METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.

Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.

FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis.

eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth in vivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.

SMYD5 methylation of rpL40 links ribosomal output to gastric cancer.

Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in samples from patients with GAC and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease, including peritoneal carcinomatosis. Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to inhibitors of PI3K and mTOR. Finally, combining SMYD5 depletion with PI3K-mTOR inhibition and chimeric antigen receptor T cell administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived peritoneal carcinomatosis. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates the evolution of malignant GAC and proposes SMYD5 targeting as part of a potential combination therapy to treat this cancer.

The FAM86 domain of FAM86A confers substrate specificity to promote EEF2-Lys525 methylation.

FAM86A is a class I lysine methyltransferase (KMT) that generates trimethylation on the eukaryotic translation elongation factor 2 (EEF2) at Lys525. Publicly available data from The Cancer Dependency Map project indicate high dependence of hundreds of human cancer cell lines on FAM86A expression. This classifies FAM86A among numerous other KMTs as potential targets for future anticancer therapies. However, selective inhibition of KMTs by small molecules can be challenging due to high conservation within the S-adenosyl methionine (SAM) cofactor binding domain among KMT subfamilies. Therefore, understanding the unique interactions within each KMT-substrate pair can facilitate developing highly specific inhibitors. The FAM86A gene encodes an N-terminal FAM86 domain of unknown function in addition to its C-terminal methyltransferase domain. Here, we used a combination of X-ray crystallography, the AlphaFold algorithms, and experimental biochemistry to identify an essential role of the FAM86 domain in mediating EEF2 methylation by FAM86A. To facilitate our studies, we also generated a selective EEF2K525 methyl antibody. Overall, this is the first report of a biological function for the FAM86 structural domain in any species and an example of a noncatalytic domain participating in protein lysine methylation. The interaction between the FAM86 domain and EEF2 provides a new strategy for developing a specific FAM86A small molecule inhibitor, and our results provide an example in which modeling a protein-protein interaction with AlphaFold expedites experimental biology.

Antibody toolkit to investigate eEF1A methylation dynamics in mRNA translation elongation.

Protein synthesis is a fundamental step in gene expression, with modulation of mRNA translation at the elongation step emerging as an important regulatory node in shaping cellular proteomes. In this context, five distinct lysine methylation events on eukaryotic elongation factor 1A (eEF1A), a fundamental nonribosomal elongation factor, are proposed to influence mRNA translation elongation dynamics. However, a lack of affinity tools has hindered progress in fully understanding how eEF1A lysine methylation impacts protein synthesis. Here we develop and characterize a suite of selective antibodies to investigate eEF1A methylation and provide evidence that methylation levels decline in aged tissue. Determination of the methyl state and stoichiometry on eEF1A in various cell lines by mass spectrometry shows modest cell-to-cell variability. We also find by Western blot analysis that knockdown of individual eEF1A-specific lysine methyltransferases leads to depletion of the cognate lysine methylation event and indicates active crosstalk between different sites. Further, we find that the antibodies are specific in immunohistochemistry applications. Finally, application of the antibody toolkit suggests that several eEF1A methylation events decrease in aged muscle tissue. Together, our study provides a roadmap for leveraging methyl state and sequence-selective antibody reagents to accelerate discovery of eEF1A methylation-related functions and suggests a role for eEF1A methylation, via protein synthesis regulation, in aging biology.

Anticoagulation control among patients on vitamin K antagonists in nine countries in Sub-Saharan Africa.

Vitamin K antagonists (VKA) is the primary anticoagulant in most settings of Sub-Saharan Africa. Understanding the quality of anticoagulation services in the continent is vital in optimising the intended benefits. This study assessed the quality of anticoagulation and associated factors among VKA-treated patients in nine SSA countries. We conducted a retrospective cohort study of randomly selected patients on anticoagulation from 20 clinics in Botswana, the Democratic Republic of Congo, Ethiopia, Gambia, Ghana, Mozambique, Nigeria, Tanzania, and South Africa. Eligible participants were those on VKAs for at least three months and with at least four international normalised ratios (INR) results in 2019-2021. We report the proportion of INR values in the therapeutic range, time-in-therapeutic range (TTR) using the Rosendaal method, and the proportion of patients with TTR ≥ 65% (optimal anticoagulation). The mean age was 51.1(16.1) years, and 64.2% were women. The most common indications for VKA included venous thromboembolism (29.6%), prosthetic valves (26.7%) and atrial fibrillation/flutter (30.1%). We analysed 6743 INR tests from 1011 participants, and of these, 48.5% were sub-therapeutic, 34.1% therapeutic, and 17.4% were supratherapeutic relative to disease-specific reference ranges. TTR was calculated for 660 patients using 4927 INR measurements. The median (interquartile range [IQR]) TTR was 35.8(15.9,57.2) %. Optimal anticoagulation control was evident in 19.2% of participants, varying from 2.7% in Tanzania to 23.1% in Ethiopia. The proportion of patients with TTR ≥ 65% was 15,4% for prosthetic heart valves, 21.1% for venous thromboembolism and 23.7% for atrial fibrillation or flutter. Countries with universal health coverage had higher odds of optimal anticoagulation control (adjusted odds ratio (aOR) 1.79, 95% confidence interval [CI], 1.15- 2.81, p = 0.01). Patients on VKAs for different therapeutic indications in SSA had suboptimal TTR. Universal health coverage increased the odds of achieving TTR by 79%. The evidence calls for more intensive warfarin management strategies in SSA, including providing VKA services without out-of-pocket payments.

A pilot study of implementing an adapted model for integration of interventions for people with alcohol use disorders in Tanzanian primary healthcare facilities.

BACKGROUND: Ensuring that evidence-based interventions for people with alcohol use disorders (AUD) are acceptable, effective, and feasible in different socio-cultural and health system contexts is essential. We previously adapted a model of integration of AUD interventions for the Tanzanian primary healthcare system. This pilot study aimed to assess the impact on AUD detection and the acceptability and feasibility of the facility-based components of this model from the perspective of healthcare providers (HCPs). METHODS: This mixed-methods study comprised a pre-post quasi-experimental study and a qualitative study. The integrated model included training HCPs in managing AUD, introducing systematic screening for AUD, documentation of AUD service utilization, and supportive supervision. We collected information on the number of people identified for AUD three months before and after piloting the service model. A non-parametric trend test, a distribution-free cumulative sum test, was used to identify a change in the identification rate of AUD beyond that observed due to secular trends or, by chance, three months before and after implementing the integrated AUD facility-based interventions. The Mann-Kendal test was used to assess the statistical significance of the trend. We conducted three focus group discussions exploring the experience of HCPs and their perspectives on facilitators, barriers, and strategies to overcome them. The focus group discussions were analyzed using thematic analysis. RESULTS: During the pre-implementation phase of the facility-based interventions of the adapted AUD model, HCPs assessed 322 people for AUD over three months, ranging from a minimum of 99 to a maximum of 122 per month. Of these, 77 were identified as having AUD. Moreover, HCPs screened 2058 people for AUD during implementation; a minimum of 528 to a maximum of 843 people were screened for AUD per month for the three months. Of these, 514 screened positive for AUD (AUDIT ≥ 8). However, this change in screening for AUD was not statistically significant (p-value = 0.06). HCPs reported that knowledge and skills from the training helped them identify and support people they would not usually consider having problematic alcohol use. Perceived barriers to implementation included insufficient health personnel compared to needs and inconvenient health management information systems. HCPs proposed strategies to overcome these factors and recommended multisectoral engagement beyond the health system. CONCLUSIONS: Although the change in the trend in the number of people screened for AUD by HCPs post-implementation was not statistically significant, it is still feasible to implement the facility-based components of the adapted integrated AUD model while addressing the identified bottlenecks and strategies for implementation. Therefore, a large-scale, adequately powered implementation feasibility study is needed. Findings from this study will be used to finalize the adapted model for integrating AUD interventions for future implementation and larger-scale evaluation.

Impact of a post-partum family planning intervention on contraception and fertility in Tanzania: two-year follow-up of a cluster-randomised controlled trial.

PURPOSE: We evaluate contraceptive use and pregnancy two years following an intervention in Tanzania, which provided antenatal post-partum family planning counselling and post-partum intrauterine device (PPIUD) services following delivery. METHODS: We analyse data from five hospitals in Tanzania using a difference-in-difference cluster randomised design, with randomisation at the hospital level. We use women-level data collected at the index birth and a follow-up survey two years later among 6,410 women. Outcomes (overall modern contraceptive use, contraceptive type, pregnancy) are modelled with an intent-to-treat (ITT) approach using linear regression. We compare with the complier average causal effect (CACE) of the intervention among those counselled. RESULTS: The intervention increased long-term PPIUD use by 5.8 percentage points (95% CI: 0.7-11.2%) through substitution away from other modern methods. There was no impact on overall modern contraceptive prevalence or pregnancy. Only 29% of women reported receiving PPIUD counselling. When accounting for this in the CACE analysis we saw a larger impact with 25.7% percentage point increase in PPIUD use (95% CI: 22.7-28.6%). CONCLUSION: The intervention provided women an additional contraceptive choice, resulting in higher use of PPIUD over two years. Increase in PPIUD use was brought about by shifting methods, not creating new modern contraceptive users.

The post-partum family planning intervention in Tanzania offered women a new contraceptive option and increased sustained use of post-partum IUD. The intervention did not attract new modern contraception users and could have a greater impact if implemented more widely.

Prevalence and correlates of alcohol use and risky drinking among undergraduate students in Johannesburg, South Africa: a cross-sectional study.

BACKGROUND: Alcohol use and risky drinking are significant public health problem globally. Young people, including university students, are among the most affected populations. We conducted the study to determine the prevalence and correlates of alcohol use and risky drinking among undergraduate students in the Faculty of Health Sciences at the University of the Witwatersrand, South Africa. METHODS: We conducted a cross-sectional study using an anonymous, self-administered online survey in REDCap. The survey questionnaire consisted of socio demographic, and alcohol use questions using the risky drinking identification screening tool (AUDIT-C). We performed descriptive statistics, bivariate and multivariable logistic regression to determine factors associated with alcohol use and risky drinking. The p-value of < 0.05 was considered statistically significant. RESULTS: The response rate was 15.7%. Most participants were female (69.6%) and majority of the participants were White (38.1%). The prevalence of lifetime use of alcohol was 79.1%, and among the lifetime users; 70.2% reported alcohol use in the last 12-months, 37.1% reported alcohol use in the last 30 days. The prevalence of risky drinking was 54.8% among lifetime drinkers. Factors significantly associated with current alcohol use were siblings alcohol use (aOR = 1.79, 95% CI: 1.02-3.15) and parents alcohol use (aOR = 2.58, 95% CI: 1.39-4.80), white race (aOR = 5.70, 95% CI: 3.12-10.41), and always or daily exposure to alcohol marketing in the media (aOR = 3.31, 95% CI: 1.07-10.24). Factors associated with risky drinking were: Indian/Asian race (aOR = 2.82, 95% CI: 1.09-7.31), White race (aOR = 2.15, 95% CI: 1.14-4.04), and exposure to alcohol marketing in the media as follows, most of the time (aOR = 3.42, 95% CI: 1.29-9.04) and Always/daily exposure (aOR = 3.31, 95% CI: 1.07-10.24). CONCLUSION: The reported alcohol use and risky drinking were common amongst undergraduate students at Wits university. There is an urgent need to design, pilot and adapt targeted interventions for this population group.

Prevalence and factors associated with potential substance use disorders among police officers in urban Tanzania: a cross-sectional study.

BACKGROUND: Substance Use Disorders (SUDs) among Police Officers has been a concern to many professionals in the field of health, research and criminal justice since their work is subjected to higher levels of stress and hence more likely to use alcohol or tobacco as a coping mechanism. However, little is known about SUDs among Police Officers in Tanzania. Therefore, we assessed the prevalence and factors associated with SUDs among Police Officers in urban Tanzania. MATERIALS AND METHODS: A cross-sectional study was conducted between April and October 2019 among Police Officers in Dar es Salaam. Multistage cluster sampling technique was used to recruit study participants. The WHO-Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) version 3.0 was used to measure potential SUDs. Bivariate and multivariate analyses were performed to establish associations between potential SUDs and predictors of interest, and an alpha of 5% was used in sample size calculation. RESULTS: A total of 497 participants were enrolled, of these, 76.6% (376/491) were males, the median age (years) and IQR was 37.0 (30.0, 47.0). The prevalence of past three months use of alcohol and tobacco were 31.3% and 6.3%, respectively. About 13.3% (62/468) and 6.2% (29/468) of Police Officers met criteria for potential Alcohol Use Disorder (AUD) and potential Tobacco Use Disorder (TUD) respectively. In adjusted analysis, participants with depression had about two times increased odds for potential AUD (aOR: 2.27, 95% CI; 1.12 - 4.58, p = 0.023) than those with no depression. Potential AUD and depression were associated with about eight times (aOR: 8.03, 95% CI; 3.52 - 18.28, p < 0.01) and more than twice (aOR: 2.63, 95% CI; 1.12 - 6.15, p = 0.026) higher odds for potential TUD respectively. CONCLUSION: Substance use and potential substance use disorders particularly AUD and TUD are common among Police Officers in urban Tanzania. Depression was found to be an important factor for potential AUD and TUD among Police Officers and, a significant co-occurrence of potential AUD with potential TUD was observed. Findings from this study call for interventions, for example, the need to routinize the brief motivational interview services for alcohol and tobacco use among Police Officers.

Prevalence and correlates of alcohol use, mental disorders, and awareness and utilization of support services among healthcare professionals in West Rand District, Gauteng, South Africa: a cross-sectional study.

INTRODUCTION: Healthcare professionals (workers) are at an increased risk for developing mental and alcohol use disorders (risky drinking) due to increased psychological distress, long working hours, medical litigation, role conflict, and verbal/physical violence from colleagues and patients. Psychological well-being in healthcare workers is crucial to provide the best quality of care to patients. Current data are limited regarding alcohol abuse (risky drinking) rates and mental health condition among healthcare professionals in South Africa. OBJECTIVES: To describe the prevalence and correlates of alcohol use disorder (risky drinking), depression, anxiety, suicidality, and covid anxiety during the coronavirus pandemic in healthcare professionals in West Rand District, Johannesburg, South Africa. METHODS: We carried out a cross-sectional study on a sample of healthcare professionals including doctors, nurses, clinical associates, and dentists working in the West Rand District of Gauteng, South Africa, during Covid-19 pandemic. Participants were invited to complete a paper-based questionnaire addressing sociodemographic questions, a set of measures for alcohol use disorder (AUDIT-C), depression (PHQ-2), anxiety (GAD-7), suicidality (PSS-3), covid anxiety (CAS), and awareness and utilization of support services. RESULTS: A total of 330 healthcare professionals (60.9% nurses, 33% doctors, 5.5% other) participated. Females comprised the majority of study participants with 78.8%, and 48.2% of the participants were in the age band 35-64 years. Overall, 20.9% of the healthcare professionals reported risky alcohol use. Females were 73% less likely to report risky alcohol use (AOR = 0.27;95% CI: 0.13-0.54). Prevalence of probable depression was 13.6% and female professionals were 5 times more likely to be classified as having probable depression (AOR = 4.86;95% CI: 1.08-21.90). The grouped prevalence of anxiety ranging from mild to severe was reported at 47.3%, female professionals were 3 times more likely to be classified as having anxiety disorder (AOR = 2.78;95% CI: 1.39-5.57). Furthermore, races other than African had higher rates of anxiety (AOR = 2.54; 95% CI: 1.00-6.42). The prevalence of suicide symptoms was 7.9% and that of covid dysfunctional anxiety 4.8%. Only 5% of participants were involved in an employee wellness program, with 60% expressing interest in joining one. CONCLUSION: Alcohol use (risky drinking) and mental disorders were common among healthcare professionals in West Rand District, Johannesburg, South Africa. There is overall poor awareness and use of support structures highlighting urgent need for interventions. Future studies could also explore in-depth the drivers of mental disorders and lack of utilization of the available service and strategies to deliver alcohol and mental disorder screening, brief intervention, and referral to treatment.

Type 2 diabetes in the Democratic Republic of Congo: an urgent need for a management framework.

Glycaemic control is of one the main goals for managing type 2 diabetes. In sub-Saharan Africa and the Democratic Republic of the Congo, studies have reported alarming poor control rates. Patients with poor glycaemic control are exposed to complications leading to high cost of care and deteriorated quality of life. In recent studies by our group, we have demonstrated that poor glycaemic control is high and driven by proximal (individual) and distal (structural) factors in Kinshasa, Democratic Republic of the Congo. Financial constraints impacted many aspects of care at multiple levels from the Government to persons living with diabetes. Financial constraints prevented good preparation, organization and access to diabetes care. Difficulties in implementing lifestyle changes, lack of health literacy and limited healthcare support were also contributing to poor glycaemic control. Through a Delphi study, a group of experts reached a consensus on five potential strategies for improving glycaemic control in the Democratic Republic of Congo as follows: changing the healthcare system for better diabetes care extended to other noncommunicable diseases, ensuring consistent financing of the healthcare, augmenting the awareness of diabetes among the general population and the persons living with diabetes, easing the adoption of lifestyle modifications and reducing the burden of undiagnosed diabetes. This paper reflects on the urgent need for an improved management framework for diabetes care in the Democratic Republic of the Congo. Specifically, the Government needs to increase the investment in the prevention and treatment of noncommunicable diseases including diabetes.

Perspectives for glycaemic control in type 2 diabetes in Kinshasa, Democratic Republic of the Congo.

Glycaemic control is a significant problem in the Democratic Republic of the Congo (DRC), the perspectives associated with glycaemic control are not fully known as previous studies rarely explored patients' perspectives and lived experiences. This qualitative study described the perspectives regarding glycaemic control among persons with type 2 diabetes in Kinshasa, DRC. A total of 23 participants were purposively selected in seven health centres in Kinshasa. In-depth interviews were used for data collection. The study used a phenomenology approach, and deductive, constructionist and thematic analysis. Data analysis was performed using the MAXQDA 2022. Five themes were identified as perspectives for glycaemic control in Kinshasa: financial constraints, limited social and relational support, difficulties with lifestyle changes, beliefs and practices about diabetes and ability to adapt for caring for the illness. Themes were integrated using social cognitive theory. Participants expressed that they were unable to achieve better glycaemic control due to financial constraints, limited social and relational support and difficulty in changing their lifestyle. Their beliefs and practices about diabetes also constituted a barrier. Our results showed that lack of adequate funding is a major determinant of glycaemic control and therefore it is crucial to integrate a consistent and reliable funding system for care of people living with diabetes. Persons with diabetes must be empowered to successfully adapt to the requirements of diabetes care. In this process, support for people living with type 2 diabetes is also essential and should involve their families as well as healthcare providers.

The International Sexual Health And REproductive Health during COVID-19 (I-SHARE) Study: A Multicountry Analysis of Adults from 30 Countries Prior to and During the Initial Coronavirus Disease 2019 Wave.

BACKGROUND: There is limited evidence to date about changes to sexual and reproductive health (SRH) during the initial wave of coronavirus disease 2019 (COVID-19). To address this gap, our team organized a multicountry, cross-sectional online survey as part of a global consortium. METHODS: Consortium research teams conducted online surveys in 30 countries. Sampling methods included convenience, online panels, and population-representative. Primary outcomes included sexual behaviors, partner violence, and SRH service use, and we compared 3 months prior to and during policy measures to mitigate COVID-19. We conducted meta-analyses for primary outcomes and graded the certainty of the evidence. RESULTS: Among 4546 respondents with casual partners, condom use stayed the same for 3374 (74.4%), and 640 (14.1%) reported a decline. Fewer respondents reported physical or sexual partner violence during COVID-19 measures (1063 of 15 144, 7.0%) compared to before COVID-19 measures (1469 of 15 887, 9.3%). COVID-19 measures impeded access to condoms (933 of 10 790, 8.7%), contraceptives (610 of 8175, 7.5%), and human immunodeficiency virus/sexually transmitted infection (HIV/STI) testing (750 of 1965, 30.7%). Pooled estimates from meta-analysis indicate that during COVID-19 measures, 32.3% (95% confidence interval [CI], 23.9%-42.1%) of people needing HIV/STI testing had hindered access, 4.4% (95% CI, 3.4%-5.4%) experienced partner violence, and 5.8% (95% CI, 5.4%-8.2%) decreased casual partner condom use (moderate certainty of evidence for each outcome). Meta-analysis findings were robust in sensitivity analyses that examined country income level, sample size, and sampling strategy. CONCLUSIONS: Open science methods are feasible to organize research studies as part of emergency responses. The initial COVID-19 wave impacted SRH behaviors and access to services across diverse global settings.

Pre-treatment HIV-1 drug resistance in antiretroviral therapy-naive adults in Eastern Africa: a systematic review and meta-analysis.

BACKGROUND: Pre-treatment HIV drug resistance (PDR) may result in increased risk of virological failure and acquisition of new resistance mutations. With recently increasing ART coverage and periodic modifications of the guidelines for HIV treatment, there is a need for an updated systematic review to assess the levels of the PDR among adults newly initiating ART in Eastern Africa. METHODS: We conducted a systematic search for studies published between 1 January 2017 and 30 April 2022 in the MEDLINE Complete and CINAHL Complete, searched simultaneously using EBSCOhost, and Web of Science. To determine the overall PDR prevalence estimates, we extracted data from eligible articles and analysed prevalence estimates using Stata 14.2. RESULTS: A total of 22 eligible observation studies were selected. The studies included a total of 5852 ART-naive people living with HIV. The overall pooled prevalence of PDR was 10.0% (95% CI: 7.9%-12.0%, I2 = 88.9%) and 9.4% (95% CI: 7.0%-11.9%, I2 = 90.4%) for NNRTIs, 2.6% (95% CI: 1.8%-3.4%, I2 = 69.2%) for NRTIs and 0.7% (95% CI: 0.3%-1.2%, I2 = 29.0%) for PIs. No major integrase strand transfer inhibitors (INSTI)-related mutations were identified. CONCLUSIONS: We observed a moderate overall PDR prevalence among new ART initiators in this study. PDR to NNRTIs is more prevalent, underscoring the importance of the current WHO recommendation for replacement of NNRTIs by INSTIs. PDR to NRTIs was low but notable, which warrants continuous surveillance of pre-existing resistance to the dolutegravir co-administered NRTI in Eastern Africa.

Sexual health (excluding reproductive health, intimate partner violence and gender-based violence) and COVID-19: a scoping review.

OBJECTIVES: The COVID-19 pandemic has exposed and exacerbated existing socioeconomic and health disparities, including disparities in sexual health and well-being. While there have been several reviews published on COVID-19 and population health disparities generally-including some with attention to HIV-none has focused on sexual health (ie, STI care, female sexual health, sexual behaviour). We have conducted a scoping review focused on sexual health (excluding reproductive health (RH), intimate partner violence (IPV) and gender-based violence (GBV)) in the COVID-19 era, examining sexual behaviours and sexual health outcomes. METHODS: A scoping review, compiling both peer-reviewed and grey literature, focused on sexual health (excluding RH, IPV and GBV) and COVID-19 was conducted on 15 September 2020. Multiple bibliographical databases were searched. Study selection conformed to Joanna Briggs Institute (JBI) Reviewers' Manual 2015 Methodology for JBI Scoping Reviews. We only included English-language original studies. RESULTS: We found that men who have sex with men may be moving back toward pre-pandemic levels of sexual activity, and that STI and HIV testing rates seem to have decreased. There was minimal focus on outcomes such as the economic impact on sexual health (excluding RH, IPV and GBV) and STI care, especially STI care of marginalised populations. In terms of population groups, there was limited focus on sex workers or on women, especially women's sexual behaviour and mental health. We noticed limited use of qualitative techniques. Very few studies were in low/middle-income countries (LMICs). CONCLUSIONS: Sexual health research is critical during a global infectious disease pandemic and our review of studies suggested notable research gaps. Researchers can focus efforts on LMICs and under-researched topics within sexual health and explore the use of qualitative techniques and interventions where appropriate.

Factors associated with phosphatidylethanol (PEth) sensitivity for detecting unhealthy alcohol use: An individual patient data meta-analysis.

BACKGROUND: Objective measurement of alcohol consumption is important for clinical care and research. Adjusting for self-reported alcohol use, we conducted an individual participant data (IPD) meta-analysis to examine factors associated with the sensitivity of phosphatidylethanol (PEth), an alcohol metabolite, among persons self-reporting unhealthy alcohol consumption. METHODS: We identified 21 eligible studies and obtained 4073 observations from 3085 participants with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) positive scores (≥3 for women and ≥4 for men) and PEth measurements. We conducted 1-step IPD meta-analysis using mixed effects models with random intercepts for study site. We examined the associations between demographic (sex, race/ethnicity, and age) and biologic (body mass index-BMI, hemoglobin, HIV status, liver fibrosis, and venous versus finger-prick blood collection) variables with PEth sensitivity (PEth≥8 ng/ml), adjusting for the level of self-reported alcohol use using the AUDIT-C score. RESULTS: One third (31%) of participants were women, 32% were African, 28% African American, 28% White, and 12% other race/ethnicity. PEth sensitivity (i.e., ≥8 ng/ml) was 81.8%. After adjusting for AUDIT-C, we found no associations of sex, age, race/ethnicity, or method of blood collection with PEth sensitivity. In models that additionally included biologic variables, those with higher hemoglobin and indeterminate and advanced liver fibrosis had significantly higher odds of PEth sensitivity; those with higher BMI and those living with HIV had significantly lower odds of PEth sensitivity. African Americans and Africans had higher odds of PEth sensitivity than whites in models that included biologic variables. CONCLUSIONS: Among people reporting unhealthy alcohol use, several biological factors (hemoglobin, BMI, liver fibrosis, and HIV status) were associated with PEth sensitivity. Race/ethnicity was associated with PEth sensitivity in some models but age, sex, and method of blood collection were not. Clinicians should be aware of these factors, and researchers should consider adjusting analyses for these characteristics where possible.

The epidemiology of tuberculosis-associated hyperglycemia in individuals newly screened for type 2 diabetes mellitus: systematic review and meta-analysis.

BACKGROUND: There is scarce evidence that tuberculosis (TB) can cause diabetes in those not previously known to be diabetic. Whilst the World Health Organization (WHO) recommends screening for Diabetes Mellitus (DM) at the onset of TB treatment, nevertheless, it remains to be elucidated which patients with TB-associated hyperglycemia are at higher risk for developing DM and stand to benefit from a more regular follow-up. This review aims to firstly quantify the reduction of newly detected hyperglycemia burden in TB patients who are on treatment over time; secondly, determine the burden of TB-associated hyperglycemia after follow-up, and thirdly, synthesize literature on risk factors for unresolved TB-associated hyperglycemia in previously undiagnosed individuals. METHODS: We searched PUBMED, EMBASE, SCOPUS, and Global Health for articles on TB-associated hyperglycemia up to September 30th, 2019. Search terms included Tuberculosis and hyperglycemia/DM, and insulin resistance. We appraised studies, extracted data, and conducted a meta-analysis to assess the change of the burden of hyperglycemia in prospective studies. The review is registered in the PROSPERO database (CRD42019118173). RESULTS: Eleven studies were included in the meta-analysis yielding a total of 677 (27,3%) of patients with newly detected hyperglycemia at baseline. The mean quality score of eligible studies using the Newcastle-Ottawa Quality Assessment Scale was 7.1 out of 9 (range 6-9). The pooled unresolved new cases of hyperglycemia at the end of follow up was 50% (95% CI: 36-64%) and the total pooled burden of hyperglycemia at 3-6 months of follow up was 11% (95% CI: 7-16%), with both estimates displaying a high heterogeneity, which remained significant after performing a sub-analysis by DM diagnostic method and 3 months of follow up. As only 2 studies explored risk factors for unresolved hyperglycemia, no meta-analysis was performed on risk factors. CONCLUSION: Our meta-analysis showed that although in half of the patients with newly observed hyperglycemia at baseline, it remained unresolved at a follow-up of 3 to 6 months, the total burden of hyperglycemia is slightly above 10%, 3 months after initiating TB treatment. Studies are warranted to assess whether risk factors including HIV positivity, smoking, and extensive pulmonary TB disease put patients at higher risk for DM.

Effect of a postpartum family planning intervention on postpartum intrauterine device counseling and choice: evidence from a cluster-randomized trial in Tanzania.

BACKGROUND: The World Health Organization recommends postpartum family planning (PPFP) for healthy birth spacing. This study is an evaluation of an intervention that sought to improve women's access to PPFP in Tanzania. The intervention included counseling on PPFP during antenatal and delivery care and introducing postpartum intrauterine device (PPIUD) insertion as an integrated part of delivery services for women electing PPIUD in the immediate postpartum period. METHODS: This cluster-randomized controlled trial recruited 15,264 postpartum Tanzanian women aged 18 or older who delivered in one of five study hospitals between January and September 2016. We present the effectiveness of the intervention using a difference-in-differences approach to compare outcomes, receipt of PPIUD counseling and choice of PPIUD after delivery, between the pre- and post-intervention period in the treatment and control group. We also present an intervention adherence-adjusted analysis using an instrumental variables estimation. RESULTS: We estimate linear probability models to obtain effect sizes in percentage points (pp). The intervention increased PPIUD counseling by 19.8 pp (95% CI: 9.1 - 22.6 pp) and choice of PPIUD by 6.3 pp (95% CI: 2.3 - 8.0 pp). The adherence-adjusted estimates demonstrate that if all women had been counseled, we would have observed a 31.6 pp increase in choice of PPIUD (95% CI: 24.3 - 35.8 pp). Among women counseled, determinants of choosing PPIUD included receiving an informational leaflet during counseling and being counseled after admission for delivery services. CONCLUSIONS: The intervention modestly increased the rate of PPIUD counseling and choice of PPIUD, primarily due to low coverage of PPIUD counseling among women delivering in study facilities. With universal PPIUD counseling, large increases in choice of PPIUD would have been observed. Giving women informational materials on PPIUD and counseling after admission for delivery are likely to increase the proportion of women choosing PPIUD. TRIAL REGISTRATION: Registered with clinicaltrials.gov (NCT02718222) on March 24, 2016, retrospectively registered.

Three-Dimensional Upper Airway Assessment in Treacher Collins Syndrome.

OBJECTIVES: The purpose of this investigation was to assess the pharyngeal dimensions and the craniofacial morphology of individuals with Treacher Collins syndrome (TCS) when compared to vertical skeletal class II individuals. It is our hypothesis that the upper airways of individuals with TCS are reduced in view of the skeletal pattern and the maxillomandibular dysmorphologies. MATERIALS AND METHODS: Cone-beam computed tomography scans of 26 individuals had the pharyngeal volume (V) and minimal cross-sectional area (mCSA) evaluated. Study group (TCS) was formed by 13 scans of patients with TCS (7 males and 6 females; 20.2 ± 4.7 years). Control group (CG) assembled 13 scans of nonaffected individuals with the same type of skeletal pattern (2 males and 11 females; 26.6 ± 5.4 years). Cephalometric data of maxillomandibular position, maxillomandibular dimensions, and growth pattern were assessed. Statistical analysis (P ≤ .05) included Student t test and Pearson correlation coefficient. RESULTS: Although reduced, pharyngeal V and mCSA of TCS were not statistically different from the CG. On both groups, mCSA was mostly at the oropharyngeal level. Individuals with TCS presented retrognathic chin, reduced maxillomandibular dimensions, and increased clockwise rotation of the palatal plane. Maxillary and mandibular lengths were correlated with pharyngeal V and mCSA. CONCLUSIONS: The pharyngeal dimensions of individuals with TCS are impacted by the micrognathia and retrognathia. In association with the skeletal pattern, the reduction of the airways, although not statistically significant, may explain the increased prevalence of airways disorder in this syndrome.