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BACKGROUND: Across sub-Saharan Africa, mid-level healthcare managers oversee implementation of national guidelines. It remains unclear whether leadership and management training can improve population health outcomes. METHODS: We sought to evaluate leadership/management skills among district-level health managers in Uganda participating in the SEARCH-IPT randomised trial to promote isoniazid preventive therapy (IPT) for persons with HIV (PWH). The intervention, which led to higher IPT rates, included annual leadership/management training of managers. We conducted a cross-sectional survey assessing leadership/management skills among managers at trial completion. The survey evaluated self-reported use of leadership/management tools and general leadership/management. We conducted a survey among a sample of providers to understand the interventions impact. Targeted minimum loss-based estimation (TMLE) was used to compare responses between trial arms. RESULTS: Of 163 managers participating in the SEARCH-IPT trial, 119 (73%) completed the survey. Intervention managers reported more frequent use of leadership/management tools taught in the intervention curriculum than control managers (+3.64, 95% CI 1.98-5.30, P < 0.001). There were no significant differences in self-reported leadership skills in the intervention as compared to the control group. Among providers, the average reported quality of guidance and supervision was significantly higher in intervention vs control districts (+1.08, 95% CI 0.63-1.53, P = 0.001). CONCLUSIONS: A leadership and management training intervention increased the use of leadership/management tools among mid-level managers and resulted in higher perceived quality of supervision among providers in intervention vs control districts in Uganda. These findings suggest improved leadership/management among managers contributed to increased IPT use among PWH in the intervention districts of the SEARCH-IPT trial.

BackgroundFour large community-randomized trials examining universal testing and treatment (UTT) to reduce HIV transmission were conducted between 2012-2018 in Botswana, Kenya, Uganda, Zambia and South Africa. In 2014, the UNAIDS 90-90-90 targets were adopted as a useful metric to monitor coverage. We systematically review the approaches used by the trials to measure intervention delivery, and estimate coverage against the 90-90-90 targets. We aim to provide in-depth understanding of the background contexts and complexities that affect estimation of population-level coverage related to the 90-90-90 targets.MethodsEstimates were based predominantly on "process" data obtained during delivery of the interventions which included a combination of home-based and community-based services. Cascade coverage data included routine electronic health records, self-reported data, survey data, and active ascertainment of HIV viral load measurements in the field.ResultsThe estimated total adult populations of trial intervention communities included in this study ranged from 4,290 (TasP) to 142,250 (Zambian PopART Arm-B). The estimated total numbers of PLHIV ranged from 1,283 (TasP) to 20,541 (Zambian PopART Arm-B). By the end of intervention delivery, the first-90 target (knowledge of HIV status among all PLHIV) was met by all the trials (89.2%-94.0%). Three of the four trials also achieved the second- and third-90 targets, and viral suppression in BCPP and SEARCH exceeded the UNAIDS target of 73%, while viral suppression in the Zambian PopART Arm-A and B communities was within a small margin (~ 3%) of the target.ConclusionsAll four UTT trials aimed to implement wide-scale testing and treatment for HIV prevention at population level and showed substantial increases in testing and treatment for HIV in the intervention communities. This study has not uncovered any one estimation approach which is superior, rather that several approaches are available and researchers or policy makers seeking to measure coverage should reflect on background contexts and complexities that affect estimation of population-level coverage in their specific settings. All four trials surpassed UNAIDS targets for universal testing in their intervention communities ahead of the 2020 milestone. All but one of the trials also achieved the 90-90 targets for treatment and viral suppression. UTT is a realistic option to achieve 95-95-95 by 2030 and fast-track the end of the HIV epidemic.

Systemic lupus erythematous (SLE) is a chronic autoimmune disease associated with genetic and environmental risk factors. However, the extent to which genetic risk is causally associated with disease activity is unknown. We utilized longitudinal-targeted maximum likelihood estimation to estimate the causal association between a genetic risk score (GRS) comprising 41 established SLE variants and clinically important disease activity as measured by the validated Systemic Lupus Activity Questionnaire (SLAQ) in a multiethnic cohort of 942 individuals with SLE. We did not find evidence of a clinically important SLAQ score difference (>4.0) for individuals with a high GRS compared with those with a low GRS across nine time points after controlling for sex, ancestry, renal status, dialysis, disease duration, treatment, depression, smoking and education, as well as time-dependent confounding of missing visits. Individual single-nucleotide polymorphism (SNP) analyses revealed that 12 of the 41 variants were significantly associated with clinically relevant changes in SLAQ scores across time points eight and nine after controlling for multiple testing. Results based on sophisticated causal modeling of longitudinal data in a large patient cohort suggest that individual SLE risk variants may influence disease activity over time. Our findings also emphasize a role for other biological or environmental factors.

Background: Universal antiretroviral therapy (ART) with annual population testing and a multidisease, patient-centered strategy could reduce new human immunodeficiency virus (HIV) infections and improve community health.Methods: We randomly assigned 32 rural communities in Uganda and Kenya to baseline HIV and multidisease testing and national guideline-restricted ART (control group) or to baseline testing plus annual testing, eligibility for universal ART, and patient-centered care (intervention group). The primary end point was the cumulative incidence of HIV infection at 3 years. Secondary end points included viral suppression, death, tuberculosis, hypertension control, and the change in the annual incidence of HIV infection (which was evaluated in the intervention group only).Results: A total of 150,395 persons were included in the analyses. Population-level viral suppression among 15,399 HIV-infected persons was 42% at baseline and was higher in the intervention group than in the control group at 3 years (79% vs. 68%; relative prevalence, 1.15; 95% confidence interval [CI], 1.11 to 1.20). The annual incidence of HIV infection in the intervention group decreased by 32% over 3 years (from 0.43 to 0.31 cases per 100 person-years; relative rate, 0.68; 95% CI, 0.56 to 0.84). However, the 3-year cumulative incidence (704 incident HIV infections) did not differ significantly between the intervention group and the control group (0.77% and 0.81%, respectively; relative risk, 0.95; 95% CI, 0.77 to 1.17). Among HIV-infected persons, the risk of death by year 3 was 3% in the intervention group and 4% in the control group (0.99 vs. 1.29 deaths per 100 person-years; relative risk, 0.77; 95% CI, 0.64 to 0.93). The risk of HIV-associated tuberculosis or death by year 3 among HIV-infected persons was 4% in the intervention group and 5% in the control group (1.19 vs. 1.50 events per 100 person-years; relative risk, 0.79; 95% CI, 0.67 to 0.94). At 3 years, 47% of adults with hypertension in the intervention group and 37% in the control group had hypertension control (relative prevalence, 1.26; 95% CI, 1.15 to 1.39).Conclusions: Universal HIV treatment did not result in a significantly lower incidence of HIV infection than standard care, probably owing to the availability of comprehensive baseline HIV testing and the rapid expansion of ART eligibility in the control group. (Funded by the National Institutes of Health and others; SEARCH ClinicalTrials.gov number, NCT01864603.). [ABSTRACT FROM AUTHOR]

This literature review offers a comprehensive overview of the use of evaluation criteria across five policy fields: social services, land-use planning, teaching in higher education, vocational education, and the environment. Though it is a key part of the evaluation process, the question of how criteria are defined, chosen, and applied generates surprisingly little debate among the evaluation community. In evaluation practice, criteria are often taken for granted - and occasionally even used in ways that are neither explicit nor transparent. This cross-field literature review shows a strong presence of routinized evaluation criteria (relating to the specifics of each policy field), while some new sets of higher-degree criteria also emerge in the face of social challenges relating to sustainability, public acceptance, or social justice. Criteria development draws on both inductive bottom-up processes (which can include policy stakeholders) and top-down deductive processes (which derive criteria from the literature, as well as from national and international standards). A more profound reflection on evaluation criteria (that is, the dimensions used by societies to assess the success of policy interventions) might be required in the future of evaluation research and planning; a deeper cross-field dialogue could support this endeavor., Competing Interests: Declaration of Competing Interest none., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polygamy is the practice of marriage to multiple partners. Approximately 6-11% of households in Uganda and 4-11% of households in Kenya are polygamous. The complex families produced by polygamous marriage customs give rise to additional considerations for healthcare providers and public health messaging around HIV care. Using 27 in-depth, semi-structured qualitative interviews with participants in two studies in rural Kenya and Uganda, we analysed challenges and opportunities that polygamous families presented in the diagnosis, treatment and prevention of HIV, and provider roles in improving HIV outcomes in these families. Overall, prevention methods seemed more justifiable to families where co-wives live far apart than when all members live in the same household. In treatment, diagnosis of one member did not always lead to disclosure to other members, creating an adverse home environment; but sometimes diagnosis of one wife led not only to diagnosis of the other, but also to greater household support., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To estimate the seroprevalence of anti-SARS-CoV-2 IgG and IgM among Massachusetts residents and to better understand asymptomatic SARS-CoV-2 transmission during the summer of 2020., Design: Mail-based cross-sectional survey., Setting: Massachusetts, USA., Participants: Primary sampling group: sample of undergraduate students at the University of Massachusetts, Amherst (n=548) and a member of their household (n=231).Secondary sampling group: sample of graduate students, faculty, librarians and staff (n=214) and one member of their household (n=78). All participants were residents of Massachusetts without prior COVID-19 diagnosis., Primary and Secondary Outcome Measures: Prevalence of SARS-CoV-2 seropositivity. Association of seroprevalence with variables including age, gender, race, geographic region, occupation and symptoms., Results: Approximately 27 000 persons were invited via email to assess eligibility. 1001 households were mailed dried blood spot sample kits, 762 returned blood samples for analysis. In the primary sample group, 36 individuals (4.6%) had IgG antibodies detected for an estimated weighted prevalence in this population of 5.3% (95% CI: 3.5 to 8.0). In the secondary sampling group, 10 participants (3.4%) had IgG antibodies detected for an estimated adjusted prevalence of 4.0% (95% CI: 2.2 to 7.4). No samples were IgM positive. No association was found in either group between seropositivity and self-reported work duties or customer-facing hours. In the primary sampling group, self-reported febrile illness since February 2020, male sex and minority race (Black or American Indian/Alaskan Native) were associated with seropositivity. No factors except geographic regions within the state were associated with evidence of prior SARS-CoV-2 infection in the secondary sampling group., Conclusions: This study fills a critical gap in estimating the levels of subclinical and asymptomatic infection. Estimates can be used to calibrate models estimating levels of population immunity over time, and these data are critical for informing public health interventions and policy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Efficient ways to identify children with HIV in the context of universal test-and-treat policies are needed. We evaluated a hybrid testing strategy combining mobile community and home-based HIV testing in 87,700 children across 32 rural communities in 2 East African countries. This approach resulted in 81% testing coverage of at-risk children and doubled the number of children diagnosed with HIV.

Objectives/design: As antiretroviral therapy (ART) rapidly expands in sub-Saharan Africa using new efficient care models, data on costs of these approaches are lacking. We examined costs of a streamlined HIV care delivery model within a large HIV test-and-treat study in Uganda and Kenya., Methods: We calculated observed per-person-per-year (ppy) costs of streamlined care in 17 health facilities in SEARCH Study intervention communities (NCT: 01864603) via micro-costing techniques, time-and-motion studies, staff interviews, and administrative records. Cost categories included salaries, ART, viral load testing, recurring goods/services, and fixed capital/facility costs. We then modeled costs under three increasingly efficient scale-up scenarios: lowest-cost ART, centralized viral load testing, and governmental healthcare worker salaries. We assessed the relationship between community-specific ART delivery costs, retention in care, and viral suppression., Results: Estimated streamlined HIV care delivery costs were $291/ppy. ART ($117/ppy for TDF/3TC/EFV [40%]) and viral load testing ($110/ppy for 2 tests/year [39%]) dominated costs versus salaries ($51/ppy), recurring costs ($5/ppy), and fixed costs ($7/ppy). Optimized ART scale-up with lowest-cost ART ($100/ppy), annual viral load testing ($24/ppy), and governmental healthcare salaries ($27/ppy), lowered streamlined care cost to $163/ppy. We found clinic-to-clinic heterogeneity in retention and viral suppression levels versus streamlined care delivery costs, but no correlation between cost and either retention or viral suppression., Conclusions: In the SEARCH Study, streamlined HIV care delivery costs were similar to or lower than prior estimates despite including viral load testing; further optimizations could substantially reduce costs further. These data can inform global strategies for financing ART expansion to achieve UNAIDS 90-90-90 targets.

Background: Country decisions to scale-up "test and treat" approaches for HIV depend on consideration of both the health and economic consequences of such investments. Evidence about economic impacts of expanded antiretroviral therapy (ART) provision is particularly relevant for decisions regarding foreign assistance levels for HIV/AIDS programs. We used baseline data from the Sustainable East Africa Research in Community Health (SEARCH) cluster randomized controlled trial in Kenya and Uganda to examine the association between HIV status, CD4+ T-cell counts, viral suppression, and multiple indicators of economic well-being., Methods and Findings: Socio-economic surveys were conducted in households with HIV-positive and HIV-negative adults sampled after a census of 32 communities participating in the SEARCH trial (NCT01864603). Data were obtained for 11,500 individuals from 5,884 households in study communities. Participants were stratified based on their own HIV status as well as CD4 counts and viral suppression status if they were HIV-positive. HIV-negative participants residing in households with no HIV-positive adults were considered separately from HIV-negative participants residing in households with ≥1 HIV-positive adult. Generalized estimating equation models were used to examine the relationship between HIV status, CD4 counts, ART, viral suppression, and outcomes of employment, self-reported illness, lost time from usual activities due to illness, healthcare utilization, health expenditures, and hospitalizations. In all models, HIV-negative participants in households with no HIV-positive persons were the reference group. There was no significant difference in the probability of being employed between HIV-positive participants with CD4>500 and the reference group of HIV-negative participants residing in households with no HIV-positive adults (marginal effect, ME, 1.49 percentage points; 95% confidence interval, CI, -1.09, 4.08). However, HIV-positive participants with CD4 351-500 were less likely to be employed than the reference group (ME -4.50, 95% CI -7.99, -1.01), as were HIV-positive participants with CD4 ≤350 (ME -7.41, 95% CI -10.96, -3.85). Similarly, there was no significant difference in employment likelihood between HIV-negative participants who resided in households with a CD4>500 HIV-positive person and the reference group (ME -1.78, 95% CI -5.16, 1.59). HIV-negative participants residing with an HIV-positive person with CD4 351-500, however, were less likely to be employed than the reference group (ME -7.03, 95% CI -11.49, -2.57), as were people residing with a household member with CD4 ≤350 (ME -6.28, 95% CI -10.76, -1.80). HIV-positive participants in all CD4 categories were more likely to have lost time from usual activities due to illness and have incurred healthcare expenditures. Those with CD4>500 had better economic outcomes than those with CD4 351-500, even among those not virally suppressed (p = 0.004) and not on ART (p = 0.01)., Conclusions: Data from a large population-representative sample of households in east Africa showed a strong association between the health of HIV-positive persons and economic outcomes. The findings suggest there may be economic benefits associated with maintaining high CD4 counts, both for HIV-positive persons and their HIV-negative household members. The association of high CD4 counts with improved outcomes is consistent with the hypothesis that early ART initiation can avert declines in employment and other economic outcomes. Prospective longitudinal evaluation is needed to assess the causal impact of early ART initiation on economic functioning of households., Competing Interests: The authors have declared that no competing interests exist.

Binary classification problems are ubiquitous in health and social sciences. In many cases, one wishes to balance two competing optimality considerations for a binary classifier. For instance, in resource-limited settings, an human immunodeficiency virus prevention program based on offering pre-exposure prophylaxis (PrEP) to select high-risk individuals must balance the sensitivity of the binary classifier in detecting future seroconverters (and hence offering them PrEP regimens) with the total number of PrEP regimens that is financially and logistically feasible for the program. In this article, we consider a general class of constrained binary classification problems wherein the objective function and the constraint are both monotonic with respect to a threshold. These include the minimization of the rate of positive predictions subject to a minimum sensitivity, the maximization of sensitivity subject to a maximum rate of positive predictions, and the Neyman-Pearson paradigm, which minimizes the type II error subject to an upper bound on the type I error. We propose an ensemble approach to these binary classification problems based on the Super Learner methodology. This approach linearly combines a user-supplied library of scoring algorithms, with combination weights and a discriminating threshold chosen to minimize the constrained optimality criterion. We then illustrate the application of the proposed classifier to develop an individualized PrEP targeting strategy in a resource-limited setting, with the goal of minimizing the number of PrEP offerings while achieving a minimum required sensitivity. This proof of concept data analysis uses baseline data from the ongoing Sustainable East Africa Research in Community Health study. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Design: Universal voluntary HIV counselling and testing followed by prompt initiation of antiretroviral therapy (ART) for all those diagnosed HIV-infected (universal test and treat, UTT) is now a global health standard. However, its population-level impact, feasibility and cost remain unknown. Five community-based trials have been implemented in sub-Saharan Africa to measure the effects of various UTT strategies at population level: BCPP/YaTsie in Botswana, MaxART in Swaziland, HPTN 071 (PopART) in South Africa and Zambia, SEARCH in Uganda and Kenya and ANRS 12249 TasP in South Africa. This report describes and contrasts the contexts, research methodologies, intervention packages, themes explored, evolution of study designs and interventions related to each of these five UTT trials., Methods: We conducted a comparative assessment of the five trials using data extracted from study protocols and collected during baseline studies, with additional input from study investigators. We organized differences and commonalities across the trials in five categories: trial contexts, research designs, intervention packages, trial themes and adaptations., Results: All performed in the context of generalized HIV epidemics, the trials highly differ in their social, demographic, economic, political and health systems settings. They share the common aim of assessing the impact of UTT on the HIV epidemic but differ in methodological aspects such as study design and eligibility criteria for trial populations. In addition to universal ART initiation, the trials deliver a wide range of biomedical, behavioural and structural interventions as part of their UTT strategies. The five studies explore common issues, including the uptake rates of the trial services and individual health outcomes. All trials have adapted since their initiation to the evolving political, economic and public health contexts, including adopting the successive national recommendations for ART initiation., Conclusions: We found substantial commonalities but also differences between the five UTT trials in their design, conduct and multidisciplinary outputs. As empirical literature on how UTT may improve efficiency and quality of HIV care at population level is still scarce, this article provides a foundation for more collaborative research on UTT and supports evidence-based decision making for HIV care in country and internationally., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Importance: Antiretroviral treatment (ART) is now recommended for all HIV-positive persons. UNAIDS has set global targets to diagnose 90% of HIV-positive individuals, treat 90% of diagnosed individuals with ART, and suppress viral replication among 90% of treated individuals, for a population-level target of 73% of all HIV-positive persons with HIV viral suppression., Objective: To describe changes in the proportions of HIV-positive individuals with HIV viral suppression, HIV-positive individuals who had received a diagnosis, diagnosed individuals treated with ART, and treated individuals with HIV viral suppression, following implementation of a community-based testing and treatment program in rural East Africa., Design, Setting, and Participants: Observational analysis based on interim data from 16 rural Kenyan (n = 6) and Ugandan (n = 10) intervention communities in the SEARCH Study, an ongoing cluster randomized trial. Community residents who were 15 years or older (N = 77 774) were followed up for 2 years (2013-2014 to 2015-2016). HIV serostatus and plasma HIV RNA level were measured annually at multidisease health campaigns followed by home-based testing for nonattendees. All HIV-positive individuals were offered ART using a streamlined delivery model designed to reduce structural barriers, improve patient-clinician relationships, and enhance patient knowledge and attitudes about HIV., Main Outcomes and Measures: Primary outcome was viral suppression (plasma HIV RNA<500 copies/mL) among all HIV-positive individuals, assessed at baseline and after 1 and 2 years. Secondary outcomes included HIV diagnosis, ART among previously diagnosed individuals, and viral suppression among those who had initiated ART., Results: Among 77 774 residents (male, 45.3%; age 15-24 years, 35.1%), baseline HIV prevalence was 10.3% (7108 of 69 283 residents). The proportion of HIV-positive individuals with HIV viral suppression at baseline was 44.7% (95% CI, 43.5%-45.9%; 3464 of 7745 residents) and after 2 years of intervention was 80.2% (95% CI, 79.1%-81.2%; 5666 of 7068 residents), an increase of 35.5 percentage points (95% CI, 34.4-36.6). After 2 years, 95.9% of HIV-positive individuals had been previously diagnosed (95% CI, 95.3%-96.5%; 6780 of 7068 residents); 93.4% of those previously diagnosed had received ART (95% CI, 92.8%-94.0%; 6334 of 6780 residents); and 89.5% of those treated had achieved HIV viral suppression (95% CI, 88.6%-90.3%; 5666 of 6334 residents)., Conclusions and Relevance: Among individuals with HIV in rural Kenya and Uganda, implementation of community-based testing and treatment was associated with an increased proportion of HIV-positive adults who achieved viral suppression, along with increased HIV diagnosis and initiation of antiretroviral therapy. In these communities, the UNAIDS population-level viral suppression target was exceeded within 2 years after program implementation., Trial Registration: clinicaltrials.gov Identifier: NCT01864683.

Background: Several cluster-randomized trials are underway to investigate the implementation and effectiveness of a universal test-and-treat strategy on the HIV epidemic in sub-Saharan Africa. We consider nesting studies of pre-exposure prophylaxis within these trials. Pre-exposure prophylaxis is a general strategy where high-risk HIV- persons take antiretrovirals daily to reduce their risk of infection from exposure to HIV. We address how to target pre-exposure prophylaxis to high-risk groups and how to maximize power to detect the individual and combined effects of universal test-and-treat and pre-exposure prophylaxis strategies., Methods: We simulated 1000 trials, each consisting of 32 villages with 200 individuals per village. At baseline, we randomized the universal test-and-treat strategy. Then, after 3 years of follow-up, we considered four strategies for targeting pre-exposure prophylaxis: (1) all HIV- individuals who self-identify as high risk, (2) all HIV- individuals who are identified by their HIV+ partner (serodiscordant couples), (3) highly connected HIV- individuals, and (4) the HIV- contacts of a newly diagnosed HIV+ individual (a ring-based strategy). We explored two possible trial designs, and all villages were followed for a total of 7 years. For each village in a trial, we used a stochastic block model to generate bipartite (male-female) networks and simulated an agent-based epidemic process on these networks. We estimated the individual and combined intervention effects with a novel targeted maximum likelihood estimator, which used cross-validation to data-adaptively select from a pre-specified library the candidate estimator that maximized the efficiency of the analysis., Results: The universal test-and-treat strategy reduced the 3-year cumulative HIV incidence by 4.0% on average. The impact of each pre-exposure prophylaxis strategy on the 4-year cumulative HIV incidence varied by the coverage of the universal test-and-treat strategy with lower coverage resulting in a larger impact of pre-exposure prophylaxis. Offering pre-exposure prophylaxis to serodiscordant couples resulted in the largest reductions in HIV incidence (2% reduction), and the ring-based strategy had little impact (0% reduction). The joint effect was larger than either individual effect with reductions in the 7-year incidence ranging from 4.5% to 8.8%. Targeted maximum likelihood estimation, data-adaptively adjusting for baseline covariates, substantially improved power over the unadjusted analysis, while maintaining nominal confidence interval coverage., Conclusion: Our simulation study suggests that nesting a pre-exposure prophylaxis study within an ongoing trial can lead to combined intervention effects greater than those of universal test-and-treat alone and can provide information about the efficacy of pre-exposure prophylaxis in the presence of high coverage of treatment for HIV+ persons.

Many of the secondary outcomes in observational studies and randomized trials are rare. Methods for estimating causal effects and associations with rare outcomes, however, are limited, and this represents a missed opportunity for investigation. In this article, we construct a new targeted minimum loss-based estimator (TMLE) for the effect or association of an exposure on a rare outcome. We focus on the causal risk difference and statistical models incorporating bounds on the conditional mean of the outcome, given the exposure and measured confounders. By construction, the proposed estimator constrains the predicted outcomes to respect this model knowledge. Theoretically, this bounding provides stability and power to estimate the exposure effect. In finite sample simulations, the proposed estimator performed as well, if not better, than alternative estimators, including a propensity score matching estimator, inverse probability of treatment weighted (IPTW) estimator, augmented-IPTW and the standard TMLE algorithm. The new estimator yielded consistent estimates if either the conditional mean outcome or the propensity score was consistently estimated. As a substitution estimator, TMLE guaranteed the point estimates were within the parameter range. We applied the estimator to investigate the association between permissive neighborhood drunkenness norms and alcohol use disorder. Our results highlight the potential for double robust, semiparametric efficient estimation with rare events and high dimensional covariates.

Background: Case-control studies are useful for rare outcomes, but typical analyses limit investigators to parametric estimation of conditional odds ratios. Several methods exist for obtaining marginal risk differences and risk ratios in a case-control setting, including a recently described semiparametric targeted approach optimized for rare outcomes., Methods: Using case-control data from a study of neighborhood poverty and very preterm birth, we demonstrate estimation of marginal risk differences and risk ratios and compare a parametric substitution estimator based on maximum likelihood estimation with targeted maximum likelihood estimation (TMLE), and a refinement of TMLE for rare outcomes that incorporates bounds on the conditional risk., Results: In this illustration, living in a neighborhood with high poverty was associated with a higher risk of very preterm birth for white women. The estimated risk differences (cases/100) were 0.6 (95% confidence interval [CI]: 0.1, 1.1) from maximum likelihood estimation, 0.5 (95% CI: -1.1, 2.1) from TMLE, and 0.5 (95% CI: 0.0, 1.0) from the rare outcomes refinement. The rare outcomes refinement, which incorporates knowledge that the conditional risk is small, produced more precise estimates than TMLE. A similar pattern was observed for the relative risk., Conclusion: Absolute and relative associations estimated from case-control data using a semiparametric targeted approach allow the scientific question to determine the analysis and avoid unwarranted parametric assumptions. A rare outcomes refinement provided more precise estimates than TMLE, and thus is well suited for the study of rare outcomes.

Background | Relapsing fever is divided into tick borne relapsing fever (TBRF) and louse borne relapsing fever (LBRF). This report describes 25 refugees from East Africa who were diagnosed to suffer from LBRF within a period of 6 month only at a single hospital in Munich / Germany. Material & Methods | The aim was to point out common clinical features as well as laboratory findings and clinical symptoms before and after initiation of treatment in 25 patients with louse borne relapsing fever (LBRF) who were diagnosed and treated at Klinikum München Schwabing from August 2015 to January 2016. To the best of our knowledge this is the largest case series of LBRF in the western world for decades. Main focus of the investigation was put on clinical aspects. Results | All 25 patients suffered from acute onset of high fever with chills, headache and severe prostration. Laboratory analysis showed high CRP and a marked thrombocytopenia. A Giemsa blood stain was procured immediately in order to look for malaria. In the blood smear spirochetes with typical shape and aspect of borrelia species could be detected.The further PCR analysis confirmed infection with Borrelia recurrentis. Treatment with Doxycycline was started forthwith. The condition improved already on the second day after treatment was started and all were restored to health in less than a week. Apart from a mild to moderate Jarisch-Herxheimer-reaction we didn`t see any side effects of the therapy. Conclusion | LBRF has to be taken into account in feverish patients who come as refugees from East-Africa. It seems that our patients belong to a cluster which probably has its origin in Libya and more patients are to be expected in the near future. As LBRF might cause outbreaks in refugee camps it is pivotal to be aware of this emerging infectious disease in refugees from East-Africa., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction | Relapsing fevers, transmitted by arthropods, are rarely encountered in Germany, thus they are often not considered as differential diagnosis in febrile patients. In the last months, more than fourty cases of louse-borne relapsing fever were diagnosed in asylum seekers in Germany. Some of the patients had to be admitted to intensive care units, one patient died despite therapy. Pathogen, disease and diagnosis | The causative agents are spirochetes of the genus borrelia, which can reach high densities in patient blood. Depending on the vector and the region, different species are prevalent worldwide. For diagnosis, appropriate techniques include direct detection by microscopy or PCR from EDTA-blood. Ordering such tests should not be delayed when there is suspicion for relapsing fever. Besides, malaria can also be excluded with microscopy of blood smears. Therapy | First-line antibiotics include tetracyclines and penicillin, acquired resistance has not yet been observed. Frequently patients develop a Jarisch-Herxheimer reaction shortly after initiation of therapy, requiring hospitalization or intensive care treatment. Managing the treatment exclusively in an outpatient setting is not recommended. Especially in migrants with febrile illness, relapsing fever is an important differential diagnosis., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Antiretroviral therapy scale-up in Sub-Saharan Africa has created a growing, aging HIV-positive population at risk for non-communicable diseases such as hypertension. However, the prevalence and risk factors for hypertension in this population remain incompletely understood., Methods: We measured blood pressure and collected demographic data on over 65,000 adults attending multi-disease community health campaigns in 20 rural Ugandan communities (SEARCH Study: NCT01864603). Our objectives were to determine (i) whether HIV is an independent risk factor for hypertension, and (ii) awareness and control of hypertension in HIV-positive adults and the overall population., Results: Hypertension prevalence was 14% overall, and 11% among HIV-positive individuals. 79% of patients were previously undiagnosed, 85% were not taking medication, and 50% of patients on medication had uncontrolled blood pressure. Multivariate predictors of hypertension included older age, male gender, higher BMI, lack of education, alcohol use, and residence in Eastern Uganda. HIV-negative status was independently associated with higher odds of hypertension (OR 1.2, 95% CI: 1.1-1.4). Viral suppression of HIV did not significantly predict hypertension among HIV-positives., Significance: The burden of hypertension is substantial and inadequately controlled, both in HIV-positive persons and overall. Universal HIV screening programs could provide counseling, testing, and treatment for hypertension in Sub-Saharan Africa.

Background: Alcohol outlet density and norms shape alcohol consumption. However, due to analytic challenges we do not know: (a) if alcohol outlet density and norms also shape alcohol use disorder, and (b) whether they act in combination to shape disorder., Methods: We applied a new targeted minimum loss-based estimator for rare outcomes (rTMLE) to a general population sample from New York City (N = 4000) to examine the separate and combined relations of neighborhood alcohol outlet density and norms around drunkenness with alcohol use disorder. Alcohol use disorder was assessed using the World Mental Health Comprehensive International Diagnostic Interview (WMH-CIDI) alcohol module. Confounders included demographic and socioeconomic characteristics, as well as history of drinking prior to residence in the current neighborhood., Results: Alcohol use disorder prevalence was 1.78%. We found a marginal risk difference for alcohol outlet density of 0.88% (95% CI 0.00-1.77%), and for norms of 2.05% (95% CI 0.89-3.21%), adjusted for confounders. While each exposure had a substantial relation with alcohol use disorder, there was no evidence of additive interaction between the exposures., Conclusions: Results indicate that the neighborhood environment shapes alcohol use disorder. Despite the lack of additive interaction, each exposure had a substantial relation with alcohol use disorder and our findings suggest that alteration of outlet density and norms together would likely be more effective than either one alone. Important next steps include development and testing of multi-component intervention approaches aiming to modify alcohol outlet density and norms toward reducing alcohol use disorder., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We report 15 imported louse-borne relapsing fever (LBRF) cases in refugees in Bavaria, Germany. One patient died. Epidemiological findings confirmed that all were young males from the Horn of Africa (12 from Somalia), who had similar migration routes converging in Sudan continuing through Libya and Italy. The majority likely acquired their infection during migration. Healthcare workers should be aware of LBRF in refugees passing through north Africa to ensure correct treatment and preventive measures.

Background: Skin testing can expose allergic subjects to potential systemic reactions, sensitization against unrelated proteins, and increased risk of future sting reactions. Therefore the continuous improvement of in vitro diagnostic methods is desirable. Recombinant allergens have been shown to improve the sensitivity of specific IgE (sIgE) detection in vitro whilst no data is available regarding their application and reliability in basophil activation test (BAT). Here we aimed to compare the specificity and sensitivity of recombinant allergens Ves v 1, Ves v 2, Ves v 3 and Ves v 5 in both specific IgE (sIgE) detection in vitro and basophil activation test., Methods: sIgE detection by ELISA or ImmunoCAP and BAT towards the panel of recombinant allergens Ves v 1, Ves v 2, Ves v 3 and Ves v 5 were performed in 43 wasp venom allergic patients with a history of anaphylactic reaction and sIgE seropositivity, as well as 17 controls defined as subjects with a history of repetitive wasp stings but absence of any allergic symptom., Results: The BAT performed with the recombinant allergens Ves v 1, Ves v 2, Ves v 3 and Ves v 5 markedly improved the specificity of diagnosis in wasp venom allergic subjects when compared to the respective sIgE detection in serum., Conclusions: BAT performed with the recombinant allergens Ves v 5, Ves v 3 and Ves v 1 provides an emerging highly specific in vitro method for the detection of wasp venom allergy, compared to the sIgE detection. Recombinant allergens applied to BAT represent a step forward in developing reliable in vitro tests for specific diagnosis of allergy.

Objectives: To determine the frequency and predictors of hypertension linkage to care after implementation of a linkage intervention in rural Uganda., Methods: During a multidisease screening campaign for HIV, diabetes and hypertension in rural Uganda, hypertensive adults received education, appointment to a local health facility and travel voucher. We measured frequency and predictors of linkage to care, defined as visiting any health facility for hypertension management within 6 months. Predictors of linkage to care were calculated using collaborative-targeted maximum likelihood estimation (C-TMLE). Participants not linking were interviewed using a standardised instrument to determine barriers to care., Results: Over 5 days, 2252 adults were screened for hypertension and 214 hypertensive adults received a linkage intervention for further management. Of these, 178 (83%) linked to care within 6 months (median = 22 days). Independent predictors of successful linkage included older age, female gender, higher education, manual employment, tobacco use, alcohol consumption, hypertension family history and referral to local vs. regional health centre. Barriers for patients who did not see care included expensive transport (59%) and feeling well (59%)., Conclusions: A community health campaign that offered hypertension screening, education, referral appointment and travel voucher achieved excellent linkage to care (83%). Young adults, men and persons with low levels of formal education were among those least likely to seek care., (© 2014 John Wiley & Sons Ltd.)

The objective of this study was to identify the oral pathogens found in odontogenic infections, to determine their susceptibilities to amoxicillin-clavulanic acid (AMC), clindamycin (CLI), doxycycline (DOX), levofloxacin (LVX), moxifloxacin (MXF), and penicillin (PEN), and to search for associations between specific pathogens and types of infection. Swabs from patients enrolled in a randomized, double-blind phase II trial comparing MXF with CLI for the treatment of odontogenic abscesses or inflammatory infiltrates were cultured on media for aerobes and anaerobes. All bacterial isolates were identified at the species level. Overall, 205 isolates were cultured from 71 patients: 77 viridans group streptococci, 56 Prevotella spp., 19 Neisseria spp., 17 Streptococcus anginosus group isolates and hemolytic streptococci, 15 other anaerobes, and 21 other bacteria. Ninety-eight percent of pathogens were susceptible to MXF, 96% to AMC, 85% to LVX, 67% to PEN, 60% to CLI, and 50% to DOX. S. anginosus group and hemolytic streptococci were found significantly more frequently (P = 0.04) in patients with abscesses (12/95) than in patients with infiltrates (5/110). In four patients with infiltrates who failed to respond to CLI therapy, three isolates of the Streptococcus mitis group and four Neisseria spp. resistant to CLI were found. In this study, S. anginosus group and hemolytic streptococci were clearly associated with odontogenic abscesses. Our analysis suggests that viridans group streptococci and Neisseria spp. play a decisive role in the etiology of odontogenic infiltrates. The high in vitro activity of MXF against odontogenic bacteria corresponds well to its clinical results in the treatment of odontogenic abscesses and infiltrates.