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BackgroundNeurocognitive impairment (NCI) is one of the most common complications of HIV infection, and has serious medical and functional consequences. South Africa has 7 million people living with HIV (PLHIV) with up to three-quarters of antiretroviral therapy (ART)-naïve individuals having NCI. South Africa’s health system struggles to meet the care needs of its millions of PLHIV; screening for NCI is typically neglected due to limited clinical staff trained to administer, score, and interpret neuropsychological tests, as well as long test batteries and limited screening tools for South African populations. Without accurate, clinically useful, and relatively brief NCI screening tests that can be administered by all levels of clinical staff, critical opportunities to provide psychoeducation, behavioral planning, additional ART adherence support, and adjuvant therapies for NCI (when they become available) are missed. To address these challenges and gap in care, we developed an mHealth app screening tool, NeuroScreen, to detect NCI that can be administered by all levels of clinical staff, including lay health workers. ObjectiveThe purpose of this study was to examine sensitivity and specificity of an adapted version of NeuroScreen to detect NCI (as determined by a gold standard neuropsychological test battery administered by a trained research psychometrist) among HIV-infected South Africans when administered by a lay health worker. MethodsA total of 102 HIV-infected black South African adults who had initiated ART at least 12 months prior were administered NeuroScreen and a gold standard neuropsychological test battery in the participants’ choice of language (ie, English or isiXhosa). Three composite z scores were calculated for NeuroScreen: (1) sum of all individual test scores, (2) sum of all individual test scores and error scores from four tests, and (3) sum of four tests (abbreviated version). Global deficit scores were calculated for the gold standard battery where a score of 0.5 or greater indicated the presence of NCI. ResultsThe mean age of participants was 33.31 (SD 7.46) years, most (59.8%, 61/102) had at least 12 years of education, and 81.4% (83/102) of the sample was female. Gold standard test battery results indicated that 26.5% (27/102) of the sample had NCI. Sensitivity and specificity of age-, education-, and sex-adjusted NeuroScreen scores were 81.48% and 74.67% for composite score 1, 81.48% and 81.33% for composite score 2, and 92.59% and 70.67% for composite score 3, respectively. ConclusionsNeuroScreen, a highly automated, easy-to-use, tablet-based screening test to detect NCI among English- and isiXhosa-speaking South African HIV patients demonstrated robust sensitivity and specificity to detect NCI when administered by lay health workers. NeuroScreen could help make screening for NCI more feasible. However, additional research is needed with larger samples and normative test performance data are needed.

IntroductionChildren who are HIV-exposed uninfected (HEU), that is, children who do not acquire HIV infection despite being born to mothers with HIV, have a higher risk of mortality, infectious morbidity and growth deficits than children who are HIV-unexposed uninfected (HUU). Prior research has focused on breast feeding and has pointed to changes in human milk oligosaccharides (HMOs) associated with maternal HIV that may influence the infant microbiome and thereby lead to these adverse outcomes. However, to our knowledge, no study has attempted to intervene along this pathway to reduce the occurrence of the adverse outcomes in children HEU. We will conduct a double-blind, randomised trial of a synbiotic intervention, which combines an HMO and probiotic, in breastfed infants HEU in South Africa to evaluate whether this intervention has promise to reduce excess infectious morbidity and growth faltering compared with controls.Methods and analysisOne hundred and forty-four breastfed infants HEU, aged 4 weeks, will be 1:1 randomised to receive either a daily synbiotic or an identical-looking placebo through age 24 weeks. Infants will be followed until age 48 weeks and outcomes of infectious morbidity, growth and biological measurements (eg, microbiota, inflammation and metabolome) will be assessed. Analyses will follow intention-to-treat principles comparing the cohorts as randomised. Infants HEU will be compared across arms with respect to the occurrence of infectious morbidity and growth outcomes through 4-24 weeks and 4-48 weeks using appropriate parametric and non-parametric statistical tests. Additionally, an observational cohort of 40 breastfed infants HUU will be recruited as a comparator group with no intervention.Ethics and disseminationEthical approval for this study has been obtained from the ethics committees at Columbia University and Stellenbosch University. The findings will be disseminated in publications.Trial registration numberClinicalTrials.gov Identifier: NCT05282485. SANCTR ID number: DOH-27-122021-6543.

BackgroundStatural growth impairment is more common in males with Crohn's disease (CD). We assessed sex differences in height Z score differences and bone age (BA) Z scores and characterized age of menarche in a novel contemporary cohort of pediatric CD patients undergoing screening for enrollment in the multicenter longitudinal Growth Study.MethodsCrohn's disease patients (females with chronological age [CA] 5 years and older and younger than 14 years; males with CA 6 years and older and younger than 16 years) participated in a screening visit for the Growth Study. Height BA-Z scores are height Z scores calculated based on BA. Height CA-Z scores are height Z scores calculated based on CA. The height Z score difference equals height CA-Z score minus height BA-Z score.ResultsOne hundred seventy-one patients (60% male) qualified for this analysis. Mean CA was 12.2 years. Mean height CA-Z score was -0.4, and mean height BA-Z score was 0.4 in females. Mean height CA-Z score was -0.1, and mean height BA-Z score was 0.2 in males. The absolute value of the mean height Z score difference was significantly greater in females (0.8) than males (0.3; P = 0.005). The mean BA-Z score in females (-1.0) was significantly lower than in males (-0.2; P = 0.002). The median CA at menarche was 13.6 (95% CI, 12.6-14.6) years.ConclusionsOur screening visit data suggest that standardized height gain is lower in males with skeletal maturation and delayed puberty is common in females in CD. We are investigating these findings in the ongoing Growth Study.

This study examined cannabis use and driving outcomes among older drivers in Colorado, which has legalized medical and recreational use. The associations of self-reported past-year cannabis use with diverse driving outcomes were assessed in 598 drivers aged 65-79 (51% female, 70% with postsecondary education), using regression analysis to adjust for health and sociodemographic characteristics. Two hundred forty four (40.8%) drivers reported ever using cannabis. Fifty-four drivers (9.0%) reported past-year use, ranging from more than once a day (13.0%) to less than once a month (50.0%). Of past-year users, 9.3% reported cannabis use within 1 h of driving in the past year. Past-year users were younger, less highly educated, lower income, and reported significantly worse mental, emotional, social and cognitive health status than drivers without past-year use. Past-year users were four times as likely to report having driven when they may have been over the legal blood-alcohol limit (adjusted OR [aOR] = 4.18; 95% CI: 2.11, 8.25) but were not more likely to report having had a crash or citation (aOR = 1.36; 95% CI: 0.70, 2.66) in the past year. Users and non-users had similar scores on self-rated abilities for safe driving (adjusted beta=-0.04; 95% CI: -0.23, 0.15) and on driving-related lapses, errors and violations in the past year (adjusted beta = 0.04; 95% CI: -0.04, 0.12). Further study is needed to establish driving risks and behaviours related to cannabis use, independent of other associated risk factors, among older adults.

AimTo determine the distribution of anthropometric parameter (AP)-z-scores and characterize associations between medications/serum biomarkers and AP-z-scores in pediatric Crohn's disease (CD).MethodsCD patients [< chronological age (CA) 21 years] were enrolled in a cross-sectional study. Descriptive statistics were generated for participants' demographic characteristics and key variables of interest. Paired t-tests were used to compare AP-z-scores calculated based on CA (CA z-scores) and bone age (BA) (BA z-scores) for interpretation of AP's. Linear regression was utilized to examine associations between medications and serum biomarkers with AP-z-scores calculated based on CA (n = 82) and BA (n = 49). We reported regression coefficients as well as their corresponding p-values and 95% confidence intervals.ResultsMean CA at the time of the study visit was 15.3 ± 3.5 (SD; range = 4.8-20.7) years. Mean triceps skinfold (P = 0.039), subscapular skinfold (P = 0.002) and mid-arm circumference (MAC) (P = 0.001) BA z-scores were higher than corresponding CA z-scores. Medications were positively associated with subscapular skinfold [adalimumab (P = 0.018) and methotrexate (P = 0.027)] and BMI CA z-scores [adalimumab (P = 0.029)]. Azathioprine/6-mercaptopurine were negatively associated with MAC (P = 0.045), subscapular skinfold (P = 0.014), weight (P = 0.002) and BMI (P = 0.013) CA z-scores. ESR, CRP, and WBC count were negatively associated, while albumin and IGF-1 BA z-scores were positively associated, with specific AP z-scores (P < 0.05). Mean height CA z-scores were higher in females, not males, treated with infliximab (P = 0.038). Hemoglobin (P = 0.018) was positively associated, while platelets (P = 0.005), ESR (P = 0.003) and CRP (P = 0.039) were negatively associated with height CA z-scores in males, not females.ConclusionOur results suggest poor efficacy of thiopurines and a possible sex difference in statural growth response to infliximab in pediatric CD. Prospective longitudinal studies are required.

Objectives: To evaluate parent knowledge and belief changes following the MySmileBuddy (MSB) early childhood caries (ECC) intervention. Methods: Pre‐ and post‐intervention surveys were completed by 669 parents of children with visually‐evident ECC from among 977 participants in a 6–12‐month pragmatic community‐based caries management trial administered by community health workers (CHWs). Six domains of knowledge about caries and motivating and facilitating determinants were assessed via 26 survey items. Principal components analysis and reliability testing reduced dataset dimensionality. Parent and CHW characteristics were analyzed as potential moderators. Paired T‐tests measured pre‐to‐post‐intervention changes. Generalized estimating equations accounted for within‐participant correlation with significance set at p < 0.05. Results: Twenty items consolidated into five factors (saliva, hygiene, diet, seriousness/susceptibility, and outcome expectations). Six additional items were evaluated individually. Positive post‐intervention changes (p < 0.0001) were observed across all factors and all but one individual item (tooth decay is very common). Greatest knowledge increases related to caries as a bacterial disease in two measures, the saliva factor and a single caries belief item tooth decay is an infectious disease (0.59 unit increase, 95% CI [0.55, 0.64] and 0.46 unit increase, 95% CI [0.4, 0.51], respectively), and in the value of fluoridated water over bottled (0.46 unit increase, 95% CI [0.39–0.53]). Most parents improved knowledge of ECC salivary (72%) and dietary risks (57%), and preventative hygiene behaviors (59%). Conclusions: MSB enhanced knowledge and beliefs about caries and confirmed hypothesized mediators of behavior change among parents of high‐risk children. Engaging peer‐like CHW interventionists may have moderated intervention effects, warranting further exploration. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2. Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle. We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381, which has evolutionarily conserved interactions with the specificity site. Atomistic molecular dynamics simulations indicate mechanisms by which RRM1 variants affect protein structure. Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis. Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation. Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS., Introduction Autosomal disorders of mitochondrial DNA (mtDNA) maintenance are clinically heterogeneous and typically severe diseases with mtDNA depletion or multiple deletions leading to focal respiratory chain deficiency in affected tissues [...]