Search

Supplemental Digital Content is Available in the Text. Background: Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented. Methods: We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes. Results: 216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown. Conclusions: Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid–based regimens. [ABSTRACT FROM AUTHOR]

Background: Environmental enteric dysfunction (EED) may be an important modifiable cause of child stunting. We described the evolution of EED biomarkers from birth to 18 months in rural Zimbabwe and tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF), on EED. Methodology and findings: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial was a 2x2 factorial cluster-randomised trial of improved IYCF and improved WASH on child stunting and anaemia at 18 months of age. 1169 infants born to HIV-negative mothers provided plasma and faecal specimens at 1, 3, 6, 12, and 18 months of age. We measured EED biomarkers that reflect all domains of the hypothesized pathological pathway. Markers of intestinal permeability and intestinal inflammation declined over time, while markers of microbial translocation and systemic inflammation increased between 1–18 months. Markers of intestinal damage (I-FABP) and repair (REG-1β) mirrored each other, and citrulline (a marker of intestinal epithelial mass) increased from 6 months of age, suggesting dynamic epithelial turnover and regeneration in response to enteric insults. We observed few effects of IYCF and WASH on EED after adjustment for multiple comparisons. The WASH intervention decreased plasma IGF-1 at 3 months (β:0.89, 95%CI:0.81,0.98) and plasma kynurenine at 12 months (β: 0.92, 95%CI:0.87,0.97), and increased plasma IGF-1 at 18 months (β:1.15, 95%CI:1.05,1.25), but these small WASH effects did not translate into improved growth. Conclusions: Overall, we observed dynamic trends in EED but few effects of IYCF or WASH on biomarkers during the first 18 months after birth, suggesting that these interventions did not impact EED. Transformative WASH interventions are required to prevent or ameliorate EED in low-income settings. Author summary: Child stunting remains a global health challenge rooted in an intergenerational cycle of poor health, reduced neurodevelopment and poverty. Environmental enteric dysfunction (EED) is an acquired condition of the small intestine likely resulting from frequent faecal-oral microbial exposure, which is hypothesized to underlie stunting. We found dynamic changes in EED biomarkers between 1 and 18 months of age in a cohort of rural Zimbabwean infants, suggesting a complex developmental period of intestinal maturation, adaptation and response to environmental insults. Randomized improved infant and young child feeding, and improved water, sanitation and hygiene (WASH) interventions had no meaningful impact on EED. Greater investment in transformative WASH is needed to prevent EED in low-income countries. [ABSTRACT FROM AUTHOR]

OBJECTIVE To examine whether community health volunteers induced significant changes in care seeking and treatment of ill children under five 2 years after their deployment in two underserved districts of Sierra Leone. METHODS A pre-test-post-test study with intervention and comparison groups was used. A household cluster survey was conducted among caregivers of 5643 children at baseline and of 5259 children at endline. RESULTS In the intervention districts, treatments provided by community health volunteers increased from 0 to 14.3% for all three conditions combined (P < 0.001). Care seeking from an appropriate provider was not statistically significant (OR = 1.50, 95% CI: 0.88-2.54) between intervention and comparison districts and coverage of appropriate treatment increased in both study groups for all three illnesses. However, the presence of community health volunteers was associated with a 105% increase in appropriate treatment for pneumonia (OR = 2.05, 95% CI: 1.22-3.42) and a 55% drop in traditional treatment for diarrhoea (OR = 0.45, 95% CI: 0.21-0.96). Community health volunteers were also associated with fewer facility treatments for malaria (OR = 0.21, 95% CI: 0.07- 0.62). CONCLUSION After implementing free care, coverage for treatment for all three illnesses in both study groups improved. Deployment of community health volunteers was associated with a reduced treatment burden at facilities and less reliance on traditional treatments. [ABSTRACT FROM AUTHOR]

Highlights: [•] The study estimated herd protection of Hib vaccine against pneumonia among children <2 years old. [•] Hib vaccine herd protection has never been examined in Bangladesh or Southeast Asia. [•] A higher vaccine coverage was associated with lower risk of pneumonia confirmed by radiographs. [•] Herd protection took place at vaccine coverage as low as 20–40%, compared to coverage of 0–20%. [•] Our results support sustained use of Hib vaccine in population with limited resources in SE Asia. [Copyright &y& Elsevier]

Objective: The BED assay was developed to estimate the proportion of recent HIV infections in a population. We used the BED assay as a proxy for acute infection to quantify the associated risk of mother-to-child-transmission (MTCT) during pregnancy and delivery. Design A total of 3773 HIV-1 sero-positive women were tested within 96 h of delivery using the BED assay, and CD4 cell count measurements were taken. Mothers were classified according to their likelihood of having recently seroconverted.Methods: The risk of MTCT in utero and intra-partum was assessed comparing different groups defined by BED and CD4 cell count, adjusting for background factors using multinomial logistic models.Results: Compared with women with BED ≥ 0.8/CD4 ≥ 350 (typical of HIV-1 chronic patients) there was insufficient evidence to conclude that women presenting with BED < 0.8/CD4 ≥ 350 (typical of recent infections) were more likely to transmit in utero [adjusted odds ratio (aOR) = 1.37, 96% confidence interval (CI) 0.90-2.08, P = 0.14], whereas women with BED < 0.8/CD4 200-349 (possibly recently infected patients) had a 2.57 (95% CI 1.39-4.77, P-value < 0.01) odds of transmitting in utero. Women who had BED < 0.8/CD4 < 200 were most likely to transmit in utero (aOR 3.73, 95% CI 1.27-10.96, P = 0.02). BED and CD4 cell count were not predictive of intra-partum infections.Conclusions: These data provide evidence that in utero transmission of HIV might be higher among women who seroconvert during pregnancy. [ABSTRACT FROM AUTHOR]

Abstract: Group-randomized study designs are useful when individually-randomized designs either are not possible, or will not be able to estimate the parameters of interest. Group-randomized trials often have small number of experimental units or groups and strong geographically-induced between-unit correlation, thereby increasing the chance of obtaining a “bad” randomization outcome. It has been suggested to highly constrain the design through restriction to those allocations that meet specified criteria based on certain covariates available at the baseline. We describe a SAS® macro that allocates treatment conditions in a two-arm stratified group-randomized design that ensures balance on relevant covariates. The application of the macro is illustrated using two examples of group-randomized designs. [Copyright &y& Elsevier]

Objective The aim of this study was to assess the relationship between receipt of routine childhood immunizations and infant mortality before 6 months of age. Methods This was an observational study of 10 274 infants, in a randomized trial of vitamin A supplementation, who received the study dose and survived to at least 1 week of age. The primary outcome was mortality before 6 months of age, analysed in Cox regression models as a function of vaccine receipt and gender. Results Receipt of Bacille Calmette Guerin (BCG) or diphtheria, tetanus, polio (DTP) vaccine was associated with significant reductions of one-half to two-thirds of mortality hazards; among girls, those who received both BCG and DTP experienced higher mortality than those who received only one of the two vaccines (hazards ratio 2.4; 95% confidence interval 1.2–5.0). Conclusion The reduced mortality rate associated with receipt of BCG or DTP may be due to both biological and selection factors; the analyses regarding the combined effect of these vaccines and gender need to be replicated in other settings. [ABSTRACT FROM AUTHOR]

Like other wars, recent Western military interventions have entailed loss of civilians in the affected countries. As a result of the 'Revolution in Military Affairs', Martin Shaw makes two claims likely to recur in debates on such wars. The first is that those losses were much smaller than the loss of life as a result of previous misrule and oppression. The second is that during these interventions civilians suffered only accidental 'small massacres'. Using victim figures from 600 local communities exposed to hostilities during Operation Enduring Freedom in Afghanistan, the authors test Shaw's claims. They model community victim counts as a function of potential explanatory factors via zero-inflated Poisson regression. Several historic as well as concurrent factors are significant. Moreover, totals work out considerably higher than those offered by previous researchers. These findings are important to several aspects of the new way of war: as a reminder that harm comes not only from direct violence but from indirect effects of munitions; underreporting of civilian losses as a likely systemic feature; and distributions of victims as mediated by histories of war of which Western interventions may be final culminations. [ABSTRACT FROM AUTHOR]

The National Immunization Program of the Centers for Disease Control and Prevention is responsible for controlling infectious diseases through vaccination, but the program also plays a key role in postlicensure vaccine safety assessment. The time has come to separate postlicensure vaccine safety assessment from vaccine risk management as recommended by the National Research Council of the National Academy of Sciences. [ABSTRACT FROM AUTHOR]

Objectives. We studied school personnel involved in the review of student's immunization status to determine whether personnel training, immunization-related knowledge, attitudes, and beliefs, use of alterna-tive medicine, and sources of vaccine information were associated with the vaccination status of school children. Methods. Surveys were mailed to a stratified and ran-dom sample of 1000 schools in Colorado, Massachusetts, Missouri, and Washington. School personnel reported their training and perceptions of disease susceptibility/ severity, vaccine efficacy/safety, key immunization be-liefs, use of alternative medicine, confidence in organi-zations, sources, and credibility of vaccine information, and the rates of vaccine exemptors in their schools. Lo-gistic regression analysis was used to explore associa-tions between personnel factors and beliefs (indepen-dent variables) with the likelihood of a child having an exemption (dependent variable). Regression models were adjusted for clustering of children in schools, type of school (public versus private), and state. Results. Surveys were returned by 69.6% of eligible participants. A child attending a school with a respon-dent who was a nurse was significantly less likely to be have an exemption than a child attending a school with a respondent who was not a nurse (odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.28--0.56). The majority of... [ABSTRACT FROM AUTHOR]

Background Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years. Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world. We aimed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine (PnCRM7) against such disease. Methods In a group-randomised study, we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations; meningococcal type conjugate vaccine (MnCC) served as the control vaccine. Vaccine schedules were determined by age at enrolment. We recorded episodes of invasive pneumococcal disease and serotyped isolates. Analyses were by intention to treat and per protocol. Findings 8292 children enrolled in the trial. In the per protocol analysis of the primary efficacy group (children enrolled by 7 months of age) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group. After group randomisation had been controlled for, the per protocol primary efficacy of PnCRM7 was 76.8% and the intention-to-treat total primary efficacy was 82.6%. Interpretation PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population. Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule. [ABSTRACT FROM AUTHOR]

Clinical investigators are increasing their use of quantitative determinations of HIV viral load in their study populations. The distributions of these measures may be highly skewed, left-censored, and with an extra spike below the detection limit of the assay. We recommended use of a mixture model in this situation, with two sets of explanatory covariates. We extend this model to incorporate multiple measures across time, and to employ shared parameters as a way of increasing model efficiency and parsimony. Data from a cohort of HIV-infected men are used to illustrate these features, and simulations are performed to assess the utility of shared parameters. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions. Methods This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes. Findings We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P <.001) and TPT prescriptions (45% vs 30%, P =.13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51–68; P <.001) more participants with TBI results and 12% (95% confidence interval, −6 to 31; P =.18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively). Interpretation In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm. Clinical Trials Registration NCT02119130. [ABSTRACT FROM AUTHOR]

Presents information on a study which compared the antibody response in recipients of Engerix-B hepatitis B vaccine administered to children and adolescents at 12-month intervals to the response to vaccine administered at 0-, 1-, and 6-month intervals. Methodology; Results of the study; Discussion of the results.

Focuses on the separation between the markers of Human Immunodeficiency Virus (HIV) disease, progression and clinical state among subjects coinfection with human T-cell lymphotropic virus type 1 (HTLV-1) and HIV. Information on the HTLV-1 coinfection; Indepth look at the methods employed; How coinfection was defined; Results of the study.

We read with interest the article by Foy and colleagues[1] on ivermectin for malaria control and are pleased such research is being conducted. We recommend that in all reports of cluster-randomised trials, the range of cluster-level outcomes be presented by arm. Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial. [Extracted from the article]

Objective: How clinics structure the delivery of antiretroviral therapy (ART) services may influence patient adherence. We assessed the relationship between models of HIV care delivery and adherence as measured by medication possession ratio (MPR) among treatment‐experienced adults in Tanzania, Uganda and Zambia. Methods: Eighteen clinics were grouped into three models of HIV care. Model 1‐Traditional and Model 2‐Mixed represented task‐sharing of clinical services between physicians and clinical officers, distinguished by whether nurses played a role in clinical care; in Model 3‐Task‐Shifted, clinical officers and nurses shared clinical responsibilities without physicians. We assessed MPR among 3,419 patients and calculated clinic‐level MPR summaries. We then calculated the mean differences of percentages and adjusted residual ratio (aRR) of the association between models of care and incomplete adherence, defined as a MPR <90%, adjusting for individual‐level characteristics. Results: In the adjusted analysis, patients in Model 1‐Traditional were more likely than patients in Model 2‐Mixed to have MPR <90% (aRR = 1.60, 95% CI 1–2.48). Patients in Model 1‐Traditional were no more likely than patients in Model 3‐Task‐Shifted to have a MPR <90% (aRR = 1.58, 95% 0.88–2.85). There was no evidence of differences in MPR <90% between Model 2‐Mixed and Model 3‐Task‐Shifted (aRR = 0.99, 95% CI 0.59–1.66). Conclusion: Non‐physician‐led ART programmes were associated with adherence levels as good as or better than physician‐led ART programmes. Additional research is needed to optimise models of care to support patients on lifelong treatment. [ABSTRACT FROM AUTHOR]

Non-clinical psychotic experiences (PEs) occur at over twice the rate of psychotic disorders along a continuum in the general population and increase risk for progression to diagnoseable disorders. Social isolation is a risk factor for psychotic disorders, although it is unclear if childhood social isolation increases risk for experience of non-clinical PEs later in life. Data come from the Gaz et Electricité (GAZEL) Youth Study (1991–1999) and the Trajectoires Épidémiologiques en Population (TEMPO) Study (2009–2011), a community-based prospective cohort study. Of 1,227 participants whose parents completed questionnaires (1999, participants aged 7–10 years) and who were followed-up (2011, participants aged 25–37 years), 333 had childhood social isolation and young adult PE data. Lifetime prevalence of PEs was 21%. Childhood social isolation was not associated with 0–1 PE in young adulthood (p = 0.74). However, childhood social isolation predicted the experience of ≥ 2 PEs in young adulthood, controlling for gender, age, and general health status (OR = 11.5, 95% CI = 2.5, 52.0, p = 0.002). Childhood social isolation predicts the risk of experiencing two or more lifetime PEs, which may increase the risk for subsequent progression to a diagnoseable psychotic disorder. [ABSTRACT FROM AUTHOR]

Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker's association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects' length-for-age Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the best-fitting subset. These were then included with covariates in linear regression models to obtain estimates of each biomarker's adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score–a coefficient value of 0.50 (0.24, 0.75) for each log2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies. Author summary: Childhood undernutrition is widespread throughout the world and has severe, long-lasting health impacts. Substances measured in blood, urine and stool could be used as biomarkers to identify children undergoing growth failure before these impacts occur. However, it is not yet known which of the many markers that can be identified are accurate and clinically useful predictors of poor growth in infants and children. This study used a large number of candidate biomarkers of immune activation, metabolism and hormones and applied statistical methods to narrow them down from 110 different substances, to the 36 best predictors of growth in 258 Peruvian infants. It also estimated how large the effect of each of these markers was on height two months later. The biomarker with the largest effect was transferrin, a glycoprotein that can be measured in blood samples. 15-month old children with elevated transferrin were around two thirds of a centimeter taller on average at 17 months than those with low levels. Transferrin and other proteins, glycoproteins, hormones and antibodies that this study identified, can be measured easily and affordably in standard laboratories making them feasible to be used broadly as prognostic markers as part of child health and nutrition programs in under-resourced settings. [ABSTRACT FROM AUTHOR]

Letters to the editor referring to a recent Journal article are encouraged up to 3 months after the article's appearance. By submitting a letter to the editor, the author gives permission for its publication in the Journal. Letters should not duplicate material being published or submitted elsewhere. The editors reserve the right to edit and abridge letters and to publish responses. Text is limited to 400 words and 10 references. Submit online at www.editorialmanager.com/ajph for immediate Web posting, or at ajph.edmgr.com for later print publication. Online responses are automatically considered for print publication. Queries should be addressed to the Editor-in-Chief, Mary E. Northridge, PhD, MPH, at men6@nyu.edu. [ABSTRACT FROM AUTHOR]

In this article, we introduce a new command, clan, that conducts a cluster-level analysis of cluster randomized trials. The command simplifies adjusting for individual- and cluster-level covariates and can also account for a stratified design. It can be used to analyze a continuous, binary, or rate outcome. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing. Methods and findings: Sixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB. Conclusions: Our trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence. Trial registration: South African National Clinical Trials Registry DOH-27-092021-4901. In a cluster randomised trial of primary care clinics in South Africa, Neil Martinson and colleagues, investigate the value of targeted testing for Tuberculosis in those at highest risk. Author summary: Why was this study done?: Tuberculosis (TB) diagnosis is made by laboratory sputum testing usually prompted by the presence of at least 1 symptom of TB (cough, fever or night sweats, loss of weight). The World Health Organization promotes screening of entire groups of people at high risk of TB irrespective of symptoms. In South Africa, high-risk groups include people living with HIV, those who report being a close contact of someone with TB, and those who have had a recent episode of TB. There is little data on the usefulness of diagnostic assays as screening tests. Our trial assessed if targeted sputum testing of people at high risk without TB symptoms helped to identify undiagnosed TB. What did the researchers do and find?: A total of 62 large primary care clinics in South Africa were randomized to either our intervention—TB testing of sputum of all people in high-risk groups, or our control—to continue symptom directed testing for TB (the standard of care). The total number of TB cases diagnosed each month in all clinics was recorded. Comparisons were made between intervention and control clinics. In trial intervention clinics, 6,777 people were diagnosed with TB, an average of 20.7 patients per clinic month versus 6,750 in control clinics, an average of 18.8 patients with TB per clinic month. After adjusting for clustering, province, and the strata of average number of TB patients diagnosed per month in the last quarter of 2017, intervention clinics diagnosed 14% more patients with TB than control clinics, but this did not reach statistical significance. Secondary analyses, including data from the year prior to the intervention, demonstrated a statistically significant increase in TB diagnoses per month, reported as a 17% relative increase. What do these findings mean?: A strategy targeting high-risk groups for universal testing for TB (TUTT) may help to improve diagnostic rates of TB in areas where prevalence is high. Universal testing strategies could be be implemented in low-resource settings provided costs of testing were addressed, and other locally relevant high-risk groups for TB could be targeted. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the behavioral determinants associated with exclusive use of arsenic-safe water in the community-led Strong Heart Water Study (SHWS) arsenic mitigation program. Methods: The SHWS is a randomized controlled trial of a community-led arsenic mitigation program designed to reduce arsenic exposure among private well users in American Indian Great Plains communities. All households received point-of-use (POU) arsenic filters installed at baseline and were followed for 2 years. Behavioral determinants selected were those targeted during the development of the SHWS program, and were assessed at baseline and follow-up. Results: Among participants, exclusive use of arsenic-safe water for drinking and cooking at follow-up was associated with higher self-efficacy for accessing local resources to learn about arsenic (OR: 5.19, 95% CI: 1.48–18.21) and higher self-efficacy to resolve challenges related to arsenic in water using local resources (OR: 3.11, 95% CI: 1.11–8.71). Higher commitment to use the POU arsenic filter faucet at baseline was also a significant predictor of exclusive arsenic-safe water use for drinking (OR: 32.57, 95% CI: 1.42–746.70) and cooking (OR: 15.90, 95% CI: 1.33–189.52) at follow-up. From baseline to follow-up, the SHWS program significantly increased perceived vulnerability to arsenic exposure, self-efficacy, descriptive norms, and injunctive norms. Changing one's arsenic filter cartridge after installation was associated with higher self-efficacy to obtain arsenic-safe water for drinking (OR: 6.22, 95% CI: 1.33–29.07) and cooking (OR: 10.65, 95% CI: 2.48–45.68) and higher perceived vulnerability of personal health effects (OR: 7.79, 95% CI: 1.17–51.98) from drinking arsenic-unsafe water. Conclusions: The community-led SHWS program conducted a theory-driven approach for intervention development and evaluation that allowed for behavioral determinants to be identified that were associated with the use of arsenic safe water and changing one's arsenic filter cartridge. These results demonstrate that theory-driven, context-specific formative research can influence behavior change interventions to reduce water arsenic exposure. The SHWS can serve as a model for the design of theory-driven intervention approaches that engage communities to reduce arsenic exposure. Trial registration: The SHWS is registered with ClinicalTrials.gov (Identifier: NCT03725592). [ABSTRACT FROM AUTHOR]

Despite international mobilization for greater humanitarian mine action and despite considerable clearance achievements, the majority of mine-affected communities have not yet been involved in formal clearance activities. They adapt to the contamination largely by local means. The differing degree to which local adaptation is successful is now better understood as a result of the Global Landmine Survey, a multi-country survey project launched in the wake of the 1997 Ottawa treaty to ban anti-personnel mines. Socio-economic impact surveys have since been completed in several countries. In addition to landmines, the Global Landmine Survey records impacts also from unexploded ordnance (UXO). The ability to avoid mine incidents is used to measure adaptation success. We use a variant of Poisson regression models in order to identify community and contamination correlates of the number of recent landmine victims. We estimate separate models using data from the Yemen, Chad and Thailand surveys. We interpret them in a common framework that includes variables from three domains: Pressure on resources, intensity of past conflict and communities’ institutional endowments. Statistically significant associations occur in all three domains and in all the three countries studied. Physical correlates are the most strongly associated, pointing to a lasting deadly legacy of violent conflict, but also significant learning effects over time are present. Despite different measurements of institutional endowments, in each country one factor signifying greater local development is correlated with reductions in victims, whereas factors commonly associated with the presence of government officials do not contribute to local capacity to diminish the landmine problem. Strong spatial effects are manifest in clusters of communities with recent victims. Two policy consequences emerge. Firstly, given humanitarian funding limits, trade-offs between clearing contaminated land and... [ABSTRACT FROM AUTHOR]

Background: Despite achieving relatively high rates of antenatal care, institutional delivery, and HIV antiretroviral therapy for women during pregnancy, neonatal mortality has remained stubbornly high in Zimbabwe. Clearer understanding of causal pathways is required to inform effective interventions. Methods: This study was a secondary analysis of data from the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial, a cluster-randomized community-based trial among pregnant women and their infants, to examine care during institutional and non-institutional deliveries in rural Zimbabwe and associated birth outcomes. Results: Among 4423 pregnant women, 529 (11.9%) delivered outside a health institution; hygiene practices were poorer and interventions to minimise neonatal hypothermia less commonly utilised for these deliveries compared to institutional deliveries. Among 3441 infants born in institutions, 592 (17.2%) were preterm (< 37 weeks gestation), while 175/462 (37.9%) infants born outside health institutions were preterm (RR: 2.20 (1.92, 2.53). Similarly, rates of stillbirth [1.2% compared to 3.0% (RR:2.38, 1.36, 4.15)] and neonatal mortality [2.4% compared to 4.8% (RR: 2.01 1.31, 3.10)] were higher among infants born outside institutions. Among mothers delivering at home who reported their reason for having a home delivery, 221/293 (75%) reported that precipitous labor was the primary reason for not having an institutional delivery while 32 (11%), 34 (12%), and 9 (3%), respectively, reported distance to the clinic, financial constraints, and religious/personal preference. Conclusions: Preterm birth is common among all infants in rural Zimbabwe, and extremely high among infants born outside health institutions. Our findings indicate that premature onset of labor, rather than maternal choice, may be the reason for many non-institutional deliveries in low-resource settings, initiating a cascade of events resulting in a two-fold higher risk of stillbirth and neonatal mortality amongst children born outside health institutions. Interventions for primary prevention of preterm delivery will be crucial in reducing neonatal mortality in Zimbabwe. Trial registration: The trial is registered with ClinicalTrials.gov, number NCT01824940. [ABSTRACT FROM AUTHOR]

Background: Despite achieving relatively high rates of antenatal care, institutional delivery, and HIV antiretroviral therapy for women during pregnancy, neonatal mortality has remained stubbornly high in Zimbabwe. Clearer understanding of causal pathways is required to inform effective interventions. Methods: This study was a secondary analysis of data from the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial, a cluster-randomized community-based trial among pregnant women and their infants, to examine care during institutional and non-institutional deliveries in rural Zimbabwe and associated birth outcomes. Results: Among 4423 pregnant women, 529 (11.9%) delivered outside a health institution; hygiene practices were poorer and interventions to minimise neonatal hypothermia less commonly utilised for these deliveries compared to institutional deliveries. Among 3441 infants born in institutions, 592 (17.2%) were preterm (< 37 weeks gestation), while 175/462 (37.9%) infants born outside health institutions were preterm (RR: 2.20 (1.92, 2.53). Similarly, rates of stillbirth [1.2% compared to 3.0% (RR:2.38, 1.36, 4.15)] and neonatal mortality [2.4% compared to 4.8% (RR: 2.01 1.31, 3.10)] were higher among infants born outside institutions. Among mothers delivering at home who reported their reason for having a home delivery, 221/293 (75%) reported that precipitous labor was the primary reason for not having an institutional delivery while 32 (11%), 34 (12%), and 9 (3%), respectively, reported distance to the clinic, financial constraints, and religious/personal preference. Conclusions: Preterm birth is common among all infants in rural Zimbabwe, and extremely high among infants born outside health institutions. Our findings indicate that premature onset of labor, rather than maternal choice, may be the reason for many non-institutional deliveries in low-resource settings, initiating a cascade of events resulting in a two-fold higher risk of stillbirth and neonatal mortality amongst children born outside health institutions. Interventions for primary prevention of preterm delivery will be crucial in reducing neonatal mortality in Zimbabwe. Trial registration: The trial is registered with ClinicalTrials.gov, number NCT01824940. [ABSTRACT FROM AUTHOR]

The effect, initially observed with the BCG vaccine [[6]] and later with influenza vaccines, can last for several months and has been postulated to be responsible for nonspecific effects of vaccines [[7]]. A slow response to this issue increases the likelihood that this study will contribute to vaccine hesitancy and undermine confidence in vaccines, leading to outbreaks of vaccine-preventable diseases. [Extracted from the article]

Background: Bangladesh introduced the 10-valent pneumococcal conjugate vaccine (PCV10) for children aged < 1 year in March 2015. Previous vaccine effectiveness (VE) studies for pneumonia have used invasive pneumococcal disease or chest X-rays. None have used ultrasound. We sought to determine the VE of PCV10 against sonographically-confirmed pneumonia in three subdistrict health complexes in Bangladesh.Methods: We conducted a matched case-control study between July 2015 and September 2017 in three subdistricts of Sylhet, Bangladesh. Cases were vaccine-eligible children aged 3-35 months with sonographically-confirmed pneumonia, who were matched with two types of controls by age, sex, week of diagnosis, subdistrict health complex (clinic controls) or distance from subdistrict health complex (community controls) and had an illness unlikely due to Streptococcus pneumoniae (clinic controls) or were healthy (community controls). VE was measured using multivariable conditional logistic regression.Results: We evaluated 8926 children (average age 13.3 months, 58% boys) with clinical pneumonia by ultrasound; 2470 had pneumonia with consolidations ≥ 1 cm; 1893 pneumonia cases were matched with 4238 clinic controls; and 1832 were matched with 3636 community controls. VE increased with the threshold used for consolidation size on ultrasound: the adjusted VE of ≥ 2 doses vs. non-recipients of PCV10 against pneumonia increased from 15.8% (95% CI 1.6-28.0%) for consolidations ≥ 1 cm to 29.6% (12.8-43.2%) for consolidations ≥ 1.5 cm using clinic controls and from 2.7% (- 14.2-17.2%) to 23.5% (4.4-38.8%) using community controls, respectively.Conclusions: PCV10 was effective at reducing sonographically-confirmed pneumonia in children aged 3-35 months of age when compared to unvaccinated children. VE increased with the threshold used for consolidation size on ultrasound in clinic and community controls alike. This study provides evidence that lung ultrasound is a useful alternative to chest X-ray for case-control studies evaluating the effectiveness of vaccines against pneumonia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Household air pollution (HAP) from biomass fuel combustion remains a leading environmental risk factor for morbidity worldwide. OBJECTIVE: Measure the effect of liquefied petroleum gas (LPG) interventions on HAP exposures in Puno, Peru. METHODS: We conducted a 1-y randomized controlled trial followed by a 1-y pragmatic crossover trial in 180 women age 25-64 y. During the first year, intervention participants received a free LPG stove, continuous fuel delivery, and regular behavioral messaging, whereas controls continued their biomass cooking practices. During the second year, control participants received a free LPG stove, regular behavioral messaging, and vouchers to obtain LPG tanks from a nearby distributor, whereas fuel distribution stopped for intervention participants. We collected 48-h kitchen area concentrations and personal exposures to fine particulate matter (PM) with aerodynamic diameter ≤ 2.5 µm (PM 2.5), black carbon (BC), and carbon monoxide (CO) at baseline and 3-, 6-, 12-, 18-, and 24-months post randomization. RESULTS. Baseline mean ± standard deviation (SD) PM2.5 (kitchen area concentrations 1,220 ± 1,010 vs. 1,190 ± 880 µg/m³; personal exposure 126 ± 214 vs. 104 ± 100 µg/m³), CO (kitchen 53 ± 49 vs. 50 ± 41 ppm; personal 7 ± 8 vs. 7 ± 8 ppm), and BC (kitchen 180 ± 120 vs. 210 ± 150 µg/m³; personal 19 ± 16 vs. 21 ± 22 µg/m³) were similar between control and intervention participants. Intervention participants had consistently lower mean (± SD) concentrations at the 12-month visit for kitchen (41 ± 59 µg/m³, 3±6 µg/m³, and 8 ± 13 ppm) and personal exposures (26 ± 34 µg/m³, 2±3 µg/m³, and 3 ± 4 ppm) to PM2.5, BC, and CO when compared to controls during the first year. In the second year, we observed comparable HAP reductions among controls after the voucher-based intervention for LPG fuel was implemented (24-month visit PM2.5, BC, and CO kitchen mean concentrations of 34 ± 74 µg/m³,3±5 µg/m³, and 6 ± 6 ppm and personal exposures of 17 ± 15 µg/m³,2±2 µg/m³, and 3 ± 4 ppm, respectively), and average reductions were present among intervention participants even after free fuel distribution stopped (24-month visit PM2.5, BC, and CO kitchen mean concentrations of 561 ± 1,251 µg/m³, 82 ± 124 µg/m³, and 23 ± 28 ppm and personal exposures of 35 ± 38 µg/m³,6±6 µg/m³, and 4 ± 5 ppm, respectively). DISCUSSION: Both home delivery and voucher-based provision of free LPG over a 1-y period, in combination with provision of a free LPG stove and longitudinal behavioral messaging, reduced HAP to levels below 24-h World Health Organization air quality guidelines. Moreover, the effects of the intervention on HAP persisted for a year after fuel delivery stopped. Such strategies could be applied in LPG programs to reduce HAP and potentially improve health. [ABSTRACT FROM AUTHOR]

Background: Transfusion-transmitted infections (TTIs) are a global health challenge. One new approach to reduce TTIs is the use of pathogen reduction technology (PRT). In vitro, Mirasol PRT reduces the infectious load in whole blood (WB) by at least 99%. However, there are limited in vivo data on the safety and efficacy of Mirasol PRT. The objective of the Mirasol Evaluation of Reduction in Infections Trial (MERIT) is to investigate whether Mirasol PRT of WB can prevent seven targeted TTIs (malaria, bacteria, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, and human herpesvirus 8).Methods: MERIT is a randomized, double-blinded, controlled clinical trial. Recruitment started in November 2019 and is expected to end in 2024. Consenting participants who require transfusion as medically indicated at three hospitals in Kampala, Uganda, will be randomized to receive either Mirasol-treated WB (n = 1000) or standard WB (n = 1000). TTI testing will be performed on donor units and recipients (pre-transfusion and day 2, day 7, week 4, and week 10 after transfusion). The primary endpoint is the cumulative incidence of one or more targeted TTIs from the Mirasol-treated WB vs. standard WB in a previously negative recipient for the specific TTI that is also detected in the donor unit. Log-binomial regression models will be used to estimate the relative risk reduction of a TTI by 10 weeks associated with Mirasol PRT. The clinical effectiveness of Mirasol WB compared to standard WB products in recipients will also be evaluated.Discussion: Screening infrastructure for TTIs in low-resource settings has gaps, even for major TTIs. PRT presents a fast, potentially cost-effective, and easy-to-use technology to improve blood safety. MERIT is the largest clinical trial designed to evaluate the use of Mirasol PRT for WB. In addition, this trial will provide data on TTIs in Uganda.Trial Registration: Mirasol Evaluation of Reduction in Infections Trial (MERIT) NCT03737669 . Registered on 9 November 2018. [ABSTRACT FROM AUTHOR]

Summary: Background: Preventive therapy for tuberculosis in patients with HIV is effective, but it has not been widely implemented in moderate or high-burden settings. We assessed the effect of widespread use of isoniazid preventive therapy on rates of tuberculosis and death in people with HIV in Brazil. Methods: We did a stepped wedge, cluster-randomised trial with patients actively enrolled in 29 HIV clinics in Rio de Janeiro. Clinic staff were trained in tuberculosis screening, use of tuberculin skin tests, and use of isoniazid preventive therapy. Clinics were randomly allocated a date to begin the intervention period, with two clinics beginning the intervention every 2 months starting from Sept 1, 2005. The primary outcome was tuberculosis incidence alone or combined with death in the control versus intervention periods until Aug 31, 2009. This trial is registered at ClinicalTrials.gov, number NCT00107887. Results: Of 17 413 patients in the cohort, 12 816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19 per 100 person-years to 59 per 100 person-years, and from 36 per 100 person-years to 144 per 100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 cases of tuberculosis were diagnosed (1·31 per 100 person-years) compared with 254 (1·10 per 100 person-years) in the intervention period (unadjusted hazard ratio [HR] 0·87; 95% CI 0·69–1·10). Rates of tuberculosis incidence or death were 3·64 and 3·04 per 100 person-years, respectively (0·76; 95% CI 0·66–0·87). When adjusted for age, sex, entry CD4 count, and use of antiretroviral therapy, the HR for tuberculosis was 0·73 (95% CI 0·54–0·99) and for tuberculosis or death was 0·69 (0·57–0·83). Interpretation: Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests, and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in settings of moderate tuberculosis incidence is achievable and should be widely implemented in Brazil and elsewhere. Funding: Bill & Melinda Gates Foundation and the National Institutes of Health. [ABSTRACT FROM AUTHOR]

Background: The African Health Initiative includes highly diverse partnerships in five countries (Ghana, Mozambique, Rwanda, Tanzania, and Zambia), each of which is working to improve population health by strengthening health systems and to evaluate the results. One aim of the Initiative is to generate cross-site learning that can inform implementation in the five partnerships during the project period and identify lessons that may be generalizable to other countries in the region. Collaborators in the Initiative developed a common evaluation framework as a basis for this cross-site learning. Methods: This paper describes the components of the framework; this includes the conceptual model, core metrics to be measured in all sites, and standard guidelines for reporting on the implementation of partnership activities and contextual factors that may affect implementation, or the results it produces. We also describe the systems that have been put in place for data management, data quality assessments, and cross-site analysis of results. Results and conclusions: The conceptual model for the Initiative highlights points in the causal chain between health system strengthening activities and health impact where evidence produced by the partnerships can contribute to learning. This model represents an important advance over its predecessors by including contextual factors and implementation strength as potential determinants, and explicitly including equity as a component of both outcomes and impact. Specific measurement challenges include the prospective documentation of program implementation and contextual factors. Methodological issues addressed in the development of the framework include the aggregation of data collected using different methods and the challenge of evaluating a complex set of interventions being improved over time based on continuous monitoring and intermediate results. [ABSTRACT FROM AUTHOR]

Background: Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment. Methods: We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival. Results: The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine–isoniazid group, 2.9 per 100 person-years in the rifampin–isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance. Conclusions: On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00057122.) [ABSTRACT FROM PUBLISHER]

Human papillomavirus (HPV) infection is a common sexually transmitted disease of growing public health importance, and over 40 genotypes have been identified in genital infections. Current HPV cohort studies often follow participants at pre-determined visits, such as every 6 months, and data generated from such epidemiology studies can be described as clustered longitudinal binary data where correlation arises in two ways: the directionless clustering due to the multiple genotypes tested within an individual, and the temporal correlation among the repeated measurements on the same genotype along time. Current analyses for identification of risk factors associated with HPV incidence and persistence often either do not fully utilize information in the data set or ignore the correlation between the multiple genotypes. Given the scientific definition of incidence and persistence, conditional probability modeling provides us a natural mathematical tool. We thus present a semi-parametric regression model for such data where full specification of the joint multivariate binary distribution is avoided by using conditioning argument to handle the temporal correlation and GEE to account for the correlation between the multiple genotypes. The model is applied to the HPV data from the Rakai male circumcision (MC) trial to evaluate the as-treated efficacy of MC and also identify modifiable risk factors for incidence and persistence of oncogenic HPV types in men. A simulation study is performed to provide empirical information on the number of individuals that is needed for satisfactory power and estimation accuracy of the association parameter estimates in future studies. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In Ethiopia, evidence is lacking about maternal care-taking and environmental risk factors that contribute to acute diarrhoea and the case management of diarrhoea. The aim of this study was to identify the risk factors and to understand the management of acute diarrhoea. A pretested structured questionnaire was used for interviewing mothers of 440 children in a prospective, matched, case-control study at the University of Gondar Referral and Teaching Hospital in Gondar, Ethiopia. Results of multivariate analysis demonstrated that children who were breastfed and not completely weaned and mothers who were farmers were protective factors; risk factors for diarrhoea included sharing drinking-water and introducing supplemental foods. Children presented with acute diarrhoea for 3.9 days with 4.3 stools per day. Mothers usually did not increase breastmilk and other fluids during diarrhoea episodes and generally did not take children with diarrhoea to traditional healers. Incorporating messages about the prevention and treatment of acute diarrhoea into child-health interventions will help reduce morbidity and mortality associated with this disease. [ABSTRACT FROM AUTHOR]

Background. Before 7-valent pneumococcal conjugate vaccine (PCV7) introduction, invasive pneumococcal disease (IPD) rates among Navajo were several-fold those of the general US population. Only 50% of IPD cases in children involved PCV7 serotypes. Methods. We conducted active, population-based surveillance for IPD for the period 1995-2006. We documented case characteristics and serotyped the isolates. Results. Over 12-year period, we identified 1508 IPD cases, 447 of which occurred in children aged <5 years. Rates of IPD due to vaccine serotypes among children aged <1 year, 1 to <2 years, and 2 to <5 years decreased from 210, 263, and 51 cases per 100,000 population, respectively in 1995-1997 to 0 cases in 2004-2006 (P<.001). Among adults aged ⩾65 years, rates of IPD due to vaccine serotypes decreased 81% (95% confidence interval, -98% to -9%; P=.02). Rates of nonvaccine serotype IPD were unchanged in all age strata except for persons aged 18 to <40 years, among whom the rate decreased by 35% from 27 to 18 cases per 100,000 population (95% confidence interval, -57% to -1%; P=.03). Conclusions. Vaccine-serotype IPD has virtually been eliminated in the PCV7 era among Navajo of all ages. Overall rates of nonvaccine-serotype IPD have not increased, although increases have occurred for some individual types. Rates of all-serotype IPD among Navajo children remain 3-5-fold greater than in the general US population. [ABSTRACT FROM AUTHOR]

Background: In epidemiological studies, subjects are often followed for a period during which study outcomes are measured at selected time points, such as by diagnostic testing performed on biological samples collected at each visit. Although test results may indicate the presence or absence of a disease or condition, they cannot provide information on when exactly it occurred. Such study designs generate arbitrarily censored time-to-event data, which can include left, interval and right censoring. Adding to this complexity, the data may be clustered such that observations within the same cluster are not independent, such as time to recovery of an infectious disease of family or community members. This data structure is observed when evaluating circumcision's effect on clearance of penile high risk human papillomavirus (HR-HPV) infections using data collected from the male circumcision(MC) trial conducted in Rakai, Uganda, where the multiple infections within individual and HPV testings performed at trial followup visits gave rise to the clustered data with arbitrary censoring. Methods: We describe the use of parametric proportional hazards frailty models and accelerated failure time frailty models to examine the relationship between explanatory variables and the survival outcomes that are subject to arbitrary censoring, while accounting for the correlation within clusters. Standard software such as SAS can be used for parameter estimation. Results: Circumcision's effect on HPV infection was a secondary end point in the Rakai MC trial, and HPV genotyping was conducted for penile samples of a subset of trial participants collected at enrollment, 6, 12 and 24-month follow up visits. At enrollment, 36.7% intervention arm men (immediate circumcision) and 36.6% control arm men (delayed circumcision at 2 years) were infected with HR-HPV, with the number of infections per man being 1-5. The proposed models were used to examine whether MC facilitated clearance of the prevalent infections. Results show that clearance of multiple infections within each man is highly correlated, and clearance was 60% faster if a man was circumcised. Conclusions: Parametric frailty models provide viable ways to study the relationship between exposure variables and clustered survival outcome that is subject to arbitrary censoring, as is often observed in HPV epidemiology studies. [ABSTRACT FROM AUTHOR]

Abstract: Despite decades of investigation in countries on three continents, an efficacious vaccine against Leishmania infections has not been developed. Although some indication of protection was observed in some of the controlled trials conducted with “first-generation” whole, inactivated Leishmania parasite vaccines, convincing evidence of protection was lacking. After reviewing all previously published or unpublished randomized, controlled field efficacy clinical trials of prophylactic candidate vaccines, a meta-analysis of qualified trials was conducted to evaluate whether there was some evidence of protection revealed by considering the results of all trials together. The findings indicate that the whole-parasite vaccine candidates tested do not confer significant protection against human leishmaniasis. [Copyright &y& Elsevier]

Background. Pneumococcal conjugate vaccines are important for the prevention of serious illness and death among infants. Factors associated with pneumococcal conjugate vaccine immunogenicity have not been explored. Methods. Children <24 months of age received 2, 3, or 4 doses of 7-valent pneumococcal conjugate vaccine (PnCRM7) or control vaccine depending on age at enrollment. Serum samples were tested for serotype-specific antibodies by enzyme-linked immunosorbant assay. Multiple linear regression was used to determine predictors of immunogenicity.Results. Among 315 PnCRM7-vaccinated subjects and 295 control subjects enrolled at <7 months of age, geometric mean concentrations (GMCs) of antibodies were significantly higher after dose 3 than after dose 2 for all serotypes except type 4. The proportion of subjects with antibody concentrations ⩾5.0 mg/mL was higher for all serotypes, but the proportion with concentrations ⩾0.35 mg/mL was higher only for types 6B and 23F. Threedose and 2-dose regimens for those 7–11 and 12–23 months of age, respectively, were highly immunogenic. Increased maternal antibody concentrations were associated with reduced responses to dose 1 and 3 but not to dose 4 of PnCRM7. Conclusions. Maternal antibody is associated with a reduced infant response to PnCRM7 but does not interfere with immune memory. In infants, a third priming dose increases the antibody GMC and the proportion achieving an antibody concentration ⩾5.0 mg/mL but has little impact on the proportion achieving a concentration ⩾0.35 mg/mL. [ABSTRACT FROM AUTHOR]

Objectives. Our goal was to determine whether school-level variability in implementation of immunization requirements is associated with the likelihood of a child having received an exemption to school immunization requirements. Methods. We surveyed 1000 school immunization personnel in Colorado, Massachusetts, Missouri, and Washington. We explored associations between school implementation of immunization requirements and the likelihood of a child having an exemption using logistic regression models. Results. School policies associated with an increased likelihood of children having exemptions included lack of provision of written instructions for completing the school immunization requirement before enrollment, administrative procedures making it easier to claim an exemption, and granting of philosophical exemptions. In the 2 states we surveyed where philosophical exemptions are not authorized (Massachusetts and Missouri), 17.0% and 18.1% of schools reported permitting philosophical exemptions. Conclusions. Inconsistencies in the interpretation and implementation of school immunization laws contribute to variability in rates of exemptions. School policies should be reviewed to ensure consistency with the intent of state laws. (Am J Public Health. 2005;95:436-440. doi:10.2105/AJPH.2004.046201). [ABSTRACT FROM AUTHOR]

Bangladesh introduced the ten-valent pneumococcal conjugate vaccine (PCV10) into its national immunization program in March 2015 creating an opportunity to assess the real-world impact of PCV on invasive pneumococcal disease (IPD). Between January 2014 and June 2018, children aged 3–35 months in three rural sub-districts of Sylhet district of Bangladesh were visited every two months to collect morbidity and care-seeking data. Children attending sub-district hospitals with pneumonia, meningitis, or sepsis were assessed for IPD after obtaining informed consent. Blood and cerebrospinal fluid were collected from enrolled children to isolate pneumococcus using culture and molecular test. Children who were age-eligible to receive the PCV and had pneumococcus isolated were enrolled as cases. Four age and sex-matched clinic and community controls were selected for each case within one to two weeks of case identification. Data on immunization status and confounders were collected. PCV coverage was estimated using vaccine coverage surveys. Case-control and incidence trend analyses were conducted to assess the impact of PCV on IPD. The community cohort yielded 217,605 child years of observations and 154,773 sick child-visits to study hospitals. Pneumococcus was isolated from 44 children who were age-eligible to receive PCV; these children were enrolled as cases. The cases were matched with 166 community- and 150 clinic-controls. The matched case-control analyses using community-controls showed 83% effectiveness (95% CI: 1.57–97.1%) and clinic controls showed 90% effectiveness (95% CI: −26.0% to 99.1%) of PCV in preventing IPD. Incidence trend analysis estimated vaccine effectiveness at 80.1% (95% CI: 38.4, 93.6). PCV in this pediatric population in Bangladesh was highly effective in preventing IPD. [ABSTRACT FROM AUTHOR]

Oral rotavirus vaccine (RVV) immunogenicity is considerably lower in low- versus high-income populations; however, the mechanisms underlying this remain unclear. Previous evidence suggests that the gut microbiota may contribute to differences in oral vaccine efficacy. We performed whole metagenome shotgun sequencing on stool samples and measured anti-rotavirus immunoglobulin A in plasma samples from a subset of infants enrolled in a cluster randomized 2 × 2 factorial trial of improved water, sanitation and hygiene and infant feeding in rural Zimbabwe (SHINE trial: NCT01824940). We examined taxonomic microbiome composition and functional metagenome features using random forest models, differential abundance testing and regression analyses to explored associations with RVV immunogenicity. Among 158 infants with stool samples and anti-rotavirus IgA titres, 34 were RVV seroconverters. The median age at stool collection was 43 days (IQR: 35–68), corresponding to a median of 4 days before the first RVV dose. The infant microbiome was dominated by Bifidobacterium longum. The gut microbiome differed significantly between early (≤42 days) and later samples (>42 days) however, we observed no meaningful differences in alpha diversity, beta diversity, species composition or functional metagenomic features by RVV seroconversion status. Bacteroides thetaiotaomicron was the only species associated with anti-rotavirus IgA titre. Random forest models poorly classified seroconversion status by both composition and functional microbiome variables. RVV immunogenicity is low in this rural Zimbabwean setting, however it was not associated with the composition or function of the early-life gut microbiome in this study. Further research is warranted to examine the mechanisms of poor oral RVV efficacy in low-income countries. [ABSTRACT FROM AUTHOR]

Although several studies indicate that drinking is responsive to price, little work has focused on whether prices have a differential effect on light, moderate, or heavy drinking. This study examines the price responsiveness of the demand for alcohol: whether heavy drinkers are less sensitive to price than light or moderate drinkers. The study uses data on alcohol consumption on the 1983 National Health Interview Survey. The results indicate that both light and heavy drinkers are much less price elastic than moderate drinkers. Further, we cannot reject the hypothesis that the very heaviest drinkers have perfectly price inelastic demands. [ABSTRACT FROM AUTHOR]

Background: Schistosoma haematobium is a parasitic helminth that causes urogenital pathology. The impact of urogenital schistosomiasis during pregnancy on birth outcomes and child growth is poorly understood.Methods: Risk factors for urogenital schistosomiasis were characterized among 4437 pregnant women enrolled in a cluster-randomized community-based trial in rural Zimbabwe. Infection was defined via urine microscopy (≥1 S. haematobium egg) and urinalysis (hematuria). Associations between infection and pregnancy outcomes were assessed in case-control analyses using conditional logistic regression. The association of maternal infection with birthweight and length-for-age Z scores (LAZ) at 1 and 18 months of age were assessed using generalized estimating equations.Results: Urogenital schistosomiasis (egg positive and/or hematuria positive) was detected in 26.8% of pregnant women. Risk factors significantly associated with infection were maternal age, education, marital status, and religion; household drinking water source and latrine; study region; and season. Urogenital schistosomiasis was not significantly associated with adverse pregnancy outcomes (miscarriage, stillbirth, preterm, and small-for-gestational age), birthweight, neonatal death, or LAZ.Conclusions: Including pregnant women in antihelminthic treatment programs would benefit a large number of women in rural Zimbabwe. However, clearance of the low-intensity infections that predominate in this context is unlikely to have additive benefits for pregnancy outcomes or child growth.Clinical Trials Registration: NCT01824940. [ABSTRACT FROM AUTHOR]

Between birth and 2 years, children's well‐being depends on the quality of care they receive from caregivers, primarily their mothers. We developed a quantitative survey instrument to assess seven psychosocial characteristics of women that determine their caregiving ability ('maternal capabilities': physical health, mental health, decision‐making autonomy, social support, mothering self‐efficacy, workload and time stress, and gender norm attitudes). We measured maternal capabilities in 4,025 mothers and growth in their 4,073 children participating in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. We used generalized estimating equation models with exchangeable correlation structure to test the association between each maternal capability during pregnancy, and infant length‐for‐age Z (LAZ) at 18 months, accounting only for within‐cluster correlation and intervention arms in unadjusted analyses and for potential confounders in adjusted analyses to examine the association between each capability, assessed during pregnancy, with child LAZ at 18 months of age. In adjusted models, each unit increase in gender norm attitudes score (reflecting more equitable gender norm attitudes) was associated with +0.09 LAZ (95% CI: 0.02, 0.16) and a decreased odds of stunting (adjusted odds ratio [AOR]: 0.86; 95% CI: 0.74, 1.01); each unit increase in social support score was associated with +0.11 LAZ (95% CI: 0.05, 0.17, p < 0.010) and decreased odds of stunting (AOR: 0.83; 95% CI: 0.73, 0.96). Each unit increase in decision‐making autonomy was associated with a 6% reduced odds of stunting (AOR: 0.94; 95% CI: 0.89, 0.996, p = 0.04). Interventions and social programming that strengthen these maternal capabilities may improve child nutritional status. [ABSTRACT FROM AUTHOR]

Background Clinical outcomes of children who are human immunodeficiency virus (HIV)–exposed in sub-Saharan Africa remain uncertain. Methods The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial evaluated improved infant and young child feeding (IYCF) and/or improved water, sanitation, and hygiene in 2 rural Zimbabwean districts with 15% antenatal HIV prevalence and > 80% prevention of mother-to-child transmission (PMTCT) coverage. Children born between February 2013 and December 2015 had longitudinal HIV testing and anthropometry. We compared mortality and growth between children who were HIV-exposed and HIV-unexposed through 18 months. Children receiving IYCF were excluded from growth analyses. Results Fifty-one of 738 (7%) children who were HIV-exposed and 198 of 3989 (5%) children who were HIV-unexposed (CHU) died (hazard ratio, 1.41 [95% confidence interval {CI}, 1.02–1.93]). Twenty-five (3%) children who were HIV-exposed tested HIV positive, 596 (81%) were HIV-exposed uninfected (CHEU), and 117 (16%) had unknown HIV status by 18 months; overall transmission estimates were 4.3%–7.7%. Mean length-for-age z score at 18 months was 0.38 (95% CI,.24–.51) standard deviations lower among CHEU compared to CHU. Among 367 children exposed to HIV in non-IYCF arms, 147 (40%) were alive, HIV-free, and nonstunted at 18 months, compared to 1169 of 1956 (60%) CHU (absolute difference, 20% [95% CI, 15%–26%]). Conclusions In rural Zimbabwe, mortality remains 40% higher among children exposed to HIV, vertical transmission exceeds elimination targets, and half of CHEU are stunted. We propose the composite outcome of "alive, HIV free, and thriving" as the long-term goal of PMTCT programs. Clinical Trials Registration NCT01824940. [ABSTRACT FROM AUTHOR]

Background Norovirus is a leading cause of acute gastroenteritis worldwide, yet there is limited information on homotypic or heterotypic protection following natural infection to guide vaccine development. Methods A total of 6020 stools collected from 299 Peruvian children between 2010 and 2014 were tested by norovirus real-time reverse-transcription polymerase chain reaction followed by sequence-based genotyping. Cox proportional hazards models were used to derive adjusted hazard ratios (HRs) of infection among children with vs without prior exposure. Results Norovirus was detected in 1288 (21.3%) samples. GII.4 (26%), GII.6 (19%), and GI.3 (9%) viruses accounted for 54% of infections. Homotypic protection for GI.3 (HR, 0.35; P  = .015), GI.7 (HR, 0.19; P  = .022), GII.4 (HR, 0.39; P  < .001), and GII.6 (HR, 0.52; P  = .006) infections was observed. Hazard analysis showed that children with prior GII.4 infection exhibited heterotypic protection with a 48% reduction of subsequent GI.3 infection (HR, 0.52; P  = .005). Prior exposure to GI.3, GII.2, and GII.17 infections enhanced susceptibility to subsequent infections with several other norovirus genotypes. Conclusions Children up to 2 years of age infected with GII.4 noroviruses demonstrated both homotypic and heterotypic protection to reinfection with other genotypes. These data support the need for ongoing vaccine development efforts with GII.4 as the main component and caution the inclusion of genotypes that may enhance susceptibility to infections. [ABSTRACT FROM AUTHOR]

Pneumococcal conjugate vaccine (PCV) effectiveness against radiographic pneumonia in South Asia is unknown. Bangladesh introduced PCV10 in 2015 using a three dose primary series (3 + 0). We sought to measure PCV10 effectiveness for two or more vaccine doses on radiographic pneumonia among vaccine-eligible children in rural Bangladesh. We conducted a matched case-control study over two years from 2015 to 2017 using clinic and community controls in three subdistricts of Sylhet, Bangladesh. Cases were vaccine eligible 3–35 month olds at Upazila Health Complex outpatient clinics with World Health Organization-defined radiographic primary endpoint pneumonia (radiographic pneumonia). Clinic controls were matched to cases within a one week time window by age, sex, and clinic and had an illness unlikely to be Streptococcus pneumoniae; community controls were healthy and similarly matched within a one week time window by age and sex, and distance from the clinic. We estimated adjusted vaccine effectiveness (aVE) using conditional logistic regression. We matched 1262 cases with 2707 clinic and 2461 community controls. Overall, aVE using clinic controls was 21.4% (95% confidence interval, −0.2%, 38.4%) for ≥2 PCV10 doses and among 3–11 month olds was 47.3% (10.5%, 69.0%) for three doses. aVE increased with higher numbers of doses in clinic control sets (p = 0.007). In contrast, aVE using community controls was 7.6% (95% confidence interval, −22.2%, 30.0%) for ≥2 doses. We found vaccine introduction in the study area faster and less variable than expected with 75% coverage on average, which reduced power. Information bias may also have affected community controls. Clinic control analyses show PCV10 prevented radiographic pneumonia in Bangladesh, especially among younger children receiving three doses. While both analyses were underpowered, community control enrollment – compared to clinic controls – was more difficult in a complex, pluralistic healthcare system. Future studies in comparable settings may consider alternative study designs. [ABSTRACT FROM AUTHOR]

Background: The prediction of future obesity patterns is crucial for effective strategic planning. However, disproportionally changing body mass index (BMI) distributions pose particular challenges. Flexible modelling of the shape of BMI distributions may improve prediction performance.Methods: We used data from repeated national health surveys conducted in Mexico, Colombia and Peru at four or five time points between 1988 and 2014. Data from all surveys except the last survey were used to construct prediction models for three obesity indicators (median BMI, overweight/obesity prevalence and obesity prevalence) for the time of the last survey. We assessed their performance using predicted curves, absolute prediction errors and comparison of actual and predicted distributions. With one method, we modelled the shape of BMI distributions assuming BMI follows a Box-Cox Power Exponential (BCPE) distribution, whose parameters were modelled as a function of interval or nominal 5-year age groups, time and their interaction terms. In a second method, we modelled each of the obesity indicators directly as a function of the same covariates using quantile and logistic regression.Results: The BCPE model with interval age groups yielded the best prediction performance in predicting obesity prevalence. Average absolute prediction errors across all age groups were 4.3 percentage points (95% percentile interval: 1.9, 7.5), 2.5 (1.2, 6.1) and 1.7 (1.0, 9.3), with data from Mexico, Colombia and Peru, respectively. This superiority was weak or none for overweight/obesity prevalence and median BMI.Conclusion: The BCPE model performed better for prediction of the extremes of BMI distribution, possibly by incorporating its shape more precisely. [ABSTRACT FROM AUTHOR]