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White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

The Alzheimers Disease Neuroimaging Initiative (ADNI) Administrative Core oversees and coordinates all ADNI activities, to ensure the success and maximize the impact of ADNI in advancing Alzheimers disease (AD) research and clinical trials. It manages finances and develops policies for data sharing, publications using ADNI data, and access to ADNI biospecimens. The Core develops and executes pilot projects to guide future ADNI activities and identifies key innovative methods for inclusion in ADNI. For ADNI4, the Administrative Core collaborates with the Engagement, Clinical, and Biomarker Cores to develop and evaluate novel, digital methods and infrastructure for participant recruitment, screening, and assessment of participants. The goal of these efforts is to enroll 500 participants, including > 50% from underrepresented populations, 40% with mild cognitive impairment, and 80% with elevated AD biomarkers. This new approach also provides a unique opportunity to validate novel methods. HIGHLIGHTS: The Alzheimers Disease Neuroimaging Initiative (ADNI) Administrative Core oversees and coordinates all ADNI activities. The overall goal is to ensure ADNIs success and help design future Alzheimers disease (AD) clinical trials. A key innovation is data sharing without embargo to maximize scientific impact. For ADNI4, novel, digital methods for recruitment and assessment were developed. New methods are designed to improve the participation of underrepresented populations.

INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimers Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. HIGHLIGHTS: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundations Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

BACKGROUND: Social desirability can negatively affect the validity of self-reported measures, including underreporting of stigmatized behaviors like alcohol consumption. The Marlowe-Crowne Social Desirability Scale (SDS) is widely implemented and comprised of Denial and Attribution Domains (i.e., tendencies to deny undesirable traits or attribute socially desirable traits to oneself, respectively). Yet, limited psychometric research has been conducted in sub-Saharan Africa, where the prevalence of unhealthy alcohol consumption is high as well as religiosity and hierarchical social norms. To address this gap, we (a) conducted an exploratory study assessing certain psychometric properties of the 28-item SDS (Runyankole-translated) among persons with HIV (PWH) in Uganda, and (b) examined the relationship between social desirability and self-reported alcohol use. METHODS: We pooled baseline data (N = 1153) from three studies of PWH engaged in alcohol use from 2017 to 2021. We assessed the translated scales construct validity (via confirmatory factor analysis), internal consistency, item performance, differential item functioning by gender, concurrent validity with the DUREL religiosity index domains, and the association between social desirability and self-reported alcohol use. RESULTS: Participants had a mean age of 40.42 years, 63% were men, and 91% had an undetectable HIV viral load. The 28-item SDS had satisfactory construct validity (Model fit indices: RMSEA = 0.07, CFI = 0.84, TLI = 0.82) and internal consistency (Denial Domain ΩTotal = 0.82, Attribution Domain ΩTotal = 0.69). We excluded Item 14 (I never hesitate to help someone in trouble) from the Attribution Domain, which mitigated differential measurement error by gender and slightly improved the construct validity (Model fit indices: RMSEA = 0.06, CFI = 0.86, TLI = 0.85) and reliability (Attribution Domain ΩTotal = 0.72) of the 27-item modified SDS. Using the 27-item SDS, we found that social desirability was weakly correlated with religiosity and inversely associated with self-reported alcohol use after adjusting for biomarker-measured alcohol use and other confounders (β = -0.05, 95% confidence interval: -0.09 to -0.01, p-value = 0.03). CONCLUSIONS: We detected and mitigated measurement error in the 28-item Runyankole-translated SDS, and found that the modified 27-item scale had satisfactory construct validity and internal consistency in our sample. Future studies should continue to evaluate the psychometric properties of the Runyankole-translated SDS, including retranslating Item 14 and reevaluating its performance.

IntroductionClinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population.MethodsThe ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese.ResultsACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception.DiscussionACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness.HighlightsThe Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

BACKGROUND: Smoking and alcohol use frequently co-occur and are the leading causes of preventable death in sub-Saharan Africa (SSA) and are common among people living with HIV (PLWH). While alcohol use has been shown to be associated with reduced adherence to antiretroviral treatment (ART), which may affect HIV viral suppression, the independent effect of smoking on HIV outcomes in SSA is unknown. We aimed to 1) describe the prevalence of current smoking and correlates of smoking; 2) assess the association of smoking with viral suppression, adjusting for level of alcohol use; 3) explore the relationship between smoking and CD4 cell count

BackgroundAlcohol use is common among people with HIV and is a risk factor for tuberculosis disease and non-adherence to isoniazid preventive therapy (IPT). Few interventions exist to reduce alcohol use and increase IPT adherence in sub-Saharan Africa. The aim of this study was to test the hypothesis that financial incentives conditional on point-of-care negative urine alcohol biomarker testing and positive urine isoniazid testing would reduce alcohol use and increase isoniazid adherence, respectively, in people with HIV who have latent tuberculosis infection and hazardous alcohol use.MethodsWe conducted an open-label, 2×2 factorial randomised controlled trial in Uganda. Eligible for the study were non-pregnant HIV-positive adults (aged ≥18 years) prescribed antiretroviral therapy for at least 6 months, with current heavy alcohol use confirmed by urine ethyl glucuronide (biomarker of recent alcohol use) and a positive Alcohol Use Disorders Identification Test-Consumption (AUDIT-C; ≥3 for women, ≥4 for men) for the past 3 months' drinking, no history of active tuberculosis, tuberculosis treatment, or tuberculosis preventive therapy, and a positive tuberculin skin test. We randomly assigned participants (1:1:1:1) initiating 6 months of IPT to: no incentives (group 1); or incentives for recent alcohol abstinence (group 2), isoniazid adherence (group 3), or both (group 4). Escalating incentives were contingent on monthly point-of-care urine tests negative for ethyl glucuronide (groups 2 and 4), or positive on IsoScreen (biomarker of recent isoniazid use; groups 3 and 4). The primary alcohol outcome was non-hazardous use by self-report (AUDIT-C

INTRODUCTION: Remote, internet-based methods for recruitment, screening, and longitudinally assessing older adults have the potential to facilitate Alzheimers disease (AD) clinical trials and observational studies. METHODS: The Brain Health Registry (BHR) is an online registry that includes longitudinal assessments including self- and study partner-report questionnaires and neuropsychological tests. New initiatives aim to increase inclusion and engagement of commonly underincluded communities using digital, community-engaged research strategies. New features include multilingual support and biofluid collection capabilities. RESULTS: BHR includes > 100,000 participants. BHR has made over 259,000 referrals resulting in 25,997 participants enrolled in 30 aging and AD studies. In addition, 28,278 participants are coenrolled in BHR and other studies with data linkage among studies. Data have been shared with 28 investigators. Recent efforts have facilitated the enrollment and engagement of underincluded ethnocultural communities. DISCUSSION: The major advantages of the BHR approach are scalability and accessibility. Challenges include compliance, retention, cohort diversity, and generalizability. HIGHLIGHTS: Brain Health Registry (BHR) is an online, longitudinal platform of > 100,000 members. BHR made > 259,000 referrals, which enrolled 25,997 participants in 32 studies. New efforts increased enrollment and engagement of underincluded communities in BHR. The major advantages of the BHR approach are scalability and accessibility. BHR provides a unique adjunct for clinical neuroscience research.

Low-cost interventions are needed to reduce alcohol use among persons with HIV (PWH) in low-income settings. Brief alcohol interventions hold promise, and technology may efficiently deliver brief intervention components with high frequency. We conducted a costing study of the components of a randomized trial that compared a counselling-based intervention with two in-person one-on-one sessions supplemented by booster sessions to reinforce the intervention among PWH with unhealthy alcohol use in southwest Uganda. Booster sessions were delivered twice weekly by two-way short message service (SMS) or Interactive Voice Response (IVR), i.e. via technology, or approximately monthly via live calls from counsellors. We found no significant intervention effects compared to the control, however the cost of the types of booster sessions differed. Start up and recurring costs for the technology-delivered booster sessions were 2.5 to 3 times the cost per participant of the live-call delivered booster intervention for 1000 participants. These results suggest technology-based interventions for PWH are unlikely to be lower cost than person-delivered interventions unless they are at very large scale.

When making decisions, the amount of time remaining matters. When time horizons are long, exploring unknown options can inform later decisions, but when time horizons are short, exploiting known options should be prioritized. While adults and adolescents adapt their exploration in this way, it is unclear when such adaptation emerges and how individuals behave when time horizons are ambiguous, as in many real-life situations. We examined these questions by having 5- to 6-year-olds (N = 43), 11- to 12-year-olds (N = 40), and adult college students (N = 49) in the United States complete a Simplified Horizons Task under short, long, and ambiguous time horizons. Adaptation to time horizons increased with age: older children and adults explored more when horizons were long than when short, and while some younger children adapted to time horizons, younger children overall did not show strong evidence of adapting. Under ambiguous horizons, older children and adults preferred to exploit over explore, while younger children did not show this preference. Thus, adaptation to time horizons is evident by ages 11-12 and may begin to emerge around 5-6 years, and children decrease their tendencies to explore under short and ambiguous time horizons with development. This developmental shift may lead to less learning but more adaptive decision making. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Parry Romberg Syndrome (PRS) and en coup de sabre (ECDS) are head variants of linear morphea with functional and structural implications. This study describes the clinical course, autoimmune co-morbidities, complications, and treatment of adults with PRS/ECDS at a tertiary referral center. We retrospectively reviewed the records of all 34 adult patients with PRS/ECDS identified through billing code search and seen by dermatologists at our institution between 2015 and 2021. Eight patients (23.5%) had ECDS, 8 (23.5%) had PRS, and 18 (52.9%) had overlap. Twenty-six patients (76.5%) reported ocular, oral, and/or neurologic symptoms, and 8 (23.5%) had concomitant autoimmune/inflammatory conditions. Sixteen patients (47.1%) had a skin biopsy, and 25 (73.5%) had imaging. Forty-six MRIs were obtained, of which 6 (13.0%) reported intracranial findings and 25 (54.3%) reported disease-related connective tissue damage. Twenty-four patients (70.6%) underwent systemic treatment during their disease course per available clinical records. Seventeen patients (70.8%) had improved or stable disease upon treatment completion, with an average duration of 22.2 months. Ten patients (41.7%) reported recurrence of disease following the treatment course. To address changes to facial contour, 6 patients (17.6%) opted for procedural treatments. One patient (16.7%) experienced morphea reactivation following a filler injection performed off-immunosuppression. Compared to findings in children, our study suggests adults with PRS/ECDS are more likely to have oral and ocular complications but experience less severe neurologic symptoms. While systemic treatments appear beneficial in most adult patients with PRS/ECDS, disease may recur following discontinuation.

OBJECTIVE: We sought to evaluate the utility of a point-of-care (POC) urine tenofovir (TFV) assay, developed to objectively assess adherence, to predict HIV drug resistance (HIVDR) in people failing first-line antiretroviral therapy (ART). DESIGN: We retrospectively analyzed TFV levels as a biomarker of adherence in urine specimens collected during a clinical trial that enrolled adults with virologic failure on first-line ART in Uganda and South Africa. METHODS: Urine specimens were analyzed from participants on TFV-containing regimens who had a viral load >1000 copies/ml and paired genotypic resistance test (GRT) results. We assessed recent ART TFV adherence with a qualitative POC lateral flow urine assay with a cut-off value of 1500 ng/ml. We then calculated performance characteristics of the POC urine TFV assay to predict HIVDR, defined as intermediate or high-level resistance to any component of the current ART regimen. RESULTS: Urine specimens with paired plasma GRT results were available from 283 participants. The most common ART regimen during study conduct was emtricitabine, tenofovir disoproxil fumarate, and efavirenz. The overall prevalence of HIVDR was 86% ( n = 243/283). Of those with TFV detected on the POC assay, 91% ( n  = 204/224) had HIVDR, vs. only 66% ( n  = 39/59) among those with no TFV detected ( P- value < 0.001). Positive and negative predictive values of the assay to predict HIVDR were 91% and 34%, respectively. CONCLUSIONS: In populations with a high prevalence of HIVDR, the POC urine TFV assay can provide a low-cost, rapid method to guide requirements for confirmatory resistance testing and inform the need for regimen change.

IntroductionUnhealthy alcohol use is associated with a range of adverse outcomes among people with HIV (PWH). Testing the efficacy and promoting the availability of effective interventions to address unhealthy alcohol use among PWH is thus a priority. Alcohol use outcomes in intervention studies are often measured by self-report alone, which can lead to spurious results due to information biases (eg, social desirability). Measuring alcohol outcomes objectively through biomarkers, such as phosphatidylethanol (PEth), in addition to self-report has potential to improve the validity of intervention studies. This protocol outlines the methods for a systematic review and individual participant data meta-analysis that will estimate the efficacy of interventions to reduce alcohol use as measured by a combined categorical self-report/PEth variable among PWH and compare these estimates to those generated when alcohol is measured by self-report or PEth alone.Methods and analysisWe will include randomised controlled trials that: (A) tested an alcohol intervention (behavioural and/or pharmacological), (B) enrolled participants 15 years or older with HIV; (C) included both PEth and self-report measurements, (D) completed data collection by 31 August 2023. We will contact principal investigators of eligible studies to inquire about their willingness to contribute data. The primary outcome variable will be a combined self-report/PEth alcohol categorical variable. Secondary outcomes will include PEth alone, self-report alone and HIV viral suppression. We will use a two-step meta-analysis and random effects modelling to estimate pooled treatment effects; I2 will be calculated to evaluate heterogeneity. Secondary and sensitivity analyses will explore treatment effects in adjusted models and within subgroups. Funnel plots will be used to explore publication bias.Ethics and disseminationThe study will be conducted with deidentified data from completed randomised controlled trials and will be considered exempt from additional ethical approval. Results will be disseminated through peer-reviewed publications and international scientific meetings.Prospero registration numberCRD42022373640.

Alcohol use is especially problematic for people living with HIV (PLWH) and was likely to be impacted by the coronavirus disease (COVID-19) pandemic and its restrictions. In a study of PLWH with latent tuberculosis infection, we measured unhealthy alcohol use with the Alcohol Use Disorders Identification Test (AUDIT-C), phosphatidylethanol (PEth) and bar attendance. We analyzed data collected before and after COVID-19 restrictions, and used Generalized Estimating Equations (GEE) logistic regression models to evaluate changes in unhealthy alcohol use. While bar attendance declined from 57.0% before to 38.3% after the restrictions started, multivariable analysis controlling for bar use showed a significant increase in unhealthy alcohol use; the adjusted odds ratio for unhealthy drinking before versus after the restrictions started was 1.37 (95% CI: 0.89-2.12) which increased to 1.64 (95% CI: 1.08-2.50) when bar attendance was added to the model. Decline in bar attendance did not decrease unhealthy alcohol use.

Technology-enabled approaches to conducting 24-h dietary recalls (24HR) may reduce dietary assessment bottlenecks in low-resource settings. However, few studies have assessed their performance relative to conventional pen-and-paper interview (PAPI) approaches and none have validated performance against a benchmark (e.g. weighed food record (WFR)) in a low- and middle-income country (LMIC). This study assessed relative accuracy and cost-effectiveness of INDDEX24, a technology-enabled approach to conducting 24HR, compared with a PAPI approach and against an observer WFR. Women aged 18-49 years from northern Viet Nam (n 234) were randomly assigned to be interviewed using INDDEX24 or PAPI 24HR following a WFR. The two one-sided t test approach assessed the equivalence of each recall modality to the benchmark. Difference-in-differences analysis compared the recall-benchmark results across modalities. Cost per percentage point of accuracy for INDDEX24 and PAPI was derived from accuracy results and the cost to conduct the 24HR. The PAPI and INDDEX24 24HR were statistically equivalent to the WFR for all nutrients except vitamin A. INDDEX24 diverged significantly less than PAPI from the WFR for Fe (0·9 v. -1·3 mg) and PAPI diverged less for protein (-3·7 v. 7·9 g). At the individual level, 26 % of PAPI and 32 % of INDDEX24 respondents had energy intakes within +/- 10 % of the WFR. INDDEX24 cost $111 004 and the PAPI cost $120 483 (USD 2019), making INDDEX24 more cost-effective across most indicators. INDDEX24 was an accurate and cost-effective method for assessing dietary intake in the study context and represents a preferred alternative to PAPI 24HR in Viet Nam and other LMIC.

Cholesterol biosynthesis is a highly regulated pathway, with over 20 enzymes controlled at the transcriptional and posttranslational levels. While some enzymes remain stable, increased sterol levels can trigger degradation of several synthesis enzymes via the ubiquitin-proteasome system. Of note, we previously identified four cholesterol synthesis enzymes as substrates for one E3 ubiquitin ligase, membrane-associated RING-CH-type finger 6 (MARCHF6). Whether MARCHF6 targets the cholesterol synthesis pathway at other points is unknown. In addition, the posttranslational regulation of many cholesterol synthesis enzymes, including the C4-demethylation complex (sterol-C4-methyl oxidase-like, SC4MOL; NAD(P)-dependent steroid dehydrogenase-like, NSDHL; hydroxysteroid 17-beta dehydrogenase, HSD17B7), is largely uncharacterized. Using cultured mammalian cell lines (human-derived and Chinese hamster ovary cells), we show SC4MOL, the first acting enzyme of C4-demethylation, is a MARCHF6 substrate and is rapidly turned over and sensitive to sterols. Sterol depletion stabilizes SC4MOL protein levels, while sterol excess downregulates both transcript and protein levels. Furthermore, we found SC4MOL depletion by siRNA results in a significant decrease in total cell cholesterol. Thus, our work indicates SC4MOL is the most regulated enzyme in the C4-demethylation complex. Our results further implicate MARCHF6 as a crucial posttranslational regulator of cholesterol synthesis, with this E3 ubiquitin ligase controlling levels of at least five enzymes of the pathway.

BACKGROUND: Alcohol use has been linked to worse human immunodeficiency virus (HIV) immunologic/virologic outcomes, yet few studies have explored the effects of alcohol use disorder (AUD). This study assessed whether AUD severity is associated with HIV viral suppression and CD4 count in the three cohorts of the Uganda Russia Boston Alcohol Network for Alcohol Research Collaboration on HIV/AIDS (URBAN ARCH) Consortium. METHODS: People with HIV (PWH) in Uganda (n = 301), Russia (n = 400), and Boston (n = 251), selected in-part based on their alcohol use, were included in analyses. Logistic and linear regressions were used to assess the cross-sectional associations between AUD severity (number of DSM-5 diagnostic criteria) and (1) HIV viral suppression, and (2) CD4 count (cells/mm3 ) adjusting for covariates. Analyses were conducted separately by site. RESULTS: The proportion of females was 51% (Uganda), 34% (Russia), and 33% (Boston); mean age (SD) was 40.7 (9.6), 38.6 (6.3), and 52.1 (10.5), respectively. All participants in Uganda and all but 27% in Russia and 5% in Boston were on antiretroviral therapy. In Uganda, 32% met criteria for AUD, 92% in Russia, and 43% in Boston. The mean (SD) number of AUD criteria was 1.6 (2.4) in Uganda, 5.6 (3.3) in Russia, and 2.4 (3.1) in Boston. Most participants had HIV viral suppression (Uganda 92%, Russia 57%, Boston 87%); median (IQR) CD4 count was 673 (506, 866), 351 (201, 542), and 591 (387, 881), respectively. In adjusted models, there were no associations between AUD severity and HIV viral suppression: adjusted odds ratios (AOR) (95%CI) per 1 additional AUD criterion in Uganda was 1.08 (0.87, 1.33); Russia 0.98 (0.92, 1.04); and Boston 0.95 (0.84, 1.08) or CD4 count: mean difference (95%CI) per 1 additional criterion: 5.78 (-7.47, 19.03), -3.23 (-10.91, 4.44), and -8.18 (-24.72, 8.35), respectively. CONCLUSIONS: In three cohorts of PWH, AUD severity was not associated with HIV viral suppression or CD4 count. PWH with AUD in the current era of antiretroviral therapy can achieve virologic control.

ImportanceClimate change is affecting the earth, resulting in more extreme temperatures and weather, rising sea levels, more frequent natural disasters, and displacement of populations of plants and animals, including people and insects. These changes affect food and housing security, vector-borne illnesses, and access to clean air and water, all of which influence human health.Evidence and resultsThere are a number of adverse health outcomes linked to heat, air pollution from wildfires, stress from natural disasters, and other elements of climate change. Pregnant people are especially vulnerable to the health harms resulting from climate change, namely, preterm birth, small for gestational age, hypertensive disorders of pregnancy, and other adverse reproductive health and birth outcomes. Strategies to minimize these harms include mitigation and adaptation.Conclusions and relevancePhysicians are in a unique position to protect the health of pregnant persons and children by advocating for policy changes that address climate change and providing clinical recommendations for patients to protect themselves from the health impacts of climate hazards.

PURPOSE: To test the efficacy of two interventions to reduce alcohol use and increase viral suppression compared to a control in persons with HIV (PWH). METHODS: In a three-arm (1:1:1) randomized controlled trial (N = 269), we compared in-person counselling (45-70 minutes, two sessions over three months) with interim monthly booster phone calls (live call arm) or twice-weekly automated booster sessions (technology arm) to a brief advice control arm. We enrolled PWH self-reporting unhealthy alcohol use (Alcohol Use Disorders Identification Test - Consumption, prior three months, women ≥3, men ≥4). Primary outcomes were number of self-reported drinking days (NDD) in the prior 21 and biomarker phosphatidylethanol (PEth) at six and nine months and viral suppression (

PurposeThe purpose of the current study, The National Institute of Child Health and Human Development (NICHD) Study of Health in Early and Adult Life (SHINE), was to build on the landmark Study of Early Child Care and Youth Development (SECCYD), a longitudinal birth cohort initiated in 1991, by conducting a health-focused follow-up of the now adult participants. This effort has produced an invaluable resource for the pursuit of life course research examining links between early life risk and resilience factors and adulthood health and disease risk.ParticipantsOf the 927 NICHD SECCYD participants available for recruitment in the current study, 705 (76.1%) participated in the study. Participants were between 26 and 31 years and living in diverse geographic locations throughout the USA.Findings to dateIn descriptive analyses, the sample exhibited risk on health status indicators, especially related to obesity, hypertension and diabetes. Of particular concern, the prevalence of hypertension (29.4%) and diabetes (25.8%) exceeded national estimates in similar-age individuals. Health behaviour indicators generally tracked with the parameters of poor health status, showing a pattern of poor diet, low activity and disrupted sleep. The juxtaposition of the sample's relatively young age (mean=28.6 years) and high educational status (55.6% college educated or greater) with its poor health status is noteworthy, suggesting a dissociation between health and factors that are typically health protective. This is consistent with observed population health trends, which show a worsening of cardiometabolic health status in younger generations of Americans.Future plansThe current study, SHINE, lays the groundwork for future analyses in which the uniquely robust measures collected as a part of the original NICHD SECCYD will be leveraged to pinpoint specific early life risk and resilience factors as well as the correlates and potential mechanisms accounting for variability in health and disease risk indicators in young adulthood.

The INDDEX24 Dietary Assessment Platform (INDDEX24) was developed to facilitate the collection of 24-h dietary recall (24HR) data. Alongside validation studies in Viet Nam and Burkina Faso in 2019-2020, we conducted activity-based costing studies to estimate the cost of conducting a 24HR among women of reproductive age using INDDEX24 compared with the pen-and-paper interview (PAPI) approach. We also modelled alternative scenarios in which: (1) 25-75 % of dietary reference data were borrowed from the INDDEX24 Global Food Matters Database (FMDB); (2) all study personnel were locally based and (3) national-scale surveys. In the primary analysis, in Viet Nam, the 24HR cost US $111 004 ($755/respondent, n 147) using INDDEX24 and $120 483 ($820/respondent, n 147) using PAPI. In Burkina Faso, the 24HR cost $78 105 ($539/respondent, n 145) using INDDEX24 and $79 465 ($544/respondent, n 146) using PAPI. In modelled scenarios, borrowing dietary reference data from the FMDB decreased the cost of INDDEX24 by 17-34 % (Viet Nam) and 5-15 % (Burkina Faso). With all locally based personnel, INDDEX24 cost more than PAPI ($498 v. $448 per respondent in Viet Nam and $456 v. $410 in Burkina Faso). However, at national scales (n 4376, Viet Nam; n 6500, Burkina Faso) using all locally based personnel, INDDEX24 was more cost-efficient ($109 v. $137 per respondent in Viet Nam and $123 v. $148 in Burkina Faso). In two countries and under most circumstances, INDDEX24 was less expensive than PAPI. Higher INDDEX24 survey preparation costs (including purchasing equipment) were more than offset by higher PAPI data entry, cleaning and processing costs. INDDEX24 may facilitate cost-efficient dietary data collection.

BackgroundStroke is the leading cause of mortality in China, with limited evidence of in-hospital burden obtained from nationwide surveys. We aimed to monitor and track the temporal trends and rural-urban disparities in cerebrovascular risk factors, management and outcomes from 2005 to 2015.MethodsWe used a two-stage random sampling survey to create a nationally representative sample of patients admitted for ischaemic stroke in 2005, 2010 and 2015. We sampled participating hospitals with an economic-geographical region-stratified random-sampling approach first and then obtained patients with a systematic sampling approach. We weighed our survey data to estimate the national-level results and assess changes from 2005 to 2015.ResultsWe analysed 28 277 ischaemic stroke admissions from 189 participating hospitals. From 2005 to 2015, the estimated national hospital admission rate for ischaemic stroke per 100 000 people increased (from 75.9 to 402.7, Ptrend

Background: Brief alcohol reduction interventions for people living with HIV (PLWH) have resulted in mixed findings with some studies showing null or limited treatment effects. To better understand factors that may contribute to their success or failure, this qualitative study sought to explore participants experiences in a randomized trial (RCT) of a brief counseling-based alcohol reduction intervention, including challenges that may have impeded alcohol reduction. Methods: We conducted in-depth semi-structured interviews with 24 PLWH engaging in unhealthy alcohol use, who were enrolled in an RCT to reduce alcohol consumption conducted in southwestern Uganda in 2019-2020 (NCT03928418). We used a collaborative thematic approach to analyze data from transcribed and translated audio recordings. Results: Perceived benefits of the intervention included increased awareness of alcohol use and its impact on personal finances, the relationship between alcohol use and violence, and a commitment to drinking reduction. Participants experienced several barriers to decreasing their alcohol use, including: prevailing social norms about alcohol use, lack of social support, and economic and social consequences of the COVID-19 pandemic. Conclusion: Factors in the immediate contexts of PLWH in low-income settings, including social norms influencing alcohol consumption and lack of social support, may impede the impact of alcohol reduction interventions, especially during times of stress such as the COVID-19 pandemic.

BACKGROUND: Unhealthy alcohol use is associated with increased progression to tuberculosis (TB) disease, but its effect on adherence to isoniazid (INH) preventive therapy is not known. METHODS: This was a prospective study of persons with HIV with latent TB in southwestern Uganda reporting any current (previous 3 months) alcohol use or no alcohol consumption in the previous year (2:1 ratio). All received INH. We defined suboptimal adherence as

Irrigation not only helps to improve food security but also creates numerous water bodies for mosquito production. This study assessed the effect of irrigation on malaria vector bionomics and transmission in a semi-arid site with ongoing malaria vector control program. The effectiveness of CDC light traps in the surveillance of malaria vectors was also evaluated relative to the human landing catches (HLCs) method. Adult mosquitoes were sampled in two study sites representing irrigated and non-irrigated agroecosystems in western Kenya using a variety of trapping methods. The mosquito samples were identified to species and assayed for host blood meal source and Plasmodium spp. sporozoite infection using polymerase chain reaction. Anopheles arabiensis was the dominant malaria vector in the two study sites and occurred in significantly higher densities in irrigated study site compared to the non-irrigated study site. The difference in indoor resting density of An. arabiensis during the dry and wet seasons was not significant. Other species, including An. funestus, An. coustani, and An. pharoensis, were collected. The An. funestus indoor resting density was 0.23 in irrigated study site while almost none of this species was collected in the non-irrigated study site. The human blood index (HBI) for An. arabiensis in the irrigated study site was 3.44% and significantly higher than 0.00% for the non-irrigated study site. In the irrigated study site, the HBI of An. arabiensis was 3.90% and 5.20% indoor and outdoor, respectively. The HBI of An. funestus was 49.43% and significantly higher compared to 3.44% for An. arabiensis in the irrigated study site. The annual entomologic inoculation rate for An. arabiensis in the irrigated study site was 0.41 and 0.30 infective bites/person/year indoor and outdoor, respectively, whereas no transmission was observed in the non-irrigated study site. The CDC light trap performed consistently with HLC in terms of vector density. These findings demonstrate that irrigated agriculture may increase the risk of malaria transmission in irrigated areas compared to the non-irrigated areas and highlight the need to complement the existing malaria vector interventions with novel tools targeting the larvae and both indoor and outdoor biting vector populations.

BackgroundEsophageal squamous cell carcinoma (ESCC) is a major cause of cancer morbidity and mortality in Eastern Africa. The majority of patients with ESCC in Eastern Africa present with advanced disease at the time of diagnosis. Several palliative interventions for ESCC are currently in use within the region, including chemotherapy, radiation therapy with and without chemotherapy, and esophageal stenting with self-expandable metallic stents; however, the comparative effectiveness of these interventions in a low resource setting has yet to be examined.MethodsThis prospective, observational, multi-center, open cohort study aims to describe the therapeutic landscape of ESCC in Eastern Africa and investigate the outcomes of different treatment strategies within the region. The 4.5-year study will recruit at a total of six sites in Kenya, Malawi and Tanzania (Ocean Road Cancer Institute and Muhimbili National Hospital in Dar es Salaam, Tanzania; Kilimanjaro Christian Medical Center in Moshi, Tanzania; Tenwek Hospital in Bomet, Kenya; Moi Teaching and Referral Hospital in Eldoret, Kenya; and Kamuzu Central Hospital in Lilongwe, Malawi). Treatment outcomes that will be evaluated include overall survival, quality of life (QOL) and safety. All patients (≥18 years old) who present to participating sites with a histopathologically-confirmed or presumptive clinical diagnosis of ESCC based on endoscopy or barium swallow will be recruited to participate. Key clinical and treatment-related data including standardized QOL metrics will be collected at study enrollment, 1 month following treatment, 3 months following treatment, and thereafter at 3-month intervals until death. Vital status and QOL data will be collected through mobile phone outreach.DiscussionThis study will be the first study to prospectively compare ESCC treatment strategies in Eastern Africa, and the first to investigate QOL benefits associated with different treatments in sub-Saharan Africa. Findings from this study will help define optimal management strategies for ESCC in Eastern Africa and other resource-limited settings and will serve as a benchmark for future research.Trial registrationThis study was retrospectively registered with the ClinicalTrials.gov database on December 15, 2021,  NCT05177393 .

Effective nutrition policies require timely, accurate individual dietary consumption data; collection of such information has been hampered by cost and complexity of dietary surveys and lag in producing results. The objective of this work was to assess accuracy and cost-effectiveness of a streamlined, tablet-based dietary data collection platform for 24-hour individual dietary recalls (24HR) administered using INDDEX24 platform v. a pen-and-paper interview(PAPI) questionnaire, with weighed food record (WFR) as a benchmark. This cross-sectional comparative study included women 18-49 years old from rural Burkina Faso (n 116 INDDEX24; n 115 PAPI). A WFR was conducted; the following day, a 24HR was administered by different interviewers. Food consumption data were converted into nutrient intakes. Validity of 24HR estimates of nutrient and food group consumption was based on comparison with WFR using equivalence tests (group level) and percentages of participants within ranges of percentage error (individual level). Both modalities performed comparably estimating consumption of macro- and micronutrients, food groups and quantities (modalities' divergence from WFR not significantly different). Accuracy of both modalities was acceptable (equivalence to WFR significant at P < 0·05) at group level for macronutrients, less so for micronutrients and individual-level consumption (percentage within ±20 % for WFR, 17-45 % for macronutrients, 5-17 % for micronutrients). INDDEX24 was more cost-effective than PAPI based on superior accuracy of a composite nutrient intake measure (but not gram amount or item count) due to lower time and personnel costs. INDDEX24 for 24HR dietary surveys linked to dietary reference data shows comparable accuracy to PAPI at lower cost.

BackgroundMalaria in western Kenya is currently characterized by sustained high Plasmodial transmission and infection resurgence, despite positive responses in some areas following intensified malaria control interventions since 2006. This study aimed to evaluate long-term changes in malaria transmission profiles and to assess patterns of asymptomatic malaria infections in school children aged 5-15 years at three sites in western Kenya with heterogeneous malaria transmission and simultaneous malaria control interventions.MethodsThe study was conducted from 2018 to 2019 and is based on data taken every third year from 2005 to 2014 during a longitudinal parasitological and mosquito adult surveillance and malaria control programme that was initiated in 2002 in the villages of Kombewa, Iguhu, and Marani. Plasmodium spp. infections were determined using microscopy. Mosquito samples were identified to species and host blood meal source and sporozoite infections were assayed using polymerase chain reaction.ResultsPlasmodium falciparum was the only malaria parasite evaluated during this study (2018-2019). Asymptomatic malaria parasite prevalence in school children decreased in all sites from 2005 to 2008. However, since 2011, parasite prevalence has resurged by > 40% in Kombewa and Marani. Malaria vector densities showed similar reductions from 2005 to 2008 in all sites, rose steadily until 2014, and decreased again. Overall, Kombewa had a higher risk of infection compared to Iguhu (χ2 = 552.52, df = 1, P

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

PurposePNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG).Patients and methodsPatients (3-25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN).ResultsOf 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2-18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome.ConclusionsUpfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.

BACKGROUND: Both human immunodeficiency virus (HIV) infection and alcohol use predispose to autonomic/sensory neuropathy, imbalance symptoms, and cognitive impairment-conditions associated with a greater risk of falls-yet it is unclear how to identify people with HIV (PWH) whose drinking is associated with falls. Research on alcohol and falls using the same instruments in different countries could help to specify the level of alcohol use associated with fall risk. We examined whether a consumption-based measure (the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]) and/or a symptom-based measure (DSM-5 criteria for alcohol use disorder [AUD]) are associated with sustaining a fall among PWH in St Petersburg, Russia and Boston, Massachusetts in the United States. METHODS: Separate multivariate logistic regressions were used for each cohort to examine cross-sectional associations for each alcohol measure predicting fall. Potential confounders included physical functioning, depressive symptoms, and other substance use (measured with the Addiction Severity Index). RESULTS: A fall was reported by 35% (87/251) of the sample in Boston and 12% (46/400) in St Petersburg. Each additional AUD criterion-but not higher AUDIT-C score-was significantly associated with a fall in both Boston (odds ratio [OR] = 1.10; 95% confidence interval [CI] 1.02, 1.18) and St Petersburg (adjusted OR AOR = 1.10; 95% CI 1.02, 1.18). Heavy alcohol use (>6 drinks/occasion, any vs. none) was associated with more than twice the odds of a fall (AOR = 2.24; 95% CI 1.21, 4.13) in Boston. CONCLUSIONS: These findings suggest that while fall risk may vary by setting and population, heavy alcohol use and AUD symptom severity are potential targets for interventions to prevent falls. Studies in diverse global settings advance our understanding of the relationship between alcohol and falls in PWH.

T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic stimulation assay, we performed genome-wide CRISPR-Cas9 screens to systematically discover regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of the INO80 and BAF chromatin remodeling complexes improved T cell persistence in tumors. In vivo Perturb-seq revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a depletion limited the acquisition of exhaustion-associated chromatin accessibility and led to improved antitumor immunity. In summary, we provide an atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of epigenetic state can improve T cell responses in cancer immunotherapy.

ObjectiveUganda is HIV-endemic with a prevalence of 5.7%. Lack of epidemic control has been attributed to low engagement with HIV testing. Collaborating with informal healthcare providers, such as traditional healers, has been proposed as a strategy to increase testing uptake. We explored acceptability and implementation of an HIV testing program where traditional healers delivered point-of-care testing and counseling to adults of unknown serostatus (clinicaltrials.gov NCT#03718871).MethodsThis study was conducted in rural, southwestern Uganda. We interviewed participating traditional healers ( N  = 17) and a purposive sample of trial participants ( N  = 107). Healers were practicing within 10 km of Mbarara township, and 18+ years old. Participants were 18+ years old; sexually active; had received care from participating healers; self-reported not receiving an HIV test in prior 12 months; and not previously diagnosed with HIV infection. Interviews explored perceptions of a healer-delivered HIV testing model and were analyzed following a content-analysis approach.ResultsMost participants were female individuals ( N  = 68, 55%). Healer-delivered HIV testing overcame structural barriers, such as underlying poverty and rural locations that limited use, as transportation was costly and often prohibitive. Additionally, healers were located in villages and communities, which made services more accessible compared with facility-based testing. Participants also considered healers trustworthy and 'confidential'. These qualities explain some preference for healer-delivered HIV testing, in contrast to 'stigmatizing' biomedical settings.ConclusionTraditional healer-delivered HIV testing was considered more confidential and easily accessible compared with clinic-based testing. Offering services through traditional healers may improve uptake of HIV testing services in rural, medically pluralistic communities.

Hazardous alcohol use and psychological distress are common among persons living with HIV (PLWH). In Uganda, HIV prevalence is 6.2% with average pure alcohol consumption per capita of 9.8 L. Social support may mitigate hazardous alcohol use. In a cohort of 443 PLWH, we measured social support using the Duke-UNC functional social support scale and self-reported alcohol consumption using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), augmented by phosphatidylethanol (PEth). We examined the association between low social support and hazardous alcohol use using multiple logistic regression models. 30% had low social support and 44% had hazardous alcohol use (AUDIT-C ≥ 3 for women and ≥ 4 for men and/or PEth ≥ 50 ng/mL). We did not detect an association between low social support and hazardous alcohol use. Social support may play no role or a minimal role in preventing PLWH from hazardous alcohol use.

BackgroundSafe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing.FindingsWe recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to

AimsAlcohol is hypothesized to have effects on the kynurenine pathway of tryptophan catabolism, a potential mechanism for alcohol-induced depression and aggression. A biomarker of this pathway, the plasma kynurenine to tryptophan ratio (K/T ratio), has been associated with HIV progression, mortality and depression. Our aim was to assess whether hazardous alcohol consumption is associated higher K/T ratio among people with HIV.MethodsParticipants were a subset of the Uganda Alcohol Research Collaboration on HIV/AIDS Cohort. Alcohol consumption was categorized (abstinent, moderate and hazardous alcohol use) using the Alcohol Use Disorders Identification Test-Consumption and phosphatidylethanol (PEth). K/T ratio was the primary outcome. We used linear regression adjusted for age, sex, FIB-4, hepatitis B surface antigen, log (HIV viral load) to estimate the association between alcohol consumption and K/T ratio.ResultsCompared to abstinent participants, hazardous drinkers and moderate drinkers had higher K/T ratio but these differences did not reach statistical significance.ConclusionsOur results suggest that hazardous alcohol consumption, in the context of untreated HIV infection, may not significantly alter kynurenine to tryptophan ratio as a measure of activity of the kynurenine pathway of tryptophan metabolism.

BackgroundActivated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).ObjectivesThis study sought to characterize HCT outcomes in APDS.MethodsRetrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.ResultsPre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.ConclusionsGraft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.

BackgroundWe aimed to describe the prevalence of PTSD symptoms and its associated factors in persons living with HIV (PLWH) in Uganda who engage in heavy alcohol use.MethodsWe analyzed baseline data from the Drinkers Intervention to Prevent Tuberculosis study which enrolls PLWH with latent tuberculosis who engage in heavy alcohol consumption. Using the primary care Post Traumatic Stress Disorder (PTSD) screening scale from the DSM-5 (PC-PTSD-5), probable PTSD was defined as reporting ≥3 of 5 assessed symptoms. We conducted the Alcohol Use Disorders Identification Test-Consumption and assessed demographics, smoking, symptoms of depression, and spirituality/religiosity.ResultsOf 421 participants enrolled from 2018 through 2020, the majority (68.2%) were male, median age was 40 years (interquartile range [IQR]: 32-47), and median AUDIT-C score was 6 [IQR: 4-8]. Half (50.1%) of the participants reported ever experiencing a traumatic event, and 20.7% reported ≥3 symptoms of PTSD. The most commonly reported PTSD symptoms in the past 1 month in the entire sample were avoidance (28.3%), nightmares (27.3%), and being constantly on guard (21.6%). In multivariable logistic regression analyses, level of alcohol use was not associated with probable PTSD (adjusted odds ratio [AOR] for each AUDIT-C point: (1.02; 95% CI: 0.92-1.14; p = 0.69); however, lifetime smoking (AOR 1.89; 95% CI: 1.10-3.24) and reporting symptoms of depression (AOR 1.89; 95% CI: 1.04-3.44) were independently associated with probable PTSD.Conclusions and recommendationsA history of traumatic events and probable PTSD were frequently reported among persons who engage in heavy drinking, living with HIV in Uganda. Level of alcohol use was not associated with probable PTSD in this sample of PLWH with heavy alcohol use, however other behavioral and mental health factors were associated with probable PTSD. These data highlight the high prevalence of PTSD in this group, and the need for screening and interventions for PTSD and mental health problems.

BackgroundThe risk of tuberculosis (TB) is high among people with HIV (PWH). Heavy alcohol drinking independently increases TB risk and approximately 25% of PWH globally engage in heavy drinking. While isoniazid (INH) preventive therapy decreases TB incidence and mortality among PWH, heavy drinking during INH is associated with liver toxicity and poor adherence. Interventions are, therefore, urgently needed to decrease alcohol use and improve adherence to INH in this population in settings with high prevalence of HIV and TB like Uganda.MethodsThe Drinkers' Intervention to Prevent TB (DIPT) study is a 2×2 factorial randomized controlled trial among HIV/TB co-infected adults (≥18 years) who engage in heavy alcohol drinking and live in Uganda. The trial will allocate 680 participants with a 1:1:1:1 individual randomization to receive 6 months of INH and one of the following interventions: (1) no incentives (control), (2) financial incentives contingent on low alcohol use, (3) financial incentives contingent on high adherence to INH, and (4) escalating financial incentives for both decreasing alcohol use and increasing adherence to INH. Incentives will be in the form of escalating lottery-based monetary rewards. Participants will attend monthly visits to refill isoniazid medications, undergo liver toxicity monitoring, and, except for controls, determine eligibility for prizes. We will estimate (a) the effect of incentives contingent on low alcohol use on reduction in heavy drinking, measured via a long-term objective and self-reported metric of alcohol use, at 3- and 6-month study visits, and (b) the effect of incentives contingent on high adherence to INH, measured as >90% pill-taking days by medication event monitoring system cap opening. We will use qualitative methods to explore the mechanisms of any influence of financial incentives on HIV virologic suppression.DiscussionThis study will provide new information on low-cost strategies to both reduce alcohol use and increase INH adherence among people with HIV and TB infection who engage in heavy drinking in low-income countries with high HIV and TB prevalence.Trial registrationClinicalTrials.gov NCT03492216 . Registered on April 10, 2018.

Hazardous drinking by persons living with HIV (PLHIV) is a well-established determinant of sub-optimal HIV care and treatment outcomes. Despite this, to date, few interventions have sought to reduce hazardous drinking among PLHIV in sub-Saharan Africa (SSA). We describe an iterative cultural adaptation of an evidence-based multi-session alcohol reduction intervention for PLHIV in southwestern Uganda. The adaptation process included identifying core, theoretically informed, intervention elements, and conducting focus group discussions and cognitive interviews with community members, HIV clinic staff and patients to modify key intervention characteristics for cultural relevance and saliency. Adaptation of evidence-based alcohol reduction interventions can be strengthened by the inclusion of the target population and key stakeholders in shaping the content, while retaining fidelity to core intervention elements.

BackgroundTreatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure.MethodsSmall hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda.ResultsAmong the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7-99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort.ConclusionsHair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.

BackgroundHIV counselling and testing are essential to control the HIV epidemic. However, HIV testing uptake is low in sub-Saharan Africa, where many people use informal health-care resources such as traditional healers. We hypothesised that uptake of HIV tests would increase if provided by traditional healers. We aimed to determine the effectiveness of traditional healers delivering HIV testing at point of care compared with referral to local clinics for HIV testing in rural southwestern Uganda.MethodsWe did a mixed-methods study that included a cluster-randomised trial followed by individual qualitative interviews among a sample of participants in Mbarara, Uganda. Traditional healers aged 18 years or older who were located within 8 km of the Mbarara District HIV clinic, were identified in the 2018 population-level census of traditional healers in Mbarara District, and delivered care to at least seven clients per week were randomly assigned (1:1) as clusters to an intervention or a control group. Healers screened their clients for eligibility, and research assistants confirmed eligibility and enrolled clients who were aged 18 years or older, were receiving care from a participating healer, were sexually active (ever had intercourse), self-reported not having received an HIV test in the previous 12 months (and therefore considered to be of unknown serostatus), and had not previously been diagnosed with HIV infection. Intervention group healers provided counselling and offered point-of-care HIV tests to adult clients. Control group healers provided referral for HIV testing at nearby clinics. The primary outcome was the individual receipt of an HIV test within 90 days of study enrolment. Safety and adverse events were recorded and defined on the basis of prespecified criteria. This study is registered with ClinicalTrials.gov, NCT03718871.FindingsBetween Aug 2, 2019, and Feb 7, 2020, 17 traditional healers were randomly assigned as clusters (nine to intervention and eight to control), with 500 clients of unknown HIV serostatus enrolled (250 per group). In the intervention group, 250 clients (100%) received an HIV test compared with 57 (23%) in the control group, a 77% (95% CI 73-82) increase in testing uptake, after adjusting for the effect of clustering (p

PurposeHeating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites.MethodA standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC).ResultsOf the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI.DiscussionThis study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

The primary goal of the unrelated population HLA diversity (UPHD) component of the 17th International HLA and Immunogenetics Workshop was to characterize HLA alleles at maximum allelic-resolution in worldwide populations and re-evaluate patterns of HLA diversity across populations. The UPHD project included HLA genotype and sequence data, generated by various next-generation sequencing methods, from 4,240 individuals collated from 12 different countries. Population data included well-defined large datasets from the USA and smaller samples from Europe, Australia, and Western Asia. Allele and haplotype frequencies varied across populations from distant geographical regions. HLA genetic diversity estimated at 2- and 4-field allelic resolution revealed that diversity at the majority of loci, particularly for European-descent populations, was lower at the 2-field resolution. Several common alleles with identical protein sequences differing only by intronic substitutions were found in distinct haplotypes, revealing a more detailed characterization of linkage between variants within the HLA region. The examination of coding and non-coding nucleotide variation revealed many examples in which almost complete biunivocal relations between common alleles at different loci were observed resulting in higher linkage disequilibrium. Our reference data of HLA profiles characterized at maximum resolution from many populations is useful for anthropological studies, unrelated donor searches, transplantation, and disease association studies.

ObjectiveWe examined whether gender is associated with heavy drinking in three cohorts of people living with HIV (PLWH) in Mbarara, Uganda; St. Petersburg, Russia; and Boston, Massachusetts.MethodWe conducted secondary analyses of baseline data collected from three cohorts in the Uganda Russia Boston Alcohol Network for Alcohol Research Collaboration on HIV/AIDS (URBAN ARCH) consortium. We used multiple logistic regression models to evaluate the association between gender and heavy drinking (defined in combination with self-report and phosphatidylethanol [PEth]) within each cohort.ResultsIn unadjusted logistic regression models, we found no significant association between gender and heavy drinking in Russia or Boston. In Uganda, women were less likely than men to engage in heavy drinking (odds ratio = 0.38, 95% CI [0.26, 0.58], p

Viruses closely related to human pathogens can reveal the origins of human infectious diseases. Human herpes simplexvirus type 1 (HSV-1) and type 2 (HSV-2) are hypothesized to have arisen via host-virus codivergence and cross-species transmission. We report the discovery of novel herpes simplexviruses during a large-scale screening of fecal samples from wild gorillas, bonobos, and chimpanzees. Phylogenetic analysis indicates that, contrary to expectation, simplexviruses from these African apes are all more closely related to HSV-2 than to HSV-1. Molecular clock-based hypothesis testing suggests the divergence between HSV-1 and the African great ape simplexviruses likely represents a codivergence event between humans and gorillas. The simplexviruses infecting African great apes subsequently experienced multiple cross-species transmission events over the past 3 My, the most recent of which occurred between humans and bonobos around 1 Ma. These findings revise our understanding of the origins of human herpes simplexviruses and suggest that HSV-2 is one of the earliest zoonotic pathogens.

BackgroundObjective 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.MethodsWe 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.ResultsOne 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.ConclusionsAmong 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.