Effectiveness of kangaroo mother care before clinical stabilisation versus standard care among neonates at five hospitals in Uganda (OMWaNA): a parallel-group, individually randomised controlled trial and economic evaluation.

BACKGROUND: Preterm birth is the leading cause of death in children younger than 5 years worldwide. WHO recommends kangaroo mother care (KMC); however, its effects on mortality in sub-Saharan Africa and its relative costs remain unclear. We aimed to compare the effectiveness, safety, costs, and cost-effectiveness of KMC initiated before clinical stabilisation versus standard care in neonates weighing up to 2000 g. METHODS: We conducted a parallel-group, individually randomised controlled trial in five hospitals across Uganda. Singleton or twin neonates aged younger than 48 h weighing 700-2000 g without life-threatening clinical instability were eligible for inclusion. We randomly assigned (1:1) neonates to either KMC initiated before stabilisation (intervention group) or standard care (control group) via a computer-generated random allocation sequence with permuted blocks of varying sizes, stratified by birthweight and recruitment site. Parents, caregivers, and health-care workers were unmasked to treatment allocation; however, the independent statistician who conducted the analyses was masked. After randomisation, neonates in the intervention group were placed prone and skin-to-skin on the caregiver's chest, secured with a KMC wrap. Neonates in the control group were cared for in an incubator or radiant heater, as per hospital practice; KMC was not initiated until stability criteria were met. The primary outcome was all-cause neonatal mortality at 7 days, analysed by intention to treat. The economic evaluation assessed incremental costs and cost-effectiveness from a disaggregated societal perspective. This trial is registered with ClinicalTrials.gov, NCT02811432. FINDINGS: Between Oct 9, 2019, and July 31, 2022, 2221 neonates were randomly assigned: 1110 (50·0%) neonates to the intervention group and 1111 (50·0%) neonates to the control group. From randomisation to age 7 days, 81 (7·5%) of 1083 neonates in the intervention group and 83 (7·5%) of 1102 neonates in the control group died (adjusted relative risk [RR] 0·97 [95% CI 0·74-1·28]; p=0·85). From randomisation to 28 days, 119 (11·3%) of 1051 neonates in the intervention group and 134 (12·8%) of 1049 neonates in the control group died (RR 0·88 [0·71-1·09]; p=0·23). Even if policy makers place no value on averting neonatal deaths, the intervention would have 97% probability from the provider perspective and 84% probability from the societal perspective of being more cost-effective than standard care. INTERPRETATION: KMC initiated before stabilisation did not reduce early neonatal mortality; however, it was cost-effective from the societal and provider perspectives compared with standard care. Additional investment in neonatal care is needed for increased impact, particularly in sub-Saharan Africa. FUNDING: Joint Global Health Trials scheme of the Department of Health and Social Care, Foreign, Commonwealth and Development Office, UKRI Medical Research Council, and Wellcome Trust; Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Primary health care preparedness to integrate diabetes care in Blantyre, Malawi: A mixed methods study.

BACKGROUND: There is limited access to diabetes care services at primary care facilities in Malawi. Assessing the capacity of facilities to provide diabetes care is an initial step to integrating services at primary care. AIM: To assess the preparedness for delivering diabetes services at primary care level within the Blantyre District Health Office (DHO) to support the response to NCD epidemic in Malawi. SETTING: Blantyre DHO primary care facilities. MATERIALS AND METHODS: A mixed methods approach nested in a national needs assessment for NCD response in Malawi was used. Fourteen primary healthcare facilities from Blantyre DHO were assessed. A tool adapted from the WHO rapid assessment questionnaire was used to identify human resource, equipment, supplies, and medication needed for comprehensive diabetes care. Descriptive statistics were done to analyze the quantitative data. Fisher's exact test was used to assess if there was a statistically significant difference between urban and rural facilities. Seventeen health care workers from the selected facilities participated in key informant interviews. Framework analysis method guided the qualitative data analysis. The quantitative and qualitative data were merged and displayed jointly. RESULTS: The quantitative assessment showed that none of the facilities assessed had capacity to provide all the interventions recommended by WHO for diabetes care at primary level. Eight (57%) of the facilities had the capacity to diagnose diabetes, monitor glucose, prevent limb amputations and manage hypoglycemia and hyperglycemia. Four themes emerged from the qualitative data: differences in level of preparedness and implementation of diabetes care; disparities in resources between urban and rural facilities; low utilization of diabetes services; and strategy and policy recommendations for improvement of diabetes care. CONCLUSION: Inadequate health financing resulted in significant disparities in the available resources between the rural and urban facilities to offer diabetes care services. There is need to develop national policies and guidelines for diabetes care to strengthen the capacity of primary care facilities to facilitate achievement of universal health coverage.

Integrated management of HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-AFRICA): a pragmatic cluster-randomised, controlled trial.

BACKGROUND: In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania. METHODS: In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688. FINDINGS: Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; pnon-inferiority<0·0001 unadjusted) and -0·36% (-1·99 to 1·28; pnon-inferiority<0·0001 adjusted). INTERPRETATION: In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. FUNDING: European Union Horizon 2020 and Global Alliance for Chronic Diseases.

Type 2 diabetes progression in an adult Ugandan population with new-onset diabetes: an observational prospective study.

BACKGROUND: The rate of progression of type 2 diabetes following diagnosis varies across individuals and populations. Studies investigating the progression of type 2 diabetes in adult African populations with newly diagnosed diabetes are limited. We aimed to investigate the prevalence and predictors of short-term (one year) diabetes progression in an adult Ugandan population with new-onset type 2 diabetes (type 2 diabetes diagnosed in < 3 months) initiated on oral hypoglycaemic agents (OHA). METHODS: Two hundred and seven adult participants with type 2 diabetes diagnosed within the previous three months were followed up for 12 months. We investigated the association of specific demographic, clinical, and metabolic characteristics, and short-term diabetes progression (defined as glycated haemoglobin or HbA1c ≥ 8% on ≥ 2 OHA and/or treatment intensification). RESULTS: One hundred sixteen participants (56%) completed the follow-up period. Sixty-four participants (55.2%, 95% CI 45.7-64.4) showed evidence of diabetes progression during the 12-month period of follow-up. An HbA1c ≥ 8% on ≥ 2 OHA and treatment intensification were noted in 44.8% and 29.3% of the participants, respectively. On multivariate analysis, only the female gender (AOR 3.2, 95% CI 1.1-9.2, p = 0.03) was noted to be independently associated with short-term diabetes progression. CONCLUSION: Short-term diabetes progression was relatively common in this study population and was independently associated with the female gender. Early intensified diabetes therapy in adult Ugandan female patients with new-onset type 2 diabetes should be emphasised to avert rapid short-term diabetes progression.

The case for precision medicine in the prevention, diagnosis, and treatment of cardiometabolic diseases in low-income and middle-income countries.

Cardiometabolic diseases are the leading preventable causes of death in most geographies. The causes, clinical presentations, and pathogenesis of cardiometabolic diseases vary greatly worldwide, as do the resources and strategies needed to prevent and treat them. Therefore, there is no single solution and health care should be optimised, if not to the individual (ie, personalised health care), then at least to population subgroups (ie, precision medicine). This optimisation should involve tailoring health care to individual disease characteristics according to ethnicity, biology, behaviour, environment, and subjective person-level characteristics. The capacity and availability of local resources and infrastructures should also be considered. Evidence needed for equitable precision medicine cannot be generated without adequate data from all target populations, and the idea that research done in high-income countries will transfer adequately to low-income and middle-income countries (LMICs) is problematic, as many migration studies and transethnic comparisons have shown. However, most data for precision medicine research are derived from people of European ancestry living in high-income countries. In this Series paper, we discuss the case for precision medicine for cardiometabolic diseases in LMICs, the barriers and enablers, and key considerations for implementation. We focus on three propositions: first, failure to explore and implement precision medicine for cardiometabolic disease in LMICs will enhance global health disparities. Second, some LMICs might already be placed to implement cardiometabolic precision medicine under appropriate circumstances, owing to progress made in treating infectious diseases. Third, improvements in population health from precision medicine are most probably asymptotic; the greatest gains are more likely to be obtained in countries where health-care systems are less developed. We outline key recommendations for implementation of precision medicine approaches in LMICs.

Waist circumference and glycaemia are strong predictors of progression to diabetes in individuals with prediabetes in sub-Saharan Africa: 4-year prospective cohort study in Malawi.

Sub-Saharan Africa is projected to have the highest increase in the number of people with diabetes worldwide. However, the drivers of diabetes in this region have not been clearly elucidated. The aim of this study was to evaluate the incidence of diabetes and the predictors of progression in a population-based cohort with impaired fasting glucose (IFG) in Malawi. We used data from an extensive rural and urban non-communicable disease survey. One hundred seventy-five, of 389 individuals with impaired fasting glucose (IFG) at baseline, age 48 ±15 years and body mass index 27.5 ±5.9 kg/m2 were followed up for a median of 4.2 years (714 person-years). Incidence rates were calculated, and predictors of progression to diabetes were analysed using multivariable logistic regression models, with overall performance determined using receiver operator characteristics (ROC) curves. The median follow-up was 4.2 (IQR 3.4-4.7) years. Forty-five out of 175 (26%) progressed to diabetes. Incidence rates of diabetes were 62.9 per 1000 person-years 95% CI, 47.0-84.3. The predictors of progression were higher; age (odds ratio [OR] 1.48, P = 0.046), BMI (OR 1.98, P = 0.001), waist circumference (OR 2.50,P<0.001), waist-hip ratio (OR 1.40, P = 0.03), systolic blood pressure (OR 1.56, P = 0.01), fasting plasma glucose (OR 1.53, P = 0.01), cholesterol (OR 1.44, P = 0.05) and low-density lipoprotein cholesterol (OR 1.80, P = 0.002). A simple model combining fasting plasma glucose and waist circumference was predictive of progression to diabetes (ROC area under the curve = 0.79). The incidence of diabetes in people with IFG is high in Malawi and predictors of progression are like those seen in other populations. Our data also suggests that a simple chart with probabilities of progression to diabetes based on waist circumference and fasting plasma glucose could be used to identify those at risk of progression in clinical settings in sub-Saharan Africa.

Medium-to-long term sustainability of a health systems intervention to improve service readiness and quality of non-communicable disease (NCD) patient care and experience at primary care settings in Uganda.

BACKGROUND: With the double burden of rising chronic non-communicable diseases (NCDs) and persistent infectious diseases facing sub-Saharan Africa, integrated health service delivery strategies among resource-poor countries are needed. Our study explored the post-trial sustainability of a health system intervention to improve NCD care, introduced during a cluster randomised trial between 2013 and 2016 in Uganda, focusing on hypertension (HT) and type-2 diabetes mellitus (DM) services. In 2020, 19 of 38 primary care health facilities (HFs) that constituted the trial's original intervention arm until 2016 and 3 of 6 referral HFs that also received the intervention then, were evaluated on i) their facility performance (FPS) through health worker knowledge, and service availability and readiness (SAR), and ii) the quality-of-patient-care-and-experience (QoCE) received. METHODS: Cross-sectional data from the original trial (2016) and our study (2020) were compared. FPS included a clinical knowledge test with 222 health workers: 131 (2016) and 91 (2020) and a five-element SAR assessment of all 22 HFs. QoCE assessment was performed among 420 patients: 88 (2016) and 332 (2020). Using a pair-matched approach, FPS and QoCE summary scores were compared. Linear and random effects Tobit regression models were also analysed. RESULTS: The mean aggregate facility performance (FPS) in 2020 was lower than in 2016: 70.2 (95%CI = 66.0-74.5) vs. 74.8 (95%CI = 71.3-78.3) respectively, with no significant difference (p = 0.18). Mean scores declined in 4 of 5 SAR elements. Overall FPS was negatively affected by rural or urban HF location relative to peri-urban HFs (p < 0.01). FPS was not independently predicted but patient club functionality showed weak association (p = 0.09). QoCE declined slightly to 8.7 (95%CI = 8.4-91) in 2020 vs 9.5 (95%CI = 9.1-9.9) in 2016 (p = 0.02) while the proportion of patients receiving adequate quality care also declined slightly to 88.2% from 98.5% respectively, with no statistical difference (p = 0.20). Only the parent district weakly predicted QoCE (p = 0.05). CONCLUSIONS: Four years after the end of research-related support, overall facility performance had declined as expected because of the interrupted supplies and a decline in regular supervision. However, both service availability and readiness and quality of HT/DM care were surprisingly well preserved. Sustainability of an NCD intervention in similar settings may remain achievable despite the funding instability following a trial's end but organisational measures to prepare for the post-trial phase should be taken early on in the intervention process.

Multi-trait discovery and fine-mapping of lipid loci in 125,000 individuals of African ancestry.

Most genome-wide association studies (GWAS) for lipid traits focus on the separate analysis of lipid traits. Moreover, there are limited GWASs evaluating the genetic variants associated with multiple lipid traits in African ancestry. To further identify and localize loci with pleiotropic effects on lipid traits, we conducted a genome-wide meta-analysis, multi-trait analysis of GWAS (MTAG), and multi-trait fine-mapping (flashfm) in 125,000 individuals of African ancestry. Our meta-analysis and MTAG identified four and 14 novel loci associated with lipid traits, respectively. flashfm yielded an 18% mean reduction in the 99% credible set size compared to single-trait fine-mapping with JAM. Moreover, we identified more genetic variants with a posterior probability of causality >0.9 with flashfm than with JAM. In conclusion, we identified additional novel loci associated with lipid traits, and flashfm reduced the 99% credible set size to identify causal genetic variants associated with multiple lipid traits in African ancestry.

Identification and characterisation of diabetes in Uganda: protocol for the nested, population-based 'Diabetes in low-resource Populations' (DOP) Study.

INTRODUCTION: Sub-Saharan Africa is experiencing an increasing burden of diabetes, but there are little reliable data, particularly at the community level, on the true prevalence or why this condition affects young and relatively lean individuals. Moreover, the detection of diabetes in Africa remains poor, not only due to a lack of resources but because the performance of available diagnostic tests is unclear. METHODS: This research aims to (1) determine the prevalence and risk factors of diabetes in a rural Ugandan population, (2) use clinical and biochemical markers to define different diabetes phenotypes and (3) study the progression of diabetes in this population. We will also assess the utility of the widely used tests (glycated haemoglobin (HbA1c), oral glucose tolerance test (OGTT) and fasting glucose) in diagnosing diabetes. DESIGN: This is a population-based study nested within the longstanding general population cohort in southwestern Uganda. We will undertake a population survey to identify individuals with diabetes based on fasting glucose, HbA1c, OGTT results or history of pre-existing diabetes. PARTICIPANTS: The study intends to enrol up to 11 700 individuals aged 18 years and above, residing within the study area and not pregnant or within 6 months post-delivery date. All participants will have detailed biophysical and biochemical/metabolic measurements. Individuals identified to have diabetes and a random selection of controls will have repeat tests to test reproducibility before referral and enrolment into a diabetic clinic. Participants will then be followed up for 1 year to assess the course of the disease, including response to therapy and diabetes-related complications. CONCLUSIONS: These data will improve our understanding of the burden of diabetes in Uganda, the risk factors that drive it and underlying pathophysiological mechanisms, as well as better ways to detect this condition. This will inform new approaches to improve the prevention and management of diabetes. ETHICS AND DISSEMINATION: This study protocol was approved by the Uganda Virus Research Institute Research Ethics Committee (REC) (number: G.C./127/21/09/858), the London School of Hygiene and Tropical Medicine REC (number: 26638) and the Uganda National Council for Science and Technology (protocol number: HS1791ES). Written informed consent will be obtained from all participants before being enrolled on to the study and conducting study-related procedures. Research findings will be disseminated in policy briefs, seminars, local and international conferences and publications in peer-reviewed open-access journals. As part of the dissemination plans, findings will also be disseminated to patient care groups and to clinicians. TRIAL REGISTRATION NUMBER: NCT05487079.

Sustainability capacity and health worker normalisation of a successful non-communicable disease (NCD) health systems intervention within primary care settings in Uganda: a quantitative approach to a qualitative question.

BACKGROUND: Interventions for non-communicable diseases are increasingly implemented and evaluated in sub-Saharan Africa, but little is known about their medium- to long-term sustainability beyond the end of research funding. A cluster randomised trial conducted between 2013 and 2016 in Uganda and Tanzania showed that an intervention package to improve hypertension (HT) and type-2 diabetes mellitus (DM) care was highly effective in increasing service readiness and quality of care. The present study assesses the sustainability of the intervention 4 years after the trial in Uganda. METHODS: The study was conducted in 2020 in 22 primary care health facilities (HFs) (3 referrals and 19 lower-level units) that had received the intervention package until trial end (2016), to assess their current capacity and practice to sustain ongoing intervention activities for HT and DM care. Through a cross-sectional survey, 4 pre-defined domains (i.e., cognitive participation, coherence, collective action, and reflexive monitoring) were examined with regard to health worker (HW) normalization and 8 pre-defined domains for intervention sustainability (i.e., organisational capacity, local environment, funding stability, partnerships, communication, evaluation, adaptation, and strategic planning), using the normalisation tool and the program sustainability tool (PSAT). Summary scores were assessed by domains and facility level. RESULTS: Overall normalization strength was adequate at 4.0 (IQR: 3.8, 4.2) of a possible 5 with no evidence of association with HF level (p = 0.40); cognitive participation (buy-in) and reflexive monitoring (appraisal) were strongest at > 4 across all HF levels. All HF levels were weak (< 4) on collective action (teamwork) and coherence (sense-making). Only collective action differed by level (p < 0.002). Overall intervention sustainability was suboptimal at 3.1 [IQR: 1.9, 4.1] of a possible 7 with weak scores on funding stability (2.0), supportive partnerships (2.2), and strategic planning (2.6). Domain differences by HF level were significant for environmental support (p = 0.02) and capacity in organisation (p = 0.01). Adequate strength at a cut-off mean of ≥5 did not differ by HF level for any domain. CONCLUSIONS: Four years after their introduction, practice-dependent intervention elements e.g., local organisational context, HW knowledge or dedication were sustained, but external elements e.g., new funding support or attracting new partners to sustain intervention efforts were not. Whenever new interventions are introduced into an existing health service, their long-term sustainability including the required financial support should be ensured. The quality of services should be upheld by providing routine in-service training with dedicated support supervision.

Scaling up integrated care for HIV and other chronic conditions in routine health care settings in sub-Saharan Africa: Field notes from Uganda.

Introduction: Integration of HIV and non-communicable disease (NCD) services is proposed to increase efficiency and coverage of NCD care in sub-Saharan Africa. Description: Between October 2018 to January 2020 in Tanzania and Uganda, working in partnership with health services, we introduced an integrated chronic care model for people with HIV, diabetes and hypertension. In this model, patients were able to access care from a single point of care, as opposed to the standard of siloed care from vertical clinics. When the study ended, routine clinical services adopted the integrated model. In this article, we discuss how the model transitioned post hand-over in Uganda and draw lessons to inform future scale-up. Discussion: The findings suggest potential for successful uptake of integrated chronic care by routine clinical services in sub-Saharan Africa. This approach may appeal to health care service providers and policy makers when they can quantify benefits that accrue from it, such as optimal utilization of health resources. For patients, integrated care may not appeal to all patients due to HIV-related stigma. Key considerations include good communication with patients, strong leadership, maintaining patient confidentiality and incorporating patient needs to facilitate successful uptake. Conclusion: Evidence on the benefits of integrated care remains limited. More robust evidence will be essential to guide scale-up beyond research sites.

Genome-wide association analysis of cystatin-C kidney function in continental Africa.

BACKGROUND: Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys. METHODS: Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA). FINDINGS: Three independent lead single nucleotide polymorphisms (SNPs) (P-value <5 × 10-8 (based on likelihood ratio test (LRT))) were identified; rs59288815 (ANK3), rs4277141 (OR51B5) and rs911119 (CST3). From fine-mapping, rs59288815 and rs911119 each had a posterior probability of causality of >99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events. INTERPRETATION: Our study found two previously unreported associated SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signalling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. Additional GWASs are required to represent the diverse regions in Africa. FUNDING: Wellcome (220740/Z/20/Z).

Statistical analysis plan and protocol updates for Gestational diabetes in Uganda and India: Design and Evaluation of Educational Films for Improving Screening and Self-management (GUIDES) trial.

BACKGROUND: Timely detection and management of gestational diabetes mellitus (GDM) have been identified as a high priority for policymakers in low- and middle-income countries (LMICs). The GUIDES trial will evaluate a package of three interconnected film-based interventions aimed at improving the timely detection and management of GDM. The protocol for this trial has previously been published; this publication outlines the statistical analysis plan for the trial. METHODS AND DESIGN: The GUIDES study is a multi-country cluster-randomised controlled trial consisting of one trial conducted in Uganda and one in India (30 clusters in each country). Mixed effects models will be used to compare the primary study outcomes of the proportion of women who are tested for GDM between 24 and 32 weeks of pregnancy and the mean fasting blood sugar of women with GDM at 34-week follow-up while accounting for clustering. Secondary analyses will compare the proportion of women with self-reported GDM diagnosis at 32 weeks of pregnancy and the proportion of women with adverse perinatal outcomes related to GDM up to 4 weeks after birth in each trial arm. TRIAL STATUS AND DISCUSSION: Follow-up is expected to end in March 2023 in Uganda and in May 2023 in India. Analyses will be carried out following this statistical analysis plan in the month following trial completion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03937050. Registered on 3 May 2019. Clinical Trials Registry India CTRI/2020/02/023605. Registered on 26 February 2020.

Physical and sexual victimization of persons with severe mental illness seeking care in central and southwestern Uganda.

Purpose: This study established the prevalence of physical and sexual victimization, associated factors and psychosocial consequences of victimization among 1,201 out-patients with severe mental illness at Butabika and Masaka hospitals in Uganda. Methods: Participants completed structured, standardized and locally translated instruments. Physical and sexual victimization was assessed using the modified adverse life events module of the European Para-suicide Interview Schedule. We used logistic regression to determine the association between victimization, the associated factors and psychosocial consequences. Results: The prevalence of physical abuse was 34.1% and that of sexual victimization was 21.9%. The age group of > = 50 years (aOR 1.02;95% CI 0.62-1.66; p = 0.048) was more likely to have suffered physical victimization, while living in a rural area was protective against physical (aOR 0.59; 95% CI 0.46-0.76; p = <0.001) and sexual (aOR 0.48, 95% CI 0.35-0.65; p < 0.001) victimization. High socioeconomic status (SES) (aOR 0.56; 95% CI 0.34-0.92; p = <0.001) was protective against physical victimization. Females were more likely to have been sexually victimized (aOR 3.38; 95% CI 2.47-4.64; p = <0.001), while being a Muslim (aOR 0.60; 95% CI 0.39-0.90; p = 0.045) was protective against sexual victimization. Risky sexual behavior was a negative outcome associated with physical (aOR 2.19; 95% CI 1.66-2.90; p = <0.001) and sexual (aOR 3.09; 95% CI 2.25-4.23; p < 0.001) victimization. Mental health stigma was a negative outcome associated with physical (aOR 1.03; 95% CI 1.01-1.05; p < 0.001) and sexual (aOR 1.03; 95% CI 1.01-1.05; p = 0.002) victimization. Poor adherence to oral anti-psychotic medications was a negative outcome associated with physical (aOR 1.51; 95% CI 1.13-2.00; p = 0.006) and sexual (aOR 1.39; 95% CI 0.99-1.94; p = 0.044) victimization. Conclusion: There is a high burden of physical and sexual victimization among people with SMI in central Uganda. There is need to put in place and evaluate complex interventions for improving detection and response to abusive experiences within mental health services. Public health practitioners, policymakers, and legislators should act to protect the health and rights of people with SMI in resource poor settings.

Tools for assessing child and adolescent stunting: Lookup tables, growth charts and a novel appropriate-technology "MEIRU" wallchart - a diagnostic accuracy study.

Stunting affects 149 million children worldwide and is a form of chronic malnutrition defined by low height-for-age. Surveys and intervention programmes depend on effective assessment and identification of affected individuals. Gold standard assessment is based on height-for-age Z-score (HAZ): HAZ <-2 defines stunting; HAZ <-3 defines severe stunting. However, a major problem for field-based programmes is that Z-scores can be time-intensive and challenging to calculate. We thus developed a novel wallchart that we have coined 'MEIRU wallchart' to easily and accurately identify stunted children and adolescents. Our study aim was to evaluate its performance and acceptability against other methods used in current clinical/field practice. We undertook a non-interventional diagnostic accuracy study in Malawi. We recruited 244 participants aged 8-19 years and determined each individual's stunting status using, in varying order: the MEIRU wallchart, traditional lookup tables, and traditional growth charts. All were compared against 'gold standard' HAZ, calculated using AnthroPlus WHO software. Local community healthcare workers performed all the assessments. The wallchart method was strongly preferred by both participants and staff. It had an overall accuracy of 95.5%(kappa = 0.91) and was faster than lookup tables by an average of 62.5%(41.4sec; p<0.001) per measurement. Lookup tables and growth charts had overall agreements of 59.4%(kappa = 0.36) and 61.9%(kappa = 0.31) respectively. At the HAZ-2 cut-off, the wallchart had a sensitivity of 97.6%(95%CI: 91.5-99.7) and specificity of 96.3%(95%CI: 92.1-98.6). We conclude that the MEIRU wallchart performs well and is acceptable for screening and identification of stunted children/adolescents by community-level health workers. It fulfils key criteria that justify a role in future screening programmes: easy to perform and interpret; acceptable; accurate; sensitive and specific. Potential future uses include: conducting rapid stunting prevalence surveys; identifying affected individuals for interventions. Current field methods, lookup tables and growth charts performed poorly and should be used with caution.

Metformin for the prevention of diabetes among people with HIV and either impaired fasting glucose or impaired glucose tolerance (prediabetes) in Tanzania: a Phase II randomised placebo-controlled trial.

AIMS/HYPOTHESIS: In sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA. METHODS: Adults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat. RESULTS: In total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days (p=0.068). At this visit, in the metformin and placebo arms, mean fasting glucose levels were 6.17 mmol/l (95% CI 6.03, 6.30) and 6.30 mmol/l (95% CI 6.18, 6.42), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 7.88 mmol/l (95% CI 7.65, 8.12) and 7.71 mmol/l (95% CI 7.49, 7.94), respectively. Using a linear mixed model controlling for respective baseline values, the mean difference between the metformin and placebo group (metformin-placebo) was -0.08 mmol/l (95% CI -0.37, 0.20) for fasting glucose and 0.20 mmol/l (95% CI -0.17, 0.58) for glucose levels 2 h post a 75 g glucose load. Weight was significantly lower in the metformin arm than in the placebo arm: using the linear mixed model adjusting for baseline values, the mean difference in weight was -1.47 kg (95% CI -2.58, -0.35). In total, 16/182 (8.8%) individuals had a serious adverse event (Grade 3 or Grade 4 in the Division of Acquired Immunodeficiency Syndrome [DAIDS] adverse event grading table) or died in the metformin arm compared with 18/182 (9.9%) in the placebo arm; these events were either unrelated to or unlikely to be related to the study drugs. CONCLUSIONS/INTERPRETATION: Blood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV. TRIAL REGISTRATION: The trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( www.isrctn.com/ ), registration number: ISCRTN76157257. FUNDING: This research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research.

The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study.

BACKGROUND: Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. METHODS: We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). FINDINGS: We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals ß = 1.1 (95% CI [0.411-1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR ß = 1.619 (95% CI [0.412-2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C ß = -0.164, (95% CI = [-1.329 to 1.00]; p = 0.782), and TG ß = -0.934 (CI = [-2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR ß = 1.228 (CI = [0.477-1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis ß = -1.3 ([-2.533 to -0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (ß = -0.117 (95% CI [-1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis. INTERPRETATION: In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry. FUNDING: Wellcome (220740/Z/20/Z).

Physical and psychiatric comorbidities among patients with severe mental illness as seen in Uganda.

While psychiatric and physical comorbidities in severe mental illness (SMI) have been associated with increased mortality and poor clinical outcomes, problem has received little attention in low- and middle-income countries (LMICs). This study established the prevalence of psychiatric (schizophrenia, bipolar affective disorder, and recurrent major depressive disorder) and physical (HIV/AIDS, syphilis, hypertension and obesity) comorbidities and associated factors among 1201 out-patients with SMI (schizophrenia, depression and bipolar affective disorder) attending care at two hospitals in Uganda. Participants completed an assessment battery including structured, standardised and locally translated instruments. SMIs were established using the MINI International Neuropsychiatric Interview version 7.2. We used logistic regression to determine the association between physical and psychiatric comorbidities and potential risk factors. Bipolar affective disorder was the most prevalent (66.4%) psychiatric diagnoses followed by schizophrenia (26.6%) and recurrent major depressive disorder (7.0%). Prevalence of psychiatric comorbidity was 9.1%, while physical disorder comorbidity was 42.6%. Specific comorbid physical disorders were hypertension (27.1%), obesity (13.8%), HIV/AIDS (8.2%) and syphilis (4.8%). Potentially modifiable factors independently significantly associated with psychiatric and physical comorbidities were: use of alcohol for both syphilis and hypertension comorbidities; and use of a mood stabilisers and khat in comorbidity with obesity. Only psychiatric comorbidity was positively associated with the negative outcomes of suicidality and risky sexual behaviour. The healthcare models for psychiatric care in LMICs such as Uganda should be optimised to address the high burden of psychiatric and physical comorbidities.

Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa.

The Uganda Genome Resource (UGR) is a well-characterized genomic database with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC), a population-based open cohort established in 1989. The UGR comprises genotype data on ∼5,000 and whole-genome sequence data on ∼2,000 Ugandan GPC individuals from 10 ethno-linguistic groups. Leveraging other platforms at MRC/UVRI and LSHTM Uganda Research Unit, there is opportunity for additional sample collection to expand the UGR to advance scientific discoveries. Here, we describe UGR and highlight how it is providing opportunities for discovery of novel disease susceptibility genetic loci, refining association signals at new and existing loci, developing and testing polygenic scores to determine disease risk, assessing causal relations in diseases, and developing capacity for genomics research in Africa. The UGR has the potential to develop to a comparable level of European and Asian large-scale genomic initiatives.

The influence of fasting and post-load glucose levels on maternal and neonatal outcomes in women with hyperglycaemia in pregnancy in Uganda: A prospective observational cohort study.

AIMS: The study aims to evaluate the strength of fasting versus post-load glucose levels in predicting adverse outcomes in women with hyperglycaemia in pregnancy (HIP). METHODS: Women attending antenatal clinics in urban and peri-urban Uganda had oral glucose tolerance test between 24 and 28 weeks of gestation to screen for HIP, and were followed up to collect data on maternal and neonatal outcomes. Univariable and multivariable Poisson regression models were used to estimate the relative risk adverse outcome associated with fasting hyperglycaemia alone post-load hyperglycaemia alone, or elevation of both fasting and post-load glucose levels. RESULTS: We included 3206 participants in the final analysis. HIP was associated with increased risk of Caesarean section, large for gestaional age babies, and neonatal intensive care admission. The risk was highest (2.54-fold compared to normal glycaemic women) when both FBG and post-load glucose levels were elevated. After adjustment for potential confounders, having elevated post-load glucose alone was not associated with increased risk of any of the outcomes, but elevated FBG alone increased the risk of Caesarian section by 1.36-fold. CONCLUSION: Fasting hyperglycemia appears to be more strongly associated with adverse pregnancy outcomes than post-load hyperglycaemia, but the risk is even higher in women with elevation of both fasting and post-load glucose levels.