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.

Prevalence and correlates of common mental disorders among participants of the Uganda Genome Resource: Opportunities for psychiatric genetics research.

Genetics research has potential to alleviate the burden of mental disorders in low- and middle-income-countries through identification of new mechanistic pathways which can lead to efficacious drugs or new drug targets. However, there is currently limited genetics data from Africa. The Uganda Genome Resource provides opportunity for psychiatric genetics research among underrepresented people from Africa. We aimed at determining the prevalence and correlates of major depressive disorder (MDD), suicidality, post-traumatic stress disorder (PTSD), alcohol abuse, generalised anxiety disorder (GAD) and probable attention-deficit hyperactivity disorder (ADHD) among participants of the Uganda Genome Resource. Standardised tools assessed for each mental disorder. Prevalence of each disorder was calculated with 95% confidence intervals. Multivariate logistic regression models evaluated the association between each mental disorder and associated demographic and clinical factors. Among 985 participants, prevalence of the disorders were: current MDD 19.3%, life-time MDD 23.3%, suicidality 10.6%, PTSD 3.1%, alcohol abuse 5.7%, GAD 12.9% and probable ADHD 9.2%. This is the first study to determine the prevalence of probable ADHD among adult Ugandans from a general population. We found significant association between sex and alcohol abuse (adjusted odds ratio [AOR] = 0.26 [0.14,0.45], p < 0.001) and GAD (AOR = 1.78 [1.09,2.49], p = 0.019) respectively. We also found significant association between body mass index and suicidality (AOR = 0.85 [0.73,0.99], p = 0.041), alcohol abuse (AOR = 0.86 [0.78,0.94], p = 0.003) and GAD (AOR = 0.93 [0.87,0.98], p = 0.008) respectively. We also found a significant association between high blood pressure and life-time MDD (AOR = 2.87 [1.08,7.66], p = 0.035) and probable ADHD (AOR = 1.99 [1.00,3.97], p = 0.050) respectively. We also found a statistically significant association between tobacco smoking and alcohol abuse (AOR = 3.2 [1.56,6.67], p = 0.002). We also found ever been married to be a risk factor for probable ADHD (AOR = 2.12 [0.88,5.14], p = 0.049). The Uganda Genome Resource presents opportunity for psychiatric genetics research among underrepresented people from Africa.

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.

Long-term impact of an integrated HIV/non-communicable disease care intervention on patient retention in care and clinical outcomes in East Africa.

OBJECTIVE: To describe rates of retention in care and control of hypertension, diabetes and HIV among participants receiving integrated care services for a period of up to 24 months in East Africa. METHODS: Between 5 October 2018 and 23 June 2019 participants enrolled into a prospective cohort study evaluating the feasibility of integrated care delivery for HIV, diabetes and hypertension from a single point of care in Tanzania and Uganda (MOCCA study). Integrated care clinics were established in 10 primary healthcare facilities and care was provided routinely according to national guidelines. Initial follow-up was 12 months. Outcomes were rates of retention in care, proportions of participants with controlled hypertension (blood pressure <140/90 mmHg), diabetes (fasting blood glucose <7.0 mmol/L) and HIV (plasma viral load <1000 copies/ml). The study coincided with the COVID-19 pandemic response. Afterwards, all participants were approached for extended follow-up by a further 12 months in the same clinics. We evaluated outcomes of the cohort at the end of long-term follow-up. RESULTS: The MOCCA study enrolled 2273 participants of whom 1911 (84.5%) were retained in care after a median follow-up of 8 months (Interquartile range: 6.8-10.7). Among these, 1283/1911 (67.1%) enrolled for a further year of follow-up, 458 (24.0%) were unreachable, 71 (3.7%) reverted to vertical clinics (clinics providing services dedicated to study conditions), 31 (1.6%) died and 68 (3.6%) refused participation. Among participants who enrolled for longer follow-up, mean age was 51.4 ± 11.7 years, 930 (72.5%) were female and 509 (39.7%) had multiple chronic conditions. Overall, 1236 (96.3%) [95% confidence interval 95.2%-97.3%] participants were retained in care, representing 1236/2273 (54.3%) [52.3%-56.4%] of participants ever enrolled in the study. Controlled hypertension, diabetes and HIV at the end of follow-up was, 331/618 (53.6%) [49.5%-57.5%], 112/354 (31.6%) [26.8%-36.8%] and 332/343 (96.7%) [94.3%-98.4%] respectively. CONCLUSION: Integrated care can achieve high rates of retention in care long term, but control of blood pressure and blood sugar remains low.

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.

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans.

Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10-8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

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.

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.

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.

Understanding the pathogenesis of lean non-autoimmune diabetes in an African population with newly diagnosed diabetes.

AIMS/HYPOTHESIS: Apparent type 2 diabetes is increasingly reported in lean adult individuals in sub-Saharan Africa. However, studies undertaking robust clinical and metabolic characterisation of lean individuals with new-onset type 2 diabetes are limited in this population. This cross-sectional study aimed to perform a detailed clinical and metabolic characterisation of newly diagnosed adult patients with diabetes in Uganda, in order to compare features between lean and non-lean individuals. METHODS: Socio-demographic, clinical, biophysical and metabolic (including oral glucose tolerance test) data were collected on 568 adult patients with newly diagnosed diabetes. Participants were screened for islet autoantibodies to exclude those with autoimmune diabetes. The remaining participants (with type 2 diabetes) were then classified as lean (BMI <25 kg/m2) or non-lean (BMI ≥25 kg/m2), and their socio-demographic, clinical, biophysical and metabolic characteristics were compared. RESULTS: Thirty-four participants (6.4%) were excluded from analyses because they were positive for pancreatic autoantibodies, and a further 34 participants because they had incomplete data. For the remaining 500 participants, the median (IQR) age, BMI and HbA1c were 48 years (39-58), 27.5 kg/m2 (23.6-31.4) and 90 mmol/mol (61-113) (10.3% [7.7-12.5]), respectively, with a female predominance (approximately 57%). Of the 500 participants, 160 (32%) and 340 (68%) were lean and non-lean, respectively. Compared with non-lean participants, lean participants were mainly male (60.6% vs 35.3%, p<0.001) and had lower visceral adiposity level (5 [4-7] vs 11 [9-13], p<0.001) and features of the metabolic syndrome (uric acid, 246.5 [205.0-290.6] vs 289 [234-347] µmol/l, p<0.001; leptin, 660.9 [174.5-1993.1] vs 3988.0 [1336.0-6595.0] pg/ml, p<0.001). In addition, they displayed markedly reduced markers of beta cell function (oral insulinogenic index 0.8 [0.3-2.5] vs 1.6 [0.6-4.6] pmol/mmol; 120 min serum C-peptide 0.70 [0.33-1.36] vs 1.02 [0.60-1.66] nmol/l, p<0.001). CONCLUSIONS/INTERPRETATION: Approximately one-third of participants with incident adult-onset non-autoimmune diabetes had BMI <25 kg/m2. Diabetes in these lean individuals was more common in men, and predominantly associated with reduced pancreatic secretory function rather than insulin resistance. The underlying pathological mechanisms are unclear, but this is likely to have important management implications.

Patient and health provider costs of integrated HIV, diabetes and hypertension ambulatory health services in low-income settings - an empirical socio-economic cohort study in Tanzania and Uganda.

BACKGROUND: Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed. METHODS: 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations. RESULTS: Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics' mean efficiency benchmark score was 0.86 (range 0.30-1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2-23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities. CONCLUSION: Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa's ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes.

Handgrip strength as a simple measure for screening prediabetes and type 2 diabetes mellitus risk among adults in Malawi: A cross-sectional study.

OBJECTIVE: Handgrip strength, a simple measure of muscle strength, has been reported as a predictor of both prediabetes and type 2 diabetes mellitus (T2DM) and has been suggested for screening prediabetes and T2DM risk. This study examined the relationship of handgrip strength with prediabetes and T2DM among rural- and urban-dwelling adults in Malawi. METHODS: This was a cross-sectional study nested in a follow-up study of prediabetic and prehypertensive individuals identified during an extensive noncommunicable disease survey in Malawi. A total of 261 participants (women: 64%) were recruited. Univariate and multivariate binary logistic regression analyses were performed to examine the association of prediabetes and T2DM with relative handgrip strength. RESULTS: The mean (SD) age of the participants was 49.7 (13.6) years, and 54.0% were between the ages of 40 and 59 years. The mean (SD) absolute handgrip strength and relative handgrip strength were 28.8 (7.3) kg and 1.16 (0.40) kg/BMI, respectively, and the mean relative handgrip strength differed significantly (p < 0.001) by T2DM status. In unadjusted model, the odds ratio (OR) of prediabetes and T2DM per unit increase in relative handgrip strength was 0.12 [95% CI; 0.04-0.33]. The result remained significant after adjusting for age (continuous), sex, place of study, hypertension, dyslipidaemia and level of education (aOR [95% CI]; 0.19 [0.03-0.95]). CONCLUSIONS: The findings suggest that handgrip strength could be a relatively inexpensive, noninvasive measure for contributing to risk scores to identify high-risk individuals for screening diabetes in SSA.

Antenatal management and maternal/fetal outcomes associated with hyperglycaemia in pregnancy (HIP) in Uganda; a prospective cohort study.

BACKGROUND: Hyperglycaemia in pregnancy (HIP) is associated with complications for both mother and baby. The prevalence of the condition is likely to increase across Africa as the continent undergoes a rapid demographic transition. However, little is known about the management and pregnancy outcomes associated with HIP in the region, particularly less severe forms of hyperglycaemia. It is therefore important to generate local data so that resources may be distributed effectively. The aim of this study was to describe the antenatal management and maternal/fetal outcomes associated with HIP in Ugandan women. METHODS: A prospective cohort study of 2917 pregnant women in five major hospitals in urban/semi-urban central Uganda. Women were screened with oral glucose tolerance test (OGTT) at 24-28 weeks of gestation. Cases of gestational diabetes (GDM) and diabetes in pregnancy (DIP) were identified (WHO 2013 diagnostic criteria) and received standard care. Data was collected on maternal demographics, anthropometrics, antenatal management, umbilical cord c-peptide levels, and pregnancy outcomes. RESULTS: Two hundred and seventy-six women were diagnosed with HIP (237 classified as GDM and 39 DIP). Women had between one and four fasting capillary blood glucose checks during third trimester. All received lifestyle advice, one quarter (69/276) received metformin therapy, and one woman received insulin. HIP was associated with large birthweight (unadjusted relative risk 1.30, 95% CI 1.00-1.68), Caesarean delivery (RR 1.34, 95% CI 1.14-1.57) and neonatal hypoglycaemia (RR 4.37, 95% CI 1.36-14.1), but not perinatal mortality or preterm birth. Pregnancy outcomes were generally worse for women with DIP compared with GDM. CONCLUSION: HIP is associated with significant adverse pregnancy outcomes in this population, particularly overt diabetes in pregnancy. However pregnancy outcomes in women with milder forms of hyperglycaemia are similar to those with normoglycaemic pregnancies. Intervention strategies are required to improve current monitoring and management practice, and more research needed to understand if this is a cost-effective way of preventing poor perinatal outcomes.

A comparison of the associations between adiposity and lipids in Malawi and the United Kingdom.

BACKGROUND: The prevalence of excess adiposity, as measured by elevated body mass index (BMI) and waist-hip ratio (WHR), is increasing in sub-Saharan African (SSA) populations. This could add a considerable burden of cardiovascular and metabolic diseases for which these populations are currently ill-prepared. Evidence from white, European origin populations shows that higher adiposity leads to an adverse lipid profile; whether these associations are similar in all SSA populations requires further exploration. This study compared the association of BMI and WHR with lipid profile in urban Malawi with a contemporary cohort with contrasting socioeconomic, demographic, and ethnic characteristics in the United Kingdom (UK). METHODS: We used data from 1248 adolescents (mean 18.7 years) and 2277 Malawian adults (mean 49.8 years), all urban-dwelling, and from 3201 adolescents (mean 17.8 years) and 6323 adults (mean 49.7 years) resident in the UK. Adiposity measures and fasting lipids were assessed in both settings, and the associations of BMI and WHR with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were assessed by sex and age groups in both studies. RESULTS: Malawian female adults were more adipose and had more adverse lipid profiles than their UK counterparts. In contrast, Malawian adolescent and adult males were leaner and had more favourable lipid profiles than in the UK. Higher BMI and WHR were associated with increased TC, LDL-C and TG and reduced HDL-C in both settings. The magnitude of the associations of BMI and WHR with lipids was mostly similar or slightly weaker in the Malawian compared with the UK cohort in both adolescents and adults. One exception was the stronger association between increasing adiposity and elevated TC and LDL-C in Malawian compared to UK men. CONCLUSIONS: Malawian adult women have greater adiposity and more adverse lipid profiles compared with their UK counterparts. Similar associations of adiposity with adverse lipid profiles were observed for Malawian and UK adults in most age and sex groups studied. Sustained efforts are urgently needed to address the excess adiposity and adverse lipid profiles in Malawi to mitigate a future epidemic of cardio-metabolic disease among the poorest populations.

Prevalence and risk factors for chronic kidney disease of unknown cause in Malawi: a cross-sectional analysis in a rural and urban population.

BACKGROUND: An epidemic of chronic kidney disease of unknown cause (CKDu) is occurring in rural communities in tropical regions of low-and middle-income countries in South America and India. Little information is available from Southern African countries which have similar climatic and occupational characteristics to CKDu-endemic countries. We investigated whether CKDu is prevalent in Malawi and identified its potential risk factors in this setting. METHODS: We conducted a cross-sectional study from January-August 2018 collecting bio samples and anthropometric data in two Malawian populations. The sample comprised adults > 18 years (n = 821) without diabetes, hypertension, and proteinuria. Estimates of glomerular filtration rate (eGFR) were calculated using the CKD-EPI equation. Linear and logistic regression models were applied with potential risk factors, to estimate risk of reduced eGFR. RESULTS: The mean eGFR was 117.1 ± 16.0 ml/min per 1.73m2 and the mean participant age was 33.5 ± 12.7 years. The prevalence of eGFR< 60 was 0.2% (95% confidence interval (95% CI) 0.1, 0.9); the prevalence of eGFR< 90 was 5% (95% CI =3.2, 6.3). We observed a higher prevalence in the rural population (5% (3.6, 7.8)), versus urban (3% (1.4, 6.7)). Age and BMI were associated with reduced eGFR< 90 [Odds ratio (OR) (95%CI) =3.59 (2.58, 5.21) per ten-year increment]; [OR (95%CI) =2.01 (1.27, 3.43) per 5 kg/m2 increment] respectively. No increased risk of eGFR < 90 was observed for rural participants [OR (95%CI) =1.75 (0.50, 6.30)]. CONCLUSIONS: Reduced kidney function consistent with the definition of CKDu is not common in the areas of Malawi sampled, compared to that observed in other tropical or sub-tropical countries in Central America and South Asia. Reduced eGFR< 90 was related to age, BMI, and was more common in rural areas. These findings are important as they contradict some current hypothesis that CKDu is endemic across tropical and sub-tropical countries. This study has enabled standardized comparisons of impaired kidney function between and within tropical/subtropical regions of the world and will help form the basis for further etiological research, surveillance strategies, and the implementation and evaluation of interventions.

How to estimate glomerular filtration rate in sub-Saharan Africa: design and methods of the African Research into Kidney Diseases (ARK) study.

BACKGROUND: Chronic kidney disease (CKD) is a substantial cause of morbidity and mortality worldwide with disproportionate effects in sub-Saharan Africa (SSA). The optimal methods to estimate glomerular filtration rate (GFR) and therefore to determine the presence of CKD in SSA are uncertain. We plan to measure iohexol excretion to accurately determine GFR in Malawi, South Africa and Uganda. We will then assess the performance of existing equations to estimate GFR and determine whether a modified equation can better improve estimation of GFR in sub-Saharan Africa. METHODS: The African Research on Kidney Disease (ARK) study is a three-country study embedded within existing cohorts. We seek to enrol 3000 adults > 18 years based on baseline serum creatinine. Study procedures include questionnaires on socio-demographics and established risk factors for kidney disease along with anthropometry, body composition, blood pressure, blood chemistry and urine microscopy and albuminuria. We will measure GFR (mGFR) by plasma clearance of iohexol at 120, 180 and 240 min. We will compare eGFR determined by established equations with mGFR using Bland-Altman plots. We will use regression methods to estimate GFR and compare the newly derived model with existing equations. DISCUSSION: Through the ARK study, we aim to establish the optimal approach to estimate GFR in SSA. The study has the advantage of drawing participants from three countries, which will increase the applicability of the findings across the region. It is also embedded within established cohorts that have longitudinal information and serial measures that can be used to characterize kidney disease over a period of time. This will help to overcome the limitations of previous research, including small numbers, selected population sub-groups, and lack of data on proteinuria. The ARK collaboration provides an opportunity for close working partnerships across different centres, using standardized protocols and measurements, and shared bio-repositories. We plan to build on the collaboration for this study for future work on kidney disease in sub-Saharan Africa, and welcome additional partners from across the continent.

Community-Level Knowledge and Perceptions of Stroke in Rural Malawi.

Background and Purpose- The incidence of stroke in Malawi is unknown but major risk factors, including hypertension, obesity, and diabetes mellitus, are highly prevalent. We sought to understand community-level knowledge about stroke. Methods- A population-based cross-sectional study was conducted in rural Malawi (2016-2017). Adults aged ≥15 years were randomly selected and interviewed about their knowledge and perceptions of stroke symptoms, risk factors, and prevention. Logistic regression was used to investigate sociodemographic factors associated with stroke knowledge. Results- Of 812 selected, 739 (91% response rate) were seen and consented; 57% were female, and the median age was 52.0 years. Knowledge of stroke was poor: 71% knew no (correct) risk factors. Witchcraft (20.6%) was mentioned as frequently as hypertension (19.8%) as a cause. Knowledge of stroke was greatest in the most educated and wealthy and lowest in men, the never married, and the youngest age group. HIV-positive individuals had higher knowledge of prevention (odds ratio, 2.91; 95% CI, 1.21-7.03) than HIV negative individuals. Conclusions- Knowledge about stroke is very low in this community, particularly among the least educated and poor. Programs to support prevention, early recognition, and timely hospital presentation after a stroke are needed.

Burden, risk factors and maternal and offspring outcomes of gestational diabetes mellitus (GDM) in sub-Saharan Africa (SSA): a systematic review and meta-analysis.

BACKGROUND: The burden, determinants and outcomes of gestational diabetes mellitus (GDM) in sub-Saharan Africa are not known. We summarized existing evidence on the prevalence, risk factors and complications of GDM in the region. METHODS: PubMed was searched from inception to January 31st 2019. Studies were included if carried out in any of the sub-Saharan Africa countries and were available as abstracts or full texts. Interventional studies and those only including qualitative data were excluded. We employed random effects modelling to estimate the pooled GDM prevalence and risk ratios (RRs) for risk factors and outcomes of GDM and their 95%CI. RESULTS: 283 papers were identified in the initial search, 33 of which met the inclusion criteria. Data on GDM burden suggest a pooled prevalence of 9% (95%CI, 7-12%). Family history of type 2 diabetes and previous history of GDM, macrosomia, stillbirth and abortion were important risk factors of GDM. In addition, being overweight or obese, over 25 years of age or hypertensive increased the risk of GDM. In terms of complications, GDM more than doubles the risk macrosomia (RR; 95%CI: 2.2; 1.1-4.4). CONCLUSIONS: There is a high burden of gestational diabetes mellitus in sub-Saharan Africa, but more studies are needed to document locally important risk factors as well as maternal and offspring outcomes. Interventions to reduce obesity among older African women might lead to reduced risk of GDM in sub-Saharan Africa.

Brain MRI and cognitive function seven years after surviving an episode of severe acute malnutrition in a cohort of Malawian children.

OBJECTIVE: To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children. DESIGN: Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children. SETTING: Blantyre, Malawi.ParticipantsChildren discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children. RESULTS: SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73). CONCLUSIONS: Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.

A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi (the Cooking and Pneumonia Study): a cluster randomised controlled trial.

BACKGROUND: WHO estimates exposure to air pollution from cooking with solid fuels is associated with over 4 million premature deaths worldwide every year including half a million children under the age of 5 years from pneumonia. We hypothesised that replacing open fires with cleaner burning biomass-fuelled cookstoves would reduce pneumonia incidence in young children. METHODS: We did a community-level open cluster randomised controlled trial to compare the effects of a cleaner burning biomass-fuelled cookstove intervention to continuation of open fire cooking on pneumonia in children living in two rural districts, Chikhwawa and Karonga, of Malawi. Clusters were randomly allocated to intervention and control groups using a computer-generated randomisation schedule with stratification by site, distance from health centre, and size of cluster. Within clusters, households with a child under the age of 4·5 years were eligible. Intervention households received two biomass-fuelled cookstoves and a solar panel. The primary outcome was WHO Integrated Management of Childhood Illness (IMCI)-defined pneumonia episodes in children under 5 years of age. Efficacy and safety analyses were by intention to treat. The trial is registered with ISRCTN, number ISRCTN59448623. FINDINGS: We enrolled 10 750 children from 8626 households across 150 clusters between Dec 9, 2013, and Feb 28, 2016. 10 543 children from 8470 households contributed 15 991 child-years of follow-up data to the intention-to-treat analysis. The IMCI pneumonia incidence rate in the intervention group was 15·76 (95% CI 14·89-16·63) per 100 child-years and in the control group 15·58 (95% CI 14·72-16·45) per 100 child-years, with an intervention versus control incidence rate ratio (IRR) of 1·01 (95% CI 0·91-1·13; p=0·80). Cooking-related serious adverse events (burns) were seen in 19 children; nine in the intervention and ten (one death) in the control group (IRR 0·91 [95% CI 0·37-2·23]; p=0·83). INTERPRETATION: We found no evidence that an intervention comprising cleaner burning biomass-fuelled cookstoves reduced the risk of pneumonia in young children in rural Malawi. Effective strategies to reduce the adverse health effects of household air pollution are needed. FUNDING: Medical Research Council, UK Department for International Development, and Wellcome Trust.