After the 2011 Great East Japan Earthquake, the resource utilization of and the problems encountered with communication devices were examined.A questionnaire survey was submitted to disaster medical assistance teams (DMATs) that were at the primary sites of destruction after the earthquake.We collected data from 196 teams. During the first 4 days after the earthquake, the use of mobile phones, laptop computers, and landline phones was rated as poor to moderate, and satisfaction was very low, while satisfaction with satellite phones was rated as good to moderate (50%). The degree of satisfaction continued to increase gradually over time. Satellite phones, however, had several problems: poor reception, line instability, voice call use only, and inability to send large amounts of data.Disaster Med Public Health Preparedness. 2014:0:1–4)To ensure effective communication during the acute phase in the aftermath of large disasters, a new satellite communication device is needed that not only is portable, battery powered, and able to send large volumes of data, but also offers stable communication. ( The Great East Japan Earthquake occurred at 14:46 on March 11, 2011. It was catastrophic, registering 9.1 on the Richter scale. After the earthquake, a large tsunami occurred in the bay of the eastern Sea of Japan. This disaster brought damage to a wide area, and ongoing effects during the first 2 weeks post-disaster destroyed the local infrastructure.,After a disaster occurs, the communication infrastructure and its associated devices are crucial to the collection of information. Problems of inadequate information acquisition and exchange between the rescue staging care units and the control task force result in a confusion of tasks. Only a few reports of the communication status after the disaster have been published.We conducted a questionnaire survey of disaster medical assistance teams (DMATs) that were at the primary sites of destruction following the Great East Japan Earthquake and resulting tsunami. In Japan, DMATs are defined as mobile medical teams that receive professional training. These teams of medical doctors, nurses, and logistics personnel are activated during the acute phase of a disaster.We sent questionnaires to 375 randomly selected DMATs in Japan that provided medical support just after the earthquake disaster and performed medical services during the acute and subacute phases after the earthquake. A letter and the questionnaire were sent to hospitals with a DMAT on October 18, 2012, and the questionnaires were collected from October 18 to November 10, 2012. The questionnaire was sent to all areas in Japan, including those affected and unaffected by the earthquake. In this disaster, DMATs performed 2 types of medical service. The first was acute-phase services in the disaster such as triage, initial treatment, and patient transport, and the second was medical care in the affected area including public health service.From the questionnaires, we collected data that concerned the location and active period during which the DMATs provided medical support, the kinds of communication tools used, the transmission status of these devices, and the teams’ satisfaction with the communication situation.Level of satisfaction with the communication situation was divided into 3 categories: good, moderate, and poor. We defined good as being able to use the communication tool without a problem; moderate as having some problem with the communication tool, although the problem was not great considering the usual condition of communication; and poor as having a serious problem with the communication tool.Data from 196 teams were collected and could be evaluated. In the acute phase after the earthquake, the percentage of time the DMATs used each device as their communication tool was as follows: mobile phones, 30%; satellite phones, 23%; laptop computers, 21%; transceivers (radio-handy type), 15%; and landline phones, 11%.During the first 2 days after the earthquake, 154 DMATs were working at staging care units in conjunction with the control task force and in hospitals within the affected area. During this period, the satisfaction with mobile phones was the worst except for 6 teams working in the cities of Sendai, Fukushima, and Mito. Satisfaction with satellite phones was similar between DMATs using these phones in affected and unaffected areas. At 3 days after the earthquake, medical teams were offering medical treatment and public health services in affected hospitals or disaster shelters such as schools, gymnasiums, and public halls in the affected area.Mobile phones, laptop computers, and landline phones were often used at the staging care units or by the task force in unaffected areas within the first 4 days after the earthquake. During these first 4 days, mobile phone use was rated as poor to moderate, and satisfaction was very low . HoweverThe reasons for poor satisfaction with mobile phones, laptop computers, and landline phones were mostly due to disconnection from the network and poor reception. Poor operability affected the satisfaction with satellite phones; they could not be used to send large amounts of data, because they could only be used to communicate by voice.After the experience of the Great East Japan earthquake, the 196 responding DMATs indicated the following features were the most necessary in future communications equipment: easy to connect (187 responses), good battery life (162 responses), stability (156 responses), speed (123 responses), portability (121 responses), operability (95 responses), durability (92 responses), and the ability to transmit high volumes of data (65 responses).The Great East Japan Earthquake resulted in profound damage and confusion to the communication system of the affected area. On the first day after the earthquake, discontinued service gradually increased and reached a peak 2 days after the earthquake on March 13.The number of mobile phone base stations without service peaked at 2 or 3 days after the earthquake and then gradually recovered.When a landline phone or mobile phone switchboard handles a large number of calls, traffic control equipment senses this condition and a computer limits the number of calls automatically. The control of landline connections was regulated in this manner, and limited the total number of connections to 10% to 20%. Mobile phone connections were handled similarly; these connections were limited to 5% to 30% of all connections. However, few limitations were placed on the sending of e-mails by mobile phone. Thus, the problem with the communication system on the first day of the disaster was that calls from landline and mobile phones were limited by as much as 80% to 90% of normal traffic.Facilitation of communication within a disaster-affected area is an important problem, along with the ability to provide timely and relevant information and communication to the affected population from the unaffected area. In Japan, almost all hospitals and local authorities have priority landline phones for use in a disaster. In this survey, we could not distinguish whether a common or priority line was used for landline communications.Also in Japan, it is required that the multichannel access (MCA) radio system be used for hospital-to-hospital or hospital-to-local authority communications. MCA is a useful communication system because it is not affected by the automatic congestion control system that affects the public telephone network. However, the DMATs could not use MCA for their activities in the field during the disaster, and the system has limits on call times and locations where it can be used.In general, information derives from many sources such as mobile phones, computers using the Internet, landline phones, and radio and television.Huge natural disasters, such as earthquakes, typhoons, tsunamis, and volcanic eruptions, usually cause a shutdown of the communications infrastructure. Many types of communications equipment are affected by the power failures and destruction of communication lines. In this incident, much information was derived from often incomplete and sketchy voice communications provided by radio transceivers, satellite phones, and disaster prevention radios. Consequently, this situation resulted in a partial understanding of the situation on the ground, which produced operational and tactical errors.–The development of a telecommunication capability that guarantees multimodal data transmission including voice, data, imagery, and videos in severely compromised conditions has become of paramount importance in the United States.,,Difficulties with post-disaster telecommunications are not restricted to wired and fixed networks but affect wireless networks just as intensely: after transmission through a short radio wave path, wireless communication systems eventually connect to a ground segment through an access point. Nevertheless, wireless technology is probably the only modality offering the potential for a relatively rapid post-disaster reconstruction of at least an embryonic version of a functional and capable telecommunications infrastructure.In Japan, portable satellite phones were useful due to narrowed roads and the varied topography in the disaster area. The earthquake and tsunami destroyed buildings and roads, leaving large piles of rubble blocking the roads and railways and creating a situation in which cars and trucks could not gain access to affected areas for rescue or to deliver relief supplies.The findings of our survey showed that the portable satellite phone was found to be a useful communication tool during this disaster. During the immediate 4-day period after the disaster, service to many of the mobile base stations and landlines in the affected area was cut. In such conditions, satellite phones and transceivers become useful devices for communication.However, some problems were also experienced with the Japanese satellite phones after the earthquake. These problems included poor reception, line instability, and the fact that these phones could only be used for voice calls, which meant that large amounts of data could not be sent. Before the Great East Japan Earthquake, DMAT members were trained to operate with simple and small amounts of data. However, the responses from this survey identified a clear need for DMATs to be able to send a large amount of data during a large-scale disaster.To lessen communication problems in future disasters, we identified the following needed resources. Exclusive communication lines are necessary for medical emergencies. Also, many DMATs thought that social networking services (SNS) through mobile phones were useful and effective in the early days after the earthquake; they used Twitter and Facebook to communicate during the disaster. If mobile phones can be used during a disaster, SNS may be one a very useful means of communication.We also noted that a new satellite phone needs to be developed that connects easily to the communication network and Internet and provides good line stability. Finally, a system is needed whereby high volumes of data can be transmitted by satellite phone. Last year, a new battery-powered Japanese satellite phone was introduced that weighs only 1300 g with battery and can be used with the Internet. We expect that this phone will become a part of the communications equipment used in future disasters.In the acute phase after the Great East Japan Earthquake of 2011, medical teams mostly used mobile phones, laptop computers, and satellite phones to communicate. During the first 7 days after the disaster, the communications infrastructure was severely disabled, and it was difficult to use mobile and landline phones and computers with Internet service with the communication system. However, by the end of this initial 7-day period, these devices could be used in the affected area. The development of a new battery-powered satellite communication device that can transmit high volumes of data, is portable, and offers stable communication is necessary to ensure effective communications in the future during the acute phase of such large-scale disasters.This work as supported by Japan Society for the Promotion of Science KAKENHI grant No. 24659799.


Mitochondrial dysfunction represents a central factor within the pathogenesis of the Alzheimer's disease (AD) spectrum. We hypothesized that in vivo measurements of lactate (lac), a by-product of glycolysis, would correlate with functional impairment and measures of brain health in a cohort of 15 amnestic mild cognitive impairment (aMCI) individuals. Lac was quantified from the precuneus/posterior cingulate (PPC) using 2-dimensional J-resolved magnetic resonance spectroscopy (MRS). Additionally, standard behavioral and imaging markers of aMCI disease progression were acquired. PPC lac was negatively correlated with performance on the Wechsler logical memory tests and on the minimental state examination even after accounting for gray matter, cerebral spinal fluid volume, and age. No such relationships were observed between lac and performance on nonmemory tests. Significant negative relationships were also noted between PPC lac and hippocampal volume and PPC functional connectivity. Together, these results reveal that aMCI individuals with a greater disease progression have increased concentrations of PPC lac. Because lac is upregulated as a compensatory response to mitochondrial impairment, we propose that J-resolved MRS of lac is a noninvasive, surrogate biomarker of impaired metabolic function and would provide a useful means of tracking mitochondrial function during therapeutic trials targeting brain metabolism. Effectively all contemporary theories of Alzheimer's disease (AD) pathogenesis integrate impaired brain metabolism into the concert of factors precipitating neurodegeneration and clinical disability. One of the earliest observable metabolic impairments consistently linked with cognitive dysfunction across the AD spectrum is reduced brain glucose metabolism . StudiesHowever, numerous other well documented metabolic impairments have been noted constituting additional and likely overlapping pathological processes . TheIn analogous clinical scenarios presenting with disrupted mitochondrial function , laAs far as we are aware, only two previous MRS reports have attempted to quantify brain lac in AD. Stoppe et al.  reportedThe purpose of this study is to first reexamine whether brain lac could be quantified in vivo using noninvasive imaging in a group aMCI subjects. We focused specifically on the PPC because of the consistent reductions reported across the FDG-PET literature in aMCI (c.f. ). To cirFifteen community-dwelling aMCI individuals  were included  high-resolution T1 sequence (repetition time (TR)/echo time (TE)/flip angle: 6.5 milliseconds (ms)/3 ms/8°; matrix size of 256 × 256 and with 170 sagittally collected slices and a slice thickness of 1 mm), which was reconstructed in real-time to guide MRS voxel placement and offline hippocampal volumetric calculation.For each subject, a 2-dimensional J-rMRS acquisition sequence  was acquAn 8-minute resting state, echo planar fMRI sequence  was acquired to quantify functional connectivity across subjects. Five “dummy” volumes were acquired but excluded from analyses in order to stabilize T1 equilibrium effects. Physiological activity was collected using a custom-made LabView monitoring system with pulse oximetry and a respiratory belt.Short echo metabolites fits and quantification were accomplished using LCmodel. Metabolite uncertainties were expressed as % standard deviations (SD). Percent SD, FWHM , and S/N  were used as determinants of spectrum quality. Free-induction decays (FIDs) were input into the software package and were zero-filled to double the points and filtered with a finite discrete convolution to account for field inhomogeneities and eddy currents. During preprocessing the residual water signal was subtracted by using a decomposition-fitting algorithm. FIDs were then zero- and first-order phase corrected and smoothed using a 1.1 Hz exponential dampening filter. A nonlinear, least squares analysis estimated the metabolite concentrations and their uncertainties.The raw 2D MRS spectra  were processed offline. One of the spectra . Metabolite values were then normalized to correct CSF partial volume effects to = 100% brain tissue using: C = Co∗(1/(1 − FCSF)) where C = concentration, Co = metabolite concentration from LCmodel output, and FCSF = estimated fraction CSF in order.Partial volume corrections were made by calculating the fraction of cerebral spinal fluid (CSF) for each voxel. CSF, gray matter (GM) and white matter (WM) volume measurements of the PPC voxel were obtained through intensity estimates using the FANTASM MIPAV algorithm  Fourier transformation (FT) of the standard chemical shift dimension (t1), which was used to convert each FID to a frequency spectrum (f1). A second FT was then applied to the data along the incremented echo time or spectral dimension (t2), converting the oscillating phases of each of the coupled metabolite peaks to their respective frequency components (f2). After the 2D FT, spectra were converted to power estimates by adding the real squared to the imaginary squared output from the 2D FT. No phasing was necessary for the final FT output due to phasings/frequency shift corrections after the 1st FT to correct for phase imperfections/instabilities of the scanner. The 2D spectra were then plotted as contour plots Figures , revealiMPRAGE scans were reconstructed into a 1 × 1 × 1 mm 3D volume. Hippocampal volumes were determined on the MPRAGE through a combination of semiautomatic segmentation and extraction using FMRIB's Integrated Registration and Segmentation Tool (FIRST) in FMRIB's Software Library (FSL) version 4.1.5. Following FIRST extraction of hippocampal masks, an expert, blind rater (EHA) inspected and made manual adjustments when necessary so each mask conformed to established rules and boundaries .The ICV for each individual was calculated using a stereologic Cavalieri technique  implemenAt the individual level, preprocessing steps to minimize nonneural sources of noise included skull stripping, motion correction with FSL MCFLIRT using a six-parameter rigid body correction and a trilinear interpolation algorithm, with alignment occurring to the middle volume, physiological correction using RETROICOR (implemented through AFNI image processing software ), spatiahttp://www.fmrib.ox.ac.uk/fsl/feat), importing the coordinates from a previous FDG-PET study of glucose metabolism of preclinical AD as the seed point location [Z-scores.Posterior cingulate seed point functional connectivity analysis was conducted using FSL FEAT toolbox (location . IndividP < 0.05). We also computed significant relationships across rsfMRI PPC functional connectivity and PPC lac concentrations at the group level. Individual seed point rsfMRI time series were orthogonalized and analyses were carried out using a mixed-effects model (FLAME) incorporating PPC MRS lac concentrations as a covariate of interest. Corrections for multiple comparisons were carried out at the cluster level using Gaussian random field theory .Statistical relationships between metabolite concentrations and clinical cognitive variables were investigated using parametric partial correlations correcting for numerous known confounds including age and CSF and WM volumes within the MRS voxel. Statistical significance across regressions was determined at a standard alpha level . However, no significant associations were observed between lac levels and neuropsychological tasks not specifically tapping memory-related processes . However after removing CSF from the regression model, the correlations were significant , suggesting an interaction between PPC CSF concentration, lac concentrations, and hippocampal volume.Given the highly specific nature of the lac-memory associations, we sought to determine if lac concentrations across participants were associated with additional indices of disease progression. We first determined left and right hippocampal volumes from the high-resolution T1 MPRAGE. After adjusting for intracranial volumes (ICV), both the left and right hippocampal volumes were negatively correlated with PPC lac levels . PartialZ-score, 2.3; cluster significance, P = 0.05, corrected). Significant negative correlations between PPC functional connectivity and lac concentrations across the group were observed throughout the temporal lobe , whole-brain, voxelwise resting state time courses were extracted from a seed point placed at the site of maximum decrease of FDG-PET consumption across probable preclinical AD patients in a previous study , a locatral lobe . In partWe observed that J-rMRS quantification of lactate, the by-product of the anaerobic metabolic process of glycolysis, within a cortical node of the system for memory retrieval is significantly associated with common cognitive and imaging markers of disease progression  in a cohort of aMCI individuals. Previous MRS efforts have failed to detect differences or a lac resonance altogether , 22. ThiCollectively, we propose J-rMRS as a complementary and/or alternative metabolic biomarker to track the metabolic status in aMCI and possibly AD. MRS is completely noninvasive. Quantification of metabolically active biomolecules with MRS requires minimal time commitment while providing in vivo access to disease-sensitive tissue of interest. Consequently MRS is appropriate and routinely used in clinical diagnostics for metabolic disorders , 38. RelPPC lac levels were only significantly associated with cognitive tests of memory  which aMCI individuals are most likely to convert to AD , 44–46. Brain lac is produced from the conversion of glucose through glycolysis occurring to a large degree within the cytosol of astrocytes . The bypBased upon quantitative reports of metabolic pathology, similar physiological pressures are at play in aMCI all of which could lead to elevated lac in aMCI individuals further along across the disease progression. The conventional interpretation would predict that progressive mitochondrial dysfunction and/or heightened hypoperfusion-induced hypoxia routinely noted throughout the AD spectrum , 51 woulHowever, this hypothesis would need to be reconciled with the known reductions of glucose metabolism in the PPC , 26, 41 Numerous pharmacological and biobehavioral efforts are underway that aim to mollify and normalize metabolic instabilities in at-risk populations , 13, 51.We show that PPC lac is significantly associated with common aMCI markers of disease progression. Despite the overwhelmingly strong correlations, we cannot specifically conclude that PPC lac is elevated in aMCI until statistical comparisons can be made against age-matched controls presenting with normal memory and cognitive function. Rather we argue that PPC lac provides a means of noninvasively tracking the metabolic status of individuals presenting with significant memory complications. Moreover, we cannot rule out the possibility of elevated lac (as a function of disease pathology) as a more global phenomenon due to the fact that lac concentrations were not quantified from a control region. Given that FDG-PET abnormalities  have been observed within other association cortices , it woulHere we provide preliminary evidence that PPC lac quantified with J-rMRS is negatively associated with markers of disease progression in aMCI, a commonly assumed prodrome of AD. Based on lac imaging of mitochondrial and metabolic disorders, we propose that the well-established alterations in normal metabolic physiology that are linked to disease progression  likely give rise to exacerbated anaerobic glycolysis and detectable brain lac in aMCI. Accordingly, these relationships suggest that our lac concentrations likely reflect the metabolic status of the PPC, brain tissue that is exceptionally vulnerable to AD pathology. Future studies will need to combine FDG-PET and J-rMRS to determine if PPC lac is associated with the typical glucose consumption deficits. As a result of the completely noninvasive nature of MR imaging, J-rMRS provides a viable and likely preferable means of tracking metabolic function and dysfunction across multiple time points throughout the AD continuum. A link between PPC FDG-PET levels and lac concentrations may suggest the possibility that J-rMRS can augment or potentially supplant the metabolic monitoring capacities of PET. Moreover, future studies will need to link specific markers of mitochondrial dysfunction and/or cerebrovascular impairment with fluctuations in lac concentration across aMCI individuals. If quantitative studies of mitochondrial and cerebrovascular function are indeed tied lac concentrations, our results suggest an in vivo means of interrogating a metabolic process that is the current focus of a number of therapeutic trials , 51. A b


While there is a growing interest in the field of research translation, there are few published examples of public health interventions that have been effectively scaled up and implemented in the community. This paper provides a case study of the community-wide implementation of the Melbourne Infant, Feeding, Activity and Nutrition Trial (InFANT), an obesity prevention program for parents with infants aged 3–18 months. The study explored key factors influencing the translation of the Program into routine practice and the respective role of policy makers, researchers and implementers.n = 4), policy makers (n = 2) and implementers (n = 22), contributed to the data collected. Thematic analysis was conducted using cross case comparisons and key themes were verified through member checking.Case studies were conducted of five of the eight prevention areas in Victoria, Australia who implemented the Program. Cases were selected on the basis of having implemented the Program for 6 months or more. Data were collected from January to June 2015 and included 18 individual interviews, one focus group and observation of two meetings. A total of 28 individuals, including research staff  contains supplementary material, which is available to authorized users. Problem definition and Solution generation relate to program development; stage three, intervention testing, represents process and impact evaluation to determine program efficacy or effectiveness; and stage four, intervention replication, refers to subsequent studies in which effective programs are adapted for other settings to determine if and how similar outcomes can be achieved in different places and populations  linking into things …we thought, well, if parents are getting this information early they’re going to be more receptive to that information when settings and services are taking that up in kinder and long day care…thinking about it broadly and where it fits into the broader system is important too” (Coordinator 22a).The extent within which the InFANT Program fitted with the broader policy environment, as well as local programs and services was a central theme influencing translation opportunities. At the conceptual level, there was a strong tension between the Department’s focus on system level approaches to prevention with an emphasis on creating supportive policies and environments for behaviour change on the one hand, and programs, such as the InFANT Program, focusing on individuals/families on the other. This tension was resolved at the local level by demonstrating how individual programs, like the InFANT Program, fitted within and complemented a system based approach“we’re operating in the local government context, it is a challenge to implement things in a timely manner when there are plans and strategies …they go over a four year period and there is already resources allocated and prioritisation that’s occurred…So for example, you know, an Infant type program wasn’t necessarily a priority with Maternal and Child Health.” (Coordinator 17a).As discussed previously, the InFANT Program fitted well with the priorities and focus of local MCH services in most areas and this was essential for partnering with this service to deliver the Program. The Program was a ‘natural’ fit with first time parent groups running in all areas. These groups formed the basis of recruitment to the Program and provided a mechanism of linking parents to other services and programs locally, an important priority of both MCH services and local council. However, in one area, MCH services were running other concurrent parenting programs which were perceived to be competing with the InFANT Program for nurse and parent attention. The same area reported that initially it was difficult for MCH Service to be engaged as priorities and resources for the service had already been allocated on the basis of previous annual council business plans:“…we’ve got a program that is being developed on good evidence, it’s been demonstrated to be effective in this way…And then there’s reality and our ability to kind of change and adapt the Program for what is realistic for us into the future, that will be challenging for us and getting support from [the university] around that” (Coordinator 17a).As expected, all areas had adapted or proposed to adapt the Program to some extent from the original trial Table . Most co“I guess the randomised control trials just cannot be repeated and used in a practical sense. So …making recommendations …what are the critical things that can't be changed, and what are some of the things that possibly could be changed or could be adapted to maintain integrity for those programs, and possibly testing them in that way as well.” (Policy makers 27a).Implementers and policy makers called for clear guidelines from researchers about what were the core components of the Program required to maintain fidelity and effectiveness and what aspects could be adapted.What would be really nice is to test some of this stuff and actually be able to …gather some information about what’s actually happening to the participants, and what benefits are the participants getting” (Research staff 2b).“While researchers were considered to have ownership over the Programs’ intellectual property, there was some discussion about the value of having a centralised evaluation framework to monitor both program fidelity and outcomes, recognising that programs do not operate in isolation but are part of the broader system wide prevention effort.“…we’re really trying to embed it in the work of Community Health. So if Healthy Together [prevention areas] is not refunded or it gets less funding that it continues, so it’s embedded within the Allied Health teams,…Child and Maternal Health structure as well, so if we are to pull away that it continues “ (Coordinator 22a).All the areas with the exception of area four , chose to pilot the implementation of the Program in one or two neighbourhoods, or in one cohort of parents. The rationale for this was to test implementation processes and models and assess the feasibility and value of the Program before considering area wide dissemination. Three of the five areas largely embedded the delivery of the Program into existing roles within MCH or allied health services, with the view of setting up sustainability systems for program delivery beyond funding of prevention areas:So what we are hopeful [of] is that if we can have enough evidence and information that can create a very strong case for council and for budgets and for Maternal and Child Health nurses, the value of this. Then it may be sustained” (Coordinator 17a).“In contrast, two areas directly funded program delivery with the view of using the pilot phase to make a business case for continued funding through local council or other external sources.I think as a program by itself, I don’t know how financially and time-wise it can expand without combining it with other programs that are already there” (Program Facilitator 25).“Local implementers recognised the challenge of obtaining ongoing funding for the Program and hence were exploring options to further integrate the Program into existing service delivery structures, roles and existing programs.There was general agreement that further program adaptions were likely to be required to better integrate the Program into what was feasible locally. Adaptions being considered included running age specific group sessions open to anyone (rather than existing parent groups), reducing the number of sessions or delivering the Program via existing groups such as playgroups.I mean there's not going to be funding available to support and fund multiple programs, I doubt in the future to come…So it will just be about how that program can be integrated within the system” (Policy Maker 27a).“From a policy perspective, there were varying views about program sustainability. One view was that state or federal funding of programs was unlikely, hence programs need to be embedded within a complex system based approach to prevention that provided an infrastructure to promote sustainability and scaling up.“… [the Program] needs to be funded by government and delivered by local council. The Government should make a commitment to early childhood and the InFANT program is one of those things…It’s not fair that some local councils implement and others don’t, …it should be universal” (Policy Maker 28).Another view was that the InFANT Program should be a universal program with re-current government funding as part of an ongoing commitment to prevention in the early years:From the research staff perspective, maintaining and updating the Program website and materials and providing training to local implementers were ongoing activities that would require research staff time and hence funding. The short term nature of funding for researchers to be involved in these translation activities was a barrier to sustained program implementation.This study provides new insights into the respective role that policy makers, researchers and implementers play in the translation of a health promotion program into practice and factors influencing this process. As discussed below, a number of key themes were identified by these stakeholders as being important in the translation of the InFANT Program from research to community level implementation.In line with the findings from this study, the evidence of program efficacy or effectiveness has been found to be only one of many intervention characteristics influencing research uptake , 33, 40.The tension of balancing program adaption against maintaining program fidelity identified in this study, has been a commonly reported theme in the dissemination of research interventions into practice , 41–44. For researchers, avenues need to be explored to fund research translation activities, including initial consultation with communities around program adaptions and ongoing program support, such as the provision training and updating of program materials. This remains a challenge, with translation activities not traditionally part of research grant proposals when the study outcomes are not yet known. More recently, specific research translation grants have become more common and this may provide an avenue for researchers to work with community partners to fund such activities. In the absence of external funding, researchers are likely to need to consider program licensing fees to cover costs associated with supporting program delivery, as has been done with other widely implemented programs such as the Standford Chronic Disease Self Management Programs . At a syStrong partnerships between researchers, policy makers and implementers, as well as local partnerships were identified as critical to the translation of the InFANT Program into practice. Partnerships between researchers and end users of research, such as policy makers and practitioners, has been consistently shown to be a facilitator of research use and scaling up in previous empirical studies , 33, 37.The findings highlight the importance of having key individuals responsible for driving and coordinating research translation across the domains of research, policy, and practice. This case study is unique in that funding was provided to support the translation efforts. At the local level, the prevention workforce as part of the local prevention infrastructure was critical in engaging and working with key partners to deliver the Program. These coordinators undertook critical research ‘translation activities’ including exploring how the Program fitted with and enhanced existing services and how it could be best adapted to ensure sustained program delivery. In the scaling up of public health programs, consideration needs to be given to who will undertake these research translation activities at the local level. From a researcher perspective, research staff need funding to support the translation of research interventions into pre-packaged programs ready for community wide implementation. This study also demonstrates the important role that policy personnel can play in supporting research translation, highlighting the value of incorporating this component into existing policy positions. Previous case studies of research interventions with positive practice and policy impacts  as well The study findings point to important lessons regarding the scaling up and sustainability of program implementation. It is yet to be seen whether the InFANT Program can be scaled up and delivered on an ongoing basis in the absence of funding from the Department for the Program. Given that ongoing funding for any program at a state or local level was unlikely at the time of this study, it appears that embedding program delivery into existing service infrastructure will be critical for both scaling up and sustainability of the Program. With the strong competing demands on practitioner time and resources, it will be important that ongoing program evaluation be conducted to support a business case for continuation of the Program locally within existing services. This points to the importance of cost effectiveness analysis to be conducted as part of intervention trials to help make the case for investing in particular intervention programs. This is in line with a recent narrative review, which identified establishing monitoring and evaluation systems and costing and economic modeling of intervention approaches as important success factors for scaling up public health interventions . AlignmeThis study has a number of strengths and limitations. The strengths include the use of multiple varied case studies and cross case comparisons to explore the important influence of local context on implementation. We did however, only have one rural site participate in the study and the inclusion of additional rural sites may have resulted in different implementation issues emerging. We also did not include sites that chose not to implement the Program, which may have provided interesting additional insights into factors influencing initial uptake. Within cases, we interviewed a range of stakeholders including coordinators, program facilitators and those involved in supporting program delivery. There was variation however in the number of people interviewed across sites ranging from nine participants (site one) to two participants (site five) and this may have limited insights gained from some sites. The inclusion of researchers and policy makers involved in supporting program delivery as participants in the study was also a strength as it enabled a comparison of views across roles, providing important new insights from these various perspectives. While the study used a range of data collection methods including individual interviews, focus groups and recording of meetings involving key players, additional methods such as observation of program sessions, analysis of key documents and interviews with parents may have yielded additional insights. While all data was collected and analysed by a single researcher (RL), the trustworthiness of the findings was verified by participants on two separate occasions and the role and background of the research was made explicit.This study highlights the important and complementary role that policy makers, researchers and practitioners can play in the translation of health promotion programs into routine practice. New avenues need to be explored to comprehensively bring together researchers and end users at all phases of the research to practice continuum. This is likely to lead to the development of more feasible and scalable programs, assist in adapting programs to fit local circumstances, while maximising program fidelity and supporting implementation at the local level. Key recommendations for researchers arising from this study include the need to develop feasible and scalable interventions from the outset; to incorporate comprehensive process evaluation measures, including cost effectiveness to inform future program roll out; and to identify core program components that are important for program fidelity. Consideration should also be given to additional mediation and dose response analysis to be conducted to inform program fidelity recommendations. Recommendations for practitioners include the importance of having a key individual responsible for coordinating translation activities in the initial startup phase, engaging key delivery partners to enable the Program to be adapted to fit and become part of existing local service delivery infrastructure. Consideration needs to be given to ongoing program evaluation at the local level to help create a business case for sustained program delivery. At the policy level, funding for research translation activities and partnerships between researchers and end users needs to be built into existing research funding schemes.


Cystathionine beta-synthase (CBS) is a key regulator of sulfur amino acid metabolism diverting homocysteine, a toxic intermediate of the methionine cycle, via the transsulfuration pathway to the biosynthesis of cysteine. Although the pathway itself is well conserved among eukaryotes, properties of eukaryotic CBS enzymes vary greatly. Here we present a side-by-side biochemical and biophysical comparison of human (hCBS), fruit fly (dCBS) and yeast (yCBS) enzymes. Preparation and characterization of the full-length and truncated enzymes, lacking the regulatory domains, suggested that eukaryotic CBS exists in one of at least two significantly different conformations impacting the enzyme’s catalytic activity, oligomeric status and regulation. Truncation of hCBS and yCBS, but not dCBS, resulted in enzyme activation and formation of dimers compared to native tetramers. The dCBS and yCBS are not regulated by the allosteric activator of hCBS, S-adenosylmethionine (AdoMet); however, they have significantly higher specific activities in the canonical as well as alternative reactions compared to hCBS. Unlike yCBS, the heme-containing dCBS and hCBS showed increased thermal stability and retention of the enzyme’s catalytic activity. The mass-spectrometry analysis and isothermal titration calorimetry showed clear presence and binding of AdoMet to yCBS and hCBS, but not dCBS. However, the role of AdoMet binding to yCBS remains unclear, unlike its role in hCBS. This study provides valuable information for understanding the complexity of the domain organization, catalytic specificity and regulation among eukaryotic CBS enzymes. Methionine (Met) is an essential sulfur amino acid for mammals and its metabolism comprises two intersecting metabolic pathways: the methionine cycle, found in all tissues, and the transsulfuration pathway, which occurs in a limited number of tissues, but mainly in liver and kidney Saccharomyces cerevisiae CBS (yCBS) does not contain heme Drosophila melanogaster CBS (dCBS) does Considering the importance of CBS in sulfur amino acid metabolism, it is interesting that domain organization, quaternary structure and regulatory mechanism of CBS enzymes are not conserved across phyla . The N-t2S as a physiologically important gaseous signaling molecule and the implication of the two transsulfuration enzymes, CBS and cystathionine gamma-lyase (CGL), in H2S biosynthesis 2S-generating reactions ) enzymes 2S  into cystathionine (Cth) and water ]-serine was obtained from PerkinElmer Life Sciences.Unless stated otherwise, all chemicals were purchased from Sigma or Fisher Scientific. L- L-serine as the labeled substrate The CBS activity in the classical reaction was determined by a previously described radioisotope assay using [The thermal pre-treatment of the enzyme prior the CBS activity assay was performed as described before 2S-generating alternative reactions were measured using a colorimetric determination of H2S described earlier , 79,000 M−1cm−1 (yCBS) and 119,700 M−1cm−1 (dCBS). Scans were performed in a 4–100°C range at 2–4°C/min scan rates.DSC measurements were performed in a capillary VP-DSC microcalorimeter  as described previously k is the first-order rate constant. The expression used to fit the experimental DSC traces , vs. Temperature) explicitly considers the experimental chemical baseline Analysis of DSC transitions was performed in all cases using a two-state irreversible denaturation model XN is the mole fraction of native state, ΔH is the denaturation enthalpy and Cp(pre) and Cp(post) are the pre- and post-transition baselines, which are considered to be a linear function of temperature, Ea stands for the activation energy and Tm for the temperature of the maximum of the transition. The two first terms in the right-hand-side of m of each domain/protein using the Kirchoffs equation, to compare them with the theoretical ΔH values.Theoretical ΔH values were evaluated using the correlation between unfolding enthalpies (at 60°) and heat capacities on the protein size (in number of residues) described by Robertson & Murphy 2SO4, pH 3.0) and proteins were mixed with the matrix in sample:matrix (1:10 v:v) ratio and analyzed using either Synapt G2 (Waters) with a nominal resolution of 40,000 or LTQ Orbitrap XL (Thermo) with a nominal resolution of 100,000. In both cases, a minimum of 100 shots were averaged to build the final spectrum. The G2 spectrometer was calibrated before each experiment, using the peaks from polyethyleneglycol to ensure that the mass accuracy was better than 5 mDa.Samples containing purified hCBS (18.4 mg/ml), yCBS (43.9 mg/ml) and dCBS (12.6 mg/ml) were examined using MALDI (matrix assisted laser desorption/ionization) mass spectrometry as described previously with a few modifications ITC measurements were carried out in an ITC200 microcalorimeter  essentially as described previously 15, α16 and α17), while the dCBS structure (PDB #3PC2) revealed only two helices (αL and αCBSD21) http://gor.bb.iastate.edu/cdm/), we identified two helices in yCBS designated as αL1 and αL2. Presence of an additional helix in hCBS (α16) significantly differs from the unorganized central regions of the linkers in dCBS and yCBS, which may have implications for the flexibility of the linker and thus conformation of the regulatory domain towards the catalytic core as illustrated in We analyzed and compared the primary sequence and the secondary structure elements of the region connecting the two functional domains in the studied enzymes Fig. 2. To experimentally define the importance of the linker for a relationship between the catalytic and the regulatory domains, we introduced four and three STOPs into the sequence of dCBS and yCBS, respectively: S356*, K366*, L379* and P387* in dCBS and S323*, L345* and K370* in yCBS Fig. 2. As illustrated in In order to compare all three eukaryotic CBS enzymes side-by-side, we successfully purified three full-length  and two truncated (45 kDa hCBS i.e. hCBS V414* and yCBS L345*) CBS enzymes to homogeneity (>95%) carrying the permanent 6xHis tag at the C-terminus Fig. 4A 2S-producing condensation of Cys and Hcy, all three enzymes expressed higher specific activities compared to the canonical reaction  and Cys+Cys condensation (β-replacement) (2S and to form Cys was demonstrated by using either Ser as a substrate (Ser sulfhydrylase – SS – activity) or its activated forms, such as OAS and OPS (CS/OASS activity). As We assayed the purified full-length CBS enzymes and determined their specific catalytic activities in the canonical as well as alternative reactions depicted in reaction Fig. 5B.We have already demonstrated in our previous work, that a gradual thermal denaturation of hCBS resulted in enzyme activation due to irreversible denaturation of the regulatory domains To study the rapid activity loss of hemeless yCBS and the resistance toward thermal denaturation of the heme-containing dCBS in more detail, we employed DSC Fig. 7. In the case of yCBS, one unfolding transition was detected with a Tm of 59.9°C and a ΔH of 158±7 kcal/mol Fig. 7A.7 h, which is five orders of magnitude higher than for the catalytic domain of hCBS Unfolding of dCBS displays one main transition with a Tm of 70.8°C and ΔH of 388±3 kcal/mol and a second small transition with a Tm of about 55°C Fig. 7B.The presence of only one main transition in DSC profiles of yCBS and dCBS suggested the absence of an independent transition for the regulatory domain. When compared to hCBS Fig. 7C,Taken together, the MS analysis suggests that a significant stabilization of dCBS regulatory domain is not due to the presence of bound AdoMet within the CBS domains. Furthermore, high catalytic activity and unresponsiveness to AdoMet stimulation of yCBS as well as dCBS cannot be explained by the presence of bound AdoMet in the protein preparations.d = 5.0±0.5 µM). The lack of yCBS activation, the similar stoichiometries and binding enthalpies between the AdoMet site in yCBS and the high-affinity site in hCBS suggest those sites are alike, even though the reduction in the rate of denaturation (kinetic stabilization) exerted in yCBS by AdoMet is negligible. Taken together, yCBS binds AdoMet, but the significance of AdoMet binding in yCBS remains unclear.The MALDI-MS analysis suggested that yCBS may bind AdoMet. Therefore, we determined binding of AdoMet to yCBS and dCBS by using ITC Fig. 9. Saccharomyces cerevisiae, Drosophila melanogaster and Homo sapiens. Despite the fact that all three enzymes are from eukaryotes and have similar protein organization containing a catalytic domain and a tandem of CBS domains in the C-terminal regulatory region  are similar, their maximal reaction velocities (Vmax) differ substantially max value for yCBS reported earlier 2S in the studied reactions as is the AdoMet-stimulated hCBS. High catalytic activities of the investigated CBSs, mainly the yCBS, could translate invivo into a higher flux of Hcy through the transsulfuration pathway and thus production of Cys and subsequently glutathione. Increased flux rate through the transsulfuration pathway is important for maintaining the cellular redox balance 2S in these alternative reactions must be tightly controlled due to its strong reducing nature, regulatory and signal transduction function at low concentrations and cellular cytotoxicity at elevated levels The relaxed substrate specificity represents the most complex property of the CBS enzymes. Comparison of kinetic parameters for the canonical Ser and Hcy condensation as well as alternative H2S and either Ser (SS reaction) or its activated form required by the related OASS: OAS or OPS (CS reactions). Our results suggest that Cys production from Ser could be the only relevant Cys-producing activity of CBS enzymes with yCBS being more than 5-fold more active than dCBS or hCBS  that has been proved to favor binding of adenosine analogs in various CBS domain proteins We showed in our previous work that the regulatory domain of hCBS has two types of AdoMet binding sites with a different stoichiometry and function Fig. 9C 2S generator in human body As our previous structural work suggested Table S1Oligonucleotides used in this study.(DOCX)Click here for additional data file.


The Great East Japan Earthquake occurred at 2:46 p.m. on March 11, 2011. The epicenter was off the coast of Miyagi prefecture, and the magnitude of the earthquake was 9.0 with a maximum seismic intensity of 7.0. Although it has already been four years, victims continue to have complex problems. In the stricken areas of Miyagi prefecture, almost ten percent of the residents continue to live in temporary housing. Life altering events that force relocation and a change of living environment are known to adversely affect mental health. The purpose of this study was to examine the mental health of mothers of infants who experienced this disaster in Miyagi prefecture.We conducted a survey using The Edinburgh Postnatal Depression Scale (10 months) and The General Health Questionnaire-28, an efficient screening tool for psychiatric distress. Eight hundred eighty-six mothers of children born from February to October, 2011 in Miyagi prefecture were surveyed 10, 16, 24, 36 and 48 months after the disaster. Data were analyzed with the use of SPSS 21.0 J for Windows. The study was approval by the review board of ethics at Tohoku University.The questionnaire was answered by the following number of mothers at the specified months after the disaster: 677 at 10 months, 384 at 16 months, 351 at 24 months, 250 at 36 months and 193 at 48 months. Results at all time periods indicated a high prevalence of psychiatric distress among the mothers surveyed. The percentage of Japanese adults with high-risk GHQ-28 scores is 14 %, thus psychological distress among the subjects in the present study is considerably more widespread. General Health Questionnaire-28 scores were significantly higher for those mothers experiencing dissatisfaction in their marital relationships. We found that mothers have experienced severe mental distress since the disaster, which we think is a possible cause of depression that is leading to poor mental health.The results indicate that the upheaval caused by the tsunami affected the mental health of the mothers. Psychological distress continued to be prevalent up to four years after the disaster. Different factors were found to be associated with their distress. The most common issues were economic problems, dissatisfaction in the marital relationship, and no support with childcare. In addition, the Fukushima nuclear power plant incident occurred and numerous residents are still unable to return to their hometown. It is difficult to predict when these people will be able to return. Even in these harsh circumstances, 19,126 babies were born in Miyagi prefecture in 2011, and mothers are currently rearing their children in an earthquake-stricken living environment.The Great East Japan Earthquake occurred at 2:46 p.m. on March 11, 2011. The epicenter was off the coast of Miyagi prefecture, and the magnitude of the earthquake was 9.0 with a maximum seismic intensity of 7.0. The giant tsunami that accompanied the earthquake destroyed many houses  and took many lives , causing devastation over a large area of the eastern coast of the Tohoku region of Japan. Although it has been four years after the disaster, 23,132 people in Miyagi prefecture still reside in temporary accommodations  living in Miyagi prefecture at the time of the Great East Japan Earthquake. The study received approval from the Ethical Review Board of Tohoku University. Subjects participated in the survey of their own free will. We informed the subjects in writing that they would not suffer any disadvantage if they did not participate. Subjects who completed the survey questionnaire returned it by mail, with 886 women providing consent to participate (25 % response rate). Although the study began with these 886 women, a gradual decrease in respondents due to large scale relocation was observed, and we had difficulty in contacting them because the mailing addresses for the survey slips changed dramatically over time. However, the subjects who reported were from among these 886 women.Period of surveySurveys were conducted in January 2012, July 2012, March 2013, March 2014, and March 2015.Content of surveyThe survey inquired about the attributes and living circumstances of the subjects and their physical and mental state as mothers. To assess their physical and mental condition we used the Edinburgh Postnatal Depression Scale (EPDS) at month 10 after the earthquake, which is useful for the assessing postnatal depressive state. The maximum score on the EPDS is 30 points, and the cutoff score is 9 points in Japan. Respondents scoring 9 or higher are at high risk for postnatal depression and require careful observation. The EPDS can be used for up to six months after giving birth as a measure of postnatal depression .Accordingly, we used the General Health Questionnaire-28 (GHQ-28) to assess the level of psychological distress of mothers at month 16 or later after the earthquake. The GHQ-28 is a questionnaire that can provide information on somatic symptoms, anxiety/sleep loss, impaired social activity and depressive tendencies using a single scale. Respondents scoring 6 points or higher on the scale are considered probable cases of psychiatric disorder .Basic attributes of subjectsThe study subjects were women who were either pregnant or were in the early postpartum period (one month or less following delivery) during the earthquake. These women were raising children aged 0–11 months in the 10th month following the earthquake. This would mean that the subject would be a mother of a 4–5 years old child in the 48th month following the earthquake.SD = 4.9, range = 17–45 years). For 168 subjects (24.8 %) this was their first pregnancy and 496 subjects (73.3 %) had experienced at least one prior pregnancy. The average number of months after having given birth after the earthquake was 5.4 . Three hundred seventy-five subjects (55.4 %) were employed and 302 subjects (44.6 %) were unemployed.The family size and employment status of the women are provided in Table SD = 4.7), 34.0 (SD = 4.5), 34.5 (SD = 5.0) and 36.4 (SD = 4.6) years, respectively. At month 24, 129 subjects (36.8 %) had one child and 222 subjects (63.2 %) had two or more children.The mean age at months 16, 24, 36 and 48 after the earthquake were 33.0  were employed and 170 subjects (48.4 %) were unemployed. At month 36, 128 subjects (51.2 %) were employed and 119 subjects (47.6 %) were unemployed.Month 10 after the disasterOf the 677 subjects reporting at month 10 after the disaster, 145 postnatal women (21.5 %) had an EPDS score of 9 or higher. In addition, 10 subjects had a score of 20 or higher  Table .Table 2AMonth 16 after the disasterOf the 384 subjects reporting at month 16 after the disaster, 256 postnatal women (66.7 %) had a GHQ-28 score of 6 or higher  had a GHQ-28 score of 6 or higher  had a GHQ-28 score of 6 or higher Fig. .Month 48 after the disasterOf the 193 subjects reporting at month 48 after disaster, 110 postnatal women (56.9 %) had a GHQ-28 score of 6 or higher , 55.3 % (month 24), 55.6 % (month 36), and 56.9 % (month 48). The percentage of Japanese adults with high-risk GHQ-28 scores is 14 % , thus thAt months 36 and 48, marital dissatisfaction was a factor as well, but in addition there were financial worries. Ten months following the earthquake, the EPDS score of non-working mothers was higher than that of working mothers. The study was conducted at 24, 36, and 48 months following the earthquake and the percentage of working mothers increased at every stage. It is reasonable to assume that mothers had to engage in economic activities. Another aspect of damage to homes from the tsunami and earthquake is the financial burden it has imposed.Those affected by the disaster have been forced to raise their children in temporary housing, which provides a poor living environment. The financial situation of the child-rearing generation may make it difficult to find a place to live that offers a better environment. In addition, because many places of work were swept away by the tsunami, many people may have lost their place of employment or have jobs that have been suspended for long periods.The presence of someone to provide support with childcare can help mothers with newborn children maintain a healthy mental state. Scores on the GHQ-28 at month 48 were potentially influenced by having the support of the husband or the mother’s parents. In addition, friends can provide psychological support, even if they do not provide direct or material assistance.We conducted a survey, from month 10 after the Great East Japan Earthquake, of women who were pregnant at the time of the earthquake to investigate their mental health during subsequent child-rearing and factors such as postnatal depression and psychological distress. The following results were found.(1) At month 10 after the earthquake, 21.5 % of the subjects were experiencing postpartum depression. The factors associated with depression were damage suffered from the earthquake (tsunami damage/damage to houses) and loss of employment.(2) The percentage of subjects that were experiencing psychological distress at months 16, 24, 36, and 48 after the earthquake were 66.7, 55.3, 55.6 and 56.9 %, respectively, and the factors associated with their distress were marital dissatisfaction, financial worries, and not having childcare support.Based on this, even though four years have passed since its occurrence, The Great East Japan Earthquake is anticipated to continue to have a huge effect on the psychophysical condition of mothers raising children. This will necessitate continued financial aid along with childcare and educational support, such as ‘child rearing techniques and communication within the marriage’.


ABL1 rearrangements. Here, we report a case of ALL associated with a t RCSD1-ABL1 rearrangement. We show how ex vivo drug response profiling (DRP) may help choose among various therapeutic options.Tyrosine kinase inhibitor (TKI)-based targeted therapy has significantly modified the outcome for patients with chronic myeloid leukemia (CML) in chronic phase. However, resistance remains a major concern in blastic phase of CML and in Philadelphia chromosome positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). Second- and third-generation TKIs have been developed to overcome resistance to first generation drugs, but selecting the appropriate drug has become a challenge. Various tests are available to determine a patient's disease status in CML including the mechanisms of resistance when involved, but clinical experience is limited in ALL, especially those with poorly defined +, CD19+, CD10+ and weak expression of CD20. Positivity of CD33 was also noticed. Cytogenetics showed an uncommon t and involvement of ABL1 was confirmed by fluorescence in situ hybridization FISH (not shown). In agreement with the previous characterization of t,3 Real time-PCR analysis from leukemic cells showed the expression of the RCSD1-ABL1 gene fusion  and FISH analysis showed a 2% residual disease on 500 nuclei. She received consolidation based on hyperCVAD dasatinib strategy and 0.2% residual disease by FISH was achieved after two cycles of consolidation. A matched-sibling hematopoietic stem cell (HSC) transplantation with reduced toxicity conditioning was performed in February 2013. The patient relapsed (R1) in December 2013. Clonal evolution was observed with newly appearing t (35% of mitosis) and t (8% of mitosis) in addition to the t. She was treated with intensive chemotherapy . She achieved a second CR in January 2014, received consolidation chemotherapy but relapsed (R2) in April 2014 with 10% marrow blasts.On the basis of these results and the cases previously reportedex vivo functional evaluation of the DRP of the patient leukemic blasts at R1 was undertaken using our DRP platform4 with a specific focus on TKIs. Each drug was tested over a 1000-fold concentration range, allowing the establishment of dose-response curves and the identification of half-maximal effective concentration responses (M), whereas measurable responses to others were noted, notably to ponatinib (EC50=0.8 μM). This differential response to ponatinib as compared with dasatinib was confirmed in a secondary dose-response study , miRNA15 and miRNA16 . These losses are likely to be associated with the t event characterized in leukemic cells from the patient at R1  and at day 72 post-injection for samples obtained at diagnosis , and both progressed then after . Genomicnt at R1 .6 cells per mice). Fifty days after engraftment, blasts were counted and animals were homogeneously distributed into three groups receiving diluent (dimethyl sulfoxide), dasatinib  or ponatinib  as described.5 As shown in P<0.0001), and a significant regression in ponatinib-treated animals, both at day 14  and day 28 . On the basis of this, the patient was started on treatment with ponatinib monotherapy (45 mg/day) in May 2014 and achieved a CR2. She received a second HSC transplant from a HLA-haplo-identical donor in July 2014 but relapsed at day 77 post transplantation with 12% BM blasts. Ponatinib was restarted at this time. BM smear at day 92 showed 4% blasts. Signs of severe graft versus host disease were present at this time. The patient died of a septic shock 2 weeks later.One mouse from the group of animals transplanted with the relapse sample was killed at day 106 and bone marrow cells were transferred to secondary recipients .6In vitro, as compared with dasatinib, ponatinib exhibits significant superior inhibitory activity against mutated forms of BCR-ABL1, but is rather similar in efficacy against wild-type BCR-ABL1.8 The differential response of the patient's leukemia cells to dasatinib as compared with ponatinib in our case was not explained by the presence of mutation(s) in ABL1 coding sequences including T315I mutation, and is thus likely the result of either the distinct signaling capability of RCSD1-ABL1,3 the broad spectrum of ponatinib targets and/or the intrinsic spatial adaptability of the inhibitor to bind different conformational states of the kinase.8 Indeed, the RCSD1-ABL1 fusion contains only a truncated ABL1 protein starting from the exon 4-encoded region, and thus results in a fusion protein that lacks the SH3 regulatory module and retains only part of the SH2 domain, which is involved in the regulation of the kinase activity of BCR-ABL1.9 This difference in structure may differentially impact dasatinib and ponatinib efficacy in contacting the active site of the ABL1 kinase. Current molecular studies are undertaken to study these hypothesis. Interestingly, ponatinib anti-leukemic activity was not affected by the occurrence of t and t at relapse.To our knowledge, this is the first report of ponatinib successful treatment of a t B-cell ALL. The superior efficacy of ponatinib as compared with dasatinib on the patient's leukemia cells, both 11 suggest that precision medicine may be better based on both genomic data and drug response (including ex vivo) data than on only one of these.More generally, this report, together with others


In this undertaking, Computer-Aided-Design (CAD) environments should play a central role for facilitating the design. Although, CAD environment is widely used to engineer artificial systems the application in synthetic biology is still in its infancy. In this article we address the problem of the design of a high level language which at the core of CAD environment. More specifically the Gubs  language is a specification language used to describe the observations of the expected behaviour. The compiler appropriately selects components such that the observation of the synthetic biological function resulting to their assembly complies to the programmed behaviour.The field of synthetic biology is looking forward engineering framework for safely designing reliable  After introducing the main features of the language . Notice that attributes are defined in the first lines of the program: e.g., protein reaction, gene network). For example, the activity of gene regulation may correspond to the observation of different thresholds in the RNA concentration inducing different regulatory activities  or a range of values, such as LaCI meaning that the agent is active in this concentration range. in Cro(high) Cro(low).Basically, a causal relation represents the control of an agent over another. In Fig. An historical definition of causality proposed by Hume , is formrm Lewis  from thece: if e occurs then c has occurred in a recent past.e occurs then c has occurred in a recent past and is still present in this moment.e occurs then, either e has occurred in a recent past or else e hasn’t occurred in a recent past and c then necessarily appeared.In the sequel, we define the strong inhibition denoted The definition of a causal relation will be refined to address the scheduling constraints between cause and effect to be able to more finely select the components corresponding expected behaviour. The causal relation primitives are defined as follows , Cro(low) and CI(low) by Contexts. In order to describe interactions of the program with the environment, we introduce here the notion of context. This notion allows us to clearly differentiate the interactions of the Gubs program from those external to the system described by the program. Precisely, a context refers to a stimulus acting on the system that can be either environmental conditions and external signalisation. The application of a k context to a set of causal relations d is written [k]d where k is an agent  meaning that the causal relations belonging to d are triggered only if the k context is present.Compartments. Finally, a Gubs program is a set of attributes definition, observation spots and causal relations encapsulated into contexts. In order to describe the spatial organization of the biological system, we introduce a last element in the language, compartments. A compartment encapsulates a set of causal relations, making them local. For example, C compartment.Gubs. Technically, the denotational semantics of Gubs is based on multi-modal hybrid logic(HL) translating a Gubs program into a formula  and G(Mid), and G(High), irrespective of the intermediate stages of evolution that occur between the both, nor the repetition identical events. We will therefore adopt a different representation called an history from a chronological division of a trace in several periods. An history is an intentional division of a trace to highlight the relevant events emphasizing the desired properties of the behaviour of the biological system. Given a trace Validation of properties is primarily based on a set of experiments measuring the evolution of physical quantities related to agents that qualifies the states of agents. A mentclass2pt{minimLow to High for G is the following discrete time intervals . The resulting history is:Gubs program operates on histories. Formally, An history corresponds to a Kripke . The variables in each world (node) correspond to events (agent’s state). Hence, An history “explains” a Gubs program if it satisfies the formula resulting from its interpretation. In some cases, an history represents a partial result of the functionalities of the program only and does not satisfy the formula interpreting the program. Hence, to validate the program it is required to gather different histories such that they will form a Kripke model satisfying the formula interpreting the program. Notice that Tableau method can generate these models  A program Qbehaviourally includes another program P, if and only if the interpretation of the latter is a logical consequence of the interpretation of the former: is based on a syntactical comparison between the source and the assembly of component programs. Hence, the compilation process will be defined by a formal system called the es Table  denoted,mentclass2pt{minimRule (Inst.) describes the fact that an observable instance of a part of a component in the library is functionally synthesized. Rule (Com.) expresses the commutativity of the assembly. Rule (Cont.) contracts the redundant formulation of programs. Finally, Rule (Asm.) details the conditions for an assembly of two components, each representing a functional synthesis of a part of the designed function. Another set of rules Adrien  not presACI-unification  will not obviously cause the unification failure.ACI-Unification is an NP-Complete problem and the algorithm explores all the possibilities until an unification is found or fail . GGC han et al. .Gubs language occupies the intermediary level dedicated to cell entity behavioural programming. The tower could be completed by methods ensuring the safety of the generated system by a verification of the non-toxicity and simulation for accurately assessing its performance. The integration of these methods could rely on the realization of a connection with existing tools based on a translation of a Gubs program into formalism dedicated to toxicity checking as in Giusto et al. (In the future, we could imagine that the design in synthetic biology will require different programming layouts based on different language paradigms structured in a tower of languages and addressing different levels of integration in biology. From a language describing collective operations on cell colonies (Giavitto et al. o et al.  and lango et al.  or Biocho et al. .


During times of limited funding and health care challenges, hospitals and clinics must continue their commitment to give excellent, ‘gold standard’ care to bereaved families. Since families only get one chance to “do it right” when their baby dies in miscarriage, stillbirth, and infant death, they deserve excellent care. A premier perinatal loss program needs solid leadership; administrative support; financial resources; system-wide communication and coordination; and well-trained and supported staff, who can then offer individualized patient-based, comprehensive, and compassionate care to bereaved families. ,2Hospital management that supports the development, continuity, and ongoing financial support of a well-planned and implemented hospital-wide perinatal loss program, is the first component found in a Gold Standard program. All areas of the hospital that work with perinatal loss, clinics, emergency departments, surgical services, and the birth center, must be included in the program. Financial support allows for staff hours dedicated for bereavement support and budget for education, training, materials, resources and events. The second component of the program is that all staff is appropriately and routinely trained, mentored, and supported, and that the program is based on comprehensive national standards, protocol, and policies . Annual,The final component of the program is that there is an integrated process that offers seamless, excellent care to each and every family from the time of their diagnosis, during their hospital stay, and with ongoing care by their medical provider team, including clinic points of contact. Initial communication and referral upon diagnosis is critical for informing and educating families regarding their options . When poBedside care of the family includes involvement of extended family and friends, sibling care, memory making, and education of parents regarding handling of baby’s body and funeral planning ,7. ConsiBarriers to the Gold Standard program are related to a lack of financial resources, staffing issues and needs, healthcare provider’s lack of interest, and communication challenges. However, a designated individual, who is responsible for advocating and directing the program, can work with leaders and providers to put bereaved families first and help them honour the lives of their babies. .Perinatal Loss Gold Standard manual, which includes checklists, assessment tools, and policy templates, was presented as one option to aid hospitals in developing and improving their own program [A  program . The RTS program .


Although many physical activity (PA) programs have been implemented and tested for effectiveness, high participation levels are needed in order to achieve public health impact. This study aimed to determine participation levels of PA programs aimed to improve PA among community-dwelling older adults.We searched five databases up until March 2013  to identify English-written studies investigating the effect of PA programs on at least one component of PA  among community-dwelling populations (i.e. not in a primary care setting and/or assisted living or nursing home) of persons aged 55 years and older. Proportions of participants starting and completing the PA programs  were determined.The search strategy yielded 11,994 records of which 16 studies were included reporting on 17 PA programs. The number of participants enrolled in the PA programs ranged between 24 and 582 persons. For 12 PA programs it was not possible to calculate initial participation because the number of older adults invited to participate was unknown due to convenience sampling. Of the five remaining programs, mean initial participation level was 9.2% (±5.7%). Mean sustained participation level of all 17 programs was 79.8% (±13.2%).Understanding how to optimize initial participation of older adults in PA programs deserves more attention in order to improve the population impact of PA programs for community-dwelling older adults.The online version of this article (doi:10.1186/1471-2458-14-1301) contains supplementary material, which is available to authorized users. The worldwide population is ageing rapidly. Between 2000 and 2050, the world’s population over 60 years will double from about 11% to 22% , and mayHigh initial and sustained participation in PA programs is important for achieving public health impact . HoweverSpecified search strategies were developed for five bibliographic databases up until March 2013: PubMed, PubMed publisher, Cochrane Library, EMBASE, and Web of Science. The full electronic search strategy for Pubmed was:((aged NOT (boy* OR girl* OR child*OR month* OR middle)) OR elder* OR senior* OR (old* AND (adult* OR people*))) AND (((communit* OR home) AND (living OR dwell* OR residen* OR based OR population*)) OR ) OR in home OR at home OR domestic*))) AND  AND (program* OR intervention* OR experiment* OR (group AND lesson*) OR government*) AND The search strategies for the other databases can be found in the Additional file Studies were included when they were: 1) written in English; 2) conducted among community-dwelling populations (i.e. not in a primary care setting and/or assisted living or nursing home); 3) among persons aged 55 years and older; 4) described programs targeting at least one component of PA ; and 5) evaluating the effect of at least one component of PA . Studies were excluded when these: exclusively targeted older adults with a specific medical condition , focused on cost-effectiveness; and/or reported on study protocols only.One reviewer (MvdD) performed the initial selection of titles and abstracts in the literature search. A second reviewer (AE) was consulted to screen a random sub-set, and in case of doubt to discuss until agreement was reached. All corresponding authors of included studies were contacted and reference lists of previously published systematic reviews were checked to make sure all relevant articles were captured. This extra search did not result in extra studies eligible for inclusion.A data extraction form was used to collect information on participation levels (dependent variable) and characteristics of participants and program characteristics (independent variables). Characteristics of participants included sex distribution  and mean age of the participants. The program characteristics included: sampling method (probability sampling vs. convenience); method of recruitment; location (home-based vs. group-based); content ; duration (months); number of contacts; supervision (yes vs. no); and  group size. Probability sampling is a method of sampling that utilizes some form of random selection, whereas convenience sampling is a technique where subjects are selected because of their convenient accessibility and proximity to the researcher (e.g. inviting through advertisements). One reviewer (MvdD) performed the data extraction and a second reviewer (AE) verified all extracted data. In case of doubt, data were discussed until agreement was reached.In order to calculate participation levels the following measures were used, numbers of persons that: 1) were invited to participate (i.e. available sample); 2) started the PA program; and 3) completed the PA program. By using these measures initial and sustained participation levels were calculated. Initial participation was defined as the number of participants that enrolled in the program divided by the number of persons invited to participate. Sustained participation was defined as the number of participants who completed the program divided by the number of participants that started the program .Studies reporting significant effects of PA programs on PA outcomes are more likely to be published as compared to studies in which no significant results were found. However, it is unlikely that this publication bias would affect our results since we focused on participation level as the main outcome, and no differences in participation level are to be expected between effective and non-effective PA programs.effective PA programs only. An effective PA program was defined as a program for which a significant effect on at least one PA outcome was reported. Pearson correlations were calculated in order to investigate the correlation between participation levels and: gender distribution of the participants; mean age of the participants; program duration; and group size.Descriptive statistics  were used to summarize the results. Mean sustained participation level was calculated for all PA programs as well as for The search strategy yielded 11,994 records. After removing duplicates, 6,759 records remained which were screened based on title and abstract. Sixteen studies reporting on 17 PA programs, were included which were published between 2002 and 2013 since no studies prior to this time met the inclusion criteria . In three programs only females participated –16. Of tProgram characteristics that showed the most variation were the location at which the program took place and the content of the program. Six programs were home-based , 17–20, The number of participants enrolled in the PA programs ranged between 24 and 582, with a mean of 174 (±165). It was not possible to calculate initial participation levels for 12 PA programs, because their applied sampling methods (e.g. convenience sampling) made it unclear how many older adults were invited to participate. The mean initial participation level of the five remaining PA programs was 9.2% (±5.7%), with a range between 1%  and 16% effective PA programs [Between 24 and 424 mean 129 ± 117) participants completed the PA programs. The mean proportion of persons completing the program was 79.8%  ranging between 50.3%  and 100%programs , 27–29 t ± 117 paThis systematic review identified 17 PA programs that aimed to improve PA among community-dwelling older adults. The mean proportion of participants starting the program  was 9.2%, but could only be calculated for five PA programs. The 17 PA programs had a mean sustained participation level of 79.8%. No significant correlations were found for participant or program characteristics with sustained participation level.The mean initial participation level of 9.2% is difficult to interpret without additional information about the method of recruitment and effort or resources invested. For example 9.2% seems high when recruitment is done by putting up an advertisement in a community building, but low when mailing people personally and subsequently phoning them. Although for public health impact it is important to have insight into the number of older adults that would participate when providing a PA program , for 12 effective PA programs was lower than the overall mean. This could imply that the effective programs have a smaller overall population impact when implemented on a larger scale as compared to programs with smaller effects but higher sustained participation levels [The overall mean sustained participation level of almost 80% found in the current systematic review was higher than expected, as lower participation levels have been found among children , 34, andn levels –13.No significant correlations were found for participant or program characteristics with sustained participation level which may be due to the small number of studies that were eligible for inclusion. Although the size of the correlations indicated that a low mean age of the participants, high proportions of females participating, short duration of the program, and a small group size are likely to increase levels of sustained participation, these factors should be investigated further as potential determinants of sustained participation. Jancey et al. (2007) showed that can be related to low socioeconomic status, overweight, low PA level at the start, low walking self-efficacy, and loneliness may also be related to low sustained participation levels of PA programs among older adults .Calculating initial participation levels of PA programs aimed to improve PA levels among community-dwelling older adults is hindered by high levels of convenience sampling. Sustained participation among those who started participating in PA programs is high. A low mean age of participants, high proportions of females participating, short duration of program, and a small group size are likely to increase levels of sustained participation. In order to improve the population impact of PA programs among community-dwelling older adults, more knowledge is needed into how initial and sustained participation levels can be optimized.Specified search strategies.(DOCX 15 KB)Additional file 1: