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

Tissue distribution of angiotensin-converting enzyme 2 (ACE2) receptor in wild animals with a focus on artiodactyls, mustelids and phocids

Natural cases of zooanthroponotic transmission of SARS-CoV-2 to animals have been reported during the COVID-19 pandemic, including to free-ranging white-tailed deer (Odocoileus virginianus) in North America and farmed American mink (Neovison vison) on multiple continents. To understand the potential for angiotensin-converting enzyme 2 (ACE2)-mediated viral tropism we characterised the distribution of ACE2 receptors in the respiratory and intestinal tissues of a selection of wild and semi-domesticated mammals including artiodactyls (cervids, bovids, camelids, suids and hippopotamus), mustelid and phocid species using immunohistochemistry. Expression of the ACE2 receptor was detected in the bronchial or bronchiolar epithelium of several European and Asiatic deer species, Bactrian camel (Camelus bactrianus), European badger (Meles meles), stoat (Mustela erminea), hippopotamus (Hippopotamus amphibious), harbor seal (Phoca vitulina), and hooded seal (Cystophora cristata). Further receptor mapping in the nasal turbinates and trachea revealed sparse ACE2 receptor expression in the mucosal epithelial cells and occasional occurrence in the submucosal glandular epithelium of Western roe deer (Capreolus capreolus), moose (Alces alces alces), and alpaca (Vicunga pacos). Only the European badger and stoat expressed high levels of ACE2 receptor in the nasal mucosal epithelium, which could suggest high susceptibility to ACE2-mediated respiratory infection. Expression of ACE2 receptor in the intestinal cells was ubiquitous across multiple taxa examined. Our results demonstrate the potential for ACE2-mediated viral infection in a selection of wild mammals and highlight the intra-taxon variability of ACE2 receptor expression, which might influence host susceptibility and infection

The gut microbiome and early-life growth in a population with high prevalence of stunting.

Stunting affects one-in-five children globally and is associated with greater infectious morbidity, mortality and neurodevelopmental deficits. Recent evidence suggests that the early-life gut microbiome affects child growth through immune, metabolic and endocrine pathways. Using whole metagenomic sequencing, we map the assembly of the gut microbiome in 335 children from rural Zimbabwe from 1-18 months of age who were enrolled in the Sanitation, Hygiene, Infant Nutrition Efficacy Trial (SHINE; NCT01824940), a randomized trial of improved water, sanitation and hygiene (WASH) and infant and young child feeding (IYCF). Here, we show that the early-life gut microbiome undergoes programmed assembly that is unresponsive to the randomized interventions intended to improve linear growth. However, maternal HIV infection is associated with over-diversification and over-maturity of the early-life gut microbiome in their uninfected children, in addition to reduced abundance of Bifidobacterium species. Using machine learning models (XGBoost), we show that taxonomic microbiome features are poorly predictive of child growth, however functional metagenomic features, particularly B-vitamin and nucleotide biosynthesis pathways, moderately predict both attained linear and ponderal growth and growth velocity. New approaches targeting the gut microbiome in early childhood may complement efforts to combat child undernutrition

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. METHODS: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. INTERPRETATION: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. FUNDING: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.The SHINE trial is funded by the Bill & Melinda Gates Foundation (OPP1021542 and OPP113707); UK Department for International Development; Wellcome Trust, UK (093768/Z/10/Z, 108065/Z/15/Z and 203905/Z/16/Z); Swiss Agency for Development and Cooperation; US National Institutes of Health (2R01HD060338-06); and UNICEF (PCA-2017-0002)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Linear growth faltering in infants in low-and middle-income countries: the intestinal microbiota, the role of antibiotics, and the timing of linear growth failure

Stunting malnutrition in early life, defined as suboptimal linear growth, affects greater than one fourth of children under 5 years old in low- and middle- income countries (LMICs). Linear growth restriction largely accrues during the 1,000 day period from conception to 24 months of age and has long-term negative effects on child physical and mental development. However, variability in the timing of growth faltering during this period has not been investigated. In addition, nutritional strategies to improve linear growth and related outcomes in children have only had modest impacts, reflecting our limited understanding of what causes stunting. A largely unexplored determinant of infant growth is the ecosystem of microbes in the human gut, termed the microbiota. Animal models have shown that the gut microbiota can induce changes in weight. Growth gains have also been observed with antibiotic use that may result from antibiotic induced changes in gut microbiota composition and function. However, the gut microbiota has not been investigated as a determinant of linear growth. The objectives of this thesis were: (1) to identify linear growth trajectories into which HIV-unexposed infants, from LMICs, fall from birth to their second birthday and the socio-demographic and epidemiological factors that are associated with each growth trajectory; (2) to determine whether antibiotic treatment leads to improvements in growth in LMICs, determine the magnitude of growth improvements, and identify moderators of this treatment effect; and (3) to determine changes in the gut microbiota that are associated with linear growth.La malnutrition qui retarde la croissance pendant l’enfance, dite croissance linéaire sous-optimale, affecte supérieure à un quart des enfants âgés de moins de 5 ans dans les pays à revenus faibles et intermédiaires (PFR-PRI). Le retard de croissance linéaire en grande partie attribué aux 1 000 premiers jours de vie, de la conception à l'âge de 24 mois, a des effets néfastes sur le développement physique et mental de l'enfant à long terme. Cependant, la chronologie de variabilité du retard de croissance sur cette période n'a pas encore été étudiée. De plus, les stratégies nutritionnelles pour améliorer la croissance linéaire et les finalités connexes chez les enfants n'ont eu que des effets modestes, reflétant notre compréhension limitée de ce qui provoque le ralentissement de la croissance.Un facteur déterminant largement inexploré de la croissance infantile reste le microbiote intestinal humain. Des modèles animaux ont montré que le microbiote intestinal peut induire des variations de poids. Des gains de croissance ont aussi été observés avec l'utilisation d'antibiotiques pouvant résulter de changements induits par les antibiotiques sur la composition et la fonction du microbiote intestinal. Toutefois, le microbiote intestinal n'a jamais été étudié en tant que facteur déterminant la croissance linéaire.Les objectifs de cette thèse ont été : (1) d'identifier les trajectoires de croissance linéaire d’enfants (non exposés au VIH et venant des PFR-PRI) qui s’effondraient entre l’âge de 0 et 24 mois, et les facteurs sociodémographiques et épidémiologiques qui sont associés à chaque trajectoire de croissance; (2) de déterminer si un traitement antibiotique pouvait conduire à l'amélioration de la croissance dans les PFR-PRI, de déterminer l’ampleur des améliorations de la croissance et d'identifier les modérateurs de cet effet de traitement; et (3) de déterminer les changements dans le microbiote intestinal qui étaient liés à une croissance linéaire

HIV seroprevalence and associated risk factors among male inmates at the Belize Central Prison Seroprevalencia al VIH y factores de riesgo asociados en hombres internados en la Prisión Central de Belice

OBJECTIVES: To determine the seroprevalence of HIV and identify associated risk factors among inmates at the Belize Central Prison, managed by the Kolbe Foundation, Belize. METHODS: A voluntary sample of 623 participants was obtained from the male inmate population incarcerated during the period from 15 January to 5 March 2005. HIV serostatus was determined on location using the Abbott Determine Assay for HIV-1/2 for screening, and the MedMira MiraWell Rapid HIV-1/2 Test for confirmatory testing. Remaining serum was tested by ELISA at the Central Medical Laboratory, Belize. Demographic and risk behavior data were collected using an interviewer administered pre-tested questionnaire. A multivariate logistic regression was used to adjust for potential confounders and to identify independent associations with HIV seropositivity. RESULTS:Of the 623 inmates in the sample, 25 tested positive for HIV-1/2 antibody for a seroprevalence of 4.0% (95% Confidence Interval 2.7, 6.0). After adjustment for confounding, HIV serostatus was positively associated with male-to-male sexual activity outside prison, age, and district of residence before current incarceration. CONCLUSIONS: The seroprevalence in the Central Prison was almost twice that estimated for the adult population of Belize in 2004 (2.4%). However, the social variables of importance to inmates appeared to reflect the epidemic in the general population, with the exception that male-to-male sex outside prison is likely more important to the male inmate population in Belize. The findings suggest that HIV is likely contracted by most inmates before their incarceration, largely due to same-sex activity.OBJETIVOS: Determinar la seroprevalencia al VIH e identificar los factores de riesgo asociados en hombres internados en la Prisión Central de Belice, administrada por la Fundación Kolbe. MÉTODOS: La muestra estuvo compuesta por 623 voluntarios hombres que se encontraban encarcelados entre el 15 de enero y el 5 de marzo de 2005. El estatus serológico con respecto al VIH se determinó en la prisión mediante la prueba de tamizaje Abbot Determine Assay y se confirmó con la prueba MedMira MiraWell Rapid, ambas para anticuerpos contra el VIH 1 y 2. El suero restante se analizó por ELISA en el Laboratorio Médico Central de Belice. Se recabaron los datos demográficos y sobre las conductas de riesgo mediante una encuesta preevaluada aplicada por un entrevistador. Se identificaron las asociaciones independientes con la seropositividad al VIH mediante análisis de regresión logística multifactorial ajustado por posibles factores de confusión. RESULTADOS: De los 623 prisioneros de la muestra, 25 resultaron positivos a anticuerpos contra el VIH-1/2, para una seroprevalencia de 4,0% (IC95%: 2,7% a 6,0%). Después de ajustar por los factores de confusión, la seropositividad se asoció con la actividad sexual con otros hombres fuera de la prisión, la edad y el distrito de residencia antes de su encarcelamiento actual. CONCLUSIONES: La seroprevalencia en la Prisión Central casi duplicó el estimado para la población adulta de Belice en 2004 (2,4%). Sin embargo, las variables sociales de importancia en los prisioneros parecieron reflejar la epidemia en la población general, aunque la relación sexual con hombres fuera de la prisión pareció tener mayor importancia en la población masculina encarcelada en Belice. Estos resultados indican que la mayoría de los prisioneros habría contraído la infección por el VIH antes de su encarcelamiento, en gran parte debido a prácticas homosexuales