Operational Issues and Trends Associated with the Pilot Introduction of Zinc for Childhood Diarrhoea in Bougouni District, Mali

Zinc for the treatment of childhood diarrhoea was introduced in a pilot area in southern Mali to prepare for a cluster-randomized effectiveness study and to inform policies on how to best introduce and promote zinc at the community level. Dispersible zinc tablets in 14-tablet blister packs were provided through community health centres and drug kits managed by community health workers (CHWs) in two health zones in Bougouni district, Mali. Village meetings and individual counselling provided by CHWs and head nurses at health centres were the principal channels of communication. A combination of methods were employed to (a) detect problems in communication about the benefits of zinc and its mode of administration; (b) identify and resolve obstacles to implementation of zinc through existing health services; and (c) describe household-level constraints to the adoption of appropriate home-management practices for diarrhoea, including administration of both zinc and oral rehydration solution (ORS). Population-based household surveys with caretakers of children sick in the previous two weeks were carried out before and four months after the introduction of zinc supplementation. Household follow-up visits with children receiving zinc from the health centres and CHWs were conducted on day 3 and 14 after treatment for a subsample of children. A qualitative process evaluation also was conducted to investigate operational issues. Preliminary evidence from this study suggests that the introduction of zinc does not reduce the use of ORS and may reduce inappropriate antibiotic use for childhood diarrhoea. Financial access to treatments, management of concurrent diarrhoea and fever, and high use of unauthorized drug vendors were identified as factors affecting the effectiveness of the intervention in this setting. The introduction of zinc, if not appropriately integrated with other disease-control strategies, has the potential to decrease the appropriate presumptive treatment of childhood malaria in children with diarrhoea and fever in malaria-endemic areas

Prevention of child wasting: Results of a Child Health & Nutrition Research Initiative (CHNRI) prioritisation exercise.

BACKGROUND: An estimated 49.5 million children under five years of age are wasted. There is a lack of robust studies on effective interventions to prevent wasting. The aim of this study was to identify and prioritise the main outstanding research questions in relation to wasting prevention to inform future research agendas. METHOD: A research prioritisation exercise was conducted following the Child Health and Nutrition Research Initiative method. Identified research gaps were compiled from multiple sources, categorised into themes and streamlined into forty research questions by an expert group. A survey was then widely circulated to assess research questions according to four criteria. An overall research priority score was calculated to rank questions. FINDINGS: The prioritised questions have a strong focus on interventions. The importance of the early stages of life in determining later experiences of wasting was highlighted. Other important themes included the identification of at-risk infants and young children early in the progression of wasting and the roles of existing interventions and the health system in prevention. DISCUSSION: These results indicate consensus to support more research on the pathways to wasting encompassing the in-utero environment, on the early period of infancy and on the process of wasting and its early identification. They also reinforce how little is known about impactful interventions for the prevention of wasting. CONCLUSION: This exercise provides a five-year investment case for research that could most effectively improve on-the-ground programmes to prevent child wasting and inform supportive policy change

Operational Issues and Trends Associated with the Pilot Introduction of Zinc for Childhood Diarrhoea in Bougouni District, Mali

Zinc for the treatment of childhood diarrhoea was introduced in a pilot area in southern Mali to prepare for a cluster-randomized effectiveness study and to inform policies on how to best introduce and promote zinc at the community level. Dispersible zinc tablets in 14-tablet blister packs were provided through community health centres and drug kits managed by community health workers (CHWs) in two health zones in Bougouni district, Mali. Village meetings and individual counselling provided by CHWs and head nurses at health centres were the principal channels of communication. A combination of methods were employed to (a) detect problems in communication about the benefits of zinc and its mode of administration; (b) identify and resolve obstacles to implementation of zinc through existing health services; and (c) describe household-level constraints to the adoption of appropriate home-management practices for diarrhoea, including administration of both zinc and oral rehydration solution (ORS). Population-based household surveys with caretakers of children sick in the previous two weeks were carried out before and four months after the introduction of zinc supplementation. Household follow-up visits with children receiving zinc from the health centres and CHWs were conducted on day 3 and 14 after treatment for a subsample of children. A qualitative process evaluation also was conducted to investigate operational issues. Preliminary evidence from this study suggests that the introduction of zinc does not reduce the use of ORS and may reduce inappropriate antibiotic use for childhood diarrhoea. Financial access to treatments, management of concurrent diarrhoea and fever, and high use of unauthorized drug vendors were identified as factors affecting the effectiveness of the intervention in this setting. The introduction of zinc, if not appropriately integrated with other disease-control strategies, has the potential to decrease the appropriate presumptive treatment of childhood malaria in children with diarrhoea and fever in malaria-endemic areas

Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals

Background Causes of mortality are a crucial input for health systems for identifying appropriate interventions for child survival. We present an updated series of cause-specific mortality for neonates and children younger than 5 years from 2000 to 2019. Methods We updated cause-specific mortality estimates for neonates and children aged 1-59 months, stratified by level (low, moderate, or high) of mortality. We made a substantial change in the statistical methods used for previous estimates, transitioning to a Bayesian framework that includes a structure to account for unreported causes in verbal autopsy studies. We also used systematic covariate selection in the multinomial framework, gave more weight to nationally representative verbal autopsy studies using a random effects model, and included mortality due to tuberculosis. Findings In 2019, there were 5·30 million deaths (95% uncertainty range 4·92-5·68) among children younger than 5 years, primarily due to preterm birth complications (17·7%, 16·1-19·5), lower respiratory infections (13·9%, 12·0-15·1), intrapartum-related events (11·6%, 10·6-12·5), and diarrhoea (9·1%, 7·9-9·9), with 49·2% (47·3-51·9) due to infectious causes. Vaccine-preventable deaths, such as for lower respiratory infections, meningitis, and measles, constituted 21·7% (20·4-25·6) of under-5 deaths, and many other causes, such as diarrhoea, were preventable with low-cost interventions. Under-5 mortality has declined substantially since 2000, primarily because of a decrease in mortality due to lower respiratory infections, diarrhoea, preterm birth complications, intrapartum-related events, malaria, and measles. There is considerable variation in the extent and trends in cause-specific mortality across regions and for different strata of all-cause under-5 mortality. Interpretation Progress is needed to improve child health and end preventable deaths among children younger than 5 years. Countries should strategize how to reduce mortality among this age group using interventions that are relevant to their specific causes of death. Funding Bill & Melinda Gates Foundation; WHO

Cultic resilience and inter-city engagement at the dawn of urban history: protohistoric Mesopotamia and the ‘city seals’, 3200-2750 BC

Within the context of early urbanism, elite groups developed the world’s earliest writing in Mesopotamia, 3200-2750 BC, comprising administrative documents in the form of inscribed clay tablets. How did these proto-literate urban communities engage with each other and what strategies did they employ to address major challenges to their survival? The ‘city seal’ evidence survives as seal impressions on clay bureaucratic artefacts, both inscribed tablets and impressed sealings. These impressions feature signs representing the names of Mesopotamian cities, many of them identifiable with known sites. The documents stand at the threshold of history, as the earliest evidence for inter-city engagement. Using an innovative methodology and interpretive framework of cultic resilience, we integrate archaeometric, iconographic, and functional analyses of the earliest stages of writing and sealing, to argue that the city seal evidence provides unique insights into inter-city cooperation by Mesopotamian cities during a critical episode of early urban development

A Pooled Analysis of Body Mass Index and Mortality among African Americans

Pooled analyses among whites and East Asians have demonstrated positive associations between all-cause mortality and body mass index (BMI), but studies of African Americans have yielded less consistent results. We examined the association between BMI and all-cause mortality in a sample of African Americans pooled from seven prospective cohort studies: NIH-AARP, 1995–2009; Adventist Health Study 2, 2002–2008; Black Women's Health Study, 1995–2009; Cancer Prevention Study II, 1982–2008; Multiethnic Cohort Study, 1993–2007; Prostate, Lung, Colorectal and Ovarian Screening Trial, 1993–2009; Southern Community Cohort Study, 2002–2009. 239,526 African Americans (including 100,175 never smokers without baseline heart disease, stroke, or cancer), age 30–104 (mean 52) and 71% female, were followed up to 26.5 years (mean 11.7). Hazard ratios (HR) and 95% confidence intervals (CI) for mortality were derived from multivariate Cox proportional hazards models. Among healthy, never smokers (11,386 deaths), HRs (CI) for BMI 25–27.4, 27.5–29.9, 30–34.9, 35–39.9, 40–49.9, and 50–60 kg/m2 were 1.02 (0.92–1.12), 1.06 (0.95–1.18), 1.32 (1.18–1.47), 1.54 (1.29–1.83), 1.93 (1.46–2.56), and 1.93 (0.80–4.69), respectively among men and 1.06 (0.99–1.15), 1.15 (1.06–1.25), 1.24 (1.15–1.34), 1.58 (1.43–1.74), 1.80 (1.60–2.02), and 2.31 (1.74–3.07) respectively among women (reference category 22.5–24.9). HRs were highest among those with the highest educational attainment, longest follow-up, and for cardiovascular disease mortality. Obesity was associated with a higher risk of mortality in African Americans, similar to that observed in pooled analyses of whites and East Asians. This study provides compelling evidence to support public health efforts to prevent excess weight gain and obesity in African Americans

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

The Effects of Stress at Work and at Home on Inflammation and Endothelial Dysfunction

This study examined whether stress at work and at home may be related to dysregulation of inflammation and endothelial function, two important contributors to the development of cardiovascular disease. In order to explore potential biological mechanisms linking stress with cardiovascular health, we investigated cross-sectional associations between stress at work and at home with an inflammation score (n's range from 406–433) and with two endothelial biomarkers (intercellular and vascular adhesion molecules, sICAM-1 and sVCAM-1; n's range from 205–235) in a cohort of healthy US male health professionals. No associations were found between stress at work or at home and inflammation. Men with high or medium levels of stress at work had significantly higher levels of sVCAM-1 (13% increase) and marginally higher levels of sICAM-1 (9% increase), relative to those reporting low stress at work, independent of health behaviors. Men with high levels of stress at home had marginally higher levels of both sVCAM-1 and sICAM-1 than those with low stress at home. While lack of findings related to inflammation are somewhat surprising, if replicated in future studies, these findings may suggest that endothelial dysfunction is an important biological mechanism linking stress at work with cardiovascular health outcomes in men

Recombination-mediated remodelling of host-pathogen interactions during Staphylococcus aureus niche adaptation

Large-scale recombination events have led to the emergence of epidemic clones of several major bacterial pathogens. However, the functional impact of the recombination on clonal success is not understood. Here, we identified a novel widespread hybrid clone (ST71) of livestock-associated Staphylococcus aureus that evolved from an ancestor belonging to the major bovine lineage CC97, through multiple large-scale recombination events with other S. aureus lineages occupying the same ruminant niche. The recombination events, affecting a 329 kb region of the chromosome spanning the origin of replication, resulted in allele replacement and loss or gain of an array of genes influencing host–pathogen interactions. Of note, molecular functional analyses revealed that the ST71 hybrid clone has acquired multiple novel pathogenic traits associated with acquired and innate immune evasion and bovine extracellular matrix adherence. These findings provide a paradigm for the impact of large-scale recombination events on the rapid evolution of bacterial pathogens within defined ecological niches