Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa.

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multi-generational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within Africa as well as how within-Africa variation can be informative for broader variant interpretation; many variants that are rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity across Africa.

Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations.

Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. We used a downsampling approach to evaluate the quality of two cost-effective data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole-genome sequencing data. We show that low-coverage sequencing at a depth of ≥4× captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1×) performed comparably to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation; 4× sequencing detects 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, effectively identify novel variation particularly in underrepresented populations, and present opportunities to enhance variant discovery at a cost similar to traditional approaches.

Perceived barriers and opportunities for implementing an integrated psychological intervention for depression in adolescents living with HIV in Tanzania.

BACKGROUND: Adolescents living with Human Immunodeficiency Virus (HIV) have an increased risk of depression, negatively affecting their adherence to antiretroviral therapy (ART) and treatment outcomes. Integrating mental health care in HIV care and treatment settings improves comprehensive care. However, integration remains challenging in Tanzania, like in other high-burden and low-resource settings. The overall objective of this work is to inform the development of a psychological intervention for depression in adolescents living with HIV (ALWHIV). We describe perceived barriers and opportunities for implementing an integrated, evidence-based psychological intervention to manage adolescent depression in HIV care and treatment centers (HIV-CTC) from the perspectives of adolescents, caregivers, and healthcare providers (HCPs) in Dar es Salaam, Tanzania. METHODS: To inform intervention development and implementation, this study utilized a qualitative design through a phenomenological approach informed by the Consolidated Framework for Implementation Research (CFIR) to explore implementation barriers and facilitators in ALWHIV, HCPs, and caregivers. Forty-five in-depth interviews were conducted in three HIV-CTCs in Kinondoni Dar es Salaam. Audio records were transcribed verbatim and analyzed deductively through NVIVO software. RESULTS: Barriers to implementing an integrated psychological intervention to address depression in ALWHIV included (A) poor mental health awareness among caregivers, adolescents, HCPs, and policy-makers, (B) high level of stigma against mental health care, (C) poor communication between adolescents and HCPs concerning mental health care, (D) lack of contextualized intervention of proven effectiveness and guidelines of mental health care, and (E) inadequate mental health care supportive supervision and mentorship. Facilitators for implementation included supportive infrastructure, positive pressure from HIV implementing partners, tension for change, and participant's perception of the advantage of a psychological intervention as compared to just usual HIV care and treatment counseling. CONCLUSION: Despite several modifiable barriers to implementing a psychological intervention in HIV CTC, there were encouraging facilitators and opportunities for implementing an integrated, evidence-based psychological intervention to address depression in ALWHIV in Kinondoni Dar es Salaam, Tanzania.

The role of a community conversation intervention in reducing stigma related to lower limb lymphoedema in Northern Ethiopia.

BACKGROUND: Stigma related to lower-limb lymphoedema poses a major psychosocial burden to affected persons and acts as a barrier to them accessing morbidity management and disability prevention (MMDP) services. Community Conversation (CC), which actively engages community members and disseminates health information amongst them, is believed to break the vicious cycle of stigma by enhancing disease-related health literacy at the community level. METHODS: A quasi-experimental study was conducted in Northern Ethiopia to assess the role of the CC intervention in reducing stigma. In two control districts, a comprehensive and holistic MMDP care package was implemented that included physical health, mental health and psychosocial interventions, whilst in the intervention district the CC intervention was added to the MMDP care package. A total of 289 persons affected by lymphoedema and 1659 community members without lymphoedema were included in the study. RESULTS: Over the course of the intervention, in all sites, community members' knowledge about the causes of lymphoedema increased, and perceived social distance and stigmatizing attitudes towards people with lymphoedema decreased in the community, whilst experienced and internalized stigma decreased amongst affected persons. There were no significant changes for perceived social support. However, the changes were greater in the control sites overall, i.e. those districts in which the holistic care package was implemented without CC. CONCLUSION: The findings suggest that the CC intervention provides no additional stigma reduction when used alongside a holistic MMDP care package. Provision of comprehensive and holistic MMDP services may be adequate and appropriate to tackle stigma related to lower-limb lymphoedema in a resource-constrained setting like Ethiopia.

Childhood trauma associated with increased post-awakening cortisol in major depressive disorder.

BACKGROUND: Enhanced post-awakening cortisol may serve as a biological marker for individuals with major depressive disorder. However, studies comparing post-awakening cortisol between patients with major depressive disorder (MDD) and healthy controls have produced conflicting findings. The aim of this study was to investigate whether this inconsistency could be due to the effects of childhood trauma. METHODS: A total of N = 112 patients with MDD and healthy controls were divided into four groups according to the presence of childhood trauma. Saliva samples were collected at awakening and 15, 30, 45, and 60 min later. The total cortisol output and the cortisol awakening response (CAR) were calculated. RESULTS: The total post-awakening cortisol output was significantly higher in patients with MDD as compared to healthy controls, but only in those individuals reporting childhood trauma. The four groups did not differ regarding the CAR. CONCLUSIONS: Elevated post-awakening cortisol in MDD may be confined to those with a history of early life stress. Tailoring and/or augmenting of currently available treatments may be required to meet the specific needs of this population.

Co-morbid mental health conditions in people with epilepsy and association with quality of life in low- and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Comorbid mental health conditions are common in people with epilepsy and have a significant negative impact on important epilepsy outcomes, although the evidence is mostly from high-income countries. This systematic review aimed to synthesise evidence on the association between comorbid mental health conditions and quality of life and functioning among people with epilepsy living in low- and middle income countries (LMICs). METHODS: We searched PubMed, EMBASE, CINAHL, Global Index medicus (GID) and PsycINFO databases from their dates of inception to January 2022. Only quantiative observational studies were included. Meta-analysis was conducted for studies that reported the same kind of quality of life and functioning outcome. Cohen's d was calculated from the mean difference in quality-of-life score between people with epilepsy who did and did not have a comorbid depression or anxiety condition. The protocol was registered with PROSPERO: CRD42020161487. RESULTS: The search strategy identified a total of 2,101 articles, from which 33 full text articles were included. Depression was the most common comorbid mental health condition (33 studies), followed by anxiety (16 studies). Meta-analysis was conducted on 19 studies reporting quality of life measured with the same instrument. A large standardized mean effect size (ES) in quality of life score was found (pooled ES = -1.16, 95% confidence interval (CI) - 1.70, - 0.63) between those participants with comorbid depression compared to non-depressed participants. There was significant heterogeneity between studies (I2 = 97.6%, p < 0.001). The median ES (IQR) was - 1.20 (- 1.40, (- 0.64)). An intermediate standard effect size for anxiety on quality of life was also observed (pooled ES = -0.64, 95% CI - 1.14, - 0.13). There was only one study reporting on functioning in relation to comorbid mental health conditions. CONCLUSION: Comorbid depression in people with epilepsy in LMICs is associated with poor quality of life although this evidence is based on highly heterogeneous studies. These findings support calls to integrate mental health care into services for people with epilepsy in LMICs. Future studies should use prospective designs in which the change in quality of life in relation to mental health or public health interventions across time can be measured.

Prevalence and characteristics of unipolar mania in a low-income country setting: population-based data from the Butajira cohort, rural Ethiopia.

PURPOSE: Previous research suggests unipolar mania, i.e., bipolar disorder without depression, to be more common in low-income countries. However, longitudinal population-based studies on unipolar mania from low-income countries are lacking. This study therefore examined unipolar mania, in Butajira, Ethiopia, and associations with possible determinants. METHODS: Key informants and 68,378 screenings with the Composite International Diagnostic Interviews (CIDI 2.1) identified suspected cases of bipolar disorder. Diagnosis was confirmed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN 2.1) (n = 2,285). 315 participants with bipolar disorder were recruited and followed up for an average of 2.5 years. Unipolar mania was defined when illness episodes consisted of at least two manic relapses. 240 cases had sufficient data to ascertain course of disorder. RESULTS: 41.7% (100 of 240 cases) of participants had unipolar mania. Unipolar mania was associated with less suicidal ideation (0% vs. 26.4%, p < 0.001), less suicidal thoughts (occasionally/often: 1%/3% vs. 19.6%/21%, p < 0.001), and less history of suicide attempt (2% vs. 11.6%, p = 0.01). The participants with unipolar mania tended to have better social functioning (OR = 2.05, p = 0.07) and less alcohol use (20.8% vs. 31.4%, p = 0.07). The study was partly based on retrospective data liable to recall bias. Some cases defined as unipolar mania in our study may later develop depression. CONCLUSION: Previous cross-sectional studies finding high proportions of unipolar mania in low-income countries appear supported. Unipolar mania trended towards better social functioning and was associated with lower suicidality. Future unipolar mania specifications could inform treatment and prognostic estimates of bipolar disorder.

Challenges for research uptake for health policymaking and practice in low- and middle-income countries: a scoping review.

BACKGROUND: An estimated 85% of research resources are wasted worldwide, while there is growing demand for context-based evidence-informed health policymaking. In low- and middle-income countries (LMICs), research uptake for health policymaking and practice is even lower, while little is known about the barriers to the translation of health evidence to policy and local implementation. We aimed to compile the current evidence on barriers to uptake of research in health policy and practice in LMICs using scoping review. METHODS: The scoping review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses-extension for Scoping Reviews (PRISMA-ScR) and the Arksey and O'Malley framework. Both published evidence and grey literature on research uptake were systematically searched from major databases (PubMed, Cochrane Library, CINAHL (EBSCO), Global Health (Ovid)) and direct Google Scholar. Literature exploring barriers to uptake of research evidence in health policy and practice in LMICs were included and their key findings were synthesized using thematic areas to address the review question. RESULTS: A total of 4291 publications were retrieved in the initial search, of which 142 were included meeting the eligibility criteria. Overall, research uptake for policymaking and practice in LMICs was very low. The challenges to research uptake were related to lack of understanding of the local contexts, low political priority, poor stakeholder engagement and partnership, resource and capacity constraints, low system response for accountability and lack of communication and dissemination platforms. CONCLUSION: Important barriers to research uptake, mainly limited contextual understanding and low participation of key stakeholders and ownership, have been identified. Understanding the local research and policy context and participatory evidence production and dissemination may promote research uptake for policy and practice. Institutions that bridge the chasm between knowledge formation, evidence synthesis and translation may play critical role in the translation process.

Comparative efficacy and safety of anti-infective drugs for patients with mild to severe COVID-19: A systematic review and network meta-analysis of randomized controlled trials.

Background: Different anti-infective drugs have been proposed for the treatment of patients with COVID-19. We carried out a network meta-analysis to assess their relative efficacy and safety. Methods: We searched relevant databases for all randomized controlled trials that reported the efficacy and or safety of any anti-infective drugs published up to April 30, 2022 for different outcomes. We did both pairwise and network meta-analysis with 95% confidence intervals using a fixed-effect model. We assessed studies for quality of evidence using an extension of the standard Grading of Recommendations, Assessment, Development and Evaluation approach considering P<0.05 to be statistically significant. Results: We included 68 RCTs for 27,680 participants on 22 anti-infective drugs. For clinical recovery at 14 days Ivermectin (OR= 3.00, 95%CI: [1.82; 4.96]; p < 0.0001; moderate certainty evidence), Baricitinib plus Remdesivir (OR= 2.20, 95%CI: [1.35; 3.53]; p = 0.005; low certainty evidence), and Favipiravir (OR= 2.16, 95%CI: [1.27; 3.68]; p = 0.004; moderate certainty evidence) were statistically effective than standard of care. There was no statistically significant difference between treatments for the viral clearance at 14 days outcome and standard of care. In terms of death outcome, only combined therapy of Baricitinib and Remdesivir showed statistically significant risks of ratio (RR= 0.47, 95%CI: [0.23; 0.99]; p = 0.03). Arbidol (RR= 0.46, 95% CI: [0.23; 0.95]; p = 0.04) was statistically safe drug than standard of care. Conclusion: This Network Meta-analysis suggests that Baricitinib plus Remdesivir is more effective than the other anti-infective drugs in treating patients with COVID-19 in terms of clinical recovery at 14 days, mortality and adverse events outcomes.

Effectiveness of a digital medication event reminder and monitor device for patients with tuberculosis (SELFTB): a multicenter randomized controlled trial.

BACKGROUND: Tuberculosis remains the leading cause of death from a single infectious disease worldwide. Trials evaluating digital adherence technologies for tuberculosis in low- and middle-income countries are urgently needed. We aimed to assess whether a digital medication event reminder and monitor (MERM) device-observed self-administered therapy improves adherence and treatment outcomes in patients with tuberculosis compared with the standard in-person directly observed therapy (DOT). METHODS: We did a two-arm, attention-controlled, effectiveness-implementation type 2 hybrid, randomized controlled trial in ten healthcare facilities in Addis Ababa, Ethiopia. We included adults with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary tuberculosis who were eligible to start anti-tuberculosis therapy. Participants were randomly assigned (1:1) to receive a 15-day tuberculosis medication supply in the evriMED500® MERM device to self-administer and return every 15 days (intervention arm) or visit the healthcare facilities each day to swallow their daily dose with DOT by healthcare providers (control arm). Both arms were followed throughout the standard two-month intensive treatment phase (2RHZE). For control participants, some provider-approved take-home doses might be allowed for extenuating circumstances in real-world practice. Data were collected on patient information (demographic, socioeconomic, behavioral, social, and clinical information), medication adherence measures (MERM vs. DOT records, IsoScreenTM urine colorimetric isoniazid test, and adherence self-report), and clinical measures (pre-post treatment sputum Xpert MTB/RIF assay or microscopy, and adverse treatment outcomes). The intention-to-treat (ITT) primary endpoints were (1) individual-level percentage adherence over the two-month intensive phase measured by adherence records compiled from MERM device vs. DOT records that also considered all take-home doses as having been ingested and (2) sputum smear conversion following the standard two-month intensive phase treatment. Secondary endpoints were (1) individual-level percentage adherence over the two-month intensive phase measured by adherence records compiled from the MERM device vs. DOT records that considered all take-home doses as not ingested, (2) negative IsoScreen urine isoniazid test, (3) adverse treatment outcome (having at least one of the three events: treatment not completed; death; or loss to follow-up), and (4) self-reported adherence. The MERM device has an electronic module and a medication container that records adherence, stores medication, emits audible and visual on-board alarms to remind patients to take their medications on time and refill, and enables providers to download the data and monitor adherence. RESULTS: Participants were enrolled into the study between 02 June 2020 and 15 June 2021, with the last participant completing follow-up on 15 August 2021. A total of 337 patients were screened for eligibility, of whom 114 were randomly assigned and included in the final analysis [57 control and 57 intervention participants]. Participants were 64.9% male, 15% with HIV, 10.5% retreatment, and 5.3% homeless. Adherence to TB medication was comparable between the intervention arm [geometric mean percentage (GM%) 99.01%, geometric standard deviation (GSD) 1.02] and the control arm [GM% 98.97%, GSD 1.04] and was within the prespecified margin for non-inferiority [mean ratio (MR) 1.00 (95% CI 0.99-1.01); p = 0.954]. The intervention arm was significantly superior to the control arm in the secondary analysis that considered all take-home doses in the control were not ingested [control GM% 77.71 (GSD 1.57), MR 1.27 (95% CI 1.33-1.43)]. Urine isoniazid testing was done on 443 (97%) samples from 114 participants; 13 participants had at least one negative result; a negative test was significantly more common among the control group compared with the intervention group [11/57 (19.3%) vs 2/57 (3.5%); p = 0.008]. There was no significant difference between the control and intervention arms for smear conversion [55 (98.2%) vs 52 (100%); p>0.999], adverse treatment outcomes [0 vs 1 (1.9%); p = 0.48], and self-report non-adherence [5 (8.9%) vs 1 (1.9%); p = 0.21]. CONCLUSIONS: In this randomized trial of patients with drug-sensitive pulmonary tuberculosis, medication adherence among participants assigned to MERM-observed self-administered therapy was non-inferior and superior by some measures when compared with the standard in-person DOT. Further research is needed to understand whether adherence in the intervention is primarily driven by allowing self-administered therapy which reduced challenges of repeated clinic visits or by the adherence support provided by the MERM system. To avoid contributing to patient barriers with DOT, tuberculosis medical programs should consider alternatives such as medication event monitors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04216420.