly for $\sigma>1/2$. From (\[ZMA\]) and (\[MME\]), we see that almost all complex zeros of $\zeta^{(m)}(s)$ lie in the neighbourhood of the critical line. The purpose of this paper is to study the corresponding results of Berndt, Aoki and Minamide for the derivatives of $L_f(s)$, namely, the relation between the number of complex zeros of $L_f(s)$ and that of $L_f^{(m)}(s)$, and the density of zeros of $L_f^{(m)}{(s)}$ in the right half plane ${\rm Re\;}s>1/2$. Let $n_f$ be the smallest integer greater than 1 such that $\lambda_f(n_f)\ne0$. Here $L^{(m)}_f(s)$ denotes the $m$-th derivative of $L_f(s)$ given by $$\begin{aligned} L_f^{(m)}(s)=\sum_{n=1}^\infty\frac{\lambda_f(n)(-\log n)^m}{n^s}=\sum_{n=n_f}^\infty\frac{\lambda_f(n)(-\log n)^m}{n^s} \quad (\text{Re }s>1),\end{aligned}$$ Differentiating both sides of (\[4AC\]), we find that $L^{(m)}_f(s)$ is holomorphic in the whole $s$-plane and has the functional equation: $$\begin{aligned} L^{(m)}_f(s)=\sum_{r=0}^m\binom{m}{r}(-1)^{r}\chi_f^{(m-r)}(s)L_f^{(r)}(1-s). \label{4DFE}\end{aligned}$$ First in order to achieve the above purpose, we shall show the zero free regions for $L_f^{(m)}(s)$ by following Berndt’s method (see [@BER]) and Spira’s method (see [@SP1], [@SP2]). \[THM0\] The following assertions hold for any $m\in\mathbb{Z}_{\geq0}$. (i) \[LRZF\] There exists $\sigma_{f,m}\in\mathbb{R}_{>1}$ such that $L_f^{(m)}(s)$ has no zero for ${\rm Re\;}s\geq\sigma_{f,m}$. (ii) \[LLZF\] For any $\varepsilon\in\mathbb{R}_{>0}$, there exists $\delta_{f,m,\varepsilon}\in\mathbb{R}_{>(k-1)/2+1}$ such that $L_f^{(m)}(s)$ has no zero for $|s|\geq\delta_{f,m,\varepsilon}$ satisfying ${\rm Re\;}s\leq -\varepsilon$ and $|{\rm Im\;}s|\geq \varepsilon$. (iii) \[LOZF\] There exists $\alpha_{f,m}\in\mathbb{R}_{<-(k-1)/2-1}$ such that $L_f^{(m)}(s)$ has only real zeros for ${\rm Re\;}s\leq\alpha_{f,m}$, and one real zero in each interval $(n-1,n)$ for $n\in\mathbb{Z}_{\leq \alpha_{f,m}}$. Next, based on Berndt’s proof, we can obtain the following formula of the numbers of complex zeros of $L_f^{(m)}(s)$: \[THM1\] For any fixed $m\in\mathbb{Z}_{\geq1}$, let $N_{f,m}(T)$ be the number of complex zeros of $L_f^{(m)}(s)$ in $0<{\rm Im\;}s\leq T$. Then for any large $T>0$, we have $$\begin{aligned} N_{f,m}(T)=\frac{T}{\pi}\log\frac{T}{2\pi e}-\frac{T}{2\pi}\log{n_f}+O(\log T).\end{aligned}$$ Moreover the relation between $N_f(T)$ and $N_{f,m}(T)$ are given by $$\begin{aligned} N_{f,m}(T)=N_{f}(T)-\frac{T}{2\pi}\log{n_f}+O(\log T).\end{aligned}$$ Finally using the mean value formula for $L_f^{(m)}(s)$ obtained in [@YY3] and Littlewood’s method, we obtain the estimate of density of zeros: \[THM2\] For any $m\in\mathbb{Z}_{\geq0}$, let $N_{f,m}(\sigma,T)$ be the number of complex zeros of $L_f^{(m)}(s)$ in ${\rm Re\;}s\geq\sigma$ and $0<{\rm Im\;}s\leq T$. For any large $T>0$, we have $$\begin{aligned} N_{f,m}(\sigma,T)=O\left(\frac{T}{\sigma-1/2}\log\frac{1}{\sigma-1/2}\right) \label{ZD2}\end{aligned}$$ uniformly for $1/2<\sigma\leq 1$. More precisely we have $$\begin{aligned} &\hspace{-12pt}N_{f,m}(\sigma,T)\notag\\ \leq& \displaystyle\frac{2m+1}{2\pi}\frac{T}{\sigma-1/2}\log\frac{1}{\sigma-1/2}+\frac{1}{2\pi}\frac{T}{\sigma-1/2}\log\frac{(2m)!n_fC_f}{|\lambda_f(n_f)|^2(\log n_f)^{2m}}+ & \notag\\ &+O(\log T)+\frac{1}{2\pi}\frac{T}{\sigma-1/2}\times & \notag\\[9pt] &\times\begin{cases} \displaystyle\log\left(1+O\left(\frac{(2\sigma-1)^{2m+1}(\log T)^{2m}}{T^{2\sigma-1}}\right)\right), & 1/2<\sigma<1, \\ \displaystyle\log\left(1+O\left(\frac{(2\sigma-1)^{2m+1}(\log T)^{2m+2}}{T}\right)\right), \hspace{6pt} & \sigma=1,\\ \displaystyle\log\left(1+O\left(\frac{(2\sigma-1)^{2m+1}}{T}\right)\right), & 1<\sigma<\sigma_{f,m}, \end{cases} \label{ZD1}\end{aligned}$$ where $\sigma_{f,m}$ is given by (\[LRZF\]) of Theorem \[THM0\]. Proof of Theorem \[THM0\] ------------------------- First in order to show , we write $L_f^{(m)}(s)=\lambda_f(n_f)(-\log n_f)^m F(s)n_f^{-s}$ where $$\begin{aligned} F(s)=1+\sum_{n=n_f+1}^\infty\frac{\lambda_f(n)}{\lambda_f(n_f)}\left(\frac{\log n}{\log n_f}\right)^m\left(\frac{n_f}{n}\right)^s \quad ({\rm Re\;}s>1). \label{FFF}\end{aligned}$$ Deligne’s result $|\lambda_f(n)|\leq d(n)\ll n^\varepsilon$ gives that there exist $c_f\in\mathbb{R}_{>0}$ and $\sigma_{f,m}\in\mathbb{R}_{>1}$ depending on $f$ and $m$ such that $$\begin{aligned} |F(\sigma+it)-1| \leq&\sum_{n=n_f+1}^\infty\left|\frac{\lambda_f(n)}{\lambda_f(n_f)}\right|\left(\frac{\log n}{\log n_f}\right)^m\left(\frac{n_f}{n}\right)^\sigma\notag\\ \leq& c_f\sum_{n=n_f+1}^\infty\frac{(\log{n}/\log{n_f})^m}{(n/n_f)^{\sigma-\varepsilon}}\leq\frac{1}{2}\label{FMZ}\end{aligned}$$ for $\sigma\in\mathbb{R}_{\geq\sigma_{f,m}}$ and $t\in\mathbb{R}$, where $\varepsilon$ is an arbitrary positive number. Hence $L_f^{(m)}(s)$ has no zeros for ${\rm Re\;}s\geq\sigma_{f,m}$, that is, is showed. Next we shall show and . Replacing $s$ to $1-s$ in and , we have $$\begin{aligned} &(-1)^mL_f^{(m)}(1-s)\notag\\ &=\sum_{r=0}^m\binom{m}{r}L_f^{(m-r)}(s)\left(2(2\pi)^{-2s}\cos(\pi s)\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2})\right)^{(r)}. \label{CLZ1}\end{aligned}$$ By the facts $(\cos(\pi s))^{(r)}=\pi^r(a_r\cos(\pi s)+b_r\sin(\pi s))$ where $a_r, b_r \in\{0,\pm 1\}$ and $((2\pi)^{-2s})^{(r)}=(-2\log 2\pi)^r(2\pi)^{-2s}$ for $r\in\mathbb{Z}_{\geq 0}$, the formula is written as $$\begin{aligned} (-1)^mL_f^{(m)}(1-s) =2(2\pi)^{-2s}\sum_{r=0}^mR_{m-r}(s)(\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2}))^{(r)}, \label{CLZ2}\end{aligned}$$ where $$\begin{aligned} R_{m-r}(s)=\cos(\pi s)\sum_{j=0}^{m-r}a_j'L_f^{(j)}(s)+\sin(\pi s)\sum_{j=0}^{m-r}b_j'L_f^{(j)}(s)\end{aligned}$$ and $a_r', b_r'\in\mathbb{R}$. It is clear that $a_0'=1$, $b_0'=0$ and $R_0(s)=L_f(s)\cos(\pi s)$. Moreover we write as $$\begin{aligned} \frac{(-1)^mL_f^{(m)}(1-s)}{2(2\pi)^{-2s}}=f(s)+g(s) \label{CLZ3}\end{aligned}$$ where $$\begin{aligned} f(s)=&R_0(s)(\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2}))^{(m)},\\ g(s)=&\sum_{r=0}^{m-1}R_{m-r}(s)(\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2}))^{(r)}. \end{aligned}$$ The formula implies that if $|f(s)|>|g(s)|$ in a some region then $L_f^{(m)}(s)$ has no zero in this region. In order to investigate the behavior of $f(s)$ and $g(s)$, we shall consider the approximate formula for $(\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2}))^{(r)}/(\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2}))$. By Stirling’s formula, it is known that $$\begin{aligned} \frac{\Gamma'}{\Gamma}(s)=\log s-\frac{1}{2s}+\int_0^\infty\frac{\{u\}-1/2}{(u+s)^2}du $$ for $s\in\mathbb{C}$ such that $|\arg s|\leq\pi-\delta$ where $\delta\in\mathbb{R}_{>0}$ is fixed (see ). Writing the right-hand side of the above formula to $G^{(1)}(s)$ and putting $G^{(j)}(s)=(d^{j-1}/ds)G^{(1)}(s)$ for $j\in\mathbb{Z}_{\geq2}$, we shall use the following lemma: \[LIB\] Let $F$ and $G$ be holomorphic function in the region $D$ such that $F(s)\ne0$ and $\log F(s)=G(s)$ for $s\in D$. Then for any fixed $r\in\mathbb{Z}_{\geq1}$, there exist $l_1,\cdots,l_r\in\mathbb{Z}_{\geq0}$ and $C_{(l_1,\cdots,l_r)}\in\mathbb{Z}_{\geq0}$ such that $$\begin{aligned} \frac{F^{(r)}}{F}(s) =\sum_{1l_1+\cdots+rl_r=r}C_{(l_1,\cdots,l_r)}(G^{(1)}(s))^{l_1}\cdots(G^{(r)}(s))^{l_r} $$ for $s\in D$. Especially $C_{(r,0,\cdots,0)}=1$. The estimates $$\begin{aligned} |u+s|^2=&u^2+|s|^2+2u|s|\cos\arg s\\\geq&\begin{cases} |s|^2, & u\leq|s|, \; |\arg s|\leq\pi/2, \\ |s|^2(\sin\arg s)^2, & u\leq|s|,\; \pi/2\leq|\arg s|\leq\pi-\delta, \\ u^2, & u\geq|s|, \;|\arg s|\leq\pi/2, \\ 4(1+\cos\arg s)u^2, & u\geq|s|,\; \pi/2\leq|\arg s|\leq\pi-\delta \end{cases}\end{aligned}$$ give $$\begin{aligned} \int_{0}^{\infty}\frac{\{u\}-1/2}{(u+s)^{j+1}}du \ll&\int_0^{|s|}\frac{du}{|s|^{j+1}}+\int_{|s|}^\infty\frac{du}{u^{j+1}}\ll\frac{1}{|s|^{j}}\end{aligned}$$ for $|\arg s|\leq\pi-\delta$ and $j\in\mathbb{Z}_{\geq1}$. Then $G^{(j)}(s)$ is calculated as $$\begin{aligned} G^{(1)}(s)=&\log s+O\left(\frac{1}{|s|}\right),\\ G^{(j)}(s)=&\frac{(-1)^{j-1}(j-2)!}{s^{j-1}}+\frac{(-1)^j(j-1)!}{2s^j}+(-1)^{j+1}j!\int_0^\infty\frac{\{u\}-1/2}{(u+s)^{j+1}}du\\ =&O\left(\frac{1}{|s|^{j-1}}\right)\end{aligned}$$ for $j\in\mathbb{Z}_{\geq2}$. Hence the approximate formula for $(\Gamma^{(r)}/\Gamma)(s)$ is written as $$\begin{aligned} \frac{\Gamma^{(r)}}{\Gamma}(s) =&(G^{(1)}(s))^r+O\left(\sum_{1q_1+\cdots+rq_r=r, \ q_1\ne r \;}\prod_{j=1}^r|G^{(j)}(s)|^{q_j}\right)\notag\\ =&\left(\log s+O\left(\frac{1}{|s|}\right)\right)^r+O\left(\frac{|\log s|^{r-1}}{|s|}\right)=(\log s)^r\sum_{j=0}^r\frac{M_j(s)}{(\log s)^{j}} \label{CLZ4}\end{aligned}$$ for $|\arg s|\leq\pi-\delta$ and $r\in\mathbb{Z}_{\geq0}$, where $M_j(s)$ is given by $M_j(s)=O(1/|s|^j)$ for $j\in\mathbb{Z}_{\geq 1}$ and $M_0(s)=1$. Using and the trivial estimates $|1\pm({k-1})/{2s}|<2<|s|^{1/2}$, $$\begin{aligned} &|s\pm\tfrac{k-1}{2}|=|s|\times|1\pm\tfrac{k-1}{2s}|\gg|s|,\notag\\ &\log|s\pm\tfrac{k-1}{2}|=(\log|s|)\times\left(1+\frac{\log|1\pm\tfrac{k-1}{2s}|}{\log|s|}\right)\gg\log|s|, \label{CLE2}\\ &\log(s\pm\tfrac{k-1}{2})\ll\sqrt{(\log|s\pm\tfrac{k-1}{2}|)^2+(\arg(s\pm\tfrac{k-1}{2}))^2}\ll\log|s|\notag\end{aligned}$$ for $|s|>(k-1)/2$, we obtain a desired formula: $$\begin{aligned} &\frac{(\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2}))^{(l)}}{\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2})}\notag\\ =&\sum_{j=0}^l\binom{l}{j}\frac{\Gamma^{(j)}}{\Gamma}(s-\tfrac{k-1}{2})\frac{\Gamma^{(l-j)}}{\Gamma}(s+\tfrac{k-1}{2})\notag\\ =&\sum_{j=0}^l\binom{l}{j}(\log(s-\tfrac{k-1}{2}))^j(\log(s+\tfrac{k-1}{2}))^{l-j}\times\notag\\ &\times\sum_{\begin{subarray}{c} 0\leq j_1+j_2\leq l,\\ 0\leq j_1\leq j,\; 0\leq j_2\leq l-j \end{subarray}}\frac{M_{j_1}(s-\tfrac{k-1}{2})}{(\log(s-\tfrac{k-1}{2}))^{j_1}}\frac{M_{j_2}(s+\tfrac{k-1}{2})}{(\log(s+\tfrac{k-1}{2}))^{j_2}}\notag\\ =&S_l(s)+T_l(s) \label{CLZ5}\end{aligned}$$ for $l\in\mathbb{Z}_{\geq0}$ and $s\in\mathbb{C}$ such that $|s|>(k-1)/2$ and $|\arg s|\leq\pi-\delta$ , where $S_l(s)$, $T_l(s)$ are given by $$\begin{aligned} S_l(s)=&(\log(s-\tfrac{k-1}{2})+\log(s+\tfrac{k-1}{2}))^l,\\ T_l(s)=&O\left(\frac{1}{|s|\log|s|}\sum_{j=0}^l(\log|s|)^j(\log|s|)^{l-j}\right)=O\left(\frac{(\log |s|)^{l-1}}{|s|}\right)\end{aligned}$$ respectively for $l\in\mathbb{Z}_{\geq 1}$, especially $S_0(s)=1$ and $T_0(s)=0$. Next using $R_r(s)$, $S_r(s)$ and $T_r(s)$, we shall write a condition which gives $|f(s)|>|g(s)|$ for some region. From and , the inequality $|f(s)|>|g(s)|$ is equivalent to $$\begin{aligned} |S_m(s)+T_m(s)|>\left|\sum_{r=0}^{m-1}\frac{R_r}{R_0}(s)(S_r(s)+T_r(s))\right|. \end{aligned}$$ Dividing the both sides of the above formula by $S_{m-1}(s)$ and applying the triangle inequality, we see that if $$\begin{aligned} |S_1(s)|>\left|\frac{T_m}{S_{m-1}}(s)\right|+\left|\sum_{r=0}^{m-1}\frac{R_r}{R_0}(s)\left(\frac{1}{S_{m-1-r}}(s)+\frac{T_r}{S_{m-1}}(s)\right)\right| \label{CLZ6}\end{aligned}$$ is true, then $|f(s)|>|g(s)|$ is true for $|s|>(k-1)/2$ and $|\arg s|\leq\pi-\delta$. To show the truth of , we shall consider an upper bound of $(1/S_r)(s)$, $T_r(s)$ and $(R_r/R_0)(s)$. The estimates and $|\log z|\geq\log|z|$ for $z\in\mathbb{C}$ give $$\begin{aligned} \left|\frac{1}{S_{r}}(s)\right|\leq\frac{1}{(\log|s-\tfrac{k-1}{2}|+\log|s+\tfrac{k-1}{2}|)^r}\leq\frac{C_1}{(\log|s|)^r} \label{CLZ7}\end{aligned}$$ for the above $s$ and $r\in\mathbb{Z}_{\geq 0}$, here and later $C_1, C_2, \dots$ denote positive constants depending on $f$, $r$ and $\delta$. Since $L_f^{(j)}(s)$ and $(1/L_f)(s)$ are absolutely convergent for ${\rm Re\;}s>1$, it follows that $$\begin{aligned} \left|\frac{R_r}{R_0}(s)\right|=\left|\sum_{j=0}^ra'_j\frac{L_f^{(j)}}{L_f}(s)+\tan(\pi s)\sum_{j=0}^rb'_j\frac{L_f^{(j)}}{L_f}(s)\right|\leq C_2+C_3|\tan(\pi s)| \label{CLZ9}\end{aligned}$$ for ${\rm Re\;}s\geq1+\varepsilon$. Here $\tan(\pi s)$ is estimated as $$\begin{aligned} |\tan\pi(\sigma+it)|=\left|\frac{e^{-2t}e^{2\pi i\sigma}-1}{e^{-2t}e^{2\pi i\sigma}+1}\right|\leq\begin{cases} 2/(1-e^{-2\varepsilon}), & \text{if } |t|\geq\varepsilon, \\ 3, & \text{if } \sigma\in\mathbb{Z} \end{cases} \label{CLZ10}\end{aligned}$$ where $\varepsilon$ is a fixed positive number. Combining –, we see that the right-hand side of is estimated as $$\begin{aligned} &\left|\frac{T_m}{S_{m-1}}(s)\right|+\left|\sum_{r=0}^{m-1}\frac{R_r}{R_0}(s)\left(\frac{1}{S_{m-1-r}}(s)+\frac{T_r}{S_{m-1}}(s)\right)\right|\notag\\ &\leq\frac{C_4}{|s|}+C_5|\tan(\pi s)|\sum_{r=0}^{m-1}\left(\frac{1}{(\log|s|)^{m-1-r}}+\frac{1}{|s|(\log|s|)^{m-r}}\right)\leq C_{f,m,\delta,\varepsilon} \label{CLZ11} \end{aligned}$$ for $|s|>(k-1)/2$ and ${\rm Re\;}s\geq1+\varepsilon$ provided $|{\rm Im\;}s|\geq\varepsilon$ or ${\rm Re\;}s\in\mathbb{Z}$, where $C_{f,m,\delta,\varepsilon}$ is a positive constant depending on $f$, $m$, $\delta$ and $\varepsilon$. Fix $\delta=\tan^{-1}(2\varepsilon/(k-1))$ and choose $r_{f,m}\in\mathbb{R}_{>(k-1)/2}$ such that $C_{f,m,\delta,\varepsilon}<(\log r_{f,m})/C_1$. The inequalities and imply that is true, that is, $L_f^{(m)}(1-s)$ has no zero for $s\in\mathbb{C}$ such that $|s|\geq r_{f,m}$, ${\rm Re\;}s\geq1+\varepsilon$ and $|{\rm Im\;}s|\geq\varepsilon$. Therefore, we conclude that for any $\varepsilon\in\mathbb{R}_{>0}$ there exists $\delta_{f,m,\varepsilon}\in\mathbb{R}_{>(k-1)/2+1}$ such that $L_f^{(m)}(s)$ has no zero in the region $|s|\geq\delta_{f,m,\varepsilon}$, ${\rm Re\;}s\leq-\varepsilon$ and $|{\rm Im\;}s|>\varepsilon$, that is, the proof of is completed. Finally we shall show applying Rouché’s theorem to $f(s)$ and $g(s)$. For $n\in\mathbb{Z}_{\geq1}$ let $D_n$ be the region $n\leq{\rm Re\;}s\leq n+1$ and $|{\rm Im\;}s|\leq 1/2$. By and , we see that there exists $\delta_{f,m,1/2}\in\mathbb{R}_{>(k-1)/2}$ such that $|f(s)|>|g(s)|$ is true in the boundary of $D_n$ and the region $|s|>\delta_{f,m,1/2}$ and ${\rm Re\;}s\geq1+1/2$. Then the number of zeros of $f(s)$ is equal to that of $f(s)+g(s)$ in the interior of $D_n$. From , and , the function $f(s)$ is written as $$\begin{aligned} f(s)=L_f(s)\cos(\pi s)\Gamma(s-\tfrac{k-1}{2})\Gamma(s+\tfrac{k-1}{2})(S_m(s)+T_m(s)). \label{FST}\end{aligned}$$ When $R_{f,m}$ is chosen such that $R_{f,m}\geq\delta_{f,m,1/2}$ and $C_6/(R_{f,m}\log R_{f,m})<1$, the formula gives $$\begin{aligned} \left|\frac{T_m}{S_m}(s)\right|\leq \frac{C_6}{|s|\log|s|}<1, \label{TS1}\end{aligned}$$ that is, $S_m(s)+T_m(s)$ has no zero for $|s|\geq R_{f,m}$. Hence $f(s)$ has the only real zero $s=n+1/2$ in $D_n$. It is clear to show $\overline{f(s)}=f(\overline{s})$ and $\overline{g(s)}=g(\overline{s})$ for $s\in\mathbb{C}$, which imply that $L_f^{(m)}(1-s)$ has a only real zero in the interior of $D_n$. Replacing $1-s$ to $s$, we obtain the fact that there exists $\alpha_{f,m}\in\mathbb{R}_{<-(k-1)/2-1}$ such that $L_f^{(m)}(s)$ has no complex zero for ${\rm Re\;}s<\alpha_{f,m}$ and one real zero in each open interval $(n-1,n)$ for $n\in\mathbb{Z}_{\leq\alpha_{f,m}}$. The proof of is completed. Proof of Theorem \[THM1\] ------------------------- Using Theorem \[THM0\], we can choose $\alpha_{f,m}\in\mathbb{R}_{<-(k-1)/2}$ and $\sigma_{f,m}\in\mathbb{R}_{>1}$ such that $L_f^{(m)}(s)$ has no zeros in the region ${\rm Re\;}s\leq\alpha_{f,m}$ and ${\rm Re\;}s\geq\sigma_{f,m}$. Moreover, choose $\tau_{f,m}\in\mathbb{R}_{>2}$ and $T\in\mathbb{R}_{>0}$ such that $L_f^{(m)}(s)$ has no zeros for $0<{\rm Im\;}s\leq\tau_{f,m}$ and ${\rm Im\;}s=T$. Using the residue theorem in the region $\alpha_{f,m}\leq{\rm Re\;}s\leq\sigma_{f,m}$ and $\tau_{f,m}\leq{\rm Im\;}s\leq T$, we get $$\begin{aligned} N_{f,m}(T)=&\frac{1}{2\pi i}\left(\int_{\alpha_{f,m}+i\tau_{f,m}}^{\sigma_{f,m}+i\tau_{f,m}}+\int_{\sigma_{f,m}+i\tau_{f,m}}^{\sigma_{f,m}+iT}+\int_{\sigma_{f,m}+iT}^{\alpha_{f,m}+iT}+\right.\notag\\ &\left.+\int_{\alpha_{f,m}+iT}^{\alpha_{f,m}+i\tau_{f,m}}\right)(\log L_f^{(m)}(s))'ds=:I_1+I_2+I_3+I_4. \label{LDB}\end{aligned}$$ First, it is clear that $$\begin{aligned} I_1=\frac{\log L_f^{(m)}(\sigma_{f,m}+i\tau_{f,m})-\log L_f^{(m)}(\alpha_{f,m}+i\tau_{f,m})}{2\pi i} =O(1). \label{LDC}\end{aligned}$$ To approximate $I_2$, we write $L_f^{(m)}(s)=\lambda_f(n_f)(-\log{n_f})^mF(s)n_f^{-s}$ where $F(s)$ is given by . Using (\[FMZ\]) we find that $1/2\leq|F(s)|\leq3/2$, ${\rm Re\;}F(s)\geq1/2$ and $|\arg F(s)|<\pi/2$ for $s=\sigma_{f,m}+it\;(t\in\mathbb{R})$. Hence $I_2$ is approximated as $$\begin{aligned} I_2=&\frac{1}{2\pi i}\left[\log\frac{\lambda_f(n_f)(-\log{n_f})^m}{n_f^s}+\log F(s)\right]_{\sigma_{f,m}+i\tau_{f,m}}^{\sigma_{f,m}+iT}\notag\\ =&\frac{-(\sigma_{f,m}+iT)\log n_f}{2\pi i}+O(1) =-\frac{T}{2\pi}\log{n_f}+O(1). \label{LDE}\end{aligned}$$ Next we shall estimate $I_3$. The formula (\[4DFE\]), the approximate functional equation for $L_f^{(m)}(s)$ (see [@YY3 Theorem 1.2]) and Rankin’s result, there exists $A\in\mathbb{R}_{\geq0}$ such that $L_f^{(m)}(\sigma+it)=O(|t|^A)$ uniformly for $\sigma\in[\alpha_{f,m},\sigma_{f,m}]$. It implies that $$\begin{aligned} I_3=&\frac{\log L_f^{(m)}(\alpha_{f,m}+iT)-\log L_f^{(m)}(\sigma_{f,m}+iT)}{2\pi i}\notag\\ =&\frac{\arg L_f^{(m)}(\alpha_{f,m}+iT)-\arg L_f^{(m)}(\sigma_{f,m}+iT)}{2\pi}+O(\log T). \label{LDF}\end{aligned}$$ To estimate the first term of the right-hand side of (\[LDF\]), we write $L_f^{(m)}(\sigma+iT)=(-1)^me^{-iT\log n_f}\lambda_f(n_f)G(\sigma+iT)$ where $$\begin{aligned} G(\sigma+iT)=\frac{(\log{n_f})^m}{n_f^{\sigma}}+\frac{1}{\lambda_f(n_f)}\sum_{n=n_f+1}^\infty\frac{\lambda_f(n)(\log n)^m}{n^{\sigma}}e^{iT\log\frac{n_f}{n}} $$ for $\sigma\in\mathbb{R}_{>1}$. Let $Q$ be the number of zeros of ${\rm Re\;}G(s)$ on the line segment $(\alpha_{f,m}+iT,\sigma_{f,m}+iT)$. Divide this line into $Q+1$ subintervals by these zeros. Then the sign of ${\rm Re\;}G(s)$ is constant, and the variation of $\arg G(s)$ is at most $\pi$ on each subinterval. Hence, there exists constant $C$ such that $\arg G(s)=\arg L_f^{(m)}(s)+C$ on the divided line, it follows that $$\begin{aligned} |\arg L_f^{(m)}(\alpha_{f,m}+iT)-\arg L_f^{(m)}(\sigma_{f,m}+iT)|\leq (Q+1)\pi. \label{LDH}\end{aligned}$$ In order to estimate $Q$, let $H(z)=(G(z+iT)+\overline{G(\overline{z}+iT)})/2$. Then we find that $$\begin{aligned} H(\sigma)=&{\rm Re\;}G(\sigma+iT)\notag\\ =&\frac{(\log n_f)^m}{n_f^\sigma}\left(1+\sum_{n=n_f+1}^\infty\frac{\lambda_f(n)}{\lambda_f(n_f)}\left(\frac{\log n}{\log n_f}\right)^m\left(\frac{n_f}{n}\right)^\sigma\cos\left(T\log\frac{n_f}{n}\right)\right) \label{LDG}\end{aligned}$$ for $\sigma\in\mathbb{R}_{>1}$. The formulas (\[FMZ\]) and (\[LDG\]) give $$\begin{aligned} \frac{1}{2}\frac{(\log n_f)^m}{{n_f}^{\sigma_{f,m}}}\leq H(\sigma_{f,m})\leq\frac{3}{2}\frac{(\log n_f)^m}{{n_f}^{\sigma_{f,m}}}. \label{HEE}\end{aligned}$$ Take $T$ sufficiently large such that $T-\tau_{f,m}>2(\sigma_{f,m}-\alpha_{f,m})$ if necessary. Since ${\rm Im}(z+iT)\geq T-(T-\tau_{f,m})>0$ for $z\in\mathbb{C}$ such that $|z-\sigma_{f,m}|<T-\tau_{f,m}$, it follows that $H(z)$ is analytic in the circle $|z-\sigma_{f,m}|<T-\tau_{f,m}$. Note that there exists a positive constant $B$ such that $H(z)=O(T^B)$ in this circle because of the fact that $L_f(\sigma+it)=O(|t|^A)$. For $u\in\mathbb{R}_{\geq0}$, let $P(u)$ be the number of zeros of $H(z)$ in $|z-\sigma_{f,m}|\leq u$. Then using the trivial estimate $$\begin{aligned} P(\sigma_{f,m}-\alpha_{f,m})&\leq\frac{1}{\log 2}\int_{\sigma_{f,m}-\alpha_{f,m}}^{2(\sigma_{f,m}-\alpha_{f,m})}\frac{P(u)}{u}du\\ &\leq\frac{1}{\log 2}\int_{0}^{2(\sigma_{f,m}-\alpha_{f,m})}\frac{P(u)}{u}du,\end{aligned}$$ Jensen’s formula (see [@TID Chapter 3.61]), the above note and (\[HEE\]), we have $$\begin{aligned} &P(\sigma_{f,m}-\alpha_{f,m})\\ &\ll\int_0^{2(\sigma_{f,m}-\alpha_{f,m})}\frac{P(u)}{u}du\\ &=\frac{1}{2\pi}\int_0^{2\pi}\log|H(\sigma_{f,m}+2(\sigma_{f,m}-\alpha_{f,m})e^{i\theta})|d\theta-\log|H(\sigma_{f,m})|\\ &\ll\int_0^{2\pi}\log T^Bd\theta+1\ll \log T,\end{aligned}$$ Therefore $Q$ is estimated as $$\begin{aligned} Q=\#\{\sigma\in(\alpha_{f,m},\sigma_{f,m})\mid F(\sigma)=0\}\ll P(\sigma_{f,m}-\alpha_{f,m})\ll \log T. \label{LDI}\end{aligned}$$ Combining (\[LDF\]), (\[LDH\]), (\[LDI\]), we obtain the estimate of $I_3$: $$\begin{aligned} I_3=O(\log T). \label{LD3}\end{aligned}$$ Finally in order to approximate $I_4$, we shall obtain the approximate formula for $\log L_f^{(m)}(\alpha_{f,m}+iT)$ as $T\to\infty$. By the proof of Theorem \[THM0\], there exists $\delta_{f,m}\in\mathbb{R}_{>0}$ such that $$\begin{aligned} \left|\frac{g}{f}(1-s)\right|< 1, \quad \left|\frac{T_m}{S_m}(1-s)\right|<1 \label{FGST}\end{aligned}$$ for $s\in\mathbb{C}$ in the region $|s-(1-(k-1)/2)|>\delta_{f,m}$, ${\rm Re\;}s<1-(k-1)/2$ and $|{\rm Im\;}s|>1/2$. Here choose $\alpha_{f,m}\in\mathbb{R}_{<0}$ such that $\alpha_{f,m}<1-(k-1)/2-\delta_{f,m}$ if necessary. Then the path of $I_4$ is contained in the above region. Replacing $s$ to $1-s$ and taking logarithmic function in the both sides of , we obtain $$\begin{aligned} \log L_f^{(m)}(\alpha_{f,m}+iT) =&-2(1-\alpha_{f,m}-iT)\log 2\pi+\log f(1-\alpha_{f,m}-iT)+\notag\\ &+\log\left(1+\frac{g}{f}(1-\alpha_{f,m}-iT)\right)+O(1). \label{I4A}\end{aligned}$$ The first formula of gives $|\arg(1+(g/f)(1-\alpha_{f,m}-iT))|<\pi/2$ and $$\begin{aligned} &\log\left(1+\frac{g}{f}(1-\alpha_{f,m}-iT)\right)\notag\\ &\ll\sqrt{\left|1+\frac{g}{f}(1-\alpha_{f,m}-iT)\right|^2+\left(\arg\left(1+\frac{g}{f}(1-\alpha_{f,m}-iT)\right)\right)^2}\ll 1. \label{LAFG}\end{aligned}$$ By , the second term of the right-hand side of is written as $$\begin{aligned} &\hspace{-12pt}\log f(1-\alpha_{f,m}-iT)\notag\\ =&\log\Gamma(1-\alpha_{f,m}-\tfrac{k-1}{2}-iT)+\log\Gamma(1-\alpha_{f,m}+\tfrac{k-1}{2}-iT)+\notag\\ &+\log S_m(1-\alpha_{f,m}-iT)+\log\left(1+\frac{T_m}{S_m}(1-\alpha_{f,m}-iT)\right)+\notag\\ &+\log L_f(1-\alpha_{f,m}-iT)+\log\cos\pi(1-\alpha_{f,m}-iT). \label{I4B}\end{aligned}$$ Now it is clear that $$\begin{aligned} &\cos\pi(1-\alpha_{f,m}-iT)=e^{\pi T}e^{i(1-\alpha_{f,m})-\log 2}(1+{e^{-2\pi(1-\alpha_{f,m})i}}/{e^{2\pi T}}),\\ &\log L_f(1-\alpha_{f,m}-iT)=\sum_{n=1}^\infty\frac{b_f(n)}{n^{1-\alpha_{f,m}-iT}}\end{aligned}$$ where $b_f(n)$ is given by $$\begin{aligned} b_f(n)=\begin{cases} (\alpha_f(p)^r+\beta_f(p)^r)/r, & n=p^r, \\ 0 , & \text{otherwise} \end{cases}\end{aligned}$$ and $\alpha_f(p)$, $\beta_f(p)$ are given by . Hence the fifth and sixth terms of the right-hand sides of are approximated as $$\begin{aligned} \log L_f(1-\alpha_{f,m}-iT)+\log\cos\pi(1-\alpha_{f,m}-iT)=\pi T+O(1).\end{aligned}$$ By the similar discussion of , the fourth term of the right-hand sides of is estimated as $$\begin{aligned} \log\left(1+\frac{T_m}{S_m}(1-\alpha_{f,m}-iT)\right)\ll 1.\end{aligned}$$ The trivial approximate formula $$\begin{aligned} \log(1-\alpha_{f,m}\pm\tfrac{k-1}{2}-iT)=\log T-(\pi/2)i+O(1/T)\end{aligned}$$ gives that the third term of the right-hand sides of is approximated as $$\begin{aligned} &\log S_m(1-\alpha_{f,m}-iT)\notag\\ &=m\log\left(\log(1-\alpha_{f,m}-\tfrac{k-1}{2}-iT)+\log(1-\alpha_{f,m}+\tfrac{k-1}{2}-iT)\right)\notag\\ &=m\log\log T+O(1).\end{aligned}$$ Using Stirling’s formula $$\log\Gamma(s)=(s-1/2)\log s-s+\log\sqrt{2\pi}+O(1/|s|)$$ and the approximate formula of $\log(1-\alpha_{f,m}\pm({k-1})/{2}-iT)$, we approximate the first and second terms of the right-hand sides of as $$\begin{aligned} &\log\Gamma(1-\alpha_{f,m}+\tfrac{k-1}{2}-iT)+\log\Gamma(1-\alpha_{f,m}-\tfrac{k-1}{2}-iT)\notag\\ &=(1-2\alpha_{f,m}-2iT)(\log T-(\pi/2)i+O(1/T))-2(1-\alpha_{f,m}-iT)+O(1)\notag\\ &=-2iT\log(T/e)-\pi T+(1-2\alpha_{f,m})\log T+O(1). \label{I4B12}\end{aligned}$$ Combining (\[I4A\])–(\[I4B12\]), we obtain a desired approximate formula as $$\log L_f^{(m)}(\alpha_{f,m}+iT)=-2iT\log\frac{T}{2\pi e}+O(\log T),$$ which implies that $$\begin{aligned} I_4=\frac{T}{\pi}\log\frac{T}{2\pi e}+O(\log T). \label{LD4}\end{aligned}$$ From (\[LDC\]), (\[LDE\]), (\[LD3\]) and (\[LD4\]), the proof of Theorem \[THM1\] is completed. Proof of Theorem \[THM2\] ------------------------- Write $L_f^{(m)}(s)=\lambda_f(n_f)(-\log n_f)^mF(s)/n_f^s$ where $F(s)$ is given by (\[FFF\]). By the proof of Theorem \[THM0\], we can choose $\sigma_{f,m}\in\mathbb{R}_{>1}$ such that $L_f(s)$ has no zero for ${\rm Re\;}s>\sigma_{f,m}$ and $$\begin{aligned} \sum_{n=n_f+1}^\infty\left|\frac{\lambda_f(n)}{\lambda_f(n_f)}\right|\left(\frac{\log n}{\log n_f}\right)^m\left(\frac{n_f}{n}\right)^{\sigma_{f,m}/2}\leq\frac{1}{2}.\end{aligned}$$ Note that and the above inequality give $$\begin{aligned} |F(s)-1|& \leq\sum_{n=n_f+1}^\infty\left|\frac{\lambda_f(n)}{\lambda_f(n_f)}\right|\left(\frac{\log n}{\log n_f}\right)^m\left(\frac{n_f}{n}\right)^{\sigma_{f,m}/2+\sigma/2} \leq\frac{1}{2}\left(\frac{n_f}{n_f+1}\right)^{\sigma/2}. \label{LAS}\end{aligned}$$ for ${\rm Re\;}s\geq\sigma_{f,m}$. Applying Littlewood’s formula (see [@TID chapter 3.8]) to $F(s)$, we obtain $$\begin{aligned} 2\pi\sum_{\begin{subarray}{c}F(\rho)=0, \\ \sigma\leq{\rm Re\;}\rho\leq\sigma_{f,m},\\ 1\leq{\rm Im\;}\rho\leq T \end{subarray}}({\rm Re\;}\rho-\sigma) =&\int_1^T\log|F(\sigma+it)|dt-\int_1^T\log|F(\sigma_{f,m}+it)|dt+\notag\\[-24pt] &+\int_\sigma^{\sigma_{f,m}}\arg{F(u+iT)}dt-\int_\sigma^{\sigma_{f,m}}\arg{F(u+i)}dt\notag\\ =&:I_1+I_2+I_3+I_4 \label{LA1}\end{aligned}$$ for $\sigma\in\mathbb{R}_{>1/2}$. Here we shall estimate $I_2$. Cauchy’s theorem gives that $$\begin{aligned} I_2=\int_1^T\log|F(v+it)|dt+\int_{\sigma_{f,m}}^{v}\log|F(u+i)|du-\int_{\sigma_{f,m}}^{v}\log |F(u+iT)|du\label{L2A}\end{aligned}$$ for all $v>\sigma_{f,m}$. The fact that $\log{|X|}\leq |X-1|$ for $X\in\mathbb{C}$ and $-\log|Y|\leq 2|Y-1|$ for $Y\in\mathbb{C}$ satisfying $|Y|\geq1/2$, and (\[LAS\]) imply that $$\begin{aligned} \int_1^T\log|F(v+it)|dt\leq\frac{(T-1)}{2}\left(\frac{n_f}{n_f+1}\right)^{{v}/{2}} \label{L2B}\end{aligned}$$ and $$\begin{aligned} &\int_{\sigma_{f,m}}^{v}\log|F(u+i)|du-\int_{\sigma_{f,m}}^{v}\log |F(u+iT)|du\notag\\ &\ll\int_{\sigma_{f,m}}^{v}\left(\frac{n_f}{n_f+1}\right)^{{u}/{2}}du\ll 1. \label{L2C}\end{aligned}$$ Combining (\[L2A\])–(\[L2C\]) we get $$\begin{aligned} I_2=O(1). \label{LI2}\end{aligned}$$ By the same discussion of an estimate of $I_3$ in proof of Theorem \[THM1\], we can obtain $$\begin{aligned} I_3+I_4=O(\log T). \label{LA3}\end{aligned}$$ To estimate $I_1$, we calculate $$\begin{aligned} I_1=\frac{T-1}{2}\log\frac{n_f^{2\sigma}}{|\lambda_f(n_f)|^2(\log n_f)^{2m}}+\frac{1}{2}\int_1^T\log|L_f^{(m)}(\sigma+it)|^2dt. \label{LA4}\end{aligned}$$ Jensen’s inequality gives $$\begin{aligned} \int_1^T\log|L_f^{(m)}(\sigma+it)|^2dt\leq(T-1)\log\left(\frac{1}{T-1}\int_1^T|L_f^{(m)}(\sigma+it)|^2dt\right). \label{LA5}\end{aligned}$$ Combining (\[LA1\]), (\[LI2\])–(\[LA5\]), we obtain $$\begin{aligned} \sum_{\begin{subarray}{c}F(\rho)=0, \\ \sigma\leq{\rm Re\;}\rho\leq\sigma_{f,m},\\ 1\leq{\rm Im\;}\rho\leq T \end{subarray}}({\rm Re\;}\rho-\sigma)\leq&\frac{T-1}{4\pi}\log\left(\frac{1}{T-1}\int_1^T|L_f^{(m)}(\sigma+it)|^2dt\right)+\notag\\[-24pt] &+\frac{T-1}{4\pi}\log\frac{n_f^{2\sigma}}{|\lambda_f(n_f)|^2(\log n_f)^{2m}}+O(\log{T}). \label{LAA}\end{aligned}$$ First, we consider the mean square of $L_f^{(m)}(s)$ for ${\rm Re\;}s>1$. Then we can calculate as follows: $$\begin{aligned} &\hspace{-12pt}\int_1^T|L_f^{(m)}(\sigma+it)|^2dt\notag\\ =&\sum_{n_1, n_2=1}^\infty\frac{\overline{\lambda_f(n_1)}\lambda_f(n_2)(\log n_1)^m(\log n_2)^m}{(n_1n_2)^\sigma}\int_{\max\{n_1,n_2\}}^T \left(\frac{n_1}{n_2}\right)^{it}dt\notag\\ =&(T-1)\sum_{n=1}^\infty\frac{|\lambda_f(n)|^2(\log n)^{2m}}{n^{2\sigma}}+\notag\\ &+\frac{1}{i}\sum_{\begin{subarray}{c} n_1, n_2=1,\\ n_1\ne n_2 \end{subarray}}^\infty\frac{\overline{\lambda_f(n_1)n_1^{-iT}}\lambda_f(n_2)n_2^{-iT}(\log n_1)^m(\log n_2)^m}{(n_1n_2)^\sigma\log(n_1/n_2)}-\notag\\ &-\frac{1}{i}\sum_{\begin{subarray}{c} n_1, n_2=1,\\ n_1\ne n_2 \end{subarray}}^\infty\frac{\overline{\lambda_f(n_1)n_1^{-i\max\{n_1,n_2\}}}\lambda_f(n_2)n_2^{-i\max\{n_1,n_2\}}(\log n_1)^m(\log n_2)^m}{(n_1n_2)^\sigma\log(n_1/n_2)}. \label{L2I}\end{aligned}$$ By the same discussion for $U_\sigma(x)$ with $$\begin{aligned} (\alpha_{n_1},\beta_{n_2})=&(\lambda_f(n_1)n_1^{-iT}(\log n_1)^m,\lambda_f(n_2)n_2^{-iT}(\log n_2)^m), \\ &(\lambda_f(n_1)n_1^{-i\max\{n_1,n_2\}}(\log n_1)^m, \lambda_f(n_2)n_2^{-i\max\{n_1,n_2\}}(\log n_2)^m)\end{aligned}$$ in [@GD1 p.348, LEMMA 6], we find that the second and third terms on the right-hand side of are $=O(1)$ uniformly for $\sigma>1$. Hence, the mean square of $L_f^{(m)}(s)$ for ${\rm Re\;}s>1$ is obtained as $$\begin{aligned} \int_1^T|L_f^{(m)}(\sigma+it)|^2dt=(T-1)\sum_{n=1}^\infty\frac{|\lambda_f(n)|^2(\log n)^{2m}}{n^{2\sigma}}+O(1). \label{LAB}\end{aligned}$$ Next the mean square of $L_f^{(m)}(s)$ for $1/2<{\rm Re\;}s\leq1$ is obtained as follows: For any $m\in\mathbb{Z}_{\geq0}$ and $T>0$, we have $$\begin{aligned} &\int_1^T|L_f^{(m)}(\sigma+it)|^2dt\notag\\ &=\begin{cases} \displaystyle (T-1)\sum_{n=1}^\infty\frac{|\lambda_f(n)|^2(\log n)^{2m}}{n^{2\sigma}}+O(T^{2(1-\sigma)}(\log T)^{2m}), & 1/2<\sigma<1, \\ \displaystyle (T-1)\sum_{n=1}^\infty\frac{|\lambda_f(n)|^2(\log n)^{2m}}{n^{2\sigma}}+O((\log T)^{2m+2}), & \sigma=1. \end{cases}\label{LAC}\end{aligned}$$ Using Rankin’s result mentioned in Introduction and the following fact $$\begin{aligned} \int_{n_f}^\infty\frac{(\log u)^{2m}}{u^{2\sigma}}du=\frac{(2m)!n_f^{1-2\sigma}}{(2\sigma-1)^{2m+1}}\sum_{j=0}^{2m}\frac{(\log{n_f})^j(2\sigma-1)^j}{j!},\end{aligned}$$ which is obtained by induction, we find that the series of main term of (\[LAC\]) is approximated as $$\begin{aligned} &\sum_{n=1}^\infty\frac{|\lambda_f(n)|^2(\log n)^{2m}}{n^{2\sigma}}\notag\\ &=-\int_{n_f}^\infty\left(\frac{(\log u)^{2m}}{u^{2\sigma}}\right)'\sum_{n_f<n\leq u}|\lambda_f(n)|^2du\notag\\ &=-\frac{C_f(\log n_f)^{2m}}{n_f^{2\sigma-1}}+C_f\int_{n_f}^{\infty}\frac{(\log u)^{2m}}{u^{2\sigma}}du+O\left(\int_{n_f}^\infty\frac{(\log u)^{2m}}{u^{2\sigma+2/5}}du\right)\notag\\ &=\frac{(2m)!n_fC_f}{n_f^{2\sigma}}\frac{1}{(2\sigma-1)^{2m+1}}+O\left(\frac{1}{(2\sigma-1)^{2m}}\right) \label{LAD}\end{aligned}$$ as $\sigma\to1/2+0$. From (\[LAA\])–(\[LAD\]), the following approximate formula is obtained: $$\begin{aligned} &\hspace{-12pt}\sum_{\begin{subarray}{c}F(\rho)=0, \\ \sigma\leq{\rm Re\;}\rho\leq\sigma_{f,m},\\ 1\leq{\rm Im\;}\leq T \end{subarray}}({\rm Re\;}\rho-\sigma)\notag\\ \leq& \displaystyle\frac{(2m+1)(T-1)}{4\pi}\log\frac{1}{2\sigma-1}+\frac{T-1}{4\pi}\log\frac{(2m)!n_fC_f}{|\lambda_f(n_f)|^2(\log n_f)^{2m}}+\notag\\ &+O(\log T)+\frac{T-1}{4\pi}\times \notag\\ &\times\begin{cases} \displaystyle\log\left(1+O\left(\frac{(2\sigma-1)^{2m+1}(\log T)^{2m}}{T^{2\sigma-1}}\right)\right), & 1/2<\sigma<1, \\ \displaystyle\log\left(1+O\left(\frac{(2\sigma-1)^{2m+1}(\log T)^{2m+2}}{T}\right)\right), \hspace{-6pt} & \sigma=1, \\ \displaystyle\log\left(1+O\left(\frac{(2\sigma-1)^{2m+1}}{T}\right)\right), & \sigma{>1}. \end{cases} \label{LBA}\end{aligned}$$ Finally, we shall give an upper bound of $N_{f,m}(\sigma,T)$. Since $N_{f,m}(\sigma,T)$ is monotonically decreasing function with respect to $\sigma$, it follows that $$\begin{aligned} N_{f,m}(\sigma,T)=&N_{f,m}(\sigma,T)-N_{f,m}(\sigma,1)+C\notag\\ \leq& \frac{1}{\sigma-\sigma_1}\int_{\sigma_1}^{\sigma_{f,m}}(N_{f,m}(u,T)-N_{f,m}(u,1))du+C, \label{LBB}\end{aligned}$$ where we put $\sigma_1=1/2+(\sigma-1/2)/2$. Note that $\sigma-\sigma_1=(\sigma-1/2)/2$, $2\sigma_1-1=\sigma-1/2$. Since the numbers of zeros of $F_m(s)$ is equal to that of $L_f^{(m)}(s)$, it follows that $$\begin{aligned} &\int_{\sigma_1}^{\sigma_{f,m}}(N_{f,m}(u,T)-N_{f,m}(u,1))du\notag\\ &=\int_{\sigma_1}^{\sigma_{f,m}}\sum_{\begin{subarray}{c} F(\rho)=0,\\ u\leq{\rm Re\;}\rho\leq\sigma_{f,m},\\ 1\leq{\rm Im\;}\leq T \end{subarray}}1du =\sum_{\begin{subarray}{c} F(\rho)=0,\\ \sigma_1\leq{\rm Re\;}\rho\leq\sigma_{f,m},\\ 1\leq{\rm Im\;}\rho\leq T \end{subarray}}\int_{\sigma_1}^{{\rm Re\;}\rho}1du\notag\\ &=\sum_{\begin{subarray}{c} F(\rho)=0,\\ \sigma_1\leq{\rm Re\;}\rho\leq\sigma_{f,m},\\ 1\leq{\rm Im\;}\rho\leq T \end{subarray}}({\rm Re\;}\rho-\sigma_1). \label{LBC}\end{aligned}$$ Combining (\[LBA\])–(\[LBC\]) we obtain (\[ZD1\]) and (\[ZD2\]). Hence the proof of Theorem \[THM2\] is completed. [20]{} M. Aoki and M. Minamide, *A zero density estimate for the derivatives of the Riemann zeta function*, Journal for Algebra and Number Theory Academia **2** (2012), 361–365. B. C. Berndt, *The number of zeros for $\zeta^{(k)}(s)$*, J. London Math. Soc. (2) **2** (1970), 577–580. A. Good, *Approximative Funktionalgleichungen und Mittelwertsätze für Dirichletreihen, die Spitzenformen assoziiert sind*, Comment. Math. Helv. **50** (1975), 327–361. E. Hecke, *Über Modulfunktionen und die Dirichletschen Reihen mit Eulerscher Produktentwicklung. I*, Math. Ann. **114** (1937), 1–28. A. A. Karatsuba and S. M. Voronin, *The Riemann Zeta-Function*, Walter de Gruyter de Gruyter Explosions in Mathematics 5, 1992. C. G. Lekkerkerker, *On the zeros of a class of Dirichlet series*, Dissertation, Utrecht, 1955. N. Levinson and H. L. Montgomery, *Zeros of the derivatives of the Riemann zeta-function*, Acta Math. **133** (1974), 49–65. R. A. Rankin, *Contributions to the theory of Ramanujan’s function $\tau(n)$ and similar functions. II. The order of the Fourier coefficients of integral modular forms*, Proc. Cambridge Phil. Soc. **35** (1939), 357–373. B. Riemann, *Über die Anzahl der Primzahlen unterhalb einer gegebenen Grösse*, Monatsber. Königl. Preuss. Akad. Wiss. Berlin (1859), 671–680. A. Speiser, *Geometrisches zur Riemannschen Zetafunktion*, Math. Ann. **110** (1935), 514–521. R. Spira, *Zero-free regions of $\zeta^{(k)}(s)$*, J. London Math. Soc. **40** (1965), 677–682. R. Spira, *Another zero-free region for $\zeta^{(k)}(s)$*, Proc. Amer. Math. Soc. **26** (1970), 246–247. E. C. Titchmarsh, *The Theory of Functions*, Oxford Univ. Press, 1939. H. von Mangoldt, *Zu Riemann’s Abhandlung ‘Ueber die Anzahl der Primzahlen unter einer gegebenen Grösse*, J. Reine Angew. Math. **114** (1895), 255–305. Y. Yashiro, *Approximate functional equation and mean value formula for the derivatives of $L$-functions attached to cusp forms*, preprint; arXiv:1402.3716. C. Y. Y[i]{}ld[i]{}r[i]{}m, *Zeros of $\zeta''(s)$ & $\zeta'''(s)$ in $\sigma<1/2$*, Turk. J. Math. **24** (2000): 89–108. [^1]: 2010 *Mathematics Subject Classification*: Primary 11M26; Secondary 11N75. [^2]: *Key words and phrases*: cusp forms, $L$-functions, derivative, zeros.

Camera 360: camera 360 apps is one of the top leading camera apps for Android phones and iPhone in the world. This is a very great app, and camera360 has over more than 200 million users over worldwide. It helps to boost the effects and filters in the camera. It is also well known for having great … [Read more...] Prisma App Alternative Prisma App Alternative is one of the trending iPhone apps around the world, many people start using this app and regard this app as one of the best photo editing app. This app became so popular on social networking sites like SnapChat, Instagram, Facebook, Twitter and so on, … [Read more...] About Me Hi, i'm Harsh Chaklasiya From Surat City. i'm very Passionate, Geek and Loves Technology.i'm pursuing 3rd year in Information Technology From DDIT,Nadiad. For more info follow our social media :)

/* * Licensed under the Apache License, Version 2.0 (the "License"); you may not use this file except in compliance with * the License. You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, software distributed under the License is distributed on * an "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. See the License for the * specific language governing permissions and limitations under the License. * * Copyright 2012-2020 the original author or authors. */ package org.assertj.core.test; import java.util.LinkedHashMap; import java.util.TreeMap; import org.assertj.core.data.MapEntry; /** * @author Alex Ruiz */ public final class Maps { @SafeVarargs public static <K, V> LinkedHashMap<K, V> mapOf(MapEntry<K, V>... entries) { LinkedHashMap<K, V> map = new LinkedHashMap<>(); for (MapEntry<K, V> entry : entries) { map.put(entry.key, entry.value); } return map; } @SafeVarargs public static <K extends Comparable<? super K>, V> TreeMap<K, V> treeMapOf(MapEntry<K, V>... entries) { TreeMap<K, V> map = new TreeMap<>(); for (MapEntry<K, V> entry : entries) { map.put(entry.key, entry.value); } return map; } private Maps() {} }

Ambrose Light (ship) Ambrose Light was a brigantine, operated by Colombian rebels. It was captured by USS Alliance as a suspected pirate vessel in 1885. The accusation of piracy was rejected by a court of law. Capture On April 24, Commander Lewis Clark, of the South Atlantic Squadron, was sailing to Cartagena, on the Caribbean coast of Colombia, when the lookouts aboard Alliance sighted the one-gun Ambrose Light. It was flying a strange flag featuring a red cross over a white background so the Americans assumed the vessel was a pirate ship. A chase began and the Americans were preparing to fire a shot over the vessel's bow when a Colombian ensign was observed and Ambrose Light came to a halt. Commander Clark put Lieutenant M. Fisher and a boarding party on the rebel ship and it was found to have been armed with one cannon and sixty heavily armed sailors. A large cache of ammunition was also discovered. The Colombians revealed their letter of marque from the rebel leader Pedro Lara, giving the men of Ambrose Light permission to blockade Cartagena. Commander Clark disregarded this and took the rebels prisoner and the brigantine as a prize. The ship was put under the command of Lieutenant Fisher with ten others and sent to be condemned in New York. After arriving on June 1, a stowaway was found, starving to death, hiding behind some casks in the cargo hold. The man immediately received medical attention. Legal case Following the court proceedings, it was agreed that Alliance had lawfully seized the rebels as pirates because Pedro Lara, or any rebel, had no right to commission warships. After a legal decision, the ship was returned to her Colombian owners, in return for costs. The court ruled that the ship could legally be used to transport troops between Colombian ports during the Colombian Civil War. When fighting broke out in Cartagena, American Secretary of State Thomas F. Bayard released Ambrose Light and her crew. This incident was the basis for a decision in case law that defines who can be called a pirate in the United States. See also West Indies Anti-Piracy Operations of the United States References Category:Pirate ships Category:Vessels captured by the United States Navy Category:United States admiralty case law Category:United States Navy in the 19th century Category:History of Colombia Category:Maritime incidents in 1885 Category:Battles and conflicts without fatalities Category:Piracy in the Caribbean Category:Brigantines