Periapical infection may affect birth outcomes via systemic inflammation.

OBJECTIVES: Maternal dental periapical infections are associated with preterm birth and intrauterine growth restriction. This study investigates whether the association is mediated through bacterial spread from periapical lesions to placenta (direct pathway) or systemic inflammatory reaction (indirect pathway). MATERIALS AND METHODS: We compared birth outcomes in Malawian mothers with and without periapical infection. As markers of a direct pathway, we identified placental bacteria using a 16S rDNA approach and assessed histological evidence of inflammation in the placenta and amniotic membranes. We measured C-reactive protein, alpha-1-acid glycoprotein, and salivary cortisol as markers of an indirect pathway. We used regression models to associate the predictor variables with duration of pregnancy and newborn size. RESULTS: Of 1,024 women, 23.5% had periapical infection. There was no association of periapical infection with either bacterial DNA or histological inflammation in placenta or membranes. Periapical infection was associated with C-reactive protein, alpha-1-acid glycoprotein, and cortisol concentrations in a dose-dependent manner at 36 weeks. Addition of alpha-1-acid glycoprotein or cortisol concentration into regression models attenuated the association between periapical infection and pregnancy outcomes. CONCLUSION: There was no evidence of direct spread of periapical bacteria to the placenta. Periapical infections and adverse pregnancy outcomes are in part mediated through systemic inflammation

Statistical analysis plan for the LAKANA trial: a cluster-randomized, placebo-controlled, double-blinded, parallel group, three-arm clinical trial testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1–11-month-old infants in Mali

BACKGROUND:The Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1–11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP). METHODS/DESIGN: LAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1–11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1–11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering. CONCLUSION: The SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT04424511. Registered on 11 June 2020

SARS-CoV-2 infection and antibody seroprevalence in routine surveillance patients, healthcare workers and general population in Kita region, Mali: an observational study 2020–2021

Objective: To estimate the degree of SARS-CoV-2 transmission among healthcare workers (HCWs) and general population in Kita region of Mali. Design: Routine surveillance in 12 health facilities, HCWs serosurvey in five health facilities and community serosurvey in 16 villages in or near Kita town, Mali. Setting: Kita region, western Mali; local health centres around the central (regional) referral health centre. Participants: Patients in routine surveillance, HCWs in local health centres and community members of all ages in populations associated with study health centres. Main outcome measures: Seropositivity of ELISA test detecting SARS-CoV-2-specific total antibodies and real-time RT-PCR confirmed SARS-CoV-2 infection. Results: From 2392 routine surveillance samples, 68 (2.8%, 95% CI: 2.2% to 3.6%) tested positive for SARS-CoV-2 by RT-PCR. The monthly positivity rate was 0% in June–August 2020 and gradually increased to 6% by December 2020 and 6.2% by January 2021, then declined to 5.5%, 3.3%, 3.6% and 0.8% in February, March, April and May 2021, respectively. From 397 serum samples collected from 113 HCWs, 175 (44.1%, 95% CI: 39.1% to 49.1%) were positive for SARS-CoV-2 antibodies. The monthly seroprevalence was around 10% from September to November 2020 and increased to over 40% from December 2020 to May 2021. For community serosurvey in December 2020, overall seroprevalence of SARS-CoV-2 antibodies was 27.7%. The highest age-stratified seroprevalence was observed in participants aged 60–69 years (45.5%, 95% CI: 32.3% to 58.6%). The lowest was in children aged 0–9 years (14.0%, 95% CI: 7.4% to 20.6%). Conclusions: SARS-CoV-2 in rural Mali is much more widespread than assumed by national testing data and particularly in the older population and frontline HCWs. The observation is contrary to the widely expressed view, based on limited data, that COVID-19 infection rates were lower in 2020–2021 in West Africa than in other settings

Predictors and pathways of language and motor development in four prospective cohorts of young children in Ghana, Malawi, and Burkina Faso

Background: Previous reviews have identified 44 risk factors for poor early child development (ECD) in low- and middle-income countries. Further understanding of their relative influence and pathways is needed to inform the design of interventions targeting ECD. Methods: We conducted path analyses of factors associated with 18-month language and motor development in four prospective cohorts of children who participated in trials conducted as part of the International Lipid-Based Nutrient Supplements (iLiNS) Project in Ghana (n = 1,023), Malawi (n = 675 and 1,385), and Burkina Faso (n = 1,122). In two cohorts, women were enrolled during pregnancy. In two cohorts, infants were enrolled at 6 or 9 months. In multiple linear regression and structural equationmodels (SEM), we examined 22 out of 44 factors identified in previous reviews, plus 12 additional factors expected to be associated with ECD. Results: Out of 42 indicators of the 34 factors examined, 6 were associated with 18-month language and/or motor development in 3 or 4 cohorts: child linear and ponderal growth, variety of play materials, activities with caregivers, dietary diversity, and child hemoglobin/iron status. Factors that were not associated with child development were indicators of maternal Hb/iron status, maternal illness and inflammation during pregnancy, maternal perceived stress and depression, exclusive breastfeeding during 6 months postpartum, and child diarrhea, fever, malaria, and acute respiratory infections. Associations between socioeconomic status and language development were consistently mediated to a greater extent by caregiving practices than by maternal or child biomedical conditions, while this pattern for motor development was not consistent across cohorts. Conclusions: Key elements of interventions to ensure quality ECD are likely to be promotion of caregiver activities with children, a variety of play materials, and a diverse diet, and prevention of faltering in linear and ponderal growth and improvement in child hemoglobin/iron status

Path analyses of risk factors for linear growth faltering in four prospective cohorts of young children in Ghana, Malawi and Burkina Faso

Stunting prevalence is an indicator of a country’s progress towards United Nations’ Sustainable Development Goal 2, which is to end hunger and achieve improved nutrition. Accelerating progress towards reducing stunting requires a deeper understanding of the factors that contribute to linear growth faltering. We conducted path analyses of factors associated with 18-month length-for-age z-score (LAZ) in four prospective cohorts of children who participated in trials conducted as part of the International Lipid-Based Nutrient Supplements Project in Ghana (n=1039), Malawi (n=684 and 1504) and Burkina Faso (n=2619). In two cohorts, women were enrolled during pregnancy. In two other cohorts, infants were enrolled at 6 or 9 months. We examined the association of 42 indicators of environmental, maternal, caregiving and child factors with 18-month LAZ. Using structural equation modelling, we examined direct and indirect associations through hypothesised mediators in each cohort. Out of 42 indicators, 2 were associated with 18-month LAZ in three or four cohorts: maternal height and body mass index (BMI). Six factors were associated with 18-month LAZ in two cohorts: length for gestational age z-score (LGAZ) at birth, pregnancy duration, improved household water, child dietary diversity, diarrhoea incidence and 6-month or 9-month haemoglobin concentration. Direct associations were more prevalent than indirect associations, but 30%–62% of the associations of maternal height and BMI with 18-month LAZ were mediated by LGAZ at birth. Factors that were not associated with LAZ were maternal iron status, illness and inflammation during pregnancy, maternal stress and depression, exclusive breast feeding during 6 months post partum, feeding frequency and child fever, malaria and acute respiratory infections. These findings may help in identifying interventions to accelerate progress towards reducing stunting; however, much of the variance in linear growth status remained unaccounted for by these 42 individual-level factors, suggesting that community-level changes may be needed to achieve substantial progress.</p

A double-blind placebo-controlled trial of azithromycin to reduce mortality and improve growth in high-risk young children with non-bloody diarrhoea in low resource settings: the Antibiotics for Children with Diarrhoea (ABCD) trial protocol

Background Acute diarrhoea is a common cause of illness and death among children in low- to middle-income settings. World Health Organization guidelines for the clinical management of acute watery diarrhoea in children focus on oral rehydration, supplemental zinc and feeding advice. Routine use of antibiotics is not recommended except when diarrhoea is bloody or cholera is suspected. Young children who are undernourished or have a dehydrating diarrhoea are more susceptible to death at 90 days after onset of diarrhoea. Given the mortality risk associated with diarrhoea in children with malnutrition or dehydrating diarrhoea, expanding the use of antibiotics for this subset of children could be an important intervention to reduce diarrhoea-associated mortality and morbidity. We designed the Antibiotics for Childhood Diarrhoea (ABCD) trial to test this intervention. Methods ABCD is a double-blind, randomised trial recruiting 11,500 children aged 2–23 months presenting with acute non-bloody diarrhoea who are dehydrated and/or undernourished (i.e. have a high risk for mortality). Enrolled children in Bangladesh, India, Kenya, Malawi, Mali, Pakistan and Tanzania are randomised (1:1) to oral azithromycin 10 mg/kg or placebo once daily for 3 days and followed-up for 180 days. Primary efficacy endpoints are all-cause mortality during the 180 days post-enrolment and change in linear growth 90 days post-enrolment. Discussion Expanding the treatment of acute watery diarrhoea in high-risk children to include an antibiotic may offer an opportunity to reduce deaths. These benefits may result from direct antimicrobial effects on pathogens or other incompletely understood mechanisms including improved nutrition, alterations in immune responsiveness or improved enteric function. The expansion of indications for antibiotic use raises concerns about the emergence of antimicrobial resistance both within treated children and the communities in which they live. ABCD will monitor antimicrobial resistance. The ABCD trial has important policy implications. If the trial shows significant benefits of azithromycin use, this may provide evidence to support reconsideration of antibiotic indications in the present World Health Organization diarrhoea management guidelines. Conversely, if there is no evidence of benefit, these results will support the current avoidance of antibiotics except in dysentery or cholera, thereby avoiding inappropriate use of antibiotics and reaffirming the current guidelines. Trial registration Clinicaltrials.gov, NCT03130114. Registered on April 26 2017

Vulnerable newborn types : analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000–2021

Objective: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. Design: Descriptive multi-country secondary data analysis. Setting: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000–2021. Population: Liveborn infants. Methods: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. Results: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). Conclusions: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs.Peer reviewe