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.

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.

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.

Factor structure of psychosis screening questionnaire in Ugandan adults.

BACKGROUND: Psychotic disorders are common and contribute significantly to morbidity and mortality of people with psychiatric diseases. Therefore, early screening and detection may facilitate early intervention and reduce adverse outcomes. Screening tools that lay persons can administer are particularly beneficial in low resource settings. However, there is limited research evaluating the validity of psychosis screening instruments in Uganda. We aimed to assess the construct validity and psychometric properties of the Psychosis Screening Questionnaire (PSQ) in Uganda in a population with no history of a psychotic disorder. METHODS: The sample consisted of 2101 Ugandan adults participating as controls in a larger multi-country case-control study on psychiatric genetics who were recruited between February 2018 and March 2020. Participants were individuals seeking outpatient general medical care, caretakers of individuals seeking care, and staff or students recruited from five medical facilities that were age 18 years or older and able to provide consent. Individuals were excluded who had acute levels of alcohol or substance use, including being under inpatient hospitalization or acute medical care for one of these conditions. We used confirmatory factor analysis (CFA) and item response theory (IRT) to evaluate the factor structure and item properties of the PSQ. RESULTS: The overall prevalence screening positive for psychotic symptoms was 13.9% 95% CI (12.4,15.4). "Strange experiences" were the most endorsed symptoms 6.6% 95% CI (5.6,7.8). A unidimensional model seemed to be a good model or well-fitting based on fit indices including the root mean square error of approximation (RMSEA of 0.00), comparative fit index (CFI of 1.000), and Tucker-Lewis Index (TLI of 1.000). The most discriminating items along the latent construct of psychosis were items assessing thought disturbance followed by items assessing paranoia, with a parameter (discrimination) value of 2.53 and 2.40, respectively. CONCLUSION: The PSQ works well in Uganda as an initial screening tool for moderate to high-level of psychotic symptoms.

Evaluation of the psychometric properties of the UBACC questionnaire in a multi-country psychiatric study in Africa.

BACKGROUND: The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) is a tool to assess the capacity of participants to consent in psychiatric research. However, little is known about the psychometric properties in low and middle-income countries. This study aimed to examine the psychometric properties of the UBACC. METHODS: We examined the reliability, latent factor structure, and item response of the first attempt of the UBACC items in a sample of 32,208 adults (16,467 individuals with psychosis and 15,741 controls) in Ethiopia, Kenya, South Africa, and Uganda; exploring these properties in the full sample and stratified by country, diagnostic status, sex, and ethnolinguistic language groups. RESULTS: Exploratory factor analysis (EFA) suggested a two-factor model for the overall sample. However, a three-factor model was more appropriate when examining the latent structure across country, language, and sex. Confirmatory factor analyses (CFA) revealed an adequately fitting three-factor model for the full sample and across country, sex, and language. A two-factor model, however, was more appropriate for English and Amharic languages. Across all groups, the internal consistency of the UBACC was low, indicating below-threshold reliability (Cronbach's α (95 % CI = 0.58 (0.57-0.59). Using a multidimensional item-response theory framework for the full sample revealed that UBACC item 8, measuring understanding of the benefits of study participation, was the most discriminating item. Many of the other items had below-threshold discriminating characteristics. CONCLUSION: EFA and CFA converged towards a two and three-dimensional structure for the UBACC, in line with the developers of the original scale. The differences in properties between populations and language groups, low internal consistency, and below-threshold item functioning suggest that investigations into the cultural and linguistic nuances are still warranted. Understanding the utility of consent tools, such as the UBACC, in underrepresented populations will be a part of the larger process which ensures that research participants are adequately protected.

Relationships between trauma types and psychotic symptoms: A network analysis of patients with psychotic disorders in a large, multi-country study in East Africa.

BACKGROUND: The link between trauma exposure and psychotic disorders is well-established. Further, specific types of trauma may be associated with specific psychotic symptoms. Network analysis is an approach that can advance our understanding of the associations across trauma types and psychotic symptoms. METHODS: We conducted a network analysis with data from 16,628 adult participants (mean age [standard deviation] = 36.3 years [11.5]; 55.8% males) with psychotic disorders in East Africa recruited between 2018 and 2023. We used the Life Events Checklist and the Mini International Neuropsychiatric Interview to determine whether specific trauma types experienced over the life course and specific psychotic symptoms were connected. We used an Ising model to estimate the network connections and bridge centrality statistics to identify nodes that may influence trauma types and psychotic symptoms. RESULTS: The trauma type "exposure to a war zone" had the highest bridge strength, betweenness, and closeness. The psychotic symptom "odd or unusual beliefs" had the second highest bridge strength. Exposure to a war zone was directly connected to visual hallucinations, odd or unusual beliefs, passivity phenomena, and disorganized speech. Odd or unusual beliefs were directly connected to transportation accidents, physical assault, war, and witnessing sudden accidental death. CONCLUSION: Specific trauma types and psychotic symptoms may interact bidirectionally. Screening for psychotic symptoms in patients with war-related trauma and evaluating lifetime trauma in patients with odd or unusual beliefs in clinical care may be considered points of intervention to limit stimulating additional psychotic symptoms and trauma exposure. This work reaffirms the importance of trauma-informed care for patients with psychotic disorders.

Psychometric properties of the mini international neuropsychiatric interview (MINI) psychosis module: a Sub-Saharan Africa cross country comparison.

BACKGROUND: The Mini International Neuropsychiatric Inventory 7.0.2 (MINI-7) is a widely used tool and known to have sound psychometric properties; but very little is known about its use in low and middle-income countries (LMICs). This study aimed to examine the psychometric properties of the MINI-7 psychosis items in a sample of 8609 participants across four countries in Sub-Saharan Africa. METHODS: We examined the latent factor structure and the item difficulty of the MINI-7 psychosis items in the full sample and across four countries. RESULTS: Multiple group confirmatory factor analyses (CFAs) revealed an adequate fitting unidimensional model for the full sample; however, single group CFAs at the country level revealed that the underlying latent structure of psychosis was not invariant. Specifically, although the unidimensional structure was an adequate model fit for Ethiopia, Kenya, and South Africa, it was a poor fit for Uganda. Instead, a 2-factor latent structure of the MINI-7 psychosis items provided the optimal fit for Uganda. Examination of item difficulties revealed that MINI-7 item K7, measuring visual hallucinations, had the lowest difficulty across the four countries. In contrast, the items with the highest difficulty were different across the four countries, suggesting that MINI-7 items that are the most predictive of being high on the latent factor of psychosis are different for each country. CONCLUSIONS: The present study is the first to provide evidence that the factor structure and item functioning of the MINI-7 psychosis vary across different settings and populations in Africa.

Effects of M-DEPTH Model of Depression Care on Maternal HIV Viral Suppression and Adherence to the PMTCT Care Continuum Among HIV-Infected Pregnant Women in Uganda: Results from a Cluster Randomized Controlled Trial at Pregnancy Completion.

Perinatal depression has been shown to impede adherence to antiretroviral therapy (ART) and the prevention of mother-to-child transmission (PMTCT) care continuum; therefore, treating perinatal depression may result in increased viral suppression and PMTCT adherence. We examined the effects of the M-DEPTH (Maternal Depression Treatment in HIV) depression care model (including antidepressants and individual Problem Solving Therapy) on depression, maternal viral suppression and adherence to PMTCT care processes in an ongoing cluster-randomized controlled trial of 391 HIV-infected pregnant women (200 usual care; 191 intervention) with at least mild depressive symptoms enrolled across 8 antenatal care clinics in Uganda. At baseline, 68.3% had clinical depression and 41.7% had detectable HIV viral load. Adjusted repeated-measures multivariable regression models found that the intervention group was nearly 80% less likely to be clinically depressed [Adjusted OR (95% CI) 0.22 (0.05, 0.89)] at the 2-month post-pregnancy assessment, compared to the control group. However, the intervention and control groups did not differ meaningfully on maternal viral suppression, ART adherence, and other PMTCT care processes and outcomes. In this sample of women who were mostly virally suppressed and ART adherent at baseline, the depression care model had a strong effect on depression alleviation, but no downstream effects on viral suppression or other PMTCT care processes.Trial Registration NIH Clinical Trial Registry NCT03892915 (clinicaltrials.gov).

Stressors and Maladaptive Coping Mechanisms Associated with Elevated Perinatal Depressive Symptoms and Suicidality Among Women Living with HIV in Uganda.

BACKGROUND: Perinatal depression is highly prevalent among women living with HIV and contributes to nonadherence to the PMTCT (prevention of mother-to-child transmission) care continuum. We examined correlates of elevated depressive symptoms and suicidality in this population. METHOD: Baseline data from 391 Ugandan women enrolled in a cluster randomized controlled trial of a depression care intervention were analyzed. Adult women with confirmed sero-positive HIV status were eligible if their gestation period was ≤ 32 weeks, and they had a Patient Health Questionnaire (PHQ-9) score ≥ 5. Correlates of elevated depressive symptoms (PHQ-9 > 9) and moderate-to-severe suicidal ideation (more than half of the days in the prior 2 weeks) were assessed using bivariate and multivariate logistic regression models, controlling for clustering within study sites by using a random effects specification (with study site as the random effect), as well as age and education. RESULTS: The mean PHQ-9 score was 12.7 (SD = 5.1); 267 (68.3%) participants had elevated depressive symptoms, and 51 (13.0%) reported moderate-to-severe suicidality. In multiple logistic regression analysis, perceived provider stigma of childbearing [OR (95% CI) = 1.81 (1.16, 2.84)], greater use of negative problem-solving [OR (95% CI) = 1.09 (1.04, 1.15)], and lower general social support [OR (95% CI) = 0.50 (0.30, 0.82)] were correlated with elevated depression symptoms, while moderate-to-severe suicidal ideation was correlated with greater experience of physical interpersonal violence (IPV) and greater use of negative problem-solving. CONCLUSIONS: Programs aimed at improving provider support for the childbearing needs of persons living with HIV, supporting women who are experiencing IPV, and helping women to develop effective problem-solving skills and social supports may reduce symptoms of perinatal depression and help optimize PMTCT care outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT03892915 (registered March 21, 2019).

The association of cognitive impairment with quality of life and functional impairment in Ugandan first-episode psychosis patients: a cross sectional study.

INTRODUCTION: Cognitive impairment is common in first-episode psychosis patients and often associated with poor quality of life and functional impairment. However, most literature on this association is from high income countries and not low resource countries like Uganda. We aimed to determine the association between cognitive impairment with quality of life and functional impairment in Ugandan first-episode psychosis patients. METHODS: At Butabika national psychiatric hospital of Uganda, we enrolled 94 first-episode psychosis patients aged 18-60 years with a confirmed first-episode of psychosis and no previous treatment with antipsychotic medication. Neuropsychological assessment was performed using the MATRICS consensus cognitive battery (MCCB). Quality of life and functional impairment were assessed using the brief version of the World Health Organisation Quality of Life scale (WHOQOL-BREF) and the MINI International Neuropsychiatric Inventory (MINI) respectively. Linear regression analyses determined the association between impairment in different cognitive domains with various quality of life and functional impairment domains while controlling for age, gender and level of education. RESULTS: High scores in the reasoning and problem solving cognitive domain were associated with better quality of life in the psychological domain of WHOQOL-BREF (p = 0.029). For functional impairment, high cognitive scores in the domains of speed of processing (p = 0.018), reasoning and problem solving (p = 0.015), working memory (p = 0.017) and visual learning and memory (p = 0.002) were associated with psychosis "having a greater impact on other members of the family" on the MINI. Higher scores in the social cognition domain were associated with "less aggressive and disruptive behaviour" (p = 0.003). CONCLUSION: Cognitive impairment in Ugandan first-episode psychotic patients is associated with both poorer quality of life and functional impairment. Remediation of cognitive function may be a plausible intervention to improve outcomes in Ugandan first-episode psychosis patients.

Prevalence and factors associated with psychological distress among patients on warfarin at the Uganda Heart Institute, Mulago Hospital.

INTRODUCTION: Cardiovascular diseases (CVD) are the leading cause of mortality worldwide and are significantly associated with multiple comorbid disorders including mental disorders such as psychological distress (PD). At increased risk of PD are CVD patient sub-categories that not only require chronic therapy but also need follow up with continuous blood tests and dose adjustments (like the patients on warfarin). However, not much has been done to ascertain the burden of PD among patients on warfarin in Uganda. OBJECTIVE: To determine the prevalence and factors associated with PD among patients on anticoagulation with warfarin at the Uganda Heart Institute (UHI). METHODS: In this analytical cross-sectional study, 197 participants were sampled from adults on warfarin attending the Uganda Heart Institute (UHI) out patient clinic. The Self Reporting Questionnaire (SRQ-20), a tool with a total maximum score of 20 and cutoff for PD at ≥6 was used to determine the presence of PD among participants, and a socio-demographic questionnaire to document the socio-demographic characteristics of the subjects. Additional questions including the underlying CVD diagnosis, medications used (besides warfarin) and presence of chronic illnesess were also assessed. Bi-variable and multi-variabe logistic regression analysis techniques were used to examine the associations between the dependent and independent variables. RESULTS: The prevalence of PD was 32%. The unemployed participants were 4.5 times more likely to have PD (adjusted odds ratio [aOR]4.56, 95% confidence interval [CI]: 1.12-18.62, p = 0.04). Participants who had experienced social stressors were more likely to have PD (aOR: 11.38, CI: 3.60-36.04, p < 0.01). Other factors associated with a higher likelihood of having PD included: presence of other chronic comorbidities (aOR: 3.69, CI: 1.24-11.02, p = 0.02) and concomitant use of loop diuretics (aOR: 4.13, CI: 1.67-10.19,p < 0.01). A shorter length of time on warfarin (7-24 months) lowered the likelihood of PD (aOR: 0.23, CI: 0.07-0.74, p = 0.01). CONCLUSION: The prevalence of PD was high among patients on warfarin in this low income setting and there is a need to characterize the specific psychiatric disorders in patients with CVD. Interventions that address the high burden of PD are urgently needed in this setting.

Equivalency of the diagnostic accuracy of the PHQ-8 and PHQ-9: a systematic review and individual participant data meta-analysis.

BACKGROUND: Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9. METHODS: We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy. RESULTS: 16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (-0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01). CONCLUSIONS: PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.

The Accuracy of the Patient Health Questionnaire-9 Algorithm for Screening to Detect Major Depression: An Individual Participant Data Meta-Analysis.

BACKGROUND: Screening for major depression with the Patient Health Questionnaire-9 (PHQ-9) can be done using a cutoff or the PHQ-9 diagnostic algorithm. Many primary studies publish results for only one approach, and previous meta-analyses of the algorithm approach included only a subset of primary studies that collected data and could have published results. OBJECTIVE: To use an individual participant data meta-analysis to evaluate the accuracy of two PHQ-9 diagnostic algorithms for detecting major depression and compare accuracy between the algorithms and the standard PHQ-9 cutoff score of ≥10. METHODS: Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, Web of Science (January 1, 2000, to February 7, 2015). Eligible studies that classified current major depression status using a validated diagnostic interview. RESULTS: Data were included for 54 of 72 identified eligible studies (n participants = 16,688, n cases = 2,091). Among studies that used a semi-structured interview, pooled sensitivity and specificity (95% confidence interval) were 0.57 (0.49, 0.64) and 0.95 (0.94, 0.97) for the original algorithm and 0.61 (0.54, 0.68) and 0.95 (0.93, 0.96) for a modified algorithm. Algorithm sensitivity was 0.22-0.24 lower compared to fully structured interviews and 0.06-0.07 lower compared to the Mini International Neuropsychiatric Interview. Specificity was similar across reference standards. For PHQ-9 cutoff of ≥10 compared to semi-structured interviews, sensitivity and specificity (95% confidence interval) were 0.88 (0.82-0.92) and 0.86 (0.82-0.88). CONCLUSIONS: The cutoff score approach appears to be a better option than a PHQ-9 algorithm for detecting major depression.

The development and tailoring of a peer support program for patients with diabetes mellitus and depression in a primary health care setting in Central Uganda.

BACKGROUND: About 20-40% of patients with diabetes mellitus (DM) suffer from depressive disorders (DD) during the course of their illness. Despite the high burden of DD among patients with DM, it is rarely identified and adequately treated at the majority of primary health care clinics in sub-Saharan Africa (SSA). The use of peer support to deliver components of mental health care have been suggested in resource constrained SSA, even though its acceptability have not been fully examined. METHODS: We conducted qualitative interviews (QI) to assess the perceptions of DM patients with an experience of suffering from a DD about the acceptability of delivering peer support to patients with comorbid DM and DD. We then trained them to deliver peer support to DM patients who were newly diagnosed with DD. We identified challenges and potential barriers to a successful implementation of peer support, and generated solutions to these barriers. RESULTS: Participants reported that for one to be a peer, they need to be mature in age, consistently attend the clinics/keep appointments, and not to be suffering from any active physical or co-morbid mental or substance abuse disorder. Participants anticipated that the major barrier to the delivery of peer support would be high attrition rates as a result of the difficulty by DM patients in accessing the health care facility due to financial constraints. A potential solution to this barrier was having peer support sessions coinciding with the return date to hospital. Peers reported that the content of the intervention should mainly be about the fact that DM was a chronic medical condition for which there was need to adhere to lifelong treatment. There was consensus that peer support would be acceptable to the patients. CONCLUSION: Our study indicates that a peer support program is an acceptable means of delivering adjunct care to support treatment adherence and management, especially in settings where there are severe staff shortages and psycho-education may not be routinely delivered.

Accuracy of the PHQ-2 Alone and in Combination With the PHQ-9 for Screening to Detect Major Depression: Systematic Review and Meta-analysis.

Importance: The Patient Health Questionnaire depression module (PHQ-9) is a 9-item self-administered instrument used for detecting depression and assessing severity of depression. The Patient Health Questionnaire-2 (PHQ-2) consists of the first 2 items of the PHQ-9 (which assess the frequency of depressed mood and anhedonia) and can be used as a first step to identify patients for evaluation with the full PHQ-9. Objective: To estimate PHQ-2 accuracy alone and combined with the PHQ-9 for detecting major depression. Data Sources: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-May 2018). Study Selection: Eligible data sets compared PHQ-2 scores with major depression diagnoses from a validated diagnostic interview. Data Extraction and Synthesis: Individual participant data were synthesized with bivariate random-effects meta-analysis to estimate pooled sensitivity and specificity of the PHQ-2 alone among studies using semistructured, fully structured, or Mini International Neuropsychiatric Interview (MINI) diagnostic interviews separately and in combination with the PHQ-9 vs the PHQ-9 alone for studies that used semistructured interviews. The PHQ-2 score ranges from 0 to 6, and the PHQ-9 score ranges from 0 to 27. Results: Individual participant data were obtained from 100 of 136 eligible studies (44 318 participants; 4572 with major depression [10%]; mean [SD] age, 49 [17] years; 59% female). Among studies that used semistructured interviews, PHQ-2 sensitivity and specificity (95% CI) were 0.91 (0.88-0.94) and 0.67 (0.64-0.71) for cutoff scores of 2 or greater and 0.72 (0.67-0.77) and 0.85 (0.83-0.87) for cutoff scores of 3 or greater. Sensitivity was significantly greater for semistructured vs fully structured interviews. Specificity was not significantly different across the types of interviews. The area under the receiver operating characteristic curve was 0.88 (0.86-0.89) for semistructured interviews, 0.82 (0.81-0.84) for fully structured interviews, and 0.87 (0.85-0.88) for the MINI. There were no significant subgroup differences. For semistructured interviews, sensitivity for PHQ-2 scores of 2 or greater followed by PHQ-9 scores of 10 or greater (0.82 [0.76-0.86]) was not significantly different than PHQ-9 scores of 10 or greater alone (0.86 [0.80-0.90]); specificity for the combination was significantly but minimally higher (0.87 [0.84-0.89] vs 0.85 [0.82-0.87]). The area under the curve was 0.90 (0.89-0.91). The combination was estimated to reduce the number of participants needing to complete the full PHQ-9 by 57% (56%-58%). Conclusions and Relevance: In an individual participant data meta-analysis of studies that compared PHQ scores with major depression diagnoses, the combination of PHQ-2 (with cutoff ≥2) followed by PHQ-9 (with cutoff ≥10) had similar sensitivity but higher specificity compared with PHQ-9 cutoff scores of 10 or greater alone. Further research is needed to understand the clinical and research value of this combined approach to screening.

Persistence of chloroquine resistance alleles in malaria endemic countries: a systematic review of burden and risk factors.

BACKGROUND: Chloroquine, a previous highly efficacious, easy to use and affordable anti-malarial agent was withdrawn from malaria endemic regions due to high levels of resistance. This review collated evidence from published-reviewed articles to establish prevalence of Pfcrt 76T and Pfmdr-1 86Y alleles in malaria affected countries following official discontinuation of chloroquine use. METHODS: A review protocol was developed, registered in PROSPERO (#CRD42018083957) and published in a peer-reviewed journal. Article search was done in PubMed, Scopus, Lilacs/Vhl and Embase databases by two experienced librarians (AK, RS) for the period 1990-to-Febuary 2018. Mesh terms and Boolean operators (AND, OR) were used. Data extraction form was designed in Excel spread sheet 2007. Data extraction was done by three reviewers (NL, BB and MO), discrepancies were resolved by discussion. Random effects analysis was done in Open Meta Analyst software. Heterogeneity was established using I2-statistic. RESULTS: A total of 4721 citations were retrieved from article search (Pubmed = 361, Lilac/vhl = 28, Science Direct = 944, Scopus = 3388). Additional targeted search resulted in three (03) eligible articles. After removal of duplicates (n = 523) and screening, 38 articles were included in the final review. Average genotyping success rate was 63.6% (18,343/28,820) for Pfcrt K76T and 93.5% (16,232/17,365) for Pfmdr-1 86Y mutations. Prevalence of Pfcrt 76T was as follows; East Africa 48.9% (2528/5242), Southern Africa 18.6% (373/2163), West Africa 58.3% (3321/6608), Asia 80.2% (1951/2436). Prevalence of Pfmdr-1 86Y was; East Africa 32.4% (1447/5722), Southern Africa 36.1% (544/1640), West Africa 52.2% (1986/4200), Asia 46.4% (1276/2217). Over half, 52.6% (20/38) of included studies reported continued unofficial chloroquine use following policy change. Studies done in Madagascar and Kenya reported re-emergence of chloroquine sensitive parasites (IC50 < 30.9 nM). The average time (years) since discontinuation of chloroquine use to data collection was 8.7 ± 7.4. There was high heterogeneity (I2 > 95%). CONCLUSION: The prevalence of chloroquine resistance alleles among Plasmodium falciparum parasites have steadily declined since discontinuation of chloroquine use. However, Pfcrt K76T and Pfmdr-1 N86Y mutations still persist at moderate frequencies in most malaria affected countries.

K13-propeller gene polymorphisms in Plasmodium falciparum parasite population in malaria affected countries: a systematic review of prevalence and risk factors.

BACKGROUND: Efficacy of artemisinin (ART) agents, a critical element of current malaria control efforts is threatened by emergence and spread of resistance. Mutations in pfkelch13 gene associated with ART-resistance evolved in Southeast Asia (SEA). k13 mutations whose role in ART-resistance remains unknown, have subsequently emerged independently across all malaria-affected regions. The aim of this systematic review was to determine the prevalence and identify risk factors of Plasmodium falciparum k13 mutations in malaria-endemic countries. METHODS: An electronic search of studies from 2014 to date was done in MEDLINE via PubMED, SCOPUS, EMBASE and LILACS/VHL databases. Mesh terms and Boolean operators (AND, OR) were used. Two librarians independently conducted this search (RS and AK). The articles were screened for inclusion using a priori criteria set following PRISMA-P and STREGA guidelines. Three independent reviewers (NL, BB, and OM) extracted the data. Data analysis was performed in Open Meta Analyst software. Random effects analysis (DL) was used and heterogeneity established using I2-statistic. RESULTS: A total of 482 articles were retrieved from Pubmed = 302, Lilacs/Vhl = 50, Embase = 80, and Scopus = 37; Bibliography/other searches = 13, of which 374 did not meet the inclusion criteria. The aggregate prevalence of single nucleotide polymorphisms (SNPs) in pfkelch13 gene was 27.6% (3694/14,827) (95% CI 22.9%, 32.3%). Sub-group analysis showed that aggregate prevalence of non-synonymous SNPs in pfkelch13 gene was higher, 45.4% (95% CI 35.4%, 55.3%) in Southeast Asia as opposed to 7.6% (95% CI 5.6%, 9.5%) in the African region. A total of 165 independent k13 mutations were identified across malaria-affected regions globally. A total of 16 non-validated k13 mutations were associated with increased ART parasite clearance half-life (t1/2 > 5 h). The majority, 45.5% (75/165), of the mutations were reported in single P. falciparum parasite infections. Of the 165 k13-mutations, over half were reported as new alleles. Twenty (20) non-propeller mutations in the pfkelch13 gene were identified. CONCLUSION: This review identified emergence of potential ART-resistance mediating k13 mutations in the African region. Diversity of mutations in pfkelch13 gene is highest in African region compared to SEA. Mutations outside the pfkelch13 propeller region associated with increased ART parasite clearance half-life occur in malaria-affected regions.

Implementation research for public sector mental health care scale-up (SMART-DAPPER): a sequential multiple, assignment randomized trial (SMART) of non-specialist-delivered psychotherapy and/or medication for major depressive disorder and posttraumatic stress disorder (DAPPER) integrated with outpatient care clinics at a county hospital in Kenya.

BACKGROUND: Mental disorders are a leading cause of global disability, driven primarily by depression and anxiety. Most of the disease burden is in Low and Middle Income Countries (LMICs), where 75% of adults with mental disorders have no service access. Our research team has worked in western Kenya for nearly ten years. Primary care populations in Kenya have high prevalence of Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD). To address these treatment needs with a sustainable, scalable mental health care strategy, we are partnering with local and national mental health stakeholders in Kenya and Uganda to identify 1) evidence-based strategies for first-line and second-line treatment delivered by non-specialists integrated with primary care, 2) investigate presumed mediators of treatment outcome and 3) determine patient-level moderators of treatment effect to inform personalized, resource-efficient, non-specialist treatments and sequencing, with costing analyses. Our implementation approach is guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. METHODS/DESIGN: We will use a Sequential, Multiple Assignment Randomized Trial (SMART) to randomize 2710 patients from the outpatient clinics at Kisumu County Hospital (KCH) who have MDD, PTSD or both to either 12 weekly sessions of non-specialist-delivered Interpersonal Psychotherapy (IPT) or to 6 months of fluoxetine prescribed by a nurse or clinical officer. Participants who are not in remission at the conclusion of treatment will be re-randomized to receive the other treatment (IPT receives fluoxetine and vice versa) or to combination treatment (IPT and fluoxetine). The SMART-DAPPER Implementation Resource Team, (IRT) will drive the application of the EPIS model and adaptations during the course of the study to optimize the relevance of the data for generalizability and scale -up. DISCUSSION: The results of this research will be significant in three ways: 1) they will determine the effectiveness of non-specialist delivered first- and second-line treatment for MDD and/or PTSD, 2) they will investigate key mechanisms of action for each treatment and 3) they will produce tailored adaptive treatment strategies essential for optimal sequencing of treatment for MDD and/or PTSD in low resource settings with associated cost information - a critical gap for addressing a leading global cause of disability. TRIAL REGISTRATION: ClinicalTrials.gov NCT03466346, registered March 15, 2018.

Community beliefs, HIV stigma, and depression among adolescents living with HIV in rural Uganda.

The availability of and increased access to antiretroviral therapy (ART) has significantly reduced the morbidity and mortality associated with HIV. As a result, perinatally infected youth are increasingly able to reach adolescence. There is limited information about the psychosocial challenges facing adolescents living with HIV (ALWH) in rural settings of sub-Saharan Africa. We sought to understand psychosocial challenges facing ALWH in rural Uganda and their effects on mental health and HIV treatment outcomes. We conducted 5 focus group discussions and 40 one-on-one in-depth interviews in Mbarara, Uganda with adolescents (aged 13-17 years) and adult women caregivers. All interviews were audio-recorded, transcribed directly into English, and coded using thematic analysis to identify themes related to psychosocial adversities and mental health. Adversities faced by adolescents included negative community perceptions (perceived aggression, presumed early mortality), HIV stigma (enacted and internalized), vulnerability factors (loss of parents, poverty), and health challenges (depression, ART non-adherence). In the conceptual model that emerged from the findings, negative community perceptions (about perceived aggression or presumed early mortality) predisposed ALWH to experience enactments and internalization of stigma that led to depression and ART non-adherence. The data also identified several protective factors, including counselling, family and religious support, and timely serostatus disclosure. Interventions to correct community misperceptions about HIV can potentially reduce stigma and thereby improve physical and mental health outcomes of ALWH.