Estimating the impact of alternative programmatic cotrimoxazole strategies on mortality among children born to mothers with HIV: A modelling study

BACKGROUND: World Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed. METHODS AND FINDINGS: Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d'Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis. CONCLUSIONS: Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings

Formative research on hygiene behaviors and geophagy among infants and young children and implications of exposure to fecal bacteria.

We conducted direct observation of 23 caregiver-infant pairs for 130 hours and recorded wash-related behaviors to identify pathways of fecal-oral transmission of bacteria among infants. In addition to testing fingers, food, and drinking water of infants, three infants actively ingested 11.3 ± 9.2 (mean ± SD) handfuls of soil and two ingested chicken feces 2 ± 1.4 times in 6 hours. Hand washing with soap was not common and drinking water was contaminated with Escherichia coli in half (12 of 22) of the households. A one-year-old infant ingesting 1 gram of chicken feces in a day and 20 grams of soil from a laundry area of the kitchen yard would consume 4,700,000-23,000,000 and 440-4,240 E. coli, respectively, from these sources. Besides standard wash and nutrition interventions, infants in low-income communities should be protected from exploratory ingestion of chicken feces, soil, and geophagia for optimal child health and growth

Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy

BackgroundThe impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear.MethodsIn the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications.ResultsIn simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction.DiscussionThis study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures

Inflammation: the driver of poor outcomes among children with severe acute malnutrition?

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes

Associations between maternal obesity and infectious morbidity in Zimbabwean infants

The prevalence of overweight and obesity is increasing among reproductive-age women in sub-Saharan Africa. Whether maternal body mass index (BMI) influences the risk of infant infections in low- and middle-income countries (LMIC) is uncertain. We used data from a birth cohort of 5344 HIV-unexposed Zimbabwean infants with available data on maternal BMI, to calculate rates of sick clinic visits for infections during the first 12 months postpartum, and adjusted hazard ratios (aHR) for each maternal BMI group. Compared to infants of mothers with normal BMI, the rate of sick clinic visits for any infection progressively rose among infants of overweight (aHR 1.05; 95%CI 0.99, 1.11) and obese women (aHR 1.15; 95%CI 1.05, 1.25). Excess clinic attendances were particularly due to skin, respiratory and ear infections. Maternal obesity may therefore influence infant infectious morbidity in LMIC over the first year after birth

The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials

Objectives To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect.Design Systematic review and meta-analysis.Data sources Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science.Study selection Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention.Results Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. in random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions.Conclusion Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. the antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations.Vanier Canada Graduate ScholarshipMcGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, CanadaZvitambo Inst Maternal Child Hlth Res, Harare, ZimbabweQueen Mary Univ London, Blizard Inst, Ctr Paediat, London, EnglandMRC, Clin Trials Unit, London, EnglandJohns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USACornell Univ, Div Nutr Sci, Program Int Nutr, Ithaca, NY 14853 USAWashington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USAUniv Malawi, Blantyre, MalawiUniv Cambridge, Dept Archaeol & Anthropol, Div Biol Anthropol, Cambridge CB2 1TN, EnglandUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilUniv British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, CanadaUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

Two Cases of BCG Osteomyelitis Diagnosed Through Polymerase Chain Reaction/Electrospray Ionization-Mass Spectrometry Technology.

Barts Charity [grant MGU0294]Wellcome Trust [grant 108065/Z/15/Z to A. J. P.]

Raising rivals’ fixed costs

This article demonstrates that raising fixed costs can serve as a credible mechanism for a well placed firm to exclude its rivals. We identify a number of credible avenues, such as increased regulation, vexatious litigation and increased prices for essential inputs, through which such a firm can raise fixed costs. We show that for a wide range of oligopoly models this may be a profitable strategy, even if the firm’s own fixed costs are affected as much (or even more) than its rivals and even if it is less efficient. The resulting reduction in the number of firms in the market is detrimental to consumer welfare and hence worthy of scrutiny by competition and regulatory authorities

A Highly Contiguous and Annotated Genome Assembly of the Lesser Prairie-Chicken (Tympanuchus pallidicinctus)

Article asserts that the Lesser Prairie-Chicken (Tympanuchus pallidicinctus; LEPC) is an iconic North American prairie grouse, renowned for ornate and spectacular breeding season displays, a species that has been declining in population across much of its historical range, with corresponding precipitous declines in contemporary population abundance, largely due to climatic and anthropogenic factors. The authors describe an annotated reference genome that was generated from a LEPC sample collected from the southern DPS