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Abstract Aims Prior research, largely focused on US male veterans, indicates an increased risk of cardiovascular disease among individuals with post-traumatic stress disorder (PTSD). Data from other settings and populations are scarce. The objective of this study is to examine PTSD as a risk factor for incident major adverse cardiovascular events (MACEs) in South Africa. Methods We analysed reimbursement claims (2011–2020) of a cohort of South African medical insurance scheme beneficiaries aged 18 years or older. We calculated adjusted hazard ratios (aHRs) for associations between PTSD and MACEs using Cox proportional hazard models and calculated the effect of PTSD on MACEs using longitudinal targeted maximum likelihood estimation. Results We followed 1,009,113 beneficiaries over a median of 3.0 years (IQR 1.1–6.0). During follow-up, 12,662 (1.3%) persons were diagnosed with PTSD and 39,255 (3.9%) had a MACE. After adjustment for sex, HIV status, age, population group, substance use disorders, psychotic disorders, major depressive disorder, sleep disorders and the use of antipsychotic medication, PTSD was associated with a 16% increase in the risk of MACEs (aHR 1.16, 95% confidence interval (CI) 1.05–1.28). The risk ratio for the effect of PTSD on MACEs decreased from 1.59 (95% CI 1.49–1.68) after 1 year of follow-up to 1.14 (95% CI 1.11–1.16) after 8 years of follow-up. Conclusion Our study provides empirical support for an increased risk of MACEs in males and females with PTSD from a general population sample in South Africa. These findings highlight the importance of monitoring cardiovascular risk among individuals diagnosed with PTSD.

ObjectivesWe extend the method of Significant Zero Crossings of Derivatives (SiZer) to address within-subject correlations of repeatedly collected longitudinal biomarker data and the computational aspects of the methodology when analyzing massive biomarker databases. SiZer is a powerful visualization tool for exploring structures in curves by mapping areas where the first derivative is increasing, decreasing or does not change (plateau) thus exploring changes and normalization of biomarkers in the presence of therapy.MethodsWe propose a penalized spline SiZer (PS-SiZer) which can be expressed as a linear mixed model of the longitudinal biomarker process to account for irregularly collected data and within-subject correlations. Through simulations we show how sensitive PS-SiZer is in detecting existing features in longitudinal data versus existing versions of SiZer. In a real-world data analysis PS-SiZer maps are used to map areas where the first derivative of weight change after antiretroviral therapy (ART) start is significantly increasing, decreasing or does not change, thus exploring the durability of weight increase after the start of therapy. We use weight data repeatedly collected from persons living with HIV initiating ART in five regions in the International Epidemiologic Databases to Evaluate AIDS (IeDEA) worldwide collaboration and compare the durability of weight gain between ART regimens containing and not containing the drug stavudine (d4T), which has been associated with shorter durability of weight gain.ResultsThrough simulations we show that the PS-SiZer is more accurate in detecting relevant features in longitudinal data than existing SiZer variants such as the local linear smoother (LL) SiZer and the SiZer with smoothing splines (SS-SiZer). In the illustration we include data from 185,010 persons living with HIV who started ART with a d4T (53.1%) versus non-d4T (46.9%) containing regimen. The largest difference in durability of weight gain identified by the SiZer maps was observed in Southern Africa where weight gain in patients treated with d4T-containing regimens lasted 59.9 weeks compared to 133.8 weeks for those with non-d4T-containing regimens. In the other regions, persons receiving d4T-containing regimens experienced weight gains lasting 38-62 weeks versus 55-93 weeks in those receiving non-d4T-based regimens.DiscussionPS-SiZer, a SiZer variant, can handle irregularly collected longitudinal data and within-subject correlations and is sensitive in detecting even subtle features in biomarker curves.

(1) Background: The Austrian supply of COVID-19 vaccine is limited for now. We aim to provide evidence-based guidance to the authorities in order to minimize COVID-19-related hospitalizations and deaths in Austria. (2) Methods: We used a dynamic agent-based population model to compare different vaccination strategies targeted to the elderly (65 ≥ years), middle aged (45–64 years), younger (15–44 years), vulnerable (risk of severe disease due to comorbidities), and healthcare workers (HCW). First, outcomes were optimized for an initially available vaccine batch for 200,000 individuals. Second, stepwise optimization was performed deriving a prioritization sequence for 2.45 million individuals, maximizing the reduction in total hospitalizations and deaths compared to no vaccination. We considered sterilizing and non-sterilizing immunity, assuming a 70% effectiveness. (3) Results: Maximum reduction of hospitalizations and deaths was achieved by starting vaccination with the elderly and vulnerable followed by middle-aged, HCW, and younger individuals. Optimizations for vaccinating 2.45 million individuals yielded the same prioritization and avoided approximately one third of deaths and hospitalizations. Starting vaccination with HCW leads to slightly smaller reductions but maximizes occupational safety. (4) Conclusion: To minimize COVID-19-related hospitalizations and deaths, our study shows that elderly and vulnerable persons should be prioritized for vaccination until further vaccines are available.

Background and Methods: Schistosomiasis is debilitating and reported to impair immune responsiveness of infected hosts. In Cameroon, mass drug administration (MDA) is used in schoolchildren to reduce transmission of S. haematobium and S. mansoni. The effects of MDA and the impact of schistosomiasis on the titers of antibodies in vaccinated children have been poorly studied. We therefore assessed the prevalence of schistosomiasis in schoolchildren, eight months after MDA, in two locations: Barombi Koto (BK), endemic for S. haematobium (N = 169) and Yoro (Y), endemic for S. mansoni (N = 356). Age, gender, residence time and frequency of contact with river water were assessed as risk factors for infection and morbidity in both localities. In 70 schoolchildren from BK and 83 from Y, ultrasound was used to assess morbidity according to the WHO guidelines. Evaluation of measles antibodies was performed in previously vaccinated schoolchildren (14 with S. haematobium and 12 egg-negative controls from BK and 47 with S. mansoni and12 egg-negative controls from Y).Principal Findings and conclusions: The prevalence of S. haematobium was 25. 4% in BK (43/169) and 34.8% for S. mansoni in Y (124/356), indicating the persistent transmission of schistosomiasis despite MDA. Older age (AOR 1.31; 95%CI 1.12–1.54) and higher frequencies of exposure to river water (AOR 1.99; 95%CI 1.03–3.86) were identified as risks for infection in BK whereas only older age (OR 1.15; 95%CI 1.04–1.27) was a risk for infection in Y. Bladder pathology (score 2 to 5) was observed in 29.2% (7/24) of egg-positive children in BK and liver pathology (pattern C) in 31.1% (19/61) of egg-positive children in Y. There was a positive correlation between S. haematobium egg burden and bladder pathology (AOR 1.01; 95% CI 0.99–1.02) and positive correlation between S. mansoni-driven liver pathology and female gender (AOR 3.01; 95% CI 0.88–10.26). Anti-measles antibodies in vaccinated children were significantly lower in S. mansoni-infected when compared to egg-negative controls (p = 0.001), which was not observed in the S. haematobium-infected group from BK. Our results demonstrate a questionable efficacy of MDA alone in halting schistosomiasis transmission and confirm a possible immunomodulatory effect of S. mansoni on response to vaccines.

BackgroundGlobally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia.Methods and findingsThrough the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria.ConclusionTo our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Retention in care is an essential component of meeting the UNAIDS "90-90-90" HIV treatment targets. In Khayelitsha township (population ~500,000) in Cape Town, South Africa, more than 50,000 patients have received antiretroviral therapy (ART) since the inception of this public-sector program in 2001. Disengagement from care remains an important challenge. We sought to determine the incidence of and risk factors associated with disengagement from care during 2013-2014 and outcomes for those who disengaged.We conducted a retrospective cohort study of all patients ≥10 years of age who visited 1 of the 13 Khayelitsha ART clinics from 2013-2014 regardless of the date they initiated ART. We described the cumulative incidence of first disengagement (>180 days not attending clinic) between 1 January 2013 and 31 December 2014 using competing risks methods, enabling us to estimate disengagement incidence up to 10 years after ART initiation. We also described risk factors for disengagement based on a Cox proportional hazards model, using multiple imputation for missing data. We ascertained outcomes (death, return to care, hospital admission, other hospital contact, alive but not in care, no information) after disengagement until 30 June 2015 using province-wide health databases and the National Death Registry. Of 39,884 patients meeting our eligibility criteria, the median time on ART to 31 December 2014 was 33.6 months (IQR 12.4-63.2). Of the total study cohort, 592 (1.5%) died in the study period, 1,231 (3.1%) formally transferred out, 987 (2.5%) were silent transfers and visited another Western Cape province clinic within 180 days, 9,005 (22.6%) disengaged, and 28,069 (70.4%) remained in care. Cumulative incidence of disengagement from care was estimated to be 25.1% by 2 years and 50.3% by 5 years on ART. Key factors associated with disengagement (age, male sex, pregnancy at ART start [HR 1.58, 95% CI 1.47-1.69], most recent CD4 count) and retention (ART club membership, baseline CD4) after adjustment were similar to those found in previous studies; however, notably, the higher hazard of disengagement soon after starting ART was no longer present after adjusting for these risk factors. Of the 9,005 who disengaged, the 2 most common initial outcomes were return to ART care after 180 days (33%; n = 2,976) and being alive but not in care in the Western Cape (25%; n = 2,255). After disengagement, a total of 1,459 (16%) patients were hospitalized and 237 (3%) died. The median follow-up from date of disengagement to 30 June 2015 was 16.7 months (IQR 11-22.4). As we included only patient follow-up from 2013-2014 by design in order to maximize the generalizability of our findings to current programs, this limited our ability to more fully describe temporal trends in first disengagement.Twenty-three percent of ART patients in the large cohort of Khayelitsha, one of the oldest public-sector ART programs in South Africa, disengaged from care at least once in a contemporary 2-year period. Fifty-eight percent of these patients either subsequently returned to care (some "silently") or remained alive without hospitalization, suggesting that many who are considered "lost" actually return to care, and that misclassification of "lost" patients is likely common in similar urban populations. A challenge to meeting ART retention targets is developing, testing, and implementing program designs to target mobile populations and retain them in lifelong care. This should be guided by risk factors for disengagement and improving interlinkage of routine information systems to better support patient care across complex care platforms.

High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America.Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0-3, 3-6, 6-12, 12-24, and 24-48 months on ART for the period 2001-2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count

There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2-5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2-5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count

Few estimates exist of the life expectancy of HIV-positive adults receiving antiretroviral treatment (ART) in low- and middle-income countries. We aimed to estimate the life expectancy of patients starting ART in South Africa and compare it with that of HIV-negative adults.Data were collected from six South African ART cohorts. Analysis was restricted to 37,740 HIV-positive adults starting ART for the first time. Estimates of mortality were obtained by linking patient records to the national population register. Relative survival models were used to estimate the excess mortality attributable to HIV by age, for different baseline CD4 categories and different durations. Non-HIV mortality was estimated using a South African demographic model. The average life expectancy of men starting ART varied between 27.6 y (95% CI: 25.2-30.2) at age 20 y and 10.1 y (95% CI: 9.3-10.8) at age 60 y, while estimates for women at the same ages were substantially higher, at 36.8 y (95% CI: 34.0-39.7) and 14.4 y (95% CI: 13.3-15.3), respectively. The life expectancy of a 20-y-old woman was 43.1 y (95% CI: 40.1-46.0) if her baseline CD4 count was ≥ 200 cells/µl, compared to 29.5 y (95% CI: 26.2-33.0) if her baseline CD4 count was

Traditional gold mining is associated with mercury exposure. Especially vulnerable to its neurotoxic effects is the developing nervous system of a child. We aimed to investigate risk factors of mercury exposure among children in a rural mining town in Chile.Using a validated questionnaire distributed to the parents of the children, a priori mercury risk factors, potential exposure pathways and demographics of the children were obtained. Mercury levels were measured through analyzing fingernail samples. Logistic regression modeling the effect of risk factors on mercury levels above the 75(th) percentile were made, adjusted for potential confounders.The 288 children had a mean age of 9.6 years (SD = 1.9). The mean mercury level in the study population was 0.13 µg/g (SD 0.11, median 0.10, range 0.001-0.86 µg/g). The strongest risk factor for children's odds of high mercury levels (>75(th) percentile, 0.165 µg/g) was to play inside a house where a family member worked with mercury (OR adjusted 3.49 95% CI 1.23-9.89). Additionally, children whose parents worked in industrial gold mining had higher odds of high mercury levels than children whose parents worked in industrial copper mining or outside mining activities.Mercury exposure through small-scale gold mining might affect children in their home environments. These results may further help to convince the local population of banning mercury burning inside the households.

Innovative models of care are required to cope with the ever-increasing number of patients on antiretroviral therapy in the most affected countries. This study, in Khayelitsha, South Africa, evaluates the effectiveness of a group-based model of care run predominantly by non-clinical staff in retaining patients in care and maintaining adherence.Participation in "adherence clubs" was offered to adults who had been on ART for at least 18 months, had a current CD4 count >200 cells/ml and were virologically suppressed. Embedded in an ongoing cohort study, we compared loss to care and virologic rebound in patients receiving the intervention with patients attending routine nurse-led care from November 2007 to February 2011. We used inverse probability weighting to estimate the intention-to-treat effect of adherence club participation, adjusted for measured baseline and time-varying confounders. The principal outcome was the combination of death or loss to follow-up. The secondary outcome was virologic rebound in patients who were virologically suppressed at study entry. Of 2829 patients on ART for >18 months with a CD4 count above 200 cells/µl, 502 accepted club participation. At the end of the study, 97% of club patients remained in care compared with 85% of other patients. In adjusted analyses club participation reduced loss-to-care by 57% (hazard ratio [HR] 0.43, 95% CI = 0.21-0.91) and virologic rebound in patients who were initially suppressed by 67% (HR 0.33, 95% CI = 0.16-0.67).Patient adherence groups were found to be an effective model for improving retention and documented virologic suppression for stable patients in long term ART care. Out-of-clinic group-based models facilitated by non-clinical staff are a promising approach to assist in the long-term management of people on ART in high burden low or middle-income settings.

BackgroundTime to detection (TTD) on automated liquid mycobacterial cultures is an emerging biomarker of tuberculosis outcomes. The M. tuberculosis W-Beijing genotype is spreading globally, indicating a selective advantage. There is a paucity of data on the association between baseline TTD and W-Beijing genotype and tuberculosis outcomes.AimTo assess baseline predictors of failure of sputum culture conversion, within the first 2 months of antitubercular therapy, in participants with pulmonary tuberculosis.DesignBetween May 2005 and August 2008 we conducted a prospective cohort study of time to sputum culture conversion in ambulatory participants with first episodes of smear and culture positive pulmonary tuberculosis attending two primary care clinics in Cape Town, South Africa. Rifampicin resistance (diagnosed on phenotypic susceptibility testing) was an exclusion criterion. Sputum was collected weekly for 8 weeks for mycobacterial culture on liquid media (BACTEC MGIT 960). Due to missing data, multiple imputation was performed. Time to sputum culture conversion was analysed using a Cox-proportional hazards model. Bayesian model averaging determined the posterior effect probability for each variable.Results113 participants were enrolled (30.1% female, 10.5% HIV-infected, 44.2% W-Beijing genotype, and 89% cavities). On Kaplan Meier analysis 50.4% of participants underwent sputum culture conversion by 8 weeks. The following baseline factors were associated with slower sputum culture conversion: TTD (adjusted hazard ratio (aHR) = 1.11, 95% CI 1.02; 1.2), lung cavities (aHR = 0.13, 95% CI 0.02; 0.95), ever smoking (aHR = 0.32, 95% CI 0.1; 1.02) and the W-Beijing genotype (aHR = 0.51, 95% CI 0.25; 1.07). On Bayesian model averaging, posterior probability effects were strong for TTD, lung cavitation and smoking and moderate for W-Beijing genotype.ConclusionWe found that baseline TTD, smoking, cavities and W-Beijing genotype were associated with delayed 2 month sputum culture. Larger studies are needed to confirm the relationship between the W-Beijing genotype and sputum culture conversion.

BackgroundIncreased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.Methods and findingsAnalyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population. Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, pConclusionsHIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic. Please see later in the article for the Editors' Summary.

This article presents a multivariate analysis of Olympic decathlon data based on maximum likelihood factor analysis. All results explicitly account for model selection uncertainty, which is inherent in any data-based selection process but mostly ignored in reports related to multivariate sports data. For this purpose, some well-established frequentist procedures that have so far been applied almost exclusively to regression analysis are adopted and transferred to the factor analytical context. The findings support the claim that decathlon contests consist of three dimensions. These dimensions seem to be similar to, but not exactly the same, as those found by Cox and Dunn (2002) via hierarchical cluster analysis. [ABSTRACT FROM AUTHOR]