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

PLoS Med

Background In 2014, the government of Togo implemented a pilot unconditional cash transfer (UCT) program in rural villages that aimed at improving children’s nutrition, health, and protection. It combined monthly UCTs (approximately US$8.40 /month) with a package of community activities (including behavior change communication [BCC] sessions, home visits, and integrated community case management of childhood illnesses and acute malnutrition [ICCM-Nut]) delivered to mother–child pairs during the first “1,000 days” of life. We primarily investigated program impact at population level on children’s height-for-age z-scores (HAZs) and secondarily on stunting (HAZ < −2) and intermediary outcomes including household’s food insecurity, mother–child pairs’ diet and health, delivery in a health facility and low birth weight (LBW), women’s knowledge, and physical intimate partner violence (IPV). Methods and findings We implemented a parallel-cluster–randomized controlled trial, in which 162 villages were randomized into either an intervention arm (UCTs + package of community activities, n = 82) or a control arm (package of community activities only, n = 80). Two different representative samples of children aged 6–29 months and their mothers were surveyed in each arm, one before the intervention in 2014 (control: n = 1,301, intervention: n = 1,357), the other 2 years afterwards in 2016 (control: n = 996, intervention: n = 1,035). Difference-in-differences (DD) estimates of impact were calculated, adjusting for clustering. Children’s average age was 17.4 (± 0.24 SE) months in the control arm and 17.6 (± 0.19 SE) months in the intervention arm at baseline. UCTs had a protective effect on HAZ (DD = +0.25 z-scores, 95% confidence interval [CI]: 0.01–0.50, p = 0.039), which deteriorated in the control arm while remaining stable in the intervention arm, but had no impact on stunting (DD = −6.2 percentage points [pp], relative odds ratio [ROR]: 0.74, 95% CI: 0.51–1.06, p = 0.097). UCTs positively impacted both mothers’ and children’s (18–23 months) consumption of animal source foods (ASFs) (respectively, DD = +4.5 pp, ROR: 2.24, 95% CI: 1.09–4.61, p = 0.029 and DD = +9.1 pp, ROR: 2.65, 95% CI: 1.01–6.98, p = 0.048) and household food insecurity (DD = −10.7 pp, ROR: 0.63, 95% CI: 0.43–0.91, p = 0.016). UCTs did not impact on reported child morbidity 2 week’s prior to report (DD = −3.5 pp, ROR: 0.80, 95% CI: 0.56–1.14, p = 0.214) but reduced the financial barrier to seeking healthcare for sick children (DD = −26.4 pp, ROR: 0.23, 95% CI: 0.08–0.66, p = 0.006). Women who received cash had higher odds of delivering in a health facility (DD = +10.6 pp, ROR: 1.53, 95% CI: 1.10–2.13, p = 0.012) and lower odds of giving birth to babies with birth weights (BWs) <2,500 g (DD = −11.8, ROR: 0.29, 95% CI: 0.10–0.82, p = 0.020). Positive effects were also found on women’s knowledge (DD = +14.8, ROR: 1.86, 95% CI: 1.32–2.62, p < 0.001) and physical IPV (DD = −7.9 pp, ROR: 0.60, 95% CI: 0.36–0.99, p = 0.048). Study limitations included the short evaluation period (24 months) and the low coverage of UCTs, which might have reduced the program’s impact. Conclusions UCTs targeting the first “1,000 days” had a protective effect on child’s linear growth in rural areas of Togo. Their simultaneous positive effects on various immediate, underlying, and basic causes of malnutrition certainly contributed to this ultimate impact. The positive impacts observed on pregnancy- and birth-related outcomes call for further attention to the conception period in nutrition-sensitive programs

Association between asymptomatic infections and linear growth in 18–24-month-old Malawian children

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha-1-acid glycoprotein [AGP]), and growth (insulin-like growth factor 1 [IGF-1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF-1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF-1 and CXM concentration at 18 months.publishedVersionPeer reviewe

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

Background: Mass drug administration (MDA) of azithromycin (AZI) has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. A large-scale cluster-randomized trial conducted in Malawi, Niger, and Tanzania suggested that the effect differs by country, may be stronger in infants, and may be concentrated within the first 3 months after treatment. Another study found no effect when azithromycin was given concomitantly with seasonal malaria chemoprevention (SMC). Given the observed heterogeneity and possible effect modification by other co-interventions, further trials are needed to determine the efficacy in additional settings and to determine the most effective treatment regimen. Methods: LAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The LAKANA trial is designed to address the mortality and health impacts of 4 or 2 annual rounds of azithromycin MDA delivered to 1–11-month-old (29–364 days) infants, in a high-mortality and malaria holoendemic Malian setting where there is a national SMC program. Participating villages (clusters) are randomly allocated in a ratio of 3:2:4 to three groups: placebo (control):4-dose AZI:2-dose AZI. The primary outcome measured is mortality. Antimicrobial resistance (AMR) will be monitored closely before, during, and after the intervention and both among those receiving and those not receiving MDA with the study drugs. Other outcomes, from a subset of villages, comprise efficacy outcomes related to morbidity, growth and nutritional status, outcomes related to the mechanism of azithromycin activity through measures of malaria parasitemia and inflammation, safety outcomes (AMR, adverse and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The enrolment commenced in October 2020 and is planned to be completed by the end of 2022. The expected date of study completion is December 2024. Discussion: If LAKANA provides evidence in support of a positive mortality benefit resulting from azithromycin MDA, it will significantly contribute to the options for successfully promoting child survival in Mali, and elsewhere in sub-Saharan Africa. Trial registration: ClinicalTrials.gov NCT04424511. Registered on 11 June 2020.publishedVersionPeer reviewe

TWG 3: Teacher professional development

This brief paper has been prepared for the researchers, practitioners and policy makers attending the EDUsummIT at UNESCO in Paris (8 – 10 June 2011). Its purpose is to inform discussion about how those responsible for the professional development of teachers may ensure that teachers are better prepared for the challenges of using ICT to promote 21st century learning. This EDUsummIT is intended to extend the work begun by EDUsummIT 2009 which emerged from work on the Handbook of IT in Primary and Secondary Education (Voogt & Knezek, 2008) and issued a Call to Action for IT in school education. The specific element from the Call to Action 2009 addressed in this brief paper is: To develop and use models for teacher professional development on technology use in schools and classrooms at the pre- and in-service levels

Impact of a conditional cash transfer and of a lipid-based nutrient supplement on child stunting in rural Mali : analysis of a cluster-randomized controlled trial

En 2014, afin de réduire le retard de croissance chez les jeunes enfants en milieu rural à Kayes au Mali, le Programme Alimentaire Mondial a intégré à un programme nutritionsanté préexistant (SNACK) i) un transfert monétaire (TM) aux femmes enceintes et mères d’enfants de moins de deux ans et ii) une supplémentation nutritionnelle à base lipidique (LNS) aux enfants de 6-23 mois; sous condition de fréquenter les centres de santé pendant les 1000 premiers jours (de la conception aux 2 ans de l'enfant). Nous avons évalué l’impact de ces interventions sur la croissance des jeunes enfants, notre critère principal de jugement étant l’indice Taille-pour-Age moyen exprimé en z-scores (TA), ainsi que sur des indicateurs intermédiaires le long des chemins d’impact du programme. Un essai contrôlé randomisé en grappe a été mené, où 76 centres de santé ont été répartis dans 4 bras : 1) SNACK (comparaison), 2) SNACK+TM, 3) SNACK+LNS et 4) SNACK+TM+LNS. Nous avons comparé des échantillons transversaux d'enfants de 12-42 mois enquêtés avant (2013, n=5046) et en fin d’intervention (2016, n=5098). Malgré une amélioration de l’indice TA moyen et une prévalence du retard de croissance (TA< -2) en baisse entre 2013 et 2016 dans les bras 2 (35,6% vs. 31,8%) et 3 (34,6% vs. 29,5%), ces évolutions n’étaient pas statistiquement significatives comparativement au bras SNACK. La combinaison des 2 interventions n’a pas eu d’impact sur la croissance, mais a permis l’amélioration modeste de l’indice moyen Poids-pour-Taille (ß=+0.16 P<0,01). Dans les bras 3 et 4, le suivi de croissance des enfants et certaines connaissances des mères ont été significativement améliorés. Des données sur la mise en œuvre du programme ont identifié plusieurs freins à l’efficacité des interventions, notamment des délais d’approvisionnement et de distribution des intrants dû à des difficultés d’accès géographique, une surcharge de travail des agents de terrain, un montant insuffisant du TM, ainsi qu’un partage du LNS dans le ménage.In 2014, on top of a community health and nutrition program running in the region of Kayes in Mali (SNACK), the World Food Program implemented distributions of i) cash to pregnant and mothers of children aged less than 24 months and ii) Lipid-Based Nutrient Supplements (LNS) to children aged 6-23 months. Both interventions were conditional upon attendance at community health centers (CHCs) for medical follow up throughout the first 1000 days of life (from conception to age 2 of the child). We evaluated the impact of these strategies on children’s anthropometric status, the mean height-for-age z-scores (HAZ) being our primary outcome, as well as on intermediary outcomes along the program’s impact pathways. We conducted a cluster randomized controlled trial, with CHCs randomized in 4 arms: 1) SNACK program only (comparison); 2) SNACK+Cash; 3) SNACK+LNS; 4) SNACK+Cash+LNS. Independent representative samples of 12-42 mo old children were surveyed at baseline (2013, n=5046) and at endline (2016, n=5098). Despite an increase in the mean HAZ and a decrease in stunting rates (HAZ<-2) between 2013 and 2016 in arm 2 (35.6% vs. 31.8%) and in arm 3 (34.6% vs. 29.5%), these changes were not statistically significant as compared with the SNACK arm. Combing the two strategies did not lead to any impact on growth outcomes, however it improved the mean weight-for-height z-scores (ß= +0.16 P<0.01). Attendance at children’s growth monitoring sessions and some of the mothers’ knowledge significantly increased in arms 3 and 4. Data on the program’s implementation suggested several barriers to impact achievement, including irregularity in cash/LNS provisioning and distributions due to low accessibility to CHCs, excessive workload of frontline workers, insufficient amount of cash transfers or sharing of LNS with siblings

Impact d'un transfert monétaire et/ou d'un supplément nutritionnel pour la prévention du retard de croissance du jeune enfant en milieu rural au Mali : analyse d'un essai randomisé par clusters

In 2014, on top of a community health and nutrition program running in the region of Kayes in Mali (SNACK), the World Food Program implemented distributions of i) cash to pregnant and mothers of children aged less than 24 months and ii) Lipid-Based Nutrient Supplements (LNS) to children aged 6-23 months. Both interventions were conditional upon attendance at community health centers (CHCs) for medical follow up throughout the first 1000 days of life (from conception to age 2 of the child). We evaluated the impact of these strategies on children’s anthropometric status, the mean height-for-age z-scores (HAZ) being our primary outcome, as well as on intermediary outcomes along the program’s impact pathways. We conducted a cluster randomized controlled trial, with CHCs randomized in 4 arms: 1) SNACK program only (comparison); 2) SNACK+Cash; 3) SNACK+LNS; 4) SNACK+Cash+LNS. Independent representative samples of 12-42 mo old children were surveyed at baseline (2013, n=5046) and at endline (2016, n=5098). Despite an increase in the mean HAZ and a decrease in stunting rates (HAZ<-2) between 2013 and 2016 in arm 2 (35.6% vs. 31.8%) and in arm 3 (34.6% vs. 29.5%), these changes were not statistically significant as compared with the SNACK arm. Combing the two strategies did not lead to any impact on growth outcomes, however it improved the mean weight-for-height z-scores (ß= +0.16 P<0.01). Attendance at children’s growth monitoring sessions and some of the mothers’ knowledge significantly increased in arms 3 and 4. Data on the program’s implementation suggested several barriers to impact achievement, including irregularity in cash/LNS provisioning and distributions due to low accessibility to CHCs, excessive workload of frontline workers, insufficient amount of cash transfers or sharing of LNS with siblings.En 2014, afin de réduire le retard de croissance chez les jeunes enfants en milieu rural à Kayes au Mali, le Programme Alimentaire Mondial a intégré à un programme nutritionsanté préexistant (SNACK) i) un transfert monétaire (TM) aux femmes enceintes et mères d’enfants de moins de deux ans et ii) une supplémentation nutritionnelle à base lipidique (LNS) aux enfants de 6-23 mois; sous condition de fréquenter les centres de santé pendant les 1000 premiers jours (de la conception aux 2 ans de l'enfant). Nous avons évalué l’impact de ces interventions sur la croissance des jeunes enfants, notre critère principal de jugement étant l’indice Taille-pour-Age moyen exprimé en z-scores (TA), ainsi que sur des indicateurs intermédiaires le long des chemins d’impact du programme. Un essai contrôlé randomisé en grappe a été mené, où 76 centres de santé ont été répartis dans 4 bras : 1) SNACK (comparaison), 2) SNACK+TM, 3) SNACK+LNS et 4) SNACK+TM+LNS. Nous avons comparé des échantillons transversaux d'enfants de 12-42 mois enquêtés avant (2013, n=5046) et en fin d’intervention (2016, n=5098). Malgré une amélioration de l’indice TA moyen et une prévalence du retard de croissance (TA< -2) en baisse entre 2013 et 2016 dans les bras 2 (35,6% vs. 31,8%) et 3 (34,6% vs. 29,5%), ces évolutions n’étaient pas statistiquement significatives comparativement au bras SNACK. La combinaison des 2 interventions n’a pas eu d’impact sur la croissance, mais a permis l’amélioration modeste de l’indice moyen Poids-pour-Taille (ß=+0.16 P<0,01). Dans les bras 3 et 4, le suivi de croissance des enfants et certaines connaissances des mères ont été significativement améliorés. Des données sur la mise en œuvre du programme ont identifié plusieurs freins à l’efficacité des interventions, notamment des délais d’approvisionnement et de distribution des intrants dû à des difficultés d’accès géographique, une surcharge de travail des agents de terrain, un montant insuffisant du TM, ainsi qu’un partage du LNS dans le ménage

Conditional cash transfer and/or lipid-based nutrient supplement targeting the first 1000 d of life increased attendance at preventive care services but did not improve linear growth in young children in rural Mali: Results of a cluster-randomized controlled trial

PRIFPRI3; ISI; CRP4; 2 Promoting Healthy Diets and Nutrition for allPHND; A4NHCGIAR Research Program on Agriculture for Nutrition and Health (A4NH