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Ancestral state reconstruction models use genetic data to characterize a group of organisms’ common ancestor. These models have been applied to salmonellosis outbreaks to estimate the number of transmissions between different animal species that share similar geographical locations, with animal host as the state. However, as far as we are aware, no studies have validated these models for outbreak analysis. In this study, salmonellosis outbreaks were simulated using a stochastic Susceptible-Infected-Recovered model, and the host population and transmission parameters of these simulated outbreaks were estimated using Bayesian ancestral state reconstruction models (discrete trait analysis (DTA) and structured coalescent (SC)). These models were unable to accurately estimate the number of transmissions between the host populations or the amount of time spent in each host population. The DTA model was inaccurate because it assumed the number of isolates sampled from each host population was proportional to the number of individuals infected within each host population. The SC model was inaccurate possibly because it assumed that each host population's effective population size was constant over the course of the simulated outbreaks. This study highlights the need for phylodynamic models that can take into consideration factors that influence the characteristics and behavior of outbreaks, e.g. changing effective population sizes, variation in infectious periods, intra-population transmissions, and disproportionate sampling of infected individuals. [ABSTRACT FROM AUTHOR]

Background: Increase in mortality involving poisoning, particularly by narcotics, is known to have been one of the factors that affected life expectancy in the US during the last two decades, especially for white Americans and Native Americans. However, the contribution of medicaments other than narcotics to mortality in different racial/age groups is less studied. Methods: We regressed annual rates of mortality involving poisoning by medicaments but not narcotics/psychodysleptics (ICD-10 codes T36-39.xx or T41-50.8 but not T40.xx present as either underlying or contributing causes of death), as well as annual rates of mortality for certain subcategories of the above, including mortality involving poisoning by psychotropic drugs but not narcotics/psychodysleptics (ICD-10 codes T43.xx but not T40.xx present as either underlying or contributing causes of death) in different age/racial groups for both the 2000–2011 period and the 2011–2017 period against calendar year. Results: Annual numbers of deaths involving poisoning by medicaments but not narcotics/psychodysleptics grew from 4,332 between 2000–2001 to 11,401 between 2016–2017, with the growth in the rates of those deaths being higher for the 2011–2017 period compared to the 2000–2011 period. The largest increases in the rates of mortality involving poisoning by medicaments but not narcotics/psychodysleptics were in non-elderly Non-Hispanic Native Americans, followed by Non-Hispanic whites. Most of those increases came from increases in the rates of mortality involving poisoning by psychotropic medications; the latter rates grew for the period of 2015–2017 vs. 2000–2002 by factors ranging from 2.75 for ages 35-44y to 5.37 for ages 55-64y. Conclusions: There were major increases in mortality involving poisoning by non-narcotic, particularly psychotropic medicaments, especially in non-elderly non-Hispanic whites and Native Americans. Our results support the need for a comprehensive evaluation of the effect of psychotropic medications on health-related outcomes, including mortality for causes other than poisoning, and the impact of medication misuse. [ABSTRACT FROM AUTHOR]

Objectives: HIV/AIDS has become the leading cause of death by infectious disease in China since 2009. However, the trend of gender disparities in HIV/AIDS has not been reported in China since 1990. Our study aimed to explore the secular trend of HIV/AIDS mortality in China from 1990 to 2016 and to identify its gender disparities over the past 27 years. Method: The mortality data of HIV/AIDS were obtained from the Global Burden of Disease Study 2016 (GBD 2016). Logistic regression was used to estimate the prevalence odds ratio (POR) of gender for HIV/AIDS mortality in different surveys. Results: The standardized mortality of HIV/AIDS in China rose dramatically from 0.33 per 100,000 people in 1990 to 2.50 per 100,000 people in 2016. The rate of HIV/AIDS mortality increased more quickly in men than in women, and the sex gap of mortality of HIV/AIDS widened. By 2016, the HIV/AIDS mortality in men was 3 times that in women and was 5.74 times that in women within the 75- to 79-year-old age group. Conclusions: The mortality of HIV/AIDS in China is increasing, with a widening gender disparity. It is critical for policymakers to develop policies to eliminate these disparities and to ensure that everyone can live a long life in full health. [ABSTRACT FROM AUTHOR]

Background: Research on contraceptive behaviour changes over time in Uganda is scarce, yet it has among the highest fertility and maternal mortality rates of any country in the East African region. Understanding temporal patterns of contraceptive use for both women and men is vital in evaluating the effectiveness of family planning interventions and strategies, and identifying those with the most unmet need. Using repeated nationally representative cross-sectional samples, this study charts the changes in Uganda’s population-based contraceptive use over recent years. Methods: Five Demographic and Health Survey datasets for Uganda over 21 years, from 1995 to 2016, were sourced and interrogated. Eligible participants included all women aged 15–49 years and men aged 15–54 years. Responses to questions on modern and any (modern or traditional) contraceptive use were analysed. Stratified by gender, weighted regression analyses were employed to detect change over time. The patterns associated with key demographic variables were also investigated. Results: Overall, 50,027 women and 14,092 men were included within the study. In 2016, 30.3% of women and 39.9% of men were using any contraceptive method, a significant non-linear increase from 13.4% of women and 20.3% of men in 1995. Furthermore, 27.3% of women and 35.9% of men were using modern contraceptive methods in 2016, an increase from 7.4% of women and 10.4% of men in 1995. All considered demographic variables were significantly associated with contraceptive use for both women and men (all P<0.001); and for women, all variables differentially changed over time (all P<0.001). Conclusion: This study showed a significant increase and dynamism across key demographic variables in contraceptive uptake by both women and men. Sustained family planning programs and interventions have successfully resulted in behaviour change across the Ugandan population. However, continued efforts are needed to further reduce Uganda’s relatively high fertility and associated maternal mortality rates. [ABSTRACT FROM AUTHOR]

The cow-calf industry in North America is in a period of rapid consolidation with corresponding increases in herd sizes and changes in management. The objectives of this study were to examine longitudinal data on reproductive performance in cow-calf herds and identify benchmarks for the most critical measures and important sources of differences among herds. To address these questions, a surveillance network was established in western Canada to collect data between 2013 to 2017 privately owned cow-calf herds during calving (n = 105 herds) and at pregnancy testing (n = 94 herds). Data were summarized for a number of indices of herd performance. However, the values considered to be most reliable and accurate were the percentage of females not pregnant when tested by a veterinarian, the percentage of calves dead within 24 hours of birth, and the percentage of calves dead from 24 hours to weaning. The mean and variation between herds for heifers, measured using standard deviation, was greater than for cows for: non-pregnancy (cows 6.8% (mean)±3.4%(SD), heifers 9.7%±8.2%), calf death from birth to 24 hours (cows 2.1%±1.6%, heifers 3.6%±4.5%), and calf death from 24 hours to weaning (cows 2.5%±2.4%, heifers 2.9%±3.9%). Benchmarks or performance targets derived from the 25th percentiles of these data for both cows and heifers were <5% for non-pregnancy risk and <1% for calf loss within 24 hours of birth. The suggested benchmark for calf loss from 24 hours to weaning was <2% for cows and <1% for heifers. All outcomes consistently displayed greater variation between herds as compared to year to year differences within herds with the exception of calf loss before 24 hours in cows. The timing of the start of breeding season was a consistent source of variation in risks of non-pregnancy and calf losses. Cows bred in April or earlier to start calving in late December or January were at increased risk of low pregnancy percentages (p<0.001) and calf losses at birth (p<0.04), as well as increased calf loss before weaning in both cows and heifers (p<0.02). There was also an increase in the risk of non-pregnancy for cows and heifers (p<0.001) where first exposure to breeding was not until July or August. In contrast, the risks of calf loss within 24 hrs of birth (p<0.001) and from 24 hrs to weaning in cows (p<0.02) first exposed to breeding in July and August were significantly lower than for herds that had earlier breeding seasons. [ABSTRACT FROM AUTHOR]

Background: To evaluate the impact of macrophage activation syndrome (MAS) on clinical features in patients with Kikuchi-Fujimoto disease (KFD) and to compare the features of MAS in KFD with those of adult-onset Still’s disease (AOSD) and systemic lupus erythematosus (SLE). Methods: The medical records of febrile patients hospitalised with KFD between November 2005 and April 2017 were reviewed. Patients fulfilling the 2016 classification criteria for MAS were classified as having MAS. Clinical and laboratory features of patients with KFD with and without MAS were evaluated. Poor hospitalisation outcomes were defined as intensive care unit admission or in-hospital mortality. The treatment outcomes of MAS in KFD, AOSD, and SLE were also compared. Results: Among 78 patients hospitalised with KFD, 24 (30.8%) patients had MAS during admission. Patients with KFD and MAS more frequently required glucocorticoid treatment (66.7% vs 40.7%, p = 0.036) and had longer hospital stays than patients with KFD without MAS (12.5 vs 8.5 days, p<0.001). In addition, patients with MAS had worse hospitalisation outcomes than patients without MAS (29.2% vs. 0.0%, p<0.001). Among patients with MAS in KFD, AOSD, and SLE, the number of patients requiring glucocorticoid treatment after 3 months was significantly lower among patients with MAS and KFD (KFD 33.3%, AOSD 88.9%, SLE 100%, p<0.001). Conclusions: The presence of MAS in KFD was associated with adverse clinical outcomes including higher steroid usage and worse hospitalisation outcomes. However, compared to those with AOSD and SLE, patients with MAS and KFD were less likely to require long-term glucocorticoid treatment. [ABSTRACT FROM AUTHOR]

Background: Melioidosis is a frequently fatal disease requiring specific treatment. The yield of Burkholderia pseudomallei from sites with a normal flora is increased by culture using selective, differential media such as Ashdown’s agar and selective broth. However, since melioidosis mainly affects people in resource-poor countries, the cost effectiveness of selective culture has been questioned. We therefore retrospectively evaluated this in two laboratories in southeast Asia. Methodology/Principal findings: The results of all cultures in the microbiology laboratories of Mahosot Hospital, Vientiane, Laos and Angkor Hospital for Children, Siem Reap, Cambodia, in 2017 were reviewed. We identified patients with melioidosis who were only diagnosed as a result of culture of non-sterile sites and established the total number of such samples cultured using selective media and the associated costs in each laboratory. We then conducted a rudimentary cost-effectiveness analysis by determining the incremental cost-effectiveness ratio (ICER) per DALY averted and compared this against the 2017 GDP per capita in each country. Overall, 29 patients in Vientiane and 9 in Siem Reap (20% and 16.9% of all culture-positive patients respectively) would not have been diagnosed without the use of selective media, the majority of whom (18 and 8 respectively) were diagnosed by throat swab culture. The cost per additional patient detected by selective culture was approximately $100 in Vientiane and $39 in Siem Reap. Despite the different patient populations (all ages in Vientiane vs. only children in Siem Reap) and testing strategies (all samples in Vientiane vs. based on clinical suspicion in Siem Reap), selective B. pseudomallei culture proved highly cost effective in both settings, with an ICER of ~$170 and ~$28 in Vientiane and Siem Reap, respectively. Conclusions/Significance: Selective culture for B. pseudomallei should be considered by all laboratories in melioidosis-endemic areas. However, the appropriate strategy for implementation should be decided locally. [ABSTRACT FROM AUTHOR]

Background: The entomopathogenic fungus Beauveria bassiana has been widely used to kill mosquito larvae and adults in the laboratory and field. However, its slow action of killing has hampered its widespread application. In our study, the B. bassiana fungus was genetically modified to express the Bacillus thuringiensis (Bt) toxin Cyt2Ba to improve its efficacy in killing mosquitoes. Methodology/Principal findings: The efficacy of the wild type (WT) of B. bassiana and a transgenic strain expressing Cyt2Ba toxin (Bb-Cyt2Ba) was evaluated against larval and adult Aedes mosquitoes (Aedes aegypti and Aedes albopictus) using insect bioassays. The Bb-Cyt2Ba displayed increased virulence against larval and adult Aedes mosquitoes compared with the WT: for Ae. aegypti adults, the median lethal time (LT50) was decreased by 33% at the concentration of 1× 108 conidia/ml, 19% at 1× 107 conidia/ml and 47% at 1× 106 conidia/ml. The LT50 for Ae. albopictus adults was reduced by 20%, 23% and 29% at the same concentrations, respectively. The LT50 for Ae. aegypti larvae was decreased by 42% at 1× 107 conidia/ml and 25% at 1× 106 conidia/ml, and that for Ae. albopictus larvae was reduced by 33% and 31% at the same concentrations, respectively. In addition, infection with Bb-Cyt2Ba resulted in a dramatic reduction in the fecundity of Aedes mosquitoes. Conclusions/Significance: In conclusion, our study demonstrated that the virulence of B. bassiana against mosquitoes can be significantly improved by introducing the Bt toxin gene Cyt2Ba into the genome to express the exogenous toxin in the fungus. The transgenic strain Bb-Cyt2Ba significantly reduced the survival and fecundity of Ae. aegypti and Ae. albopictus compared with the WT strain, which suggested that this recombinant B. bassiana has great potential for use in mosquito control. [ABSTRACT FROM AUTHOR]

The Bornean orangutan is critically endangered and monitoring its population is needed to inform effective conservation management. In this paper, we present results of 2014–17 aerial nest surveys of the major orangutan populations in Sabah and compare them with baseline data produced during surveys conducted in 2002–03 using similar methods. Our results show three important points: a) by increasing the survey effort (estimated at 15–25% cover), sparsely scattered orangutan sub-populations not recorded in the previous aerial surveys were located and the accuracy of the nest count estimates is expected to improve; b) large populations in the interior forests of Sabah, occupying sustainably managed logged and unlogged forests, have been stable over 15 years and are of vital importance for the species’ conservation; c) fragmented populations located in eastern Sabah, that are surrounded by extensive oil palm plantations, have declined at varying rates. [ABSTRACT FROM AUTHOR]

Introduction: Acute mesenteric ischemia is associated with high rates of mortality. The aim of this study was to investigate the prognostic value of the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) on 30-day outcomes in patients with acute mesenteric ischemia. Material and methods: Consecutive patients who were admitted for an acute mesenteric ischemia were retrospectively included. The full white blood count at the time of admission to the hospital was recorded. The population was divided into 4 subgroups according to the quartiles of the NLR and the PLR. The 30-day outcomes including the mortality and the complications were compared among the subgroups. Results: In total, 106 patients were included. A surgical treatment including revascularization and/or digestive resection was performed for 56 patients (52.8%). The 30-day all-cause mortality was 72 patients (67.9%). Patients with higher PLR value (PLR >429.3) had significantly higher rate of mortality compared to the other groups (80.8% vs 46.2%, 66.7% and 77.8%, p = 0.03). No significant difference on 30-day outcome was observed among the subgroups divided according to the NLR. Conclusion: The PLR, but not the NLR, is a predictive factor of 30-day mortality in patients with acute mesenteric ischemia. [ABSTRACT FROM AUTHOR]

Car traffic in urban systems has been studied intensely in past decades but models are either limited to a specific aspect of traffic or applied to a specific region. Despite the importance and urgency of the problem we have a poor theoretical understanding of the parameters controlling urban car use and congestion. Here, we combine economical and transport ingredients into a statistical physics approach and propose a generic model that predicts for different cities the share of car drivers, the CO2 emitted by cars and the average commuting time. We confirm these analytical predictions on 25 major urban areas in the world, and our results suggest that urban density is not the most relevant variable controlling car-related quantities but rather are the city’s area size and the density of public transport. Mitigating the traffic (and its effect such as CO2 emissions) can then be obtained by reducing the urbanized area size or, more realistically, by improving either the public transport density or its access. In particular, increasing the population density is a good idea only if it also increases the fraction of individuals having access to public transport. [ABSTRACT FROM AUTHOR]

Background: The combination of red blood cell distribution width and body mass index (COR-BMI) is indicated as a new prognostic index of survival in patients with laryngeal cancer. However, the ability of this prediction in other types of cancer or whether its use can be expanded to non-oncological patients is unknown. The aim of this study was to investigate the prediction of prognosis of in-hospital mortality of the COR-BMI in oncological and non-oncological patients. Methods: A retrospective study was performed with all hospitalized patients between 2014 and 2016, totaling 2930 patients, 262 oncological and 2668 non-oncological. The COR-BMI was divided into three classes: 0, RDW ≤ 13.1% and BMI ≥ 25 kg/m2; 1, RDW ≤ 13.1% and BMI < 18.5 or ≥ 18.5 but < 25 kg/m2 and RDW > 13.1% and BMI ≥ 18.5 but < 25 or BMI ≥ 25 kg/m2; and 2, RDW > 13.1% and BMI < 18.5 kg/m2. In order to analyze the relationship between COR-BMI and in-hospital mortality in the studied population, the Cox Proportional Hazards Model was used in a multivariate analysis based on a conceptual model. Results: The COR-BMI was an independent predictor of in-hospital mortality in non-oncological patients (1 versus 0: HR = 3.34; CI = 1.60–6.96, p = 0.001; 2 versus 0: HR = 3.38; CI = 1.22–9.39, p = 0.019). The survival rate of these patients was lower among those with the highest scores on the COR-BMI. This prediction was not found in oncological patients. Conclusion: The present study suggests that the COR-BMI may have its practical use expanded to non-oncological patients as an independent predictor of in-hospital mortality. [ABSTRACT FROM AUTHOR]

Background: Globally in 2016, 1.7 million people died of Tuberculosis (TB). This study aimed to estimate all-cause mortality rate, identify features associated with mortality and describe trend in mortality rate from treatment initiation. Method: A 5-year (2012–2016) retrospective analysis of electronic TB surveillance data from Kilifi County, Kenya. The outcome was all-cause mortality within 180 days after starting TB treatment. The risk factors examined were demographic and clinical features at the time of starting anti-TB treatment. We performed survival analysis with time at risk defined from day of starting TB treatment to time of death, lost-to-follow-up or completing treatment. To account for ‘lost-to-follow-up’ we used competing risk analysis method to examine risk factors for all-cause mortality. Results: 10,717 patients receiving TB treatment, median (IQR) age 33 (24–45) years were analyzed; 3,163 (30%) were HIV infected. Overall, 585 (5.5%) patients died; mortality rate of 12.2 (95% CI 11.3–13.3) deaths per 100 person-years (PY). Mortality rate increased from 7.8 (95% CI 6.4–9.5) in 2012 to 17.7 (95% CI 14.9–21.1) in 2016 per 100PY (Ptrend<0.0001). 449/585 (77%) of the deaths occurred within the first three months after starting TB treatment. The median time to death (IQR) declined from 87 (40–100) days in 2012 to 46 (18–83) days in 2016 (Ptrend = 0·04). Mortality rate per 100PY was 7.3 (95% CI 6.5–7.8) and 23.1 (95% CI 20.8–25.7) among HIV-uninfected and HIV-infected patients respectively. Age, being a female, extrapulmonary TB, being undernourished, HIV infected and year of diagnosis were significantly associated with mortality. Conclusions: We found most deaths occurred within three months and an increasing mortality rate during the time under review among patients on TB treatment. Our results therefore warrant further investigation to explore host, disease or health system factors that may explain this trend. [ABSTRACT FROM AUTHOR]

Megacities are facing serious water pollution problems due to urbanization, rapid population growth and economic development. Water is an essential resource for human activities and socio-economic development and water quality in urban settings has important implications for human and environmental health. Urbanization and lack of sewerage has left the water in Jakarta, Indonesia in a heavily polluted condition. Rigorous assessment of urban water quality is necessary to understand the factors controlling water quality conditions. We use trend analysis to assess the current water quality conditions in Jakarta, focusing on Biochemical Oxygen Demand (BOD), Dissolved Oxygen (DO), and Total Suspended Solids (TSS). In most monitoring stations analyzed, BOD and TSS concentrations have decreased over time, but from large starting concentrations. DO in most monitoring stations has increased. Although Jakarta’s water quality has shown some improvement, it remains heavily impaired. The average value of BOD is low in upper stream stations compared to middle and lower stream stations. BOD and TSS trends of some water quality stations in middle and lower streams show increasing trends. Cluster analysis results suggest three groups for BOD and TSS, and four groups for DO. Understanding water quality conditions and factors that control water quality suggest strategies for improving water quality given current trends in climate, population growth and urban development. Results from this study suggest research directions and management strategies to address water quality challenges. [ABSTRACT FROM AUTHOR]

Background: Pre-operative stress testing is widely used to evaluate patients for non-cardiac surgeries. However, its value in predicting peri-operative mortality is uncertain. The objective of this study is to assess the type and quality of available evidence in a comprehensive and statistically rigorous evaluation regarding the effectiveness of pre-operative stress testing in reducing 30-day post -operative mortality following non -cardiac surgery. Methods: The databases of MEDLINE, EMBASE, and CENTRAL databases (from inception to January 27, 2016) were searched for all studies in English. We included studies with pre-operative stress testing prior to 10 different non-cardiac surgery among adults and excluded studies with sample size<15. The data on study characteristics, methodology and outcomes were extracted independently by two observers and checked by two other observers. The primary outcome was 30-day mortality. We performed random effects meta-analysis to estimate relative risk (RR) and 95% confidence intervals (95% CI) in two-group comparison and pooled the rates for stress test alone. Heterogeneity was assessed using I2 and methodological quality of studies using Newcastle-Ottawa Quality Assessment Scale. The predefined protocol was registered in PROSPERO #CRD42016049212. Results: From 1807 abstracts, 79 studies were eligible (297,534 patients): 40 had information on 30-day mortality, of which 6 studies compared stress test versus no stress test. The risk of 30-day mortality was not significant in the comparison of stress testing versus none (RR: 0.79, 95% CI = 0.35–1.80) along with weak evidence for heterogeneity. For the studies that evaluated stress testing without a comparison group, the pooled rates are 1.98% (95% CI = 1.25–2.85) with a high heterogeneity. There was evidence of potential publication bias and small study effects. Conclusions: Despite substantial interest and research over the past 40 years to predict 30-day mortality risk among patients undergoing non-cardiac surgery, the current body of evidence is insufficient to derive a definitive conclusion as to whether stress testing leads to reduced peri-operative mortality. [ABSTRACT FROM AUTHOR]

Taking inspiration from the archaeology of the Texas Coastal Plain (TCP), we develop an ecological theory of population distribution among mobile hunter-gatherers. This theory proposes that, due to the heterogeneity of resources in space and time, foragers create networks of habitats that they access through residential cycling and shared knowledge. The degree of cycling that individuals exhibit in creating networks of habitats, encoded through social relationships, depends on the relative scarcity of resources and fluctuations in those resources. Using a dynamic model of hunter-gatherer population distribution, we illustrate that increases in population density, coupled with shocks to a biophysical or social system, creates a selective environment that favors habitat partitioning and investments in social mechanisms that control the residential cycling of foragers on a landscape. Our work adds a layer of realism to Ideal Distribution Models by adding a time allocation decision process in a variable environment and illustrates a general variance reduction, safe-operating space tradeoff among mobile human foragers that drives social change. [ABSTRACT FROM AUTHOR]

Background: Patients with acute-on-chronic liver failure (ACLF) precipitated by hepatic injury and extrahepatic insults had distinct clinical phenotypes, and prognosis. This study aimed to validate prognostic models for ACLF and to explore their discriminative abilities in ACLF population categorized by the etiologies of precipitating events. Methods: This study collected data from 343 consecutive cirrhotic patients hospitalized with the diagnosis of ACLF according to the EASL-CLIF-Consortium definition. The discrimination abilities of prognostic models at the onset of ACLF were tested with the concordance index and area under the receiver operating characteristic curve. Results: Among the entire cohort, 103 patients survived with medical management, nine patients were transplanted, and 231 patients died without liver transplantation. The predictive accuracy of the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) for 28-day mortality was similar to the CLIF Consortium Organ Failure (CLIF-C OF) but significantly higher than the CLIF Consortium ACLF, the Child-Turcotte-Pugh, the model for end-stage liver disease (MELD), the MELD-sodium, the integrated MELD, and the Acute Physiology and Chronic Health Evaluation II. Of note, 44 patients had acute hepatic insult triggering ACLF (hepatic-ACLF), 244 were exclusively precipitated by bacterial infection or gastrointestinal bleeding (extrahepatic-ACLF), and 55 cases had no any identifiable potential precipitating events. Patients with hepatic-ACLF had significantly higher 28-day mortality than extrahepatic-ACLF patients. The CLIF-SOFA and CLIF-C OF displayed the highest accuracy significantly outperforming other scoring systems in predicting mortality among patients with hepatic-ACLF and those with extrahepatic-ACLF. Conclusion: The CLIF-SOFA and simpler CLIF-C OF are reliable measures of mortality risk in ACLF patients precipitated by either hepatic or extrahepatic insults. Both validated models could be used to stratify the risk of death and improve management of ACLF. [ABSTRACT FROM AUTHOR]

Background: There is a lack of reliable epidemiological data on long-term survival trends of first-ever stroke patients in Lithuanian population. Aims: To evaluate trends in long-term survival after stroke and to determine the influence of some sociodemographic and lifestyle factors, time and subtype of stroke, and stroke care on survival. Methods: All stroke events included in Kaunas stroke register database were ascertained and validated according to the standardized criteria outlined by the WHO MONICA Project. The study included all patients in Kaunas (Lithuania) city aged 25 to 64 years who experienced a stroke between 1986 and 2011. Death time was confirmed by the Office for National Death Statistics. Estimates of stroke long-term survival data and factors influencing survival changes were made by applying the Kaplan-Meier and Cox regression analysis. Results: During the study period, 4,129 persons aged 25–64 years suffered from a first-ever stroke: 2,215 (53.6%) of them were men and 1,914 (46.4%)—women. Ischemic stroke was significantly more frequent in males than in females (80.6% and 78.6%, respectively, p<0.05) and subarachnoid hemorrhage was more common in women than in men (9.0% and 7.0% respectively, p <0.05). Of all first-ever stroke patients, 3,272 (79.2%) survived 1 year and 2,905 (70.4%) survived 5 years after stroke onset. The 1- and 5-years survival rate after a first-ever stroke in women was significantly higher as compared with that in men (Log-rank test p = 0.0001). The older (55–64 year) persons had poorer 1-year and 5-years survival rate as compared with persons in the younger (25–54 years) age group (Log-rank test p = 0.0001). Among persons with a first-ever stroke who had their stroke in 2007–2011, 1- and 5-year survival rate was higher compared with that in persons who had had a stroke in 1986–1990 and in 1997–2001 (Log-rank test p = 0.0001). The persons with a first-ever ischemic stroke had a better chance to survive first 1- and 5-years after stroke compared with persons who had intracerebral or subarachnoid haemorrhage. Only female gender was associated with higher 1- and 5-year survival rate after first-ever stroke. The older age, previous myocardial infarction and diabetes mellitus were associated with lower 1- and 5-year survival rate after first-ever stroke. Conclusions: This population-based study of patients with first-ever stroke demonstrated that the long-term survival was better in women than men, and improved significantly in both men and women during the past decade. Long-term survival was better of those with first-ever ischemic stroke and of younger age– 25 to 54 years. [ABSTRACT FROM AUTHOR]

Background: Factors associated with hospital mortality are unclear in patients with acute exacerbation of COPD (AECOPD) requiring intensive care unit (ICU) admission. We aimed to characterize these patients and identify factors associated with hospital mortality. Patients and methods: We used a retrospective observational case-control design and recruited patients between January 2015 and March 2017. Of 146 patients enrolled, 24 (16.4%) died during their hospital stay, while 122 survived. Results: Multivariate logistic regression analyses revealed factors associated with hospital mortality: age (adjusted odds ratio [AOR] 1.12, 95% CI: 1.03–1.23), C-reactive protein (CRP) level >7.5 mg/dL at the emergency room (AOR 4.52, 95% CI: 1.27–16.04), peak eosinophil-to-neutrophil ratio (ENR)×102 on days 8–14 of treatment (AOR 0.22, 95% CI: 0.08–0.63), and in-hospital complications (AOR 4.23, 95% CI: 1.12–15.98) (all P<0.05). After receiver operating characteristic curve analyses, cutoff level for peak ENR×102 was 0.224. To examine the synergistic effects of CRP level and peak ENR, we divided patients into four groups: (G0, reference group) Peak ENR×102 >0.224 on days 8–14 and initial CRP <7.5 mg/dL; (G1) Peak ENR×102 >0.224 on days 8–14 and initial CRP >7.5 mg/dL; (G2) Peak ENR×102 <0.224 on days 8–14 and initial CRP <7.5 mg/dL; and (G3) Peak ENR×102 <0.224 on days 8–14 and initial CRP >7.5 mg/dL. For G2 and G3 patients, the AOR of mortality was significantly different from that of the reference group (G2: AOR 10.00, P = 0.020; G3: AOR 61.79, P<0.001). The relationship between 28-day mortality and the four groups was statistically significant (log-rank test, P<0.001). Conclusion: Older age, initial CRP >7.5 mg/dL, peak ENR on days 8–14, and in-hospital complications were associated with hospital mortality in patients with AECOPD requiring ICU admission. Patients with both biomarkers, initial CRP >7.5 mg/dL, and peak ENR×102 <0.224 on days 8–14 of treatment, had an increased risk of hospital mortality. [ABSTRACT FROM AUTHOR]

Background: The cesarean section (CS) rate has risen globally during the last two decades. Effective and feasible strategies are needed to reduce it. The aim of this study was to assess the CS rate change after a two-stage intervention package that was designed to reduce the overall CS rate in Guangzhou, China.Methods and Findings: This intervention package was implemented by the Health Commission of Guangzhou Municipality in 2 stages (October 2010-September 2014 and October 2014-December 2016) and included programs for population health education, skills training for healthcare professionals, equipment and technical support for local healthcare facilities, and capacity building for the maternal near-miss care system. A retrospective repeated cross-sectional study was conducted to evaluate influences of the intervention on CS rates. A pre-intervention period from January 2008 to September 2010 served as the baseline. The primary outcome was the CS rate, and the secondary outcomes included maternal mortality ratio (MMR) and perinatal mortality rate (PMR), all obtained from the Guangzhou Perinatal Health Care and Delivery Surveillance System (GPHCDSS). The Cochran-Armitage test was used to examine the trends of the overall CS rate, MMR, and PMR across different stages. Segmented linear regression analysis was used to assess the change of the CS rate over the intervention period. A total of 1,921,932 records of births and 108 monthly CS rates from 2008 to 2016 were analyzed. The monthly CS rate declined across the intervention stages (Z = 75.067, p < 0.001), with an average rate of 42.4% at baseline, 39.8% at Stage 1, and 35.0% at Stage 2. The CS rate declined substantially among nulliparous women who delivered term singletons, with an accelerating decreasing trend observed across Stage 1 and Stage 2 (the difference in slopes: -0.09 [95% CI -0.16 to -0.02] between Stage 1 and baseline, p = 0.014; -0.11 [95% CI -0.20 to -0.02] between Stage 1 and Stage 2, p = 0.017). The CS rate in the remaining population increased during baseline and Stage 1 and subsequently decreased during Stage 2. The sensitivity analysis suggested no immediate impact of the universal two-child policy on the trend of the CS rate. The MMR (Z = -4.368, p < 0.001) and PMR (Z = -13.142, p < 0.001) declined by stage over the intervention period. One of the main limitations of the study is the lack of a parallel control group. Moreover, the influence of temporal changes in the study population on the CS rate was unknown. Given the observational nature of the present study, causality cannot be confirmed.Conclusions: Apparent decline in the overall CS rate was observed in Guangzhou, China, after the implementation of a two-stage intervention package. The decline was most evident among nulliparous women who delivered term singletons. Despite some limitations for causal inference, Guangzhou's experience in controlling the CS rate by implementing composite interventions with public health education and perinatal healthcare service improvement could have implications for other similar areas with high rates of CS. [ABSTRACT FROM AUTHOR]

Harmful algal blooms are an ongoing threat to many aquatic systems throughout the world. In the Chowan River, North Carolina, the frequency of toxin producing Microcystis aeruginosa blooms has increased since 1975 along with an average 0.71°C rise in water temperature. The combined effect of microcystin-LR toxin and rising temperatures on a dominant zooplankter in the system, Bosmina longirostris, was the focus of this study. Laboratory studies were conducted to determine how microcystin-LR, produced from M. aeruginosa blooms, affected B. longirostris mortality under different temperature regimes. At 25°C, the LC50 for B. longirostris was 26.3 μg L-1 suggesting that B. longirostris can survive typical current bloom microcystin-LR concentrations ranging 0.1μg L-1 to 2.0 μg L-1, but would be susceptible to higher concentrations they may be periodically exposed to. Mortality was assessed at a constant microcystin-LR concentration of 26.3 μg L-1 over 15–35°C, and it was found that B. longirostris mortality increased at higher temperatures. B. longirostris mortality increased approximately 18% due to microcystin-LR alone over 2°C between 25°C and 27°C when exposed to the LC50 concentration. The increased prevalence of toxic M. aeruginosa blooms and increasing temperatures due to climate change may reduce B. longirostris populations, potentially affecting larval fish and fisheries in the Chowan River, North Carolina. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to develop and validate deep-learning-based artificial intelligence algorithm for predicting mortality of AHF (DAHF). Methods and results: 12,654 dataset from 2165 patients with AHF in two hospitals were used as train data for DAHF development, and 4759 dataset from 4759 patients with AHF in 10 hospitals enrolled to the Korean AHF registry were used as performance test data. The endpoints were in-hospital, 12-month, and 36-month mortality. We compared the DAHF performance with the Get with the Guidelines–Heart Failure (GWTG-HF) score, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score, and other machine-learning models by using the test data. Area under the receiver operating characteristic curve of the DAHF were 0.880 (95% confidence interval, 0.876–0.884) for predicting in-hospital mortality; these results significantly outperformed those of the GWTG-HF (0.728 [0.720–0.737]) and other machine-learning models. For predicting 12- and 36-month endpoints, DAHF (0.782 and 0.813) significantly outperformed MAGGIC score (0.718 and 0.729). During the 36-month follow-up, the high-risk group, defined by the DAHF, had a significantly higher mortality rate than the low-risk group(p<0.001). Conclusion: DAHF predicted the in-hospital and long-term mortality of patients with AHF more accurately than the existing risk scores and other machine-learning models. [ABSTRACT FROM AUTHOR]

Background: A common means of vaccination coverage measurement is the administrative method, done by dividing the aggregated number of doses administered over a set period (numerator) by the target population (denominator). To assess the quality of national target populations, we defined nine potential denominator data inconsistencies or flags that would warrant further exploration and examination of data reported by Member States to the World Health Organization (WHO) and UNICEF between 2000 and 2016. Methods and findings: We used the denominator reported to calculate national coverage for BCG, a tuberculosis vaccine, and for the third dose of diphtheria-tetanus-pertussis-containing (DTP3) vaccines, usually live births (LB) and surviving infants (SI), respectively. Out of 2,565 possible reporting events (data points for countries using administrative coverage with the vaccine in the schedule and year) for BCG and 2,939 possible reporting events for DTP3, 194 and 274 reporting events were missing, respectively. Reported coverage exceeding 100% was seen in 11% of all reporting events for BCG and in 6% for DTP3. Of all year-to-year percent differences in reported denominators, 12% and 11% exceeded 10% for reported LB and SI, respectively. The implied infant mortality rate, based on the country’s reported LB and SI, would be negative in 9% of all reporting events i.e., the country reported more SI than LB for the same year. Overall, reported LB and SI tended to be lower than the UN Population Division 2017 estimates, which would lead to overestimation of coverage, but this difference seems to be decreasing over time. Other inconsistencies were identified using the nine proposed criteria. Conclusions: Applying a set of criteria to assess reported target populations used to estimate administrative vaccination coverage can flag potential quality issues related to the national denominators and may be useful to help monitor ongoing efforts to improve the quality of vaccination coverage estimates. [ABSTRACT FROM AUTHOR]

Introduction. We suspected that the incidence of NEC in Denmark had increased during the last 20 years but hypothesized that this could be explained by the increased neonatal survival. Methods. We conducted a retrospective, observational cohort study of all registered liveborn infants in Denmark in the period from January 1, 1994 to December 31, 2014. Data were obtained from the Medical Birth Registry, National Patient Register, and Cause of Death register in Denmark. The primary outcome was the registration of NEC (ICD-10: DP77.9) during a hospital admission within 6 months after birth. The statistical analysis used ‘death before NEC’ as a competing risk. Results. The cohort consisted of 1,351,675 infants, of which 8,059 died. There was a strongly significant decreasing risk of death over the period for the all infants (p<0.0001 in all gestational age groups). In total, 994 infants were diagnosed with NEC which lead to an incidence of 7.4 per 10,000 live-born infants. During the observation period, the incidence increased from 6.3 to 7.9 per 10,000 births (p = 0.006). When accounting for ‘death before NEC’ as a competing risk, the increase could be explained by the increased neonatal survival. There was, however, a GA-group/epoch interaction (p = 0.008) in the cause-specific hazard ratios with a trend towards an increasing risk of NEC in the most preterm infants and a decreasing risk of NEC in the term infants. Conclusion. While the overall incidence of NEC increased over the study period, the overall risk of NEC did not increase when considering the increased survival. Nevertheless, there seemed to be an increased risk of NEC in the most premature infants which was masked by a decreased risk in the term infants. This study suggests that research to prevent NEC in the most preterm infants is more important now than ever. [ABSTRACT FROM AUTHOR]

Recent research in machine learning pointed to the core problem of state-of-the-art models which impedes their widespread adoption in different domains. The models’ inability to differentiate between noise and subtle, yet significant variation in data leads to their vulnerability to adversarial perturbations that cause wrong predictions with high confidence. The study is aimed at identifying whether the algorithms inspired by biological evolution may achieve better results in cases where brittle robustness properties are highly sensitive to the slight noise. To answer this question, we introduce the new robust gradient descent inspired by the stability and adaptability of biological systems to unknown and changing environments. The proposed optimization technique involves an open-ended adaptation process with regard to two hyperparameters inherited from the generalized Verhulst population growth equation. The hyperparameters increase robustness to adversarial noise by penalizing the degree to which hardly visible changes in gradients impact prediction. The empirical evidence on synthetic and experimental datasets confirmed the viability of the bio-inspired gradient descent and suggested promising directions for future research. The code used for computational experiments is provided in a repository at . [ABSTRACT FROM AUTHOR]

Background: Additional approaches are needed to identify and provide targeted interventions to populations at continued risk for HIV-associated mortality. We sought to describe care utilization and mortality following an index hospitalization for people with HIV in South Africa. Methods: We conducted a prospective cohort study among hospitalized patients admitted to medicine wards at a single hospital serving a large catchment area. Participants were followed to 6 months post-discharge. Hospital records were used to describe overall admission numbers and inpatient mortality. Poisson regression was used to assess for associations between readmission or death and independent variables. Results: Of 124 enrolled participants, 121 lived to hospital discharge. At the time of discharge the median length of stay of sampled patients was 5.5 days and 105 (87%) participants were referred for follow-up, most within 2 weeks of discharge. By 6 months post-discharge, only 18% of participants had attended the clinic to which they were referred and within the referred timeframe; 64 (53%) had been readmitted at least once and 31 (26%) had died. Self-reported skipping care due to difficulty in access (relative risk 1.3, p = 0.02) and not attending follow-up care on time or at the scheduled clinic or not attending clinic at all (relative risk 1.8 and 2.4, respectively, p = 0.001) were associated with readmission or mortality. Conclusions: The post-hospital period is a period of medical vulnerability and high mortality. Improving post-hospital retention in care may reduce post-hospital mortality. [ABSTRACT FROM AUTHOR]

We systematically reviewed the evidence on secular trends in main chronic conditions, disability and self-assessed general health among adults in the United Kingdom, as reported in primary/secondary care databases and population-based surveys. Searches were conducted separately for: (1) trends in age-standardised or age-specific prevalence of major non-communicable diseases, disability, and self-reported general health; (2) trends in health expectancy. The databases searched were MEDLINE, EMBASE/EMBASE Classic and Web of Science (all from 1946/7). The evidence was synthesised narratively. There were 39 studies reporting trends in prevalence of health conditions and 15 studies in health expectancy. We did not find evidence for improvement in the age-standardised or age-specific prevalence of any of the studied major chronic conditions over the last few decades, apart from Alzheimer's disease and other dementias. Both increasing or stable prevalence rates with simultaneous rising life expectancy support the expansion of morbidity theory, meaning that people are expected to spend a greater number of years with chronic condition(s). The evidence on disability—expressed as prevalence or health expectancy—was mixed, but also appeared to support the expansion of morbidity among those aged 65 or over. The evidence on trends in disability for younger age is lacking. Across the studied period (1946–2017), the UK population endured more years with chronic morbidity and disability, which may place a serious strain on the health care system, the economy and the society. [ABSTRACT FROM AUTHOR]

Background: Tenofovir-containing regimens comprise the preferred first-line antiretroviral therapy (ART) in many countries including South Africa, where utilization of second-line regimens is limited. Considerable HIV drug resistance has occurred among persons failing tenofovir-containing first-line ART. We evaluated drug resistance at the population level using mathematical modeling. Setting: Heterosexual HIV epidemic in KwaZulu-Natal, South Africa. Methods: We constructed a stochastic individual-based model and simulated scenarios of ART implementation, either CD4-based (threshold < 500 cells/mL) or Fast-track (81% coverage by 2020), with consideration of major drug-associated mutations (M184V, K65R and non-nucleoside reverse transcriptase inhibitor (NNRTI)). Using base case and uncertainty analyses, we assessed (majority) drug resistance levels. Results: By 2030, the median total resistance (proportion of HIV-infected persons with drug resistance) is predicted to reach 31.4% (interquartile range (IQR): 16.5%-50.2%) with CD4-based ART, decreasing to 14.5% (IQR: 7.7%-25.8%) with Fast-track implementation. In both scenarios, we find comparably high prevalence (~80%) of acquired NNRTI-associated, M184V and K65R mutations. Over 48% of individuals with acquired resistance harbor dual, 44% triple and 7% just single drug mutations. Drug-resistant HIV is predicted to comprise 40% (IQR: 27%-50%) of incident infections, while 70% of prevalent transmitted resistance is NNRTI-associated. At 2018, the projected total resistance is 15% (IQR: 7.5%-25%), with 18% (IQR: 13%-24%) of incident infections from transmitted drug-resistant HIV. Conclusions: WHO-recommended preferred first-line ART could lead to substantial drug resistance. Effective surveillance of HIV drug resistance and utilization of second-line as well as alternative first-line regimens is crucial. [ABSTRACT FROM AUTHOR]

We investigated what factors may foster or hinder physicians’ cancer screening risk literacy–specifically the ability to understand evidence regarding screening effectiveness and make evidence-based recommendations to patients. In an experiment, physicians in training (interns and residents) read statistical information about outcomes from screening for cancer, and had to decide whether to recommend it to a patient. We manipulated the effectiveness of the screening (effective vs. ineffective at reducing mortality) and the demand of the patient to get screened (demand vs. no demand). We assessed participants’ comprehension of the presented evidence and recommendation to the patient, as well as a-priori screening beliefs (e.g., that screening is always a good choice), numeracy, science literacy, knowledge of screening statistics, statistical education, and demographics. Stronger positive a-priori screening beliefs, lower knowledge of screening statistics, and lower numeracy were related to worse comprehension of the evidence. Physicians recommended against the ineffective screening but only if they showed good comprehension of the evidence. Physicians’ recommendations were further based on the perceived benefits from screening but not on perceived harms, nor the patient’s demands. The current study demonstrates that comprehension of cancer screening statistics and the ability to infer the potential benefits for patients are essential for evidence-based recommendations. However, strong beliefs in favor of screening fostered by promotion campaigns may influence how physicians evaluate evidence about specific screenings. Fostering physician numeracy skills could help counteract such biases and provide evidence-based recommendations to patients. [ABSTRACT FROM AUTHOR]

Background: Truenat is a novel molecular assay that rapidly detects tuberculosis (TB) and rifampicin-resistance. Due to the portability of its battery-powered testing platform, it may be valuable in peripheral healthcare settings in India. Methods: Using a microsimulation model, we compared four TB diagnostic strategies for HIV-negative adults with presumptive TB: (1) sputum smear microscopy in designated microscopy centers (DMCs) (SSM); (2) Xpert MTB/RIF in DMCs (Xpert); (3) Truenat in DMCs (Truenat DMC); and (4) Truenat for point-of-care testing in primary healthcare facilities (Truenat POC). We projected life expectancy, costs, incremental cost-effectiveness ratios (ICERs), and 5-year budget impact of deploying Truenat POC in India’s public sector. We defined a strategy “cost-effective” if its ICER was

Background: The Ischemic Stroke System is a novel device designed to deliver stimulation to the sphenopalatine ganglion(SPG).The SPG sends parasympathetic innervations to the anterior cerebral circulation. In rat stroke models, SPG stimulation results in increased cerebral blood flow, reduced infarct volume, protects the blood brain barrier, and improved neurological outcome. We present here the results of a prospective, multinational, single-arm, feasibility study designed to assess the safety, tolerability, and potential benefit of SPG stimulation inpatients with acute ischemic stroke(AIS). Methods: Patients with anterior AIS, baseline NIHSS 7–20 and ability to initiate treatment within 24h from stroke onset, were implanted and treated with the SPG stimulation. Patients were followed up for 90 days. Effect was assessed by comparing the patient outcome to a matched population from the NINDS rt-PA trial placebo patients. Results: Ninety-eight patients were enrolled (mean age 57years, mean baseline NIHSS 12 and mean treatment time from stroke onset 19h). The observed mortality rate(12.2%), serious adverse events (SAE)incidence(23.5%) and nature of SAE were within the expected range for the population. The modified intention to treat cohort consisted of 84 patients who were compared to matched patients from the NINDS placebo arm. Patients treated with SPG stimulation had an average mRS lower by 0.76 than the historical controls(CMH test p = 0.001). Conclusion: The implantation procedure and the SPG stimulation, initiated within 24hr from stroke onset, are feasible, safe, and tolerable. The results call for a follow-up randomized trial (funded by BrainsGate; clinicaltrials.gov number, NCT03733236). [ABSTRACT FROM AUTHOR]

Seahorses are considered one of the most iconic examples of a monogamous species in the animal kingdom. This study investigates the relationship between stocking density and mating and competitive behavior from the context of the field biology of the dwarf seahorse, Hippocampus zosterae (Jordan & Gilbert). Animals were housed in 38 liter tanks at a range of densities and sex ratios (from 2–8 animals per tank), and their reproductive and other social behaviors were monitored from tank introduction through copulation. At low tank densities and even sex ratios but comparatively high field densities, frequency of both mating and competitive behaviors was low in trials. A higher level of males in tanks across all densities increased competition, activity levels, and aggression leading to egg transfer errors and brood expulsion, resulting in lower reproductive success. Across seahorse species, mean and maximum wild densities were consistently lower than those used in ex situ breeding, with adult sex ratios that were significantly female biased. However, significant variation exists in wild seahorse densities across species, with higher densities detected in focal/mark recapture studies and on artificial habitat structures than reported with belt transect sampling techniques. Interchange of knowledge gained in both aquarium and wild contexts will allow us to better understand the biology of this genus, and improve reproduction in captivity. Interpreting ex situ reproductive behaviors of seahorses within various densities reported from natural populations will help us predict the impact of conservation efforts and increase the likelihood of long-term persistence of populations for this threatened genus. [ABSTRACT FROM AUTHOR]

Background: Over the past 15 years, scaling up of cost effective interventions resulted in a remarkable decline of under-five mortality rates (U5MR) in sub-Saharan Africa. However, the reduction shows considerable heterogeneity. We estimated the association of child, maternal, and household interventions with U5MR in Burkina Faso at national and subnational levels and identified the regions with least effective interventions. Methods: Data on health-related interventions and U5MR were extracted from the Burkina Faso Demographic and Health Survey (DHS) 2010. Bayesian geostatistical proportional hazards models with a Weibull baseline hazard were fitted on the mortality outcome. Spatially varying coefficients were considered to assess the geographical variation in the association of the health interventions with U5MR. The analyses were adjusted for child, maternal, and household characteristics, as well as climatic and environmental factors. Findings: The average U5MR was as high as 128 per 1000 ranging from 81 (region of Centre-Est) to 223 (region of Sahel). At national level, DPT3 immunization and baby post-natal check within 24 hours after birth had the most important association with U5MR (hazard rates ratio (HRR) = 0.89, 95% Bayesian credible interval (BCI): 0.86–0.98 and HRR = 0.89, 95% BCI: 0.86–0.92, respectively). At sub-national level, the most effective interventions are the skilled birth attendance, and improved drinking water, followed by baby post-natal check within 24 hours after birth, vitamin A supplementation, antenatal care visit and all-antigens immunization (including BCG, Polio3, DPT3, and measles immunization). Centre-Est, Sahel, and Sud-Ouest were the regions with the highest number of effective interventions. There was no intervention that had a statistically important association with child survival in the region of Hauts Bassins. Interpretation: The geographical variation in the magnitude and statistical importance of the association between health interventions and U5MR raises the need to deliver and reinforce health interventions at a more granular level. Priority interventions are DPT3 immunization, skilled birth attendance, baby post-natal visits in the regions of Sud-Ouest, Sahel, and Hauts Bassins, respectively. Our methodology could be applied to other national surveys, as it allows an incisive, data-driven and specific decision-making approach to optimize the allocation of health interventions at subnational level. [ABSTRACT FROM AUTHOR]

Objective: To analyze the mortality trend in Spain before, during and after the economic crisis and austerity policies in the working-age population. Methods: From 2005 to 2016 we calculated the annual all-cause mortality rate and the annual mortality rate from the main causes of death in the population aged 15 to 64. We also estimated the linear trends in mortality rates during four time intervals—2005–2007 (before crisis), 2008–2010 (first part of the crisis), 2011–2013 (second part of the crisis and implementation of austerity policies) and 2014–2016 (after the crisis)- by the annual percentage change (APC). Results: The all-cause mortality rate in men and women showed the greatest decline in 2008–2010 and the smallest decline in 2014–2016. The decline in 2011–2013 was higher than in 2014–2016. The APCs in 2005–2007, 2008–2010, 2011–2013 and 2014–2016 were -2.8, -4.1, -3.0 and -1.5 in men and -1.0. -2.1, -1.1 and -0.6 in women, respectively, although the APC in 2014–2016 in women was not significant. In 2014–2016, cancer mortality showed the largest decrease, mortality from cardiovascular diseases (men), respiratory diseases and traffic accidents reversed and showed an upward trend, and the downward trend in mortality from infectious diseases and digestive diseases was equal to or greater than that observed before the crisis. Conclusion: The decline in all-cause mortality in the working-age population during the economic crisis and the introduction of austerity measures was greater than that observed before and after the economic crisis. The slowing of the decline after the crisis was due to the reversal of the trend in mortality from cardiovascular and respiratory diseases. [ABSTRACT FROM AUTHOR]

Introduction: The Temprano and START trials provided evidence to support early ART initiation recommendations. We projected long-term clinical and economic outcomes of immediate ART initiation in Côte d’Ivoire. Methods: We used a mathematical model to compare three potential ART initiation criteria: 1) CD4 <350/μL (ART<350/μL); 2) CD4 <500/μL (ART<500/μL); and 3) ART at presentation (Immediate ART). Outcomes from the model included life expectancy, 10-year medical resource use, incremental cost-effectiveness ratios (ICERs) in $/year of life saved (YLS), and 5-year budget impact. We simulated people with HIV (PWH) in care (mean CD4: 259/μL, SD 198/μL) and transmitted cases. Key input parameters to the analysis included first-line ART efficacy (80% suppression at 6 months) and ART cost ($90/person-year). We assessed cost-effectiveness relative to Côte d’Ivoire’s 2017 per capita annual gross domestic product ($1,600). Results: Immediate ART increased life expectancy by 0.34 years compared to ART<350/μL and 0.17 years compared to ART<500/μL. Immediate ART resulted in 4,500 fewer 10-year transmissions per 170,000 PWH compared to ART<350/μL. In cost-effectiveness analysis, Immediate ART had a 10-year ICER of $680/YLS compared to ART<350/μL, ranging from cost-saving to an ICER of $1,440/YLS as transmission rates varied. ART<500/μL was “dominated” (an inefficient use of resources), compared with Immediate ART. Immediate ART increased the 5-year HIV care budget from $801.9M to $812.6M compared to ART<350/μL. Conclusions: In Côte d’Ivoire, immediate compared to later ART initiation will increase life expectancy, decrease HIV transmission, and be cost-effective over the long-term, with modest budget impact. Immediate ART initiation is an appropriate, high-value standard of care in Côte d’Ivoire and similar settings. [ABSTRACT FROM AUTHOR]

Background: Monitoring Caesarean Section (CS) rates is essential to ensure optimal use of the procedure. Information on CS rates in the South African private sector is limited and information from this study will assist in planning for the proposed NHI in South Africa. Objectives: The objectives of this paper are to assess mode of delivery patterns and to determine CS rates amongst South African private health insurance scheme members; and to assess the extent to which CS rates are influenced by age and health status of the mother. Methods: The 2015 claims for members of 10 health insurance schemes were analysed to assess delivery type patterns. Mode of delivery patterns were assessed by 6 delivery types: emergency, elective and “other” for caesarean deliveries; and non-assisted, assisted and “other” for vaginal deliveries; as well as by age and health condition of the mother. Results: Of a total of 6,542 births analysed, 4,815 were CS giving a CS rate of 73·6% (95% CI 72·5%;74·7%). Emergency CS were the most common mode of delivery (39·7%), followed by elective CS (39·5%). CS rates increased with increasing maternal age and were higher for women with a medical condition. Conclusions: CS rates for the South African private sector are considerably higher than the safe rates recommended by the WHO. The high CS rates is a cause for concern for the health system under the proposed NHI. To support initiatives encouraging evidence based practice, further research is required to understand the drivers for the high CS rates. [ABSTRACT FROM AUTHOR]

Evidence of involvement of novel biomarkers in disease pathogenesis from research cohorts often precedes an understanding of their distributions in broader populations. This study aimed to estimate the distribution of fibroblast growth factor 23 (FGF-23), an endocrine hormone that helps to regulate serum phosphate levels, in the overall US population and in important subgroups. We used a predictive model generated using data from the Framingham Health Study to estimate FGF-23 values for adults in the US National Health and Nutrition Examination Survey and the size of patient subgroups with levels of FGF-23 above selected thresholds. To assess the face validity of our FGF-23 estimates, we examined the relationship between estimated FGF-23 and cardiovascular and all-cause mortality within NHANES using Kaplan-Meier estimates and Cox proportional-hazards regression models and compared it to that observed in Framingham. Estimated FGF-23 values from NHANES were lower (median [interquartile range] 47.4 [35.8, 64.0] vs. 67.0 [54.0, 85.0] RU/mL) than the observed FGF-23 values from the Framingham cohort. Age- and sex-adjusted 10-year all-cause mortality was significantly higher (hazard ratio 2.43 [95% confidence interval: 1.42, 4.16]) for subjects with estimated FGF-23 levels in the highest versus lowest quartile. Estimating the distribution of biomarker values in the general population by applying predictive equations from smaller research cohorts is feasible and can inform drug research decision making. [ABSTRACT FROM AUTHOR]

Aims: Guidelines divide patients with heart failure (HF) into 3 distinct groups based on left ventricular ejection fraction (LVEF) We used the Minnesota Living with Heart Failure Questionnaire (MLHFQ) to quantify the health-related quality of life in patients with HF. Methods: Patients were stratified into three cohorts: preserved LVEF (>50%), mid-range LVEF (40–49%) and reduced LVEF (<40%). The MLHFQ scores were evaluated using one-way ANOVA, and differences were observed among the groups. The association of New York Heart Association (NYHA) class with the physical scores was analyzed by Spearman’s correlation analysis. The predictive utility of the total MLHFQ scores was assessed with Kaplan-Meier curves for death and HF-related hospitalization. The Cox proportional hazards model was used to identify the risk factors for prognosis. Internal reliability was assessed with Cronbach’s α. Results: There were significant differences in the total MLHFQ scores and the MLHFQ subscale scores among the three groups (p<0.05). MLHFQ domains demonstrated high internal consistency among the three groups (Cronbach’s α = 0.92, 0.96 and 0.93). The MLHFQ physical subscale scores were significantly associated with NYHA class in HFrEF (r = 0.59, p<0.001) and HFmrEF patients (r = 0.537, p<0.001). The survival analysis indicated that there was a significant difference among the three groups regarding high MLHFQ scores (p = 0.038). In the groups with low MLHFQ scores, the HFmrEF group exhibited significantly increased rates of death and HF-related hospitalization compared with the HFpEF group (p = 0.035). Conclusions: The features and clinical outcomes varied among heart failure patients with different EF values. The MLHFQ appears to be a valid and reliable measurement of health status and offers excellent prognostic ability. [ABSTRACT FROM AUTHOR]

Attaching/Effacing (A/E) bacteria include human pathogens enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and their murine equivalent Citrobacter rodentium (CR), of which EPEC and EHEC are important causative agents of foodborne diseases worldwide. While A/E pathogen infections cause mild symptoms in the immunocompetent hosts, an increasing number of studies show that they produce more severe morbidity and mortality in immunocompromised and/or immunodeficient hosts. However, the pathogenic mechanisms and crucial host-pathogen interactions during A/E pathogen infections under immunocompromised conditions remain elusive. We performed a functional screening by infecting interleukin-22 (IL-22) knockout (Il22-/-) mice with a library of randomly mutated CR strains. Our screen reveals that interruption of the espF gene, which encodes the Type III Secretion System effector EspF (E. coli secreted protein F) conserved among A/E pathogens, completely abolishes the high mortality rates in CR-infected Il22-/- mice. Chromosomal deletion of espF in CR recapitulates the avirulent phenotype without impacting colonization and proliferation of CR, and EspF complement in ΔespF strain fully restores the virulence in mice. Moreover, the expression levels of the espF gene are elevated during CR infection and CR induces disruption of the tight junction (TJ) strands in colonic epithelium in an EspF-dependent manner. Distinct from EspF, chromosomal deletion of other known TJ-damaging effector genes espG and map failed to impede CR virulence in Il22-/- mice. Hence our findings unveil a critical pathophysiological function for EspF during CR infection in the immunocompromised host and provide new insights into the complex pathogenic mechanisms of A/E pathogens. [ABSTRACT FROM AUTHOR]

The scale-up of antiretroviral therapy (ART) in South Africa substantially reduced AIDS-related deaths and new HIV infections. However, its success is threatened by the emergence of resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI). The MARISA (Modelling Antiretroviral drug Resistance In South Africa) model presented here aims at investigating the time trends and factors driving NNRTI resistance in South Africa. MARISA is a compartmental model that includes the key aspects of the local HIV epidemic: continuum of care, disease progression, and gender. The dynamics of NNRTI resistance emergence and transmission are then added to this framework. Model parameters are informed using data from HIV cohorts participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) and literature estimates, or fitted to UNAIDS estimates. Using this novel approach of triangulating clinical and resistance data from various sources, MARISA reproduces the time trends of HIV in South Africa in 2005–2016, with a decrease in new infections, undiagnosed individuals, and AIDS-related deaths. MARISA captures the dynamics of the spread of NNRTI resistance: high levels of acquired drug resistance (ADR, in 83% of first-line treatment failures in 2016), and increasing transmitted drug resistance (TDR, in 8.1% of ART initiators in 2016). Simulation of counter-factual scenarios reflecting alternative public health policies shows that increasing treatment coverage would have resulted in fewer new infections and deaths, at the cost of higher TDR (11.6% in 2016 for doubling the treatment rate). Conversely, improving switching to second-line treatment would have led to lower TDR (6.5% in 2016 for doubling the switching rate) and fewer new infections and deaths. Implementing drug resistance testing would have had little impact. The rapid ART scale-up and inadequate switching to second-line treatment were the key drivers of the spread of NNRTI resistance in South Africa. However, even though some interventions could have substantially reduced the level of NNRTI resistance, no policy including NNRTI-based first line regimens could have prevented this spread. Thus, by combining epidemiological data on HIV in South Africa with biological data on resistance evolution, our modelling approach identified key factors driving NNRTI resistance, highlighting the need of alternative first-line regimens. [ABSTRACT FROM AUTHOR]

Gavin Yamey and co-authors discuss approaches to providing support for middle-income countries transitioning away from health aid. [ABSTRACT FROM AUTHOR]

Mangroves play an essential ecological role in the maintenance of the coastal zone and are extremely important for the socioeconomics of coastal communities. However, mangrove ecosystems are impacted by a range of anthropogenic pressures, and the loss of this habitat can be attributed primarily to the human occupation of the coastal zone. In the present study, we analyzed the spatial patterns of land use in the mangrove of the Brazilian Amazon coast, and evaluated the anthropogenic drivers of this impact, using a remote sensing approach. We mapped the road network using RapidEye images, and human settlements using global data. The results of these analyses indicate that the Brazilian Amazon coast has a low population density and low rates of anthropogenic impact in most of the coastal microregions investigated, factors that contribute to the maintenance and conservation of the region’s mangrove. The study also revealed that the paved road network is one of the principal drivers of land use in the mangrove, whereas other factors, such as population density, urban centers, and the number of settlements are much less important. While the region has 2024 km of paved highways, unpaved roads (17,496 km) facilitate access to the mangrove, with approximately 90% of anthropogenic impact being recorded within a 3 km radius of these roads. While the network of paved highways is relatively reduced in extension, preventive measures are urgently required to impede any major shift in the current scenario, caused by the expansion of major development programs. The results of the study indicate that biophysical, economic, and political factors may also contribute to the reduction, stability, and development of one of the world’s largest areas of mangrove forest. [ABSTRACT FROM AUTHOR]

The older adult population in developed countries is rapidly increasing, as is the number of older adults with cervical spondylosis. Previous studies on the surgical outcomes of older adults with cervical spondylosis have reported contradictory results. This study aimed to compare the surgical outcomes in adults with cervical spondylosis who were <80 and ≥80 years old. We retrospectively investigated data from adults who underwent surgical treatment for cervical spondylosis between 2006 and 2016. The clinical outcomes and postoperative complications of patients who were <80 years old were compared to those of patients who were ≥80 years old. Of the 108 patients included in the study, 14 (13.0%) were ≥80 years old. The preoperative neurosurgical cervical spine score was significantly different between patients who were <80 (9.1 ± 2.4) and ≥80 (6.1 ± 2.1) years old (p < .001). The recovery rate was 58.2 ± 30.0% and 41.3 ± 24.7% in patients who were <80 and ≥80 years old, respectively (p = .05). However, the number of recovery points scored was 2.8 ± 2.0 and 3.4 ± 2.3 in patients who were <80 and ≥80 years old, respectively, which was not significantly different. Although 12 patients had medical comorbidities, they had no surgical complications. This study clarifies the benefits of surgical treatment for older adults with cervical spondylosis. Generally, older adults have lower recovery rates and are unlikely to experience full recovery; however, surgery for cervical spondylosis appears to improve patients’ quality of life. [ABSTRACT FROM AUTHOR]

In the past 20 years, free living populations of feral wild boar have re-established in several locations across the UK. One of the largest populations is in the Forest of Dean where numbers have been steadily increasing since monitoring began in 2008, with estimates from 2016 reporting a population of more than 1500. Feral wild boar have significant ecological and environmental impacts and may present a serious epidemiological risk to neighbouring livestock as they are a vector for a number of important livestock diseases. This includes foot-and-mouth disease (FMD) which is currently absent from the UK. We developed an individual-based spatially explicit modelling approach to simulate feral wild boar populations in the Forest of Dean (England, UK) and use it to explore whether current or future populations might be sufficient to produce long-lived outbreaks of FMD in this potential wildlife reservoir. Our findings suggest that if you exclude the spread from feral wild boar to other susceptible species, the current population of boar is insufficient to maintain FMD, with 95% of unmanaged simulations indicating disease burn-out within a year (not involving boar management specifically for disease). However, if boar are allowed to spread beyond their current range into the adjacent landscape, they might maintain a self-sustaining reservoir of infection for the disease. [ABSTRACT FROM AUTHOR]

Temperature can be a major factor for the distribution of insects, especially among invasive insects. Sirex noctilio (Hymenoptera: Siricidae) has invaded many regions in China, causing enormous ecological and economic losses. We aimed to explore the trend and potential of diffusion by researching the thermal survival limits of S. noctilio. We measured the supercooling point (SCP), critical thermal temperature (CTmax), high lethal temperature (HLT) and low lethal temperature (LLT) for S. noctilio population in China and assessed life stage-related variation in thermal tolerance. Moreover, we determined the temperature tolerance range of S. noctilio and identified the temperature parameters for its potential invasive distribution risk analysis. The SCP of adults was -11.78 ± 0.67 (mean ± SEM), the CTmax was 37.67 ± 0.54, and those of larvae were -20.77 ± 0.44 and 40.53 ± 0.27, respectively. The LLT increased with exposure time, and the HLT was generally near 43°C. S. noctilio adults can tolerate higher temperatures than larvae, and the larvae showed high resistance to cold temperature. We calculated several temperature indexes based on our results, such as the lower temperature threshold (DV0) at -2.7°C, the upper temperature threshold (DV3) at 31°C, the temperature threshold for both heat stress (TTHS) at 35°C and cold stress (TTCS) at -32.5°C. We observed that, S. noctilio was not resistant to high temperatures, its CTmax is slightly lower than the lethal temperature, and the adults were more tolerant than larvae. Our next goal was to combine the temperature tolerance of symbiotic fungi, information on climate change and the current distribution of this species to predict its potential global distribution. [ABSTRACT FROM AUTHOR]

Background: Recognition of HLA-C2 group alleles on recipient cells by activating killer immunoglobulin like receptors, KIR2DS1 on donor natural killer cells may lead to increased graft-versus-leukemia effect or immunomodulation in patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) influencing disease free and overall survival (OS). Objective: In the present study, 314 consecutive, allo-HSCT recipient and donor pairs were included with retrospective donor KIR-genotyping and clinical parameters analyzes. Results: After a median follow-up of 23.6 months, recipients with HLA-C2 group allele (rC2) showed improved (p = 0.046) OS if transplanted with KIR2DS1 positive donors (d2DS1) compared to those without one or both of this genetic attribute. Within the myeloablative conditioning (MAC) subgroup (n = 227), rC2 homozygous+d2DS1 patients (n = 14) showed a 5 years OS of 93% followed by rC2 heterozygous+d2DS1 patients (n = 48, 65%) compared to rC2 and/or d2DS1 negatives (47%, p = 0.018). Multivariate analyses indicated rC2+d2DS1 positivity as an independent predictor of OS (HR:0.47, 0.26–0.86, p = 0.014) besides donor type, presence of CMV-reactivation or chemoresistant disease. Among MAC-treated patients, the combined rC2+d2DS1 presence was associated with a markedly decreased cumulative incidence of transplant related mortality (p = 0.0045). Conclusion: The combination of rC2+d2DS1 may be a favorable genetic constellation in allo-HSCT with MAC potentially reducing transplant related mortality. [ABSTRACT FROM AUTHOR]

The toxicity of zinc (Zn), copper (Cu), and cadmium (Cd) to the nematode Caenorhabditis elegans was characterised under single metal and mixture scenarios at different organisational levels. The effects on population size and body length were investigated at two concentrations corresponding to the 24 h LC5 and LC20 levels. Metal toxicity was dependent on metal concentration, exposure time and mixture composition. Populations exposed to LC20 levels of Cd, ZnCu, CuCd and ZnCuCd plummeted, while for all LC5 concentrations, population size continued to increase, albeit that single metals were less harmful than mixtures. Combinations of the LC20 concentration of Cd with a range of Zn concentrations showed concentration dependent mitigating effects on population size and antagonistic effects on mortality. By combining effects at different organisational levels, more insight into metal toxicity was obtained. Metal effects were more evident on population size than on body length or mortality, suggesting that population size could be considered as a sensitive endpoint. Furthermore, our observations of ZnCd mixture effects at the individual and population levels are consistent with literature data on the dose-dependent expression of the cdf-2 gene, which is involved in mediation of Zn and Cd toxicity. [ABSTRACT FROM AUTHOR]

Excessive alcohol consumption contributes significantly to premature mortality, injuries and morbidity, and a range of U.S. state policies have been shown to reduce these behaviors. Monitoring state alcohol policy environments is essential, but methodologically challenging given that new laws may be passed (or repealed) each year, resulting in considerable variation across states. Existing measures have not been made public or have only a single year available. We develop a new replicable measure, the state alcohol policy score, for each state and year 2004–2009, that captures the essential features of a state’s evidence-based alcohol policies. We evaluate its similarity to two existing alcohol policy measures and validate it by replicating findings from a previous study that used one of those measures to assess its relationship with several binge drinking outcomes. Estimates of the association between one-year lagged state alcohol policy scores and state binge drinking outcomes, obtained from the 2005–2010 Behavioral Risk Factor Surveillance System surveys (n = 440,951, 2010), were produced using Generalized Linear Models that controlled for state and individual-level co-variates, with fixed effects for year and region. We find a 10-percentage point increase in the state alcohol policy score was associated with a 9% lower odds of binge drinking (aOR = 0.91, 95% CI 0.89, 0.92; N = 1,992,086), a result consistent for men, women and for most age and race subgroups. We find that gender gaps in binge drinking behaviors narrowed in states with higher state alcohol policy scores. These results were nearly identical to those found in other studies using different scores obtained with the aid of expert opinions. We conclude that the score developed here is a valid measure that can be readily updated for monitoring and evaluating the variation and impact of state alcohol policies and make available our state scores for the years of the study. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is a major contributor to the burden from non-communicable diseases in Sub-Saharan Africa and hypertension is the leading risk factor for CVD. The objective of this modeling study is to assess the cost-effectiveness of a risk stratified approach to medication management in Kenya in order to achieve adequate blood pressure control to reduce CVD events. Methods: We developed a microsimulation model to evaluate CVD risk over the lifetime of a cohort of individuals. Risk groups were assigned utilizing modified Framingham study distributions based on individual level risk factors from the Kenya STEPwise survey which collected details on blood pressure, blood glucose, tobacco and alcohol use and cholesterol levels. We stratified individuals into 4 risk groups: very low, low, moderate and high risk. Mortality could occur due to acute CVD events, subsequent future events (for individual who survive the initial event) and other causes. We present cost and DALYs gained due to medication management for men and women 25 to 69 years. Results: Treating high risk individuals only was generally more cost-effective that treating high and moderate risk individuals. At the anticipated base levels of effectiveness, medication management was only cost-effective under the low cost scenario. The incremental cost per DALY gained with low cost ranged from $1,505 to $3,608, which is well under $4,785 (3 times GPD per capita) threshold for Kenya. Under the low cost scenario, even lower levels of effectiveness of medication management are likely to be cost-effective for high-risk men and women. Conclusions: In Kenya, our results indicate that the risk stratified approach to treating hypertension may be cost-effective especially for men and women at a high risk for CVD events, but these results are highly sensitive to the cost of medications. Medication management would require significant financial investment and therefore other interventions, including lifestyle changes, should be evaluated especially for those with elevated blood pressure and overall 10-year risk that is less than 20%. [ABSTRACT FROM AUTHOR]

Background: The last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality. Methods and findings: We conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level. Conclusions: SGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention. Trial registration: PROSPERO . [ABSTRACT FROM AUTHOR]