A comparison between symmetric and asymmetric MZI sensors and the advantage of the latter is also mentioned.This work presents a loop terminated asymmetric Mach–Zehnder interferometer (LT-aMZI) structure based on the widespread silicon-on-insulator (SOI) platform. Four different path length differences of the LT-aMZI, which correspond to free spectral ranges (FSR) from 0.8 to 6.4 nm, are designed. These designs are compared to the common asymmetric Mach–Zehnder interferometer (C-aMZI) and are shown to be more compact. These devices are suitable for optical filtering as well as wavelength demultiplexing (WDM) applications. A compact analytical model is derived that accurately describe the operation of the LT-MZI devices. The designs are then fabricated using Electron Beam Lithography (EBL) and characterized. The experimental data show good agreement when compared to the simulation results. To our knowledge, this is the first time LT-aMZI fabrication and characterization. Moreover, the LT-MZI spectrum can be tuned not only by the interferometer arms phase difference like C-MZI, but also by using its directional couplers coefficients, forming a spectral tunable filter. Finally, we determine the performance parameters of optical sensors and modulators and show that our proposed LT-MZI structure will enhance the sensor figure of merit (FOM) and modulator speed, power consumption and V Silicon on Insulator (SOI) is a widespread silicon photonics technology which supports submicron optical waveguides due to its high refractive index contrast. This platform supports many other optical components and devices such as Y-junctions, couplers, interferometers, gratings and resonators11 which form the building blocks of many photonic circuits and systems13.The rapid growth of Si-photonic industry over the past two decades, driven by the huge investments in the CMOS electronics industry, has made this new technology a potential cost effective solution for many new applications such as LIDAR systems14, optical switches16 and electro-optical modulators19 to biosensors21. One of the advantages of MZI is its high immunity to temperature fluctuations when compared to resonators22. However, they suffer from large footprint. This large footprint become critical when many MZIs are required on the same chip and when very large length is necessary for achieving certain performance.One of the most widely used optical devices is the Mach–Zehnder Interferometer (MZI). The simplest MZI configuration consists of two Y-junctions, one acts as a beam splitter and the other as a beam combiner and two waveguide arms. MZI is used in wide range of applications from wavelength division multiplexers24. Our structure is the integrated version of the fiber reflection MZI (FRMZI) proposed by CA Millar et al.25. This configuration allows the propagating light to travel back and forth in the interferometer arms rather than just once; resulting in smaller footprint and boost the performance of the conventional MZI in different applications. This paper is an exhaustive extension to our previously published work26.In this paper, we propose loop-terminated asymmetric MZI (LT-aMZI) design based on the widespread SOI technology. The LT-MZI is simply constructed from the conventional MZI with directional coupler (DC) splitter and combiner and a loop reflector25, several important advantages are added. Mass production using widespread CMOS process will result in significant reduction in the cost of such devices. In addition, easily on-chip integration of a whole system with source, detector and electronic parts allowing for compact handheld devices. Hence, integrated high performance optical sensors, electro-optical modulators and even gyroscopes using the loop reflector24 can be implemented using our structure. Similar structures to our proposed one were published previously. In28, the same LT-MZI structure was presented but in the symmetric configuration and was used as a mirror with controllable reflectivity which then used by27 to construct a Fabry–Perot cavity. While in29 Michelson interferometer was proposed employing two loop mirrors compared to just one used in LT-MZI, i.e. more compact. Also, in30 authors use asymmetric LT-MZI together with ring resonator to construct a Vernier sensor. Their work is based on numerical design and optimization using the transfer matrix method. Here we have derived a simple and compact analytical model that accurately describes the LT-aMZI structure rather than the complex transfer matrix method used in30. Using our structure, we have designed optical filters and compared these designs with the common MZI showing our designs to be more compact. Simulation of the optical filter designs have been performed using Lumerical Interconnect31 which is fast circuit simulation software. These LT-aMZI designs have also been fabricated and characterized for the first time, with measurements showing good matching with Interconnect simulations as well as the analytical model. In addition, unlike conventional MZIs and Michelson interferometer in29 the transmission spectrum of our proposed LT-MZI can be engineered using the DCs coupling coefficients and not just by the interferometer arms phase difference, which can be used as spectral tunable filter. Finally, using our compact model we show that our proposed LT-MZI structure enhance significantly the performance of optical sensors and electro-optical modulators that were using the widespread conventional MZI. Analysis also shows that the asymmetric MZI (aMZI) configuration offers an advantage over the symmetric MZI (sMZI) in sensing as both sensitivity and FOM can be engineered independently in aMZI, which is not applicable in the case of sMZI and also ring resonators.By integrating the structure presented in1 and φ2 and then another DC is used to combine the two arms waves. The outputs of the second DC are connected through a bend waveguide utilizing loop reflector as the one in24. This loop reflect the waves back to the interferometer and the output is taken from the first DC as shown in Fig. DC, and loop reflector. Hence, the transmission of our proposed LT-MZI can be derived using the C-MZIDC forward tfrw and cross tcr transmission coefficients shown in Fig. Our proposed loop terminated asymmetric Mach–Zehnder Interferometer (LT-aMZI) is shown in Fig. The intensity transmission of our LT-MZI can be expressed as:1, b1 are the forward and cross coupling coefficients of the first DC and ɑ2, b2 are the forward and cross coupling coefficients of the second DC. Also, φ1 and φ2 are the phase shifts of the upper and lower arms of the interferometer, respectively. We here focus on asymmetric  MZI, i.e. arms with different lengths L1 and L2 and with identical waveguides at both arms, i.e. β1 = β2 = β. Hence, φ1 = βL1, φ2 = βL2 and Δφ = φ2 − φ1 = βΔL with ΔL = L2 − L1 is the interferometer path length difference.res), free spectral range (FSR) and full width half maximum (FWHM) as:From Eq.  we can seff and ng are the waveguide mode effective index and group index, respectively. Note that, FWHM is the spectral width Δλ with transmission greater than or equal to Tmax/2, which can be derived from Eq. . In addition, some results have been verified with analytical modeling Eq.  shown in Table ling Eq.  showing Y simulation with ΔL = 44.7 µm. From this result we can see that, as mentioned before, for the same interferometer path length difference ΔL the FSR of the LT-aMZI is half that of the C-aMZI. The DC and y-junction used in the simulations are optimized designs from Lumerical E-Beam Compact Model Library (CML)33 that result in even power splitting at both outputs over 100 nm bandwidth around 1.55 µm wavelength.Figure 34 on standard SOI wafers with silicon device layer of 220 nm. We fabricated three copies for each design to account for the fabrication tolerance. Figure 2 clad. As can be seen, bend waveguide loop is crucial in determining the device footprint thus, LT-MZI structure is favorable over the Michelson interferometer where two loop mirrors are needed and hence will increase the footprint significantly. A tunable laser is used to span the wavelength region from 1500 to 1600 nm. A polarization maintaining fiber array containing 4 fibers separated by 127 µm is used to couple light in and out of the chip through the grating couplers while a detector is used to measure the output power from the fibers. The GC used is also from the library in33. A typical SOI MZI have around 0.5 dB losses (with arms’ length in micrometer dimensions)36 and we can expect roughly that our device losses will be twice that value.The dimensions of the fabricated LT-aMZIs designs are included in Table The measurement results of the fabricated designs are compared with different modelling methods to ensure the feasibility of the proposed LT-aMZI structure. Figure As mentioned above, the four designs, ΔL = 44.7 µm, 89.4 µm, 178.8 µm and 357.6 µm, were fabricated with three copies for each design to account for the fabrication tolerances. Figure Figure 30 however, they just investigated three sets <ɑ1 − ɑ2> of DCs coefficients and they studied the effect of fabrication tolerances for this specific sets. Here, we discuss the different possible trends of the LT-MZI transmission spectrum which occur due to specific relation between DC1 and DC2 coupling coefficients and which are of interest for spectral filter applications.Another unique characteristic of our proposed LT-MZI is that its transmission spectrum can be tuned using the DCs coupling coefficients, working as spectral tunable filter. While this effect is mentioned in12 = ɑ22 = 0.5). In this case, H = 0 and the transmission spectrum reduce to cos2 function, see Eqs. . Modulation speed is mainly limited by the RF losses, walk-off between the electrical and optical signal and RC time constant. On the other hand, energy consumption are determined by the RF losses, capacitive loading and the 50 Ω termination resistor. For state-of-the-art modulators such as the ones based on silicon organic hybrid (SOH) platform40, the modulator’s length can be as small as 500 µm. At such compact length RF losses are reduced38 and the modulator behave as a lumped element that can be derived without the 50-Ω termination40. Accordingly, walk-off is negligible and RC time constant is the main bandwidth limitation, f3dB = 1/2πRC38. Also, the energy consumption is reduced and determined mainly by the capacitive load40, which is proportional to CV2. Hence, decreasing the capacitance of such modulators will further enhance their performance.Our proposed LT-MZI design is very promising to enhance the performance of electro-optical modulators that use C-MZI, similar to the Michelson interferometer modulator proposed in1 = L2 = L, where the applied voltage V changes the interferometer arms effective index and hence switching the output power from high to low. For LT-aMZI and C-aMZI with Now assume a symmetric  interferometer, LHence to switch from ON to OFF we need:eff is proportional to the applied ΔV. For the same waveguide configuration and same applied voltage V, both C-MZI and LT-MZI will have the same Δneff, Hence, Eq. (5) shows that the Vπ × L term will be two times smaller for our proposed LT-MZI. This shows that LT-MZI design is more compact (LLT-MZI = LC-MZI/2). On the other hand, the capacitance of the modulator expressed by Eq. (LT-MZI = CC-MZI/2). Accordingly, for compact state-of-the-art modulators this will effectively reduce the energy consumption and increase the modulation speed for the LT-MZI design.r is the permittivity of the capacitor dielectric material, d is the conducting plate separation, h is the waveguide thickness and L is the interferometer arm’s length.Δnd by Eq.  will als41:med is the refractive index of the sensed medium. The resonance wavelengths for LT-aMZI and C-aMZI are:eff,sens, Lsens and neff,ref, Lref are the effective index, arm length of the sensing and reference arm, respectively. Hence, the wavelength sensitivity of both interferometers can be derived to be:wg = dneff/dnmed is the sensing arm waveguide sensitivity. So, both LT-aMZI and C-aMZI configuration have the same wavelength sensitivity S for the same waveguide structure and same dimensions. This sensitivity increase as Lsens → (nref/nsens) × Lref. On the other hand, FWHM is expressed as:The main performance parameter of optical sensors is the figure of merit (FOM) which is defined assens → (nref/nsens) × Lref. Accordingly:The FWHM of LT-aMZI is half that of C-aMZI, while both increase as Lsens and its waveguide sensitivity Swg. In general, aMZI  sensor offers advantage over the sMZI. For the symmetric LT-MZI (LT-sMZI) where Lsens = Lref = L we have:FOM of LT-aMZI is double that of C-aMZI with both proportional to sensing arm length Lref and Lsens, Eq. (9) and Eq. (wg and neff), while in the case of symmetric MZI the sensor sensitivity is determined only by the waveguide structure, Eq. (Hence, for the LT-sMZI the sensitivity is independent of L while FWHM decrease as L increase and FOM expression is the same as in the case of LT-aMZI. However, in the asymmetric MZI sensor you can engineer both S and FOM independently using L and Eq. , and indure, Eq. . This isIn conclusion a LT-aMZI structure using the popular SOI technology have been proposed, this design is a compact version of the widespread C-aMZI. Four designs for optical filters and WDM applications with different FSR were implemented and characterized both numerically and experimental as well as analytically using our derived compact model. The different modelling techniques show good matching with the experimental results of the fabricated devices. It was also shown that, our LT-MZI spectrum can be tuned by changing its DCs coefficients for spectral tunable filter application. Finally, using our compact model the interferometer proved to have better performance when compared with the widespread C-MZI in sensing and modulation applications, and we also demonstrated that LT-aMZI sensor configuration is preferable over the LT-sMZI.34 on standard SOI wafers with silicon device layer of 220 nm. We fabricated three copies for each design to account for the fabrication tolerance.The designs were fabricated at the UW NNCI Washington Nanofabrication Facility using Electron Beam lithography43. A tunable laser is used to span the wavelength region from 1500 to 1600 nm. A polarization maintaining fiber array containing 4 fibers separated by 127 µm is used to couple light in and out of the chip through the grating couplers while a detector is used to measure the output power from the fibers. Also note, that the SEM photos are taken before depositing the SiO2 clad.The device measurements were performed by the team of Lukas Chrostowski at The University of British Columbia and by Maple Leaf Photonics


To predict the trend of AIDS in specific age groups and to determine the objective population for AIDS screening, this study explored the three transmission routes and characterized each patient group using the APC model based on the whole, local, and immigrant populations in Zhejiang, China.The data recruited in this paper was obtained from the national Comprehensive AIDS Prevention and Control Information System - Antiviral Therapy Management database and the Chinese Disease Prevention and Control Information System and the Statistical Yearbook of Zhejiang, China. An APC model was used to estimate the impact of age, period, and cohort on the incidence of AIDS, as well as to predict the AIDS incidence in specific age groups based on different sexes with different transmission routes.The AIDS incidence peaked in males aged 20–35 years; the incidence of males was higher than that of females due to the impact of period; obvious cohort effect was observed among the immigrants. In the whole and local populations, the incidences of males in all age groups and females in both the 35-year-old group and the whole age group were predicted to increase sharply in 5 years. In the immigrant population, the AIDS incidences in both sexes in all age groups were expected to increase significantly in 5 years. Under the influence of period, the incidence of AIDS via homosexual transmission in the whole population and the local population increased and remained stable after 2015. At the same time, the incidence of AIDS transmitted by homosexual and heterosexual routes in the immigrants also showed an increasing trend.The results elucidate that there are sex differences in AIDS incidence, and the incidence of AIDS through various transmission routes in all groups is predicted to exhibit an upward trend in the 5 years to come. Effective intervention strategies should be developed and implemented by the public health departments in Zhejiang to control the epidemic of AIDS.The online version contains supplementary material available at 10.1186/s12889-021-11050-x. An APC model was applied to different populations in Zhejiang Province of China to analyze the incidence trend of AIDS via three transmission routes in each group.The incidence of AIDS among 20–35 years old men and women in each group was significantly affected by age effect.The incidence of AIDS and the increase rate in men were both higher than that in women.The AIDS incidence in the immigrant population was expected to increase significantly in the next 5 years, which differs from the other populations.The incidence of AIDS was predicted to increase in the next 5 years.Acquired immunodeficiency syndrome (AIDS), a global health crisis caused by human immunodeficiency virus (HIV) , can affIn China, the first case of AIDS was an Argentinean man travelling to China in 1985. The first local case of HIV infection, found in the same year, was a hemophiliac in Zhejiang Province in eastern China . Since tAPC model, a statistical method based on Poisson distribution, can analyze the birth cohort factor and period factor at the same time, while the traditional modeling technology can only focus on one of the factors. APC model is widely used in research about incidence and mortality of cancer –13, but Zhejiang is an economically developed province along the southeast coast of China. By the end of October 2018, there had been 26,575 HIV/AIDS patients living in Zhejiang province. Sexual contact is the main route of HIV infection for these people, among whom 38.4% are infected through homosexual transmission, the major epidemic pattern of AIDS in China at present. Therefore, we chose Zhejiang and used the APC model to analyze the temporal trend of AIDS incidence in Zhejiang. Specifically, we assessed the age-period-cohort effect on AIDS incidence between 2004 and 2018 based on the whole population  in Zhejiang, and studied the heterogeneity of AIDS incidence. In addition, we explored the characteristics of three transmission routes  in these population groups.Zhejiang Statistical Yearbook. In this study, the migrant population refers to the people who flow into the city from other places, work and live in the city, but do not have the registered permanent residence of the city. The whole population is composed of local born population and migrant population. Therefore, the migrant population was calculated by subtracting the local population from the whole population , we were unable to obtain the annual local population data in 2018. Therefore, the AIDS case data of 2018 were excluded from the further analysis on local and immigrant populations.The case data of this study were from the national Comprehensive AIDS Prevention and Control Information System - Antiviral Treatment Management database. We reviewed and downloaded the data of HIV/AIDS cases  reported in Zhejiang province from 2004 to 2018. Baseline population data included two data sources: age composition of the permanent residents in Zhejiang province  between 2004 and 2018 from the Chinese disease prevention and control information system; the annual local population data between 2004 and 2017 from the Incidence and mortality reflect the prevalence and death risk of the target population, as well as the health risk throughout their life , 15. TheIn order to facilitate the subsequent analysis and research, we processed the data of AIDS cases in the whole, local and immigrant populations as follows: (1) For AIDS cases in the whole and local populations, the first 15 age groups (groups aging 0–14 years) were clustered because the overall number of cases under 15 years of age was less than 0.1%. Since the overall number of AIDS cases over the age of 70 was less than 3%, we grouped the last 30 age groups (groups aging 71–100 years) together. We combined the whole population data (2004–2018) and local population data (2004–2017) with above two AIDS age groups respectively and divided them into 55 age groups. (2) For the AIDS cases in the immigrant population, since the number of AIDS cases between 0 and 15 years old was less than 0.1%, the first 15 age groups (group aging 0–14 years) were clustered as the group under 15 years old; since the number of AIDS cases over 50 years of age was less than 3%, the last 50 age groups (group aging 51–100 years) were clustered as one group. We combined data of immigrant population with immigrant AIDS cases from 2008 to 2017, and classified them into 35 age groups.μxtk = e ⋅ ax ⋅ bt ⋅ ck, where μxtk was a component of system, referring to influences of the X age group, the t cycle, and the k cohort . ax was the parameter of age xth, bt was the parameter of period tth, ck was the parameter of cohort kth. Adding natural logarithms on both sides of the equation, we got a logarithmic linear regression function: yxtk = Inμxtk = Ine + Inax + Inbt + Inck. After converting, we got: yxtk = β1xxtk1 + β2xxtk2 + β3xxtk3 + β4xxtk4, among which xxtkj was a pseudo-variable, if jth beta parameter was related to the age-period-queue category, and xxtkj was equal to 1. We improved the function μxtk was the system composition, referring to the age group X, the period t, and the influence of the cohort k, βj was the effect of N unknown parameters (currently three), xxtkj, j was the pseudo variable of set {x,  t,  k} and j.According to Willekens (1993) , logistiThe prediction of the APC model requires the extrapolation of estimated parameters, which must be done without introducing identification problems , 18. ForWe analyzed the AIDS patients in single age groups using APC model based on Poisson distribution. Then APC analysis was performed for the annual incidence of AIDS transmitted through homosexual, heterosexual, and other routes (such as blood transfusion and intravenous drug abuse) in single age groups. In terms of minimizing bias and Akaike (AIC) information criteria , 21, theThe APC model was supposed to estimate the second order difference due to the existence of linear correlation among age, period, and cohort . LogaritAll analyses, data visualization, and models were programmed in R (version 3.6.0). R package “apc” was used to fit the apc model and predict future trends .Table In Fig. Figure Figures In the whole population, as well as the local and immigrant populations, the AIDS incidence in males peaked between 20 and 35 years old. In all population and the local population, the AIDS incidence in males showed a relatively stable trend after 35 years old and peaked between 60 and 70 years old again. In immigrant population, the incidence of AIDS in males aged over 35 decreased sharply. For females, the age effect on AIDS incidence was relatively lower than in males. In whole and local females, AIDS incidence showed a slowly increasing trend between 20 and 35 years old; it remained stable after 35 years old and gradually decreased over 65 years old. In immigrant females, the incidence of AIDS peaked between 20 and 35 years old, and then decreased slowly. Based on the above results, the effect of age on AIDS incidence could be divided into two stages: over 35 years old and below 35 years old.Influenced by period, the AIDS incidence in males was higher, and increased at a faster speed than females. In the whole and local populations, the incidence in males rose sharply after 2005, reaching to 6–8 cases per 100,000 population during the study period. The incidence in females rose slowly from 2005 to 2018 . Among the immigrant population, the AIDS incidence of males rose sharply from 2008 to 2010, then leveled off between 2010 and 2012 , and rose sharply between 2012 and 2017 . The AIDS incidence in females leveled off throughout the study period, maintaining at 3–5 cases per 100,000 population.The cohort effect showed a similar pattern for the whole and local populations, with the incidence of AIDS peaking in males born in 1950, 1965 and 1985–1990, and falling sharply in those born after 1990. The cohort effect exerted little influence on the incidence of AIDS among females. There was a small peak in AIDS incidence among the females born between 1985 and 1990 in the whole population, and the incidence declined slowly thereafter. In local population, the incidence of AIDS peaked in females born around 1950. The incidence of AIDS among immigrant population was significantly affected by the cohort effect, reaching a peak in both males and females born between 1985 and 1990, and declining sharply thereafter.The AIDS incidence showed an upward trend from 2004 to 2008 in males over 35 years old, below 35 years old and of all age groups, and in females over 35 years old and of all age groups; it was also estimated that a sharply increasing trend would occur in the 5 years to come, and the final incidence in people over 35 years old would be higher than those below 35 . Throughout the whole study period, the incidence of AIDS via heterosexual transmission rose sharply to about 2–3 per 100,000 people, and remained higher than that via homosexual transmission. In general, the incidence of HIV/AIDS through homosexual and heterosexual transmission in the immigrant population was on the rise. From 2012 to 2016, the incidence of HIV/AIDS transmitted homosexually and heterosexually had increased rapidly, from 2 to 5–6 cases per 100,000 people. Before 2012–2013, the incidence of AIDS via transsexual transmission was higher than that via heterosexual transmission, and then turned lower after 2013. The period effect had little effect on the incidence of AIDS transmitted by other routes in the total, local and immigrant populations.In the whole and local populations, the incidence of AIDS via homosexual transmission peaked among those born in 1990. Significantly affected by the cohort effect, the incidence of AIDS via heterosexual transmission rose sharply among those born between 1940 and 1950, then fluctuated until a sharp decline among those born around 1985. In patients born before 1985, the incidence of AIDS via heterosexual transmission was significantly higher than that via homosexual transmission. And for those born after 1985, the incidence of AIDS via heterosexual transmission was significantly lower than that via homosexual transmission. In the immigrant population, the cohort effect exerted a significant impact on the incidence of AIDS via transsexual and heterosexual transmission among those born between 1985 and 1990. The cohort effect had little impact on the incidence of AIDS transmitted by other routes, whether in the total, local, or immigrant populations.Figure APC model, which is usually used for chronic diseases –28, can Age is an important influencing factor of AIDS. Our results showed that the incidence of AIDS was significantly affected by age in both males and females between 20 and 35 years old in the whole, local and immigrant populations, suggesting a higher AIDS risk among young people. This might be attributed to unprotected sex and multiple sexual partners . A largeThe policy of reform and opening-up of China has promoted population mobility, and this also has an impact on the HIV epidemic in a variety of interrelated ways . In our The period effect showed that the incidence of HIV/AIDS in males was consistently higher than that in females during the study period, and the rate of increase in males was significantly higher than that in females, which conforms to the results of other studies , 44. TheCohort effects reflect changes in early life environments and assume that people in the same birth cohort have equal exposure to the risk factors of a disease. Exposure to adverse environmental factors early in life may exert adverse effects on later life . In the The age density diagrams of HIV/AIDS onset and transmission routes in both sexes Fig.  showed wOur predictive results showed that in the whole and local populations, the AIDS incidence in males and females of all age groups would rise sharply in the next 5 years; in 2023, the AIDS incidence among the population over 35 years old would be significantly higher than those under 35 years old. The incidence in women under 35 years of age in the whole population was expected to increase slightly in the future. The trend remained the same for women under 35 years of age in the local population. Among the immigrant population, both males and females under 35 and over 35, as well as all age groups, were expected to have a significantly increased incidence in the next 5 years. The prevalence of HIV in all three groups of transmission routes would rise in the next 5 years. We therefore recommend that public health authorities in Zhejiang focus on the control of AIDS epidemic in the above-mentioned populations. Our findings also indicate the sex differences in AIDS incidence and suggest measures be devised specifically for males and females to control AIDS.In this study, we analyzed the prevalence of HIV/AIDS in the local and immigrant populations of Zhejiang, a representative of economically developed regions, and further explored the characteristics of HIV/AIDS through different transmission routes. The main limitation of our study is the rough statistics of age distribution in the study populations, which may incur small noises and errors to the estimation. Therefore, more detailed statistics and census are needed to improve the accuracy of estimation and prediction.Our results suggest that HIV/AIDS exerts a significant impact on young people in different population groups, especially college students, and its incidence will continue to increase in the future. Due to unprotected sex, multiple sex partners, and lack of sex and AIDS prevention education, the burden of AIDS may still increase in Zhejiang in the next few years. The results of the study also indicate the sex difference in the incidence of AIDS, so measures to control AIDS incidence should be proposed specifically for males and females. It is hoped that public health departments in Zhejiang could focus on these issues so as to better control the AIDS epidemic.Additional file 1.


Background: The epidemiology of early-onset sepsis (EOS) may change over time. Longitudinal surveillance of causative pathogens, antibiotic susceptibility patterns and antibiotic therapy is important for optimal therapy strategies.Objectives: To describe the incidence of culture-confirmed EOS, causative pathogens, antibiotic susceptibility patterns and antibiotic therapy over a 23-year period.Methods: Retrospective population-based study from a single-center neonatal intensive care unit at Stavanger University Hospital, Norway, covering a population in South-West Norway, during the 23-year period 1996–2018.Results: Of 104,377 live born infants, 101 infants  had culture-confirmed EOS; 89 with Gram positive and 12 with Gram-negative bacteria. The EOS-attributable mortality was 6/101 (5.8%). For the three most prevalent pathogens the incidences were; Group B streptococcus (GBS) 0.57/1,000, Escherichia coli 0.11/1,000 and viridans group streptococci (VGS) 0.10/1,000. GBS was the most common pathogen  in infants with gestational age (GA) ≥ 28 weeks. In contrast, among extremely preterm infants (GA <28 weeks) the incidence of E. coli infection was higher than for GBS infection. The second most common bacterial pathogens causing EOS among term infants were VGS. There was no change in the incidence of EOS for the entire study period, but from 2000 to 2018 there was a mean decline in EOS by 6% per year (95% CI 1%−10%) (p = 0.019). The incidences of GBS and E. coli did not change during the study period. The initial empirical antibiotic regimen for EOS was in all cases a combination of benzylpenicillin or ampicillin and an aminoglycoside, but in 21/101 (21%) of cases a broad-spectrum antibiotic was either added or substituted this regimen. In 2/101 (2%) EOS cases, the pathogens were nonsusceptible to the empirical antibiotic regimen. All E. coli isolates were susceptible to aminoglycosides.Conclusion: GBS was the most common causative pathogens in EOS, but E. coli dominated in infants with GA <28 weeks. There was no change in the incidence of EOS during the entire study period. The current empiric regimen with benzylpenicillin and gentamicin provides a very high coverage for EOS in our setting. Escherichia coli is often the most frequently detected pathogen (Early-onset sepsis (EOS) remains a major contributor to neonatal morbidity and mortality . Althougpathogen . PatternIn infants with suspected EOS, empirical antibiotic therapy is commenced before blood culture results are available. Longitudinal surveillance for identification of changes in causative pathogens, clinical outcomes including mortality, and antibiotic susceptibility is important when tailoring optimal prevention and empiric therapy strategies , 8, 9. HIn this population-based study including more than 100,000 live born (LB) infants, we aimed to describe the incidence of culture-confirmed EOS, causative pathogens, antibiotic susceptibility patterns and antibiotic therapy over 23 years in South-West Norway.Stavanger University Hospital in South-West Norway is the only hospital for a well-defined population of around 370,000 inhabitants, offering primary, secondary and tertiary obstetric and neonatal intensive care. There have been 4,000–5,000 annual deliveries during the last decades. All infants born in the catchment area and who receive intravenous antibiotic therapy for EOS have been admitted to the neonatal intensive care unit (NICU) in Stavanger.This is a single-center, population-based retrospective study over a 23-year period from January 1996 to December 2018. The annual number of live births with a GA of ≥22 weeks during the study period were obtained from the maternity unit. Newborn infants with positive blood cultures obtained during the first 72 h of life were identified by the local microbiology laboratory blood culture registry, and causative pathogens and antibiotic susceptibility were registered. Detailed clinical information was extracted from the medical records for all infants with culture-confirmed EOS, including GA, birthweight (BW), symptoms and signs of EOS, infection-attributable mortality, maximum value of C-reactive protein (CRP), choice of antibiotics and duration of therapy. The diagnosis of clinical chorioamnionitis was extracted from the mother's medical record.EOS was defined as growth of pathogenic bacteria in a blood culture obtained ≤ 72 h of life, and treatment with antibiotics ≥5 or <5 days if death occurred . CultureStreptococcus mitis and Streptococcus alactolyticus and “Other streptococci” in this report include Streptococcus pyogenes and Streptococcus pneumoniae. A blood culture pathogen was defined as susceptible to an antibiotic when the final interpretation report indicated S (susceptible) and nonsusceptible when the report indicated R (resistant) or I (intermediate). Antibiotic susceptibility testing followed the guidelines from the Norwegian working group for antibiotics  throughout the study period. Matrix-assisted laser desorption ionization - time-of-flight (MALDI-TOF) mass spectrometry was introduced in 2012, gradually replacing traditional phenotypic species identification. Micrococci, propionibacteria, corynebacteria, or diphtheroids grown alone in a single culture, growth of more than one bacteria, and all coagulase-negative staphylococci (CoNS) were considered contaminants  from 1996 to 2010, and benzylpenicillin and gentamicin from 2011 to 2018.The local institutional review board and data protection officer approved the study as a local quality improvement project that did not need approval by the regional ethics committee.t-test or Mann-Whitney test as appropriate for continuous data, and the chi-square test or Fisher-exact test for categorical data. Regression models were used to test for trends over time (linear) where year was the continuous predictor. All tests were two-tailed. P-values of <0.05 were considered statistically significant.Data were analyzed using IBM-SPSS version 24 statistical software . Results are expressed as mean with 95% confidence interval (CI) or median with interquartile range (IQR), as appropriate. Differences between groups and time periods (1996–2006 vs. 2007–2018) were analyzed with During the 23-year study period, 104,377 infants were LB. Of these; 96,024 (92%) infants were born at term, and 8,353 (8%) infants were born preterm before 37 weeks gestation. Among the preterm infants, 7,890 (7.6%) had GA between 28–36 weeks and 463 (0.4%) GA <28 weeks. There were 101 infants with culture-confirmed EOS . The oveE. coli. In extremely preterm infants however, there were four cases of E. coli infection and only one GBS case (p < 0.001). VGS was the second largest group of pathogens with 10/101 cases (10%), predominantly occurring in term infants (9/10).Among term and moderately preterm infants, GBS was a more frequent cause of EOS than GBS case . The incp = 0.49). There was no change in the incidence during the study period for all infants with EOS or for EOS caused by different pathogens (data not shown). However, for the period from 2000 through 2018 analyzed separately, there was a mean decline in the incidence of EOS by 6% per year (95% CI 1–10%) (p = 0.019). There was no change in the incidence of EOS during the study period for any of the GA groups when analyzed separately (data not shown).The yearly incidence of EOS for different pathogens are shown in p = 0.047.In total, 14/101 infants with EOS had been exposed to chorioamnionitis; 10/71 (14%) term, no moderately preterm, and 4/8 (50%) extremely preterm infants. Among infants with EOS exposed to chorioamnionitis, all extremely preterm infants and 7/10 term infants developed symptoms of EOS within the first 6 h of life. Overall, 95/101 (94%) infants with EOS had onset of symptoms within the first 24 h of life. The median (IQR) time to start of EOS-symptoms was 3.0 h . The proportion of infants with symptoms at birth was higher among preterm 18/30 (60%) compared to term infants 26/71 (37%), p = 0.025). The maximum CRP values were higher in infants with Gram-positive compared to Gram-negative EOS, p = 0.003.The mortality and maximum value of CRP for different groups of GA with EOS are shown in The antibiotic regimen for EOS was in all cases a combination of benzylpenicillin or ampicillin and an aminoglycoside. In 21/101 (21%) of cases, a broad-spectrum antibiotic was either added or substituted later the empiric regimen. There was no change in the number of infants given broad-spectrum antibiotics between the periods 1996–2006 and 2007–2018.p < 0.013).The median (IQR) duration of antibiotic therapy for EOS declined from 14 (10–14) days in the period 1996–2006 compared to 8 (7–10) days in the period 2007–2018 . 10/11 (91%) of E. coli isolates were nonsusceptible to ampicillin , but susceptible to an aminoglycoside. Six out of nine S. aureus EOS isolates were nonsusceptible to benzylpenicillin. All other Gram-positive EOS isolates in this study were uniformly susceptible to benzylpenicillin. The overall non-susceptibility rate to the current empirical regimen benzylpenicillin and gentamicin was 2/101 (2%) (Among the nine 101 (2%) .E. coli dominates in infants with GA <28 weeks. The incidence of EOS remained stable for the entire study period, but with a possible decline in incidence for the period 2000–2018 analyzed separately. Finally, we demonstrated a low level of antibiotic nonsusceptibility, and the current recommended empirical antibiotic regimen (benzylpenicillin and gentamicin) continues to have an excellent coverage for EOS in our area.This study reports the epidemiology of EOS and antibiotic susceptibility over more than two decades in a well-defined population in South-West Norway. Key findings are that GBS is the most common causative pathogen in EOS, but The overall incidence of EOS was 0.97/1000 LB, comparable to reports from other epidemiological studies from Sweden (0.9) , United E. coli, was interestingly the second largest group of pathogens that caused EOS, predominantly in term infants. All infants with VGS-EOS had clinical symptoms suggestive of sepsis, CRP levels above 10 mg/L and received ≥5 days of antibiotics, indicating a clinically relevant sepsis episode. In many other studies, VGS are excluded as “unspecific”  of EOS isolates were susceptible to the current empirical antibiotic regimen; benzylpenicillin and gentamicin. Although numbers are small, the Gram-negative antibiotic nonsusceptibility rate, remained unchanged. This is comparable to a recent study, from the USA where they found a stable 009–2017 . The non009–2017 . Furtherly found . This, cly found , 29. In  strains . Our resKey strengths of this study are the 23-year long study period and the strictly population-based design. The number of infants included in our study roughly equals the total number of births in Norway over a 2-year period. We have complete data sets on all infants with positive blood cultures, including antibiotic susceptibility patterns, antibiotic use, and neonatal and maternal data for the entire study period. The data were collected by a single researcher. The study includes detailed maternal and neonatal information. We only included culture-confirmed episodes regarded as the “gold standard” for the definition of neonatal sepsis. There are also limitations. The data were collected from a single-center and the findings may not be generalizable to other countries with high antibiotic consumption driving high antibiotic nonsusceptibility rates, settings with higher burden of neonatal sepsis, or settings with limited resources and weak healthcare systems. Another important limitation is the low rate of extremely preterm infants. Albeit being in line with other regions of Norway, it may be lower compared to countries outside Scandinavia. Finally, there are inherent limitations with retrospective data.E. coli dominated. We found no change in the incidence of EOS during the whole 23-year period, but with a possible decrease in incidence during 2000–2018. Empirical benzylpenicillin and gentamicin in combination provides a very high coverage for EOS pathogens in our setting.In this population-based study of EOS over 23 years, we found that that GBS was the most common causative pathogens in EOS, but among extremely preterm infants The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.AV conceptualized and designed the project, collected and analyzed data, wrote the first version of the manuscript, and revised the manuscript. She had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. KØ conceptualized and designed the project, directed and organized all phases of the project, analyzed data, contributed with statistical analyses and supervised AV during all the phases of the project. CK and SR supervised AV during final phases of the project, analyzed data, revised the manuscript for intellectual content and approved the final manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To investigate the clinical manifestations of orbital involvement in a large cohort of Chinese patients with IgG4-related disease (IgG4-RD).A total of 573 patients with IgG4-related disease were included. We described and compared the demographic, clinical, laboratory and histopathologic findings from 314 patients with IgG4-related ophthalmic disease (IgG4-ROD) and 259 with extra-ophthalmic IgG4-RD.Male predominance was found significant in extra-ophthalmic IgG4-RD only. Patients with IgG4-ROD showed younger age at diagnosis and longer duration from onset till diagnosis. In patients with extra-ophthalmic IgG4-RD, the most commonly involved extra-ophthalmic organ was pancreas; while in IgG4-ROD patients, salivary gland was most frequently affected. Multivariate analysis exhibited IgG4-ROD was associated with allergy history, higher serum IgG4/IgG ratio, multiple organs involvement and sialoadenitis. Orbital images were reviewed in 173 (55.1%) IgG4-ROD patients. Fifty-one (29.5%) patients had multiple lesions. Lacrimal gland involvement was detected in 151 (87.3%) patients, followed by extraocular muscles , other orbital soft tissue  and trigeminal nerve . Biopsy was performed from various organs in 390 cases. A dense lymphoplasmacytic infiltration and fibrosis were the main feature in orbital specimens. Storiform fibrosis and obliterative phlebitis were absent in lacrimal gland.Lacrimal gland involvement was the most common orbital manifestation of IgG4-ROD. Patients with IgG4-ROD showed different characteristic in demographic, clinical, laboratory findings compared to patients with extra-ophthalmic IgG4-RD. These features might indicate potential differences in the pathogenesis of these two subgroups of IgG4-RD.The online version contains supplementary material available at 10.1186/s12886-021-02210-z. IgG4-related disease (IgG4-RD) is a recently recognized systemic fibro-inflammatory condition, histologically characterized by numerous lymphoplasmacytic infiltrations with a predominance of IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis in tumour-like lesions of multiple organs , usuallyIn published cases series, the head and neck region is the second most common site for IgG4-RD after the pancreas , 4. The Given its relatively recent recognition, most publications on this entity are case reports and small series. Larger case series are needed to better understand this rare disease and provide a higher level of evidence to improve patient care. Herein, based on data of 573 patients from our prospective cohort, we compared the clinical, laboratory, and pathological characteristics of 314 patients with IgG4-ROD and 259 with extra-ophthalmic IgG4-RD.ClinicalTrials.gov ID: NCT01670695). All included patients fulfilled the 2019 ACR/EULAR classification criteria for IgG4-RD 20]. WhilWith regard to ophthalmic lesions, lacrimal gland was the most frequently involved anatomic location of IgG4-ROD. Most studies reported that the frequency of lacrimal gland involvement varies form 66–83% , 5, whicSerum IgG4 elevation was found in 93.8% IgG4-RD patients in this study. Published data also showed serum IgG4 elevation occurred in 55–97% of cases, especially in Asian patients , 17, 18.Other serological findings in patients with IgG4-RD are largely non-specific. Although patients with IgG4-ROD were found to have lower C3, C4, ESR, CRP and IgA levels than patients with extra-ophthalmic IgG4-RD, multivariate analysis detected no statistical significance. Hypocomplementemia at baseline may suggest kidney involvement . An assoHistopathologic findings of IgG4-RD include three characteristic features: dense lymphocytic infiltration, storiform fibrosis and obliterative phlebitis . In thisHigh number of IgG4+ plasma cells on immunohistochemistry is a disease hallmark . SimilarThis study has limitations. Although it is based on a prospective cohort, the analysis itself is retrospective in nature. Some laboratory and histopathologic information was not available. And 44.9% of patients with IgG4-ROD needed additional orbital imaging studies to identify exact anatomic locations in detail. Finally, not all patients underwent thorough examinations of the whole body, some affected organs might remain undetected at initial evaluation.In conclusion, we have described demographic, clinical, laboratory and histopathologic differences between patients with IgG4-ROD and extra-ophthalmic IgG4-RD based on a large cohort. Patients with IgG4-ROD were more even in gender and consisted of younger people with longer time from onset to diagnosis. Allergic history and multi-organ involvement were more common in the IgG4-ROD group. IgG4-ROD was positively associated with higher serum IgG4/IgG ratio and more frequent salivary gland involvement, but less internal organ involvement was observed. Lacrimal gland involvement was the most common manifestation of IgG4-ROD. But other anatomic areas were also frequently affected. These features might indicate potential differences in pathogenesis of these two subgroups.Additional file 1.


In this paper, the mechanical properties of coral concrete with different strength and different polyvinyl alcohol (PVA) fiber content under compression were experimentally investigated. The results show that adding an appropriate amount of PVA fiber could obtain satisfactory mechanical properties of coral concrete. The stress–strain constitutive relationship of plain and PVA fiber-reinforced coral concrete was investigated by prism uniaxial compression test. The results shown that the incorporation of PVA fiber had a significant effect on limiting the development of concrete internal cracks, and effectively improved the mechanical properties of coral concrete after cracking, especially the toughness. Different constitutive models from previous research were used to describe the axial compressive stress–strain relationship of plain and PVA fiber-reinforced coral concrete, and a piecewise function model was finally selected which is most consistent with the experimental curve and its characteristic points. In addition, determination of critical parameters for the selected constitutive model was proposed, and experimental validations confirmed its accuracy. In recent years, many countries have increased their investment in ocean engineering in response to the increasing depletion of land resources. For example, the construction of artificial islands is receiving more attention in many coastal countries, and the sea sand-broken reef aggregate concrete material is also becoming a research focus in construction materials. For off-shore islands and reefs lacking traditional construction materials, the problem of cost increase is inevitable and unacceptable. Fortunately, the coral resources in many off-shore islands and reefs are rich. Therefore, inventing a new kind of concrete with the best use of coral resources becomes a potential approach in off-shore islands and reef engineering construction.As early as the 1950s, the application and research of coral concrete had been started in the United States. Dempsey  describeIn 2000, Sun  studied In general, due to the particularity of the marine environment, the durability of concrete structures with different kinds of fibers is obviously different. Coral concrete, as a special building material in the marine environment, not only requires the fiber to play a role of toughening and strengthening, but also to present the properties of weather resistance and corrosion resistance etc. Therefore, compared with other fibers, polyvinyl alcohol (PVA) fiber with low price and excellent performance might be a better choice.PVA fiber is a kind of synthetic fiber with many advantages, such as high strength, high elasticity, good wear resistance, strong acid-base resistance, and good corrosion resistance . Due to In this study, the experiments on cube compressive strength, prism axial compressive strength of plain and PVA fiber-reinforced coral concrete were carried out. Based on the experiment results, the influences of PVA fiber on the compression strength, elastic modulus and Poisson’s ratio of coral concrete were studied. Furthermore, the compression stress–strain curve characteristics of plain and PVA fiber-reinforced coral concrete were comparatively studied, and the constitutive model for uniaxial compression stress–strain curve of plain and PVA fiber-reinforced coral concrete was also proposed. The results might be referable for engineering application or performance-based engineering design.The coral from a Southern China Sea island was broken into irregular particles with a maximum diameter of 26.5 mm. After sieving, aggregate with continuous particle size of 4.75 to 26.5 mm was used as coarse aggregate a, and paOrdinary Portland Cement P. O 42.5 (OPC), slag (SG) and silica fume (SF) were used in the tested mixtures, their chemical compositions are shown in 3, 1.625 kg/m3, 3.25 kg/m3 and 6.5 kg/m3, respectively, as shown in According to Chinese technical specification for lightweight aggregate concrete (JGJ51-2002)  and ChinDue to the water-absorption and water-release characteristics of coral aggregates ,30, the The test methods of mechanical properties of coral concrete were conducted according to Chinese standard for method of mechanical properties on ordinary concrete (GB/T 50081-2002) , and eigThe electro-hydraulic servo universal testing machine  was used for uniaxial compression test, with a maximum capacity of 2000 kN, as shown in Three rubber-based strain gauges were pasted on each stress–strain curve test specimen, in which two longitudinal strain gauges were arranged at sides B and D, and one transverse strain gauge at side C, respectively, as shown in The tests of slump and dispersion were conducted according to Chinese standard GB/T 50080-2016 , as show3 in marine environment construction. Besides, the dispersion of pumped concrete should not be less than 500 mm [3 if using pumping construction.From ironment , it is sn 500 mm , and thuDuring compression loading, almost all of the specimens shown obviously brittle failure. Most of the specimens began to appear obvious destructive cracks after bearing about 90% of the ultimate load. With the load approaching the peak load, the cracks spread rapidly and some of the concrete at the corners of the test specimens was torn into slag and dropped. Finally, the test specimen was destroyed immediately with a sound of cracking.The typical failure of plain coral concrete specimen was mainly compression crushing, as shown in However, the brittleness of coral concrete was obviously improved by adding PVA fiber. Compared with the plain coral concrete group (C40), the integrity of the specimen with PVA fibers (FC1 to FC4) was better due to the bridging and toughening effect of PVA fiber, and the local chipping and peeling was also significantly reduced, some specimens still remained integrity after failure, as shown in The mechanical properties of experimental specimens are summarized in In this paper, the slope of the linear segment between two points ; According to Equations (3) and (4), the measured load and longitudinal displacement were converted into stress imen see b before In order to analyze the stress–strain curve and toughness index accurately, the author normalized the measured data as follows:Firstly, the stress values and the strain values of the stress–strain curve were divided by the peak stress and peak strain, respectively, as follows:Secondly, on the basis of the equal or close strain values  and residual point (R) to ensure the consistency with the original curve shapes, taking group 5 as an example, shown in Finally, according to the above steps, the normalized curves of all test groups were obtained, and the stress and strain values (dimensionless) of the normalized stress–strain curves were multiplied by the average peak stress and average peak strain of the same group, respectively, so as to obtain the average stress–strain curves of each group, as shown in As shown in With an increase of concrete strength, the slope of stress–strain relationship increases correspondingly, indicating the elastic modulus of coral concrete increases, and the peak strain also increases, as shown in 3,1.625 kg/m3,3.25 kg/m3, 6.5 kg/m3, the peak stress of coral concrete increased by −3.1%, 3.1%, 7.3%, 2.5%, the peak strain increased by −1.7%, −2.5%, 4.7%, 8.0%, the residual stress after failure increased by 27.1%, 20.3%, 25.4%, 66.1%, and the Poisson’s ratio increased by 6.7%, 23.8%, 25.8%, 3.3%, respectively, indicating that the addition of an appropriate amount of PVA fiber had a positive toughening effect. However, the initial elastic modulus was rarely influenced by fiber content before 50% of the peak stress. In addition, the shape and the feature point of the normalized stress–strain curves of the coral concrete with different fiber content had a minor difference.As can be seen from δ is the toughness index of coral concrete; β is the brittleness index of coral concrete; Toughness is an important index to evaluate the deformation ability of materials or structures after reaching the ultimate load . ReferriA2 decreases obviously while the area parameter A1 rarely changes. Thus, the corresponding toughness index δ decreases and brittleness index β increases.As shown in A1 of fiber reinforced coral concrete increased slightly, but the influence of different fiber content is not obvious among the different specimen fiber contents. However, the fiber has significant influence on area parameter A2. Compared with group C40 without fiber, when the fiber content is 0.8125 kg/m3, 1.625 kg/m3, 3.25 kg/m3 and 6.5 kg/m3, the parameter A2 increases by 23.6%, 37.9%, 54.0% and 49.4%, respectively, and the toughness index δ increased by 7.5%, 12.3%, 15.0% and 14.5%, respectively. Correspondingly, the brittleness index β declined by 18.9%, 27.6%, 31.8% and 31.1%, respectively, which shows that the ductility of the coral concrete is effectively improved by adding fiber.As shown in The existing literatures show that there is no unified conclusion about the expression of the uniaxial compression stress–strain curve of coral concrete. Based on the existing concrete constitutive models and the test data, there is no unified constitutive models to describe the compression behavior of coral concrete. Considering the significant differences in the stress–strain curve between the ascending and declining stages of coral concrete, piecewise functions are used to describe the curve.In this paper, according to the curve characteristics of coral concrete, three models with different mathematical presentations are selected to calculate the ascending and declining stages of the curve, as shown in As can be seen from  by Yang  can be u by Yang  can be uAs important parameters of concrete, elastic modulus and peak strain are both critical parameters to reflect uniaxial compression behavior. Several studies have identified that there are many factors affecting the elastic modulus and peak strain of concrete, such as concrete strength and aggregate type ,48.wc [Ec can be established with the prism compression strength fc and concrete density wc by regression analysis with 78 specimen test data, as shown in Equation (13). The validation of the prediction approach for elastic modulus is shown in R2 = 0.799. As shown in fc, elastic modulus Ec and fiber content mf. The validation of the prediction approach for peak strain is shown in R2 = 0.661. Among the experimental specimens, fc representing the prism compression strength varies from 25 MPa to 75 MPa, wc representing the concrete density varies from 1900 kg/m3 to 2300 kg/m3, and mf representing the fiber content varies from 1 kg/m3 to 6.2 kg/m3.As shown in wc . Thus, ba and b in Equations (11) and (12) needs to be determined for plain and PVA fiber reinforced coral concrete.As discussed above, Equations (11) and (12) are used to describe the uniaxial compression stress–strain behavior of plain and PVA fiber-reinforced coral concrete. Herein, the critical undetermined parameters a, the plumper the curve, and the lower the strain growth rate of concrete in the loading process, then the more energy it would absorb. Similarly, the smaller the value of parameter b, the plumper the curve, the lower the slope of the curve in the unloading process, the slower the failure process, and the more energy released, which means the ductility of the coral concrete will be better. According to a and b should decrease with increasing coral concrete strength and increase with increasing fiber content.As can be seen from a or b and the toughness index of coral concrete. The results show that with the decrease of parameter a or b, the toughness parameters A1 or A2 tends to increase, simultaneously, A2 or “A1 + A2” is positively correlated with the toughness index δ, and negatively correlated with the brittleness index β, but the relationship between A1 and δ or β is not obvious. That is to say, with smaller parameters a and b, the corresponding A1 and A2 will become larger, and “A1 + A2” will also become larger, resulting in a larger toughness index δ and lower brittleness index β, indicating better deformation performance of the coral concrete. This is consistent with the conclusion of As shown in a and b are both related to the fiber content and the compressive strength of coral concrete. In addition, the parameter a influencing the curve shape of the ascending stage may be also related to the elastic modulus Ec and peak strain εcr of coral concrete because they also influenced the curve shape, the toughness index δ and the brittleness index β. Therefore, the critical undetermined parameters a and b in Equations (11) and (12) are fitted by regression analysis of the experimental results, with consideration of potential influencing parameters including concrete strength fc, PVA fiber content mf, elastic modulus Ec and peak strain εcr. The stress–strain expression calculated by the proposed model for all the specimen groups tested in this work and the determination approach for critical parameter a and b are shown in a and b in Based on the analysis of the calculated results of the proposed model and the experimental data, the parameters a and b are capable of accurately describing the constitutive relationship of plain and PVA fiber-reinforced coral concrete.As shown in a and b in a and b increase correspondingly, meaning that the brittleness index β increases and the toughness index δ decreases. As is known from experimental results, with increasing concrete strength, the elastic modulus and the brittleness of concrete also increases, evidencing that the prediction approach gives good consideration of the influence of concrete strength. In addition, with the increase of PVA fiber content, the parameter a and b decrease firstly when 3, and then increase after mf exceeds 4 kg/m3. As presented above, the smaller parameter a and b, the better toughness and smaller brittleness of coral concrete. That is to say, the best content of PVA fiber may be about 4 kg/m3, which coincides with the experimental results. This phenomenon could be attributed to the bridging effect of PVA fiber, which effectively prevents the expansion of transverse cracks and consumes energy when fracture. However, when the fiber content is too large, it would cause fiber winding and clusters, forming weak areas in the coral concrete, resulting in the reduction of fiber toughening effect. As shown in 3. Therefore, the best content of PVA fiber can be suggested as 4 kg/m3 regardless of concrete strength.In addition, the best PVA fiber content for coral concrete with different compressive strength is also analyzed using Equations (11) and (12) and the suggested determination approach of parameter According to a certain proportion of silica fume, slag, P.O. 42.5 cement, coral coarse and fine aggregate, artificial sea water, etc., coral aggregate–seawater concrete with the compressive strength of 30 to 50 MPa and good performance can be prepared.3 in marine environment construction, and not exceed 2 kg/m3 if using pumping construction.With an increase of PVA fiber content, the slump and dispersion of coral concrete decreases significantly. In order to ensure the working performance of coral concrete, it is suggested that the PVA fiber content of coral concrete should not exceed 5 kg/mWith increasing strength of coral concrete, the elastic modulus, Poisson’s ratio and peak strain increase, but the residual stress and the toughness decrease.fcu is up to 9.9%. The optimal amount of PVA fibers to optimize mechanical properties of coral concrete is about 2–3 kg/m3.PVA fiber effectively improves the compression strength of coral concrete, as well as the ductility and mechanical properties after peak load. Compared with the reference coral concrete, the maximum growth rate of cubic compressive strength 3, the toughness index δ of coral concrete increases by 2.9% to 10.1%, and the brittleness index β decreases by 15.3–28.8%.PVA fiber has remarkable effect on improving the toughness of coral concrete. When the fiber content ranges from 0.8 to 6.5 kg/ma and b. In addition, through analysis of the model, the optimal PVA fiber content of coral concrete may be 4 kg/m3.The constitutive relationship of plain and PVA fiber-reinforced coral concrete can be described by the recommended piecewise function model and the proposed approach to determining critical parameter To meet the requirements of structure design and environmental benefits, it plays a very important guiding role in the engineering application of coral concrete to optimize the mix ratio design and improve the corrosion resistance, high temperature resistance and drying shrinkage resistance of coral concrete structure. However, more validation experiments are needed though.


Persons who inject drugs (PWID) are at increased risk of invasive bacterial infections. Increasing data supports the efficacy of transition to oral antibiotic therapy to complete treatment of invasive bacterial infections including osteomyelitis and endocarditis. The aim of this study is to evaluate the impact of transition to oral antibiotics on a prospective observational cohort of PWID. We prospectively analyzed PWID admitted 2/2020 - 2/2021 at Barnes-Jewish Hospital in St. Louis with osteomyelitis, endocarditis, epidural abscesses or septic arthritis. All patients were offered multidisciplinary support during their inpatient hospitalization including addiction medicine consultation and medications for opioid use disorder, if appropriate. Health coaches and case managers met with patients during their hospitalization and followed patients for up to 90 days after discharge. Patients were offered the option of transition to oral antibiotics if they were not able to complete recommended IV antibiotics. Patients discharged on oral antibiotics were offered post-discharge infectious diseases follow-up. Antibiotic adherence was documented by health coaches through phone out-reach. We collected data on demographics, comorbidities, microbiologic data, antibiotic selection, mortality and readmission rates. We compared 90-day readmission rates between PWID who completed IV antibiotics inpatient and those who discharged early with oral antibiotics. Of 166 PWID, 61 completed IV antibiotics inpatient (37%) while 105 were discharged with oral antibiotics (63%). Causative pathogens were not significantly different between inpatient IV vs oral antibiotics; MSSA , MRSA , or streptococcal species . Of patients discharged on oral antibiotics 7.6% had documented non-adherence to therapy, 23% had unknown adherence and 67% had documented adherence. There was no significant difference in all-cause 90-day readmission rates (p=0.819) . All-cause readmissions by antibiotic strategyOral antibiotic regimens provided similar efficacy to IV antibiotics in our prospective cohort analysis of PWID.All Authors: No reported disclosures


This study sought to examine the performance design of concrete mix proportions to ensure chloride resistance and early strength with respect to C35 (35 MPa), which is the minimum compressive strength class of concrete used in a marine environment. For the proposed concrete mixture, C24 (24 MPa) was selected and binders for concrete were manufactured using a blend of OPC (ordinary Portland cement), EPC (early Portland cement), and GGBS (ground granulated blast-furnace slag). The results of the experiment confirmed that the combined use of EPC and GGBS greatly improve the early-strength development and chloride resistance of concrete. An analysis revealed that the time for removal of forms can be reduced by 5–9 h from the aspect of early concrete strength. Moreover, in terms of construction productivity, EPC and GGBS were reduced by up to 16.39 h/cycle compared to other concretes. Regarding economic and environmental impacts, EPC and GGBS were more effective than C35 concrete. This study is significant as its findings help make it possible to examine the most economical concrete mix design in relation to strength development according to the application of EPC, GGBS, and PC-based admixtures. C35_O100 is more expensive than C24_G20 and C24_E50_G20 for two reasons. First, the cement cost is higher than other materials’ costs, such as GGBS, sand, and gravel The analysis of raw materials revealed that EPC can help improve the early-strength development of concrete. In addition, it was confirmed that the use of EPC and ground granulated blast-furnace slag (GGBS) as concrete binders in combination with a PC-based superplasticizer can improve the early and long-term strengths of concrete while significantly reducing the total binder.(2)The results of the chloride ion diffusion coefficient and chloride penetration depth showed that when EPC and GGBS are used, chloride resistance is improved by the watertightness of the surface and by the chloride ion binding phenomenon as the rapid strength development progresses at early ages. In particular, its chloride diffusion coefficient was decreased significantly by about 30% compared with C35_O100.(3)The evaluation of the internal porosity of concrete confirmed that the mix proportions using EPC and GGBS could reduce the total pore volume and increase the watertightness of concrete, thereby improving its chloride resistance. It was also confirmed that C24_E50_G20 and C24_G20 have different degrees of porosity at early ages but exhibit almost similar degrees of porosity at long-term ages.(4)The analysis of the effects of EPC and GGBS on the compressive strength and chloride resistance of concrete revealed that the application of a chemical superplasticizer to concrete makes it possible to reduce the cement quantity and the unit water content of the existing C35 concrete mix. Based on the study results, it is possible to secure high chloride resistance at a low strength compared to C35_100, and to reduce the time for the removal of forms by 5–9 h in terms of the early strength.(5)The construction productivity was analyzed based on the elapsed time on concretes. The results were as follows. C24_E50_G20 was 68.24 h/cycle, which was superior to other concretes in terms of construction productivity. If C24_E50_G20 was applied to the structure works in a construction project, the construction period would be decreased compared to other concretes. Moreover, it was found that when C35_O100 was replaced with C24_G20 or C24_E50_G20, the economic and environmental impacts could be reduced by up to 15.16% and 38.00%, respectively.In this study, the chloride resistance performance of concrete was evaluated, and life cycle assessment was conducted on concrete using a binder based on early Portland cement (EPC) and chemical superplasticizer admixture. The results of the analysis of the experiment results are summarized as follows.The limitations of this study are as follows. First of all, it lacks a review of the mix proportions according to various EPC and GGBS replacement levels. Therefore, it is necessary to use a variety of materials for the economic review. In addition, there is a need to confirm the reproducibility of the early strength at the ready-mix concrete plant. Secondly, in terms of economic impact, C24_G20 was cheaper than C24_E50_G20; however, in terms of productivity for a 7-day cycle, it can be expected that C24_E50_G20 will be cheaper than C24_G20, so future research should be done to perform a productivity analysis between C24_G20 and C24_E50_G20 for a 7-day cycle.The results of this study are expected to be used as basic data with reference to process management for the early removal of forms and the economical mix proportions of concrete at construction sites.


The differential diagnosis of IgG4-related hypophysitis and other inflammatory diseases or tumors involving sellar region is challenging even after sellar biopsy. Sellar germinoma is usually infiltrated by lymphocytes or plasma cells, and may be confused with hypophysitis.A 36-year-old man with diabetes insipidus, elevated serum IgG4 level (336 mg/dl), and sellar mass was suspected to have IgG4-related hypophysitis, and no other lesion of IgG4-related disease was detected. After treated by prednisone and mycophenolate mofetil, the serum IgG4 decreased to 214 mg/dl. However, after withdrawal of the drugs, the IgG4 level increased to 308 mg/dl. Endocrine assessments revealed panhypopituitarism, and the sellar mass enlarged. Transsphenoidal sellar exploration and biopsy was conducted. Pathological examination showed that the lesion was germinoma with lymphocytes and plasma cells infiltration, and IgG4-staining was positive . The patient was then treated by cisplatin and etoposide. After four cycles of chemotherapy, the serum IgG4 was 201 mg/dl, and the sellar mass was invisible.Sellar germinoma can mimic the clinical characteristics of IgG4-related hypophysitis. Poor response to glucocorticoids can be used as an exclusion criterion in the clinical diagnosis of IgG4-related hypophysitis. IgG4-related disease is a spectrum of immune-mediated conditions characterized by tumefactive lesions infiltrated by IgG4-producing plasma cells or lymphocytes , 2. It cIntracranial germ-cell tumors (GCTs) mainly affect children and adolescents, while adult patients are relatively rare . The lesWe report here a patient presented with diabetes insipidus and hypopituitarism who was initially misdiagnosed as IgG4-related hypophysitis. This patient fulfilled the clinical diagnostic criteria of IgG4-related hypophysitis, but consequent biopsy of the pituitary lesion revealed that it was actually an intracranial germinoma.2O  and serum Na+ was 145 mmol/L . Blood glucose was normal and urine glucose was negative. Endocrine assessment of anterior pituitary was generally normal . Although the cortisol was slightly higher, the patient had no symptom or sign of hypercortisolism. The serum IgG4 (336 mg/dl)  and IgE (399 IU/ml)  concentration was elevated. Contrast enhanced MRI demonstrated a mass occupying posterior pituitary and pituitary stalk, and the diameter of the pituitary stalk was 3.4 × 3.4 mm  for two weeks, but the serum osmolarity was still 317 mOsm/kgHPrednisone treatment was initiated at a dose of 60 mg q.d. in April 2019. The dose of prednisone was tapered to 40 mg q.d. in June 2019, and mycophenolate mofetil of 0.75 mg b.i.d. was added. The serum IgG4 level gradually decreased and reached its nadir (214 mg/dl) in September 2019 , AFP undetectable], and no tumor cell was found. The thyroid ultrasonography and abdominal CT results were generally normal, and 18F-FDG-PET showed modest FDG uptake at the pituitary stalk (SUVmax = 1.0). Neurosurgeons conducted transsphenoidal sellar exploration and biopsy for the patient in August 2020, and found that the grayish-white lesion compressed the pituitary and invaded the suprasellar region through the pituitary stalk. Pathological examination Fig.  confirmeFour cycles of chemotherapy consisting of cisplatin and etoposide were given from Oct 2020 to Dec 2020. The sellar and suprasellar mass was invisible on the pituitary MRI evaluated after two and four cycles of chemotherapy, and the diameter of the pituitary stalk was 2.2 × 2.1 mm  in 2019 . AnotherNo matter which set of criteria was adopted, the symptoms of CDI, laboratory examinations of hypopituitarism, pituitary mass and stalk thickening on MRI, and elevated serum IgG4 were all in accordance with the clinical diagnosis of IgG4-related hypophysitis in the current case. However, some features of this patient were distinct from typical IgG4-related hypophysitis. In previous reports, male patients with IgG4-related hypophysitis were usually elderly , 20, whiThe 2019 ACR/EULAR classification criteria for IgG4-RD consists of entry criteria, exclusion criteria, and a scoring system. Similarly, we believed that adding exclusion criteria to the diagnostic criteria of IgG4-related hypophysitis would be helpful, though it may be too rare to develop such a scoring system. IgG4-related hypophysitis is a benign disease that can be treated by glucocorticoid , so otheThe pathological diagnosis of IgG4-RD relies on both morphological findings and immunohistochemical staining for IgG4. The key morphological features include dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis, but variable features may be present in some organs . In IgG4The relation between germinoma and the IgG4 reaction is unknown in this case. However, it could be speculated that the IgG4 reaction was secondary to germinoma, since no other organ was found to be involved by IgG4-RD in this patient, and serum IgG4 level dropped after the remission of germinoma. IgG4-RD was generally considered to be initiated by autoimmunity, followed by activation of type 2 helper T cells and regulatory T (Treg) cells, which can prompt the production of IgG4 . PreviouIn summary, we present the first case of sellar germinoma mimicking the clinical and pathological features of IgG4-related hypophysitis. The diagnostic criteria of IgG4-related hypophysitis may need some modifications, and the response to glucocorticoid should be taken into consideration. Besides, it provided clues to understand the role of IgG4 in the pathogenesis of primary or secondary hypophysitis.


Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activity in multiple malignances including breast cancer. However, the responses can vary. This meta-analysis was conducted to evaluate the efficacy and safety profile of adding ICIs to neoadjuvant chemotherapy against triple-negative breast cancer (TNBC) and assess correlation of PD-L1 tumor status with responses.versus ICI-free neoadjuvant therapy were included in this study. Meta-analyses were performed using Review Manager Version 5.2 software.Eligible studies were retrieved from the PubMed, Embase, and Web of Science databases. Randomized controlled trials (RCTs) that investigated ICI-containing P < 0.001). In subgroup analysis, the addition of ICI to neoadjuvant chemotherapy was significantly associated with increased pCR rate in both PD-L1-positive TNBC  and PD-L1-negative TNBC . Patients with TNBC receiving ICI-containing neoadjuvant therapy had a better event-free survival  than those who receiving ICI-free neoadjuvant therapy. A significantly higher risk of adverse events including adrenal insufficiency, increased aspartate aminotransferase, dry skin, hepatitis, hyperthyroidism, hypothyroidism, infusion related reaction, pyrexia, and stomatitis was associated with ICI-containing neoadjuvant therapy.This study included four RCTs containing 1795 patients with early TNBC. Compared with ICI-free neoadjuvant therapy, ICI-containing neoadjuvant therapy significantly increased the pathological complete response (pCR) rates in TNBC (odds ratio [OR] = 2.14, 95% confidence interval [CI]: 1.37–3.35, ICI-containing neoadjuvant therapy significantly increased the pCR rate in TNBC patients, independently of PD-L1 status. The addition of ICI to neoadjuvant chemotherapy may be considered an option for TNBC patients. Neoadjuvant treatment is widely used to reduce the size and extent of tumors in high risk early breast cancer (BC). Patients who achieve a pathological complete response (pCR) after neoadjuvant therapy have better survival outcomes than those with residual invasive disease . CurrentImmune-checkpoint therapy targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is a promising strategy for several malignances . With thTo provide up to date evidence on this emerging topic, we performed a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of adding ICIs to neoadjuvant chemotherapy in early TNBC.Literatures published before October 01, 2020 were retrieved from the PubMed, Embase, and Web of Science databases with the use of the following keywords: immune checkpoint inhibitors, nivolumab, pembrolizumab, ipilimumab, avelumab, tremelimumab, atezolizumab, durvalumab, and TNBC without further restrictions. The citation lists of relevant studies, reviews, and meta-analyses were manually screened for potentially eligible publications. The literature search was independently performed by two of the authors (LYH and XL). Any discrepancy was solved by discussion with a third author (YXD).The inclusion and exclusion criteria were prespecified. Eligible studies had to satisfy the following criteria: (a) phase II or phase III RCTs; (b) RCTs including early TNBC patients who received ICI-containing neoadjuvant therapy in the experimental arm and ICI-free neoadjuvant therapy in the control arm; and (c) RCTs with available data on pCR rates in the experimental and control arms for the estimation of an odds ratio (OR) and 95% confidence interval (CI). Studies were excluded if they were: (a) non-RCTs conducted to evaluate the role of ICI-containing neoadjuvant therapy in TNBC patients; (b) single-arm studies; (c) studies to determine appropriate dosages; and (d) ongoing trials or abstracts with insufficient results. If multiple publications from the same trial were identified or if there was case overlap between publications, only the latest or most complete publication was included. Two reviewers (LYH and LF) independently evaluated the risk of bias of the eligible studies using the Cochrane Collaboration risk of bias tool .Data were independently extracted by two of the authors (LYH and XL). The following data obtained from the eligible studies were recorded in accordance with a prespecified protocol: name of the trial, year of publication, study design, number of randomized patients, details of neoadjuvant therapy regimens administered, number of patients achieving pCR, follow-up information, and number of adverse events (AEs). Hazard ratio (HR) and 95% CI of event-free survival (EFS), OS, and distant recurrence-free survival were extracted when available. If not reported, the HRs and associated statistical data were indirectly calculated using the methods reported by Parmar  with an versus ICI-free neoadjuvant therapy in TNBC patients, in terms of pCR, which was defined as the absence of invasive tumors in the breast and regional nodes at the time of surgery (ypT0/is pN0). If not reported, other definitions of pCR (ypT0 ypN0 and ypT0/is) were substituted. The secondary objectives were as follows (1): the EFS for patients who experienced disease progression, local or distant recurrence, developing a second primary tumor, or death; and (2) the number of patients who had AEs for all grades and grade 3 or higher. We hypothesized that there was no significant correlation between molecular subtypes and AEs. Therefore, if the AEs of patients with TNBC were not available, we included the number of AEs from all molecular subtypes of breast cancer patients.The primary objective of this study was to compare the efficacy of ICI-containing neoadjuvant therapy I2 statistics, and a P < 0.10 or I2 statistic > 50% was considered to indicate substantial heterogeneity. Clinical heterogeneity  and methodological heterogeneity  were regarded as potential source of heterogeneity. A random-effects model was used by default due to potential clinical or methodological heterogeneity, or both in the included studies. The Mantel-Haenszel method was used to calculate pooled ORs with corresponding 95% CIs. Pooled HRs and corresponding 95% CIs were calculated using the inverse variance method. All analyses were performed using Review Manager 5.2 software . The pooled ORs and HRs were considered statistically significant if the 95% CI did not include 1.0 with a P <0.05 (two-sided).ORs and 95% CIs were calculated for pCR and AEs. An OR > 1 indicated higher pCR and AEs rates, whereas an OR < 1 indicated lower pCR and AEs rates in the ICI-containing group than in the ICI-free group. The HR with 95% CI was calculated to estimate the impact of ICI-containing neoadjuvant therapy on survival outcomes. A HR > 1 indicated worse survival outcomes, whereas a HR < 1 indicates better survival outcomes in the ICI-containing group compared with the ICI-free group. Heterogeneity was assessed using the Cochran Q and A systematic search of the literature identified 2156 records. After removing duplicates, the titles and abstracts of the remaining 1410 records were screened, and 1397 non-relevant records were excluded. Thirteen potentially eligible articles were evaluated in greater detail, of which nine did not met the eligibility criteria for this study. Finally, four RCTs [GeparNuevo , IMpassiA total of 1795 patients with TNBC were included in the study, of whom 1066 (59.4%) received ICI-containing and 729 (40.6%) received ICI-free neoadjuvant therapy. The four RCTs were published between 2019 and 2020. All patients were enrolled between 2015 and 2018 from multicenter. There were two phase II studies (GeparNuevo and I-SPY2) and two phase III studies (IMpassion031 and KEYNOTE-522). The GeparNuevo, IMpassion031, and KEYNOTE-522 trials included only TNBC patients, whereas the I-SPY2 trial included both TNBC and hormone receptor-positive/HER2-negative BC patients. Taxane and/or anthracycline plus cyclophosphamide were included in the neoadjuvant regimens in the four RCTs, whereas the agents in the KEYNOTE-522 trial also contained carboplatin. Durvalumab and atezolizumab were added to the neoadjuvant chemotherapy in the GeparNuevo and IMpassion031 trials, respectively. Pembrolizumab was added to the neoadjuvant chemotherapy in the KEYNOTE-522 and I-SPY2 trials. A placebo was given to the control group in the GeparNuevo, IMpassion031, and KEYNOTE-522 trials. The main characteristics of the four RCTs are presented in P < 0.001; heterogeneity: I2 = 66%, P = 0.03; P = 0.09; heterogeneity: I2 = 87%, P = 0.006; P = 0.001; heterogeneity: I2 = 0%, P = 0.39; P < 0.001; heterogeneity: I2 = 0%, P = 0.55; P = 0.01; heterogeneity: I2 = 0%, P = 0.78; P = 0.01; heterogeneity: I2 = 0%, P = 0.85; P < 0.001; heterogeneity: I2 = 0%, P = 0.47; The pCR rates were analyzed for 1223 TNBC patients. Overall, 422 (61.8%) of 683 patients in the ICI-containing group and 228 (42.2%) of 540 patients in the ICI-free group achieved a pCR after neoadjuvant treatment  than ICI-free neoadjuvant therapy in TNBC patients  than the control group  with EFS information. The pooled data showed that ICI-containing neoadjuvant therapy was significantly associated with a better EFS , dry skin, hepatitis, hyperthyroidism, hypothyroidism, infusion related reaction, pain, and pyrexia than ICI-free neoadjuvant therapy Table 2.Several immunotherapeutic agents, including atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab, are currently being investigated for the treatment of early and metastatic BC –19. ThisIn subgroup analysis, ICI-containing neoadjuvant therapy significantly increased the pCR rate in both PD-L1-positive and -negative subgroups. Inconsistently, the IMpassion130 study reported that atezolizumab showed PFS and OS benefit for patients with advanced TNBC only in the PD-L1-positive cohort . The incIn regards to survival outcomes, only EFS was reported by three of the four RCTs. The EFS involving disease progression, local or distant recurrence, development of a second primary tumor, or death were better in the ICI-containing group than the ICI-free group among patients with TNBC. In subgroup analysis, we found that the addition of pembrolizumab to neoadjuvant chemotherapy was significantly associated with better EFS than control group. However, in the KEYNOTE-522 trial , there wEndocrine dysfunctions, such as adrenal insufficiency, hypothyroidism, hyperthyroidism, hypophysitis, and insulin-deficient diabetes, are the most common immune-related AEs reported in clinical trials involving ICIs –24. ConsP-value of EFS were not directly reported in the I-SPY2 trial .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Antibiotic treatment failure of infection is common and frequently occurs in the absence of genetically encoded antibiotic resistance mechanisms. In such scenarios, the ability of bacteria to enter a phenotypic state that renders them tolerant to the killing activity of multiple antibiotic classes is thought to contribute to antibiotic failure. Phagocytic cells, which specialize in engulfing and destroying invading pathogens, may paradoxically contribute to antibiotic tolerance and treatment failure. Macrophages act as reservoirs for some pathogens and impede penetration of certain classes of antibiotics. In addition, increasing evidence suggests that subpopulations of bacteria can survive inside these cells and are coerced into an antibiotic-tolerant state by host cell activity. Uncovering the mechanisms that drive immune-mediated antibiotic tolerance may present novel strategies to improving antibiotic therapy. Staphylococcus aureus bloodstream infections, contributing to more than 20,000 deaths annually [Antibiotic resistance, defined as the genetically heritable capacity to grow in the presence of an antibiotic, is continuing to evolve and spread and represents a major threat to global health . Howeverannually ,5. Whileannually . Importaannually .Identifying the cause of antibiotic failure in patients relies on further probing interactions between the pathogen, host, and antibiotic. Antimicrobial chemotherapy and bacterial pathogenicity have generally remained separate areas of study that has limited our understanding of how our antibacterials are working, or not working, in the context of the host immune environment.Antibiotics have been used to treat patients since the 1940s , but howS. aureus through reactive oxygen species (ROS) that cause collapse of the tricarboxylic acid (TCA) cycle an entrance to a low ATP state [S. aureus intracellular tolerance [S. aureus abscess patient isolates [Salmonella Typhimurium, antibiotic-tolerant persister subpopulations are induced intracellularly through acid stress, nutritional deprivation, and the activation of toxin–antitoxin modules [Mycobacterium tuberculosis (Mtb) suggest that antibiotic tolerance is predominantly mediated through nitrosative stress and is increased following cytokine activation of macrophages or immunization of mice [Immune cells evoke a plethora of stresses  to eliminate invading pathogens, but there is mounting evidence that components of the innate immune response are antagonistic to antibiotics –7,9. It’TP state . Additioisolates . In Salm of mice .S. aureus is improved by reducing phagocytic burst: S. aureus was more susceptible to antibiotics in Ncf1−/− and Nox2−/y mice deficient in oxidative burst [Mtb was more susceptible to antibiotics in macrophages lacking an inducible nitric oxide synthase (Nos2−/−) gene [Identifying the stresses encountered by bacteria, as well as the bacterial response to these stresses, during infection that prevent lethality of antibiotics may be key to improving their therapeutic potential during infection . Severalve burst ,23 and wve burst . In addiS. aureus [S. aureus [S. aureus, while also increasing antibiotic susceptibility. Another study found that combinatorial treatment with the glucocorticoid dexamethasone and antibiotics led to improved outcome and decreased infection severity in a murine model of S. aureus arthritis by decreasing macrophage recruitment and inflammation [S. aureus infection [Studies that employ strategies such as treatment with antioxidants ,25–27 an. aureus . As decr. aureus  and ROS . aureus , antibioammation . Glucocoammation ,32,33. Wnfection . Howevernfection .S. aureus, host-derived reactive species have been shown to induce the formation of Mtb persisters [Mtb in the absence of antibiotics while also preventing the formation of Mtb persisters [Mtb in human monocytes [Mtb [Similar to rsisters . Additiorsisters . The usersisters –27. In aonocytes  and imprtes [Mtb , suggestMtb and S. aureus infection, this may not hold true for all pathogens. S. Typhimurium persisters reprogram the macrophage response from a pro-inflammatory to an anti-inflammatory state, dampening the antimicrobial strategies of the macrophages and allowing slow-growing Salmonella persisters to evade both antibiotic and immune-mediated killing [Salmonella persisters are able to survive by shifting the macrophage response away from a pro-inflammatory state, it reasons that restimulation of a pro-inflammatory immune response may improve killing of S. Typhimurium persisters.Although the reduction of ROS appears to be advantageous for the clearance of  killing . As SalmAlthough a lot remains to be learned, targeting the host response to bacterial infection will likely increase the efficacy of existing antibiotics, an intriguing strategy given the shortage of new and effective antibiotics in development .S. aureus and Mtb? Or in the case of Salmonella, is amplification of the pro-inflammatory response a better treatment strategy?Interactions between the innate immune system and bacterial pathogens have definite impacts on antibiotic efficacy. This realization opens the door to using immunomodulators to maximize antibiotic efficacy to improve the treatment of infection. Ideally, a specific immunomodulator would increase antibiotic susceptibility of a specific pathogen without any negative impacts on the hosts’ ability to fight the infection. If antibacterial strategies associated with activated immune cells are driving tolerance, is acute immunosuppressive therapy in combination with bactericidal antibiotics a viable treatment option for The potential of immunomodulatory strategies to improve antibiotic efficacy is appealing, but immunomodulation during bacterial infection is certainly complicated and not without risk. Although there is more work to be done to understand potential challenges and drawbacks of immunomodulation, this strategy has been a game changer for patients living with other diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn disease, and various types of cancers –39. HUMI