Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

Children's physical activity and sedentary behaviour in before school care: An observational study.

OBJECTIVE: In Australia, less than one quarter of children aged 5-12 years meet national physical activity (PA) guidelines. Before school care operates as part of Out of School Hours Care (OSHC) services and provide opportunities for children to meet their daily PA recommendations. The aim of this study was to explore factors associated with children meeting 15 min of moderate-to-vigorous-intensity physical activity (MVPA) while attending before school care. METHODS: A cross-sectional study was conducted in 25 services in New South Wales, Australia. Each service was visited twice between March and June 2021. Staff behaviours and PA type and context were captured using staff interviews and the validated System for Observing Staff Promotion of Physical Activity and Nutrition (SOSPAN) time sampling tool. Child PA data were collected using Actigraph accelerometers and associations between program practices and child MVPA analysed. RESULTS: PA data were analysed for 654 children who spent an average of 39.2% (±17.6) of their time sedentary; 45.4% (±11.4) in light PA; and 14.9% (±11.7) in MVPA. Only 17% of children (n = 112) reached ≥15 min MVPA, with boys more likely to achieve this. Children were more likely to meet this recommendation in services where staff promoted and engaged in PA; PA equipment was available; children were observed in child-led free play; and a written PA policy existed. CONCLUSIONS: Before school care should be supported to improve physical activity promotion practices by offering staff professional development and guidance on PA policy development and implementation practices.

The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner.

Obesity is linked to cognitive decline and metabolic dysregulation in the brain, yet the role of sex is relatively unexplored. We sought to explore the effects of obesity and sex on the brain metabolome. In male and female ob/ob and wild-type mice, we assessed whole brain untargeted metabolomics by liquid chromatography-mass spectrometry, behavior by open field test, and cognitive function by Y-maze and Morris water maze. The metabolic profiles of ob/ob and wild-type mice differed in both sexes. There were more obesity-altered brain metabolites in males than females. Thirty-nine metabolites were unique to males, 15 were unique to females, and five were common to both sexes. Two of the common metabolites were involved in nicotinamide adenine dinucleotide homeostasis. A key feature of the metabolites identified in males was an increase in free fatty acids. In females, a unique feature was the presence of the neuro-modulatory metabolites 2-linoleoyl glycerol and taurine. The behavioral effects of obesity were only seen in females. These results demonstrate that most impacts of obesity on the brain metabolomic profile are sex-specific. Our work has implications for understanding the role of obesity in brain metabolism and the differential contribution of obesity to cognitive decline in males and females.

The feasibility, acceptability and potential efficacy of a parental text message and social media program on children's vegetable consumption and movement behaviours: A pilot randomised controlled trial.

ISSUE ADDRESSED: Australian children fall short of meeting the dietary, physical activity and sedentary behaviour guidelines. This study aimed to test the feasibility, acceptability and potential efficacy of a parental text message and social media program on, primarily, their school-aged children's vegetable consumption and movement behaviours, and, secondarily, their own. METHODS: Between August and November 2022, we conducted a two-armed randomised controlled trial with 242 parents/caregivers of primary school-aged children in New South Wales. The 'Adventure & Veg' intervention ran for 8 weeks, promoting vegetable eating behaviours, local outdoor physical activity opportunities and ideas for reducing screen time. Feasibility and acceptability were assessed via recruitment and retention data, intervention metrics and self-reported participant data. Vegetable intake and movement behaviour data were collected via online-surveys and effect sizes were examined. RESULTS: Most participants reported that they enjoyed receiving the text messages (88%) and the delivery frequency was acceptable (94%). Limitations to Facebook as a delivery platform were reported. The majority of participants used the text messages to influence the vegetable eating (65%) and movement (77%) behaviours of their child. Significant effects were observed among intervention child participants compared with control for mean daily vegetable consumption (0.45 serves, CI: .19; .71, p = .001, d = .5); weekly vegetable variety (1.85, CI: .25; 3.45, p < .001, d = .6); and weekly physical activity variety (.64 CI: .09; 1.19, p = .022, d = .3). Parents in the intervention group increased their daily vegetable intake by .44 serves (CI: .11; .78, p = .01, d = .4). CONCLUSIONS: A parental text message and social media program has potential to support children's vegetable intake and movement behaviours. Further research is required to explore different online delivery methods to promote local outdoor activity options. SO WHAT?: The Adventure & Veg program holds promise as a stand-alone health promotion intervention or as a useful adjunct to current family or school-based healthy lifestyle programs.

Healthy kids vids: Development and acceptability of narrative healthy lifestyle videos and text messages for parents of young children from socioeconomically disadvantaged populations.

ISSUE ADDRESSED: Dietary intake and physical activity behaviours of many Australian children are not meeting recommendations, particularly for those living in socioeconomically disadvantaged circumstances. This study aimed to design and assess the feasibility and acceptability of a suite of narrative videos and text messages focused on healthy eating and physical activity behaviours appropriate for parents of young children from socioeconomically disadvantaged backgrounds. METHODS: Parents of 1-5-year-old children (n = 6) were recruited to develop a suite of 12 narrative videos on healthy eating and physical activity behaviours, underpinned by theory. Twelve complementary text messages were subsequently developed. A different group of parents (n = 16) recruited from socioeconomically disadvantaged areas reviewed the videos and text messages over 6 weeks and provided feedback via surveys and qualitative interviews (n = 13). RESULTS: There was a high level of engagement with and acceptability of the videos and text message content. Participants found the videos easy to access and they liked the narrative style. Screen time videos and text messages relating to screen time, play and physical activity, role modelling and fussy eating were most useful. CONCLUSIONS: Narrative style healthy eating, physical activity and screen time videos and complementary text messages were highly acceptable to the sample of parents of 1-5-year-old children from socioeconomically disadvantaged areas recruited from the Illawarra Shoalhaven region of NSW, Australia. SO WHAT?: Short narrative style videos and text messages are an easy to process and acceptable method of delivering healthy lifestyle promotion content to parents.

Feasibility, acceptability and potential efficacy of a virtual physical activity program in primary and secondary schools in New South Wales, Australia: A quasi-experimental study.

ISSUE ADDRESSED: Child and youth participation in physical activity (PA) is fundamental for healthy development and obesity prevention. Government policy requires schools to offer 150 minutes of PA each week, however compliance is low. Race around Australia (RAA) is a New South Wales (NSW) Department of Education, virtual PA program aimed at assisting schools in meeting the PA guidelines. METHODS: A pre- and post-intervention, quasi-experimental study was conducted using a mixed-methods approach comprising teacher interviews, a student questionnaire and a 1.6 kilometre (km) timed run. Data were collected from April to September 2021 among students and teachers in Grades 5 to 8, from 10 schools in NSW, Australia. RESULTS: The analytical sample included data from 918 students and 17 teachers. The RAA program was deemed feasible and acceptable in primary schools, whereas there were several systemic and intrapersonal barriers to implementation success for secondary schools. In primary schools, RAA increased PA opportunities and the 1.6 km timed runs revealed a statistically significant treatment by time effect in favour of the intervention group for cardiorespiratory fitness (-36.91 seconds, 95% CI [-63.14, -10.68], P = .006). CONCLUSIONS: RAA has demonstrated feasibility and potential efficacy in improving cardiorespiratory fitness. We recommend that program refinement be made to deliver an intervention that addresses the unique barriers of the secondary school setting through a multi-level ecological approach. SO WHAT?: Despite evident benefits, implementation of PA initiatives in the school setting reveals many challenges. Stronger consideration of the Health Promotion with Schools Framework is evidently needed.

Pharmacokinetics and Safety of 3 Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women.

BACKGROUND: Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy. METHODS: IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics. RESULTS: Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P < .001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg × hour/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (P < .001), resulting in lower AUCss (522 mg × hour/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or tuberculosis cases in women or infants. CONCLUSIONS: 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT02651259.

Pharmacokinetics and Dose Optimization Strategies of Para-Aminosalicylic Acid in Children with Rifampicin-Resistant Tuberculosis.

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.

PIGN encephalopathy: Characterizing the epileptology.

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Correlates of physical activity and sedentary behaviour in children attending before and after school care: a systematic review.

BACKGROUND: Out of School Hours Care (OSHC) offers structured care to elementary/primary-aged children before and after school, and during school holidays. The promotion of physical activity in OSHC is important for childhood obesity prevention. The aim of this systematic review was to identify correlates of objectively measured physical activity and sedentary behaviour in before and after school care. METHODS: A systematic search was conducted in Scopus, ERIC, MEDLINE (EBSCO), PsycINFO and Web of Science databases up to December 2021. Study inclusion criteria were: written in English; from a peer-reviewed journal; data from a centre-based before and/or after school care service; children with a mean age < 13 years; an objective measure of physical activity or sedentary behaviour; reported correlations and significance levels; and if an intervention study design these correlates were reported at baseline. Study quality was assessed using the Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. The PRISMA guidelines informed the reporting, and data were synthesised according to shared correlations and a social ecological framework. RESULTS: Database searches identified 4559 papers, with 18 cross-sectional studies meeting the inclusion criteria.There were a total of 116 physical activity correlates and 64 sedentary behaviour correlates identified. The most frequently reported correlates of physical activity were child sex (males more active), staff engaging in physical activity, an absence of elimination games, and scheduling physical activity in daily programming (all more positively associated). The most frequently reported correlates of sedentary behaviour were child sex (females more sedentary) and age (older children more sedentary). CONCLUSIONS: Encouraging physical activity engagement of female children, promoting positive staff behaviours, removing elimination elements from games, and scheduling more time for physical activity should be priorities for service providers. Additional research is needed in before school care services.

Foods and beverages provided in out of school hours care services: an observational study.

INTRODUCTION: Out of school hours care (OSHC) is a fast-growing childcare setting in Australia, however the types of foods and beverages offered are relatively unknown. This study describes the food and beverages offered and investigates sector-level and setting-level factors which may impact OSHC in meeting the Australian Dietary Guidelines (ADG). METHODS: This cross-sectional, observational study was conducted in 89 OSHC services (between 2018 and 2019). Food and beverages offered, kitchen facilities and menus were captured via direct observation. Foods were categorised into five food groups or discretionary foods, based on the ADG, and frequencies determined. Short interviews with OSHC directors ascertained healthy eating policies, staff training, food quality assessment methods and food budgets. Fisher's exact test explored the influence of sector-level and setting-level factors on food provision behaviours. RESULTS: Discretionary foods (1.5 ± 0.68) were offered more frequently than vegetables (0.82 ± 0.80) (p < .001), dairy (0.97 ± 0.81) (p = .013) and lean meats (0.22 ± 0.54) (p < .001). OSHC associated with long day care and reported using valid food quality assessment methods offered more lean meats (p= .002, and p= .004). Larger organisations offered more vegetables (p = .015) and discretionary foods (p= .007). Menus with clearly worded instructions to provide fruits and vegetables daily offered more fruit (p= .009), vegetables (p < .001) and whole grains (p= .003). No other sector or setting-level factors were associated with services aligning with the ADG. CONCLUSION: Future interventions could benefit from trialling menu planning training and tools to assist OSHC services in NSW meet the ADG requirements.

A health and wellbeing programme for preadolescents in underserved Australian communities: child and stakeholder perspectives.

Social inequities in childhood affect children's health and development. Active In-Betweens is a weekly, healthy lifestyle and outdoor activity after-school programme, tailor-made for preadolescent children (9-12 year olds), incorporating a strengths-based, trauma-informed, co-designed and place-based approach. This study evaluated the extent to which the programme strategies and activities met the anticipated short- to medium-term programme outcomes during its first year of operation in two socio-economically disadvantaged housing communities in New South Wales, Australia. A qualitative case study used data from semi-structured interviews with child participants (n = 11) and key stakeholders (n = 10). A broad range of positive outcomes were described. Children's feedback indicated they had experienced opportunities which facilitated the development of new physical activity skills; new healthy eating experiences and knowledge; positive relationships with peers and facilitators and new connections with neighbourhood programmes and outdoor environments. Stakeholders valued the programme for the positive outcomes they observed among the children and the strong organizational partnerships which resulted. The importance of skilled facilitators to deliver the programme, the engagement of local stakeholders and a long-term commitment to programme delivery, with secure funding to ensure continuity, were clearly identified as integral for effective, sustainable outcomes.

High Glycemia and Soluble Epoxide Hydrolase in Females: Differential Multiomics in Murine Brain Microvasculature.

The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia.

The barriers and enablers to implementing the New South Wales Healthy School Canteen Strategy in secondary schools in the Illawarra and Shoalhaven regions - A qualitative study.

ISSUE ADDRESSED: In 2017, the New South Wales Healthy School Canteen Strategy (Strategy) was introduced into primary and secondary schools. Studies have reported that secondary schools have a lower level of compliance with healthy canteen policies compared with primary schools. This study aims to identify and describe the barriers and enablers to implementing the Strategy in Department of Education (DoE) secondary schools in the Illawarra and Shoalhaven regions. METHODS: The framework underpinning the study was the systems theory. Canteen managers (CM) and principals from the 21 DoE secondary schools in the Illawarra and Shoalhaven regions were invited to participate in semi-structured interviews. The interviews were structured around the five focus areas of the Strategy, including questions on school nutrition policies and the role of the canteen. Data were collated using the interview guides as a framework and qualitative content analysis, using manual coding, was undertaken. RESULTS: Eight (38%) schools participated with seven CMs and six principals interviewed. Barriers to implementing the Strategy included the changing role of the canteen, the increased demands placed on CMs and inconsistencies between the school food environment and the Strategy. Enablers included monitoring implementation, and internal and external support. This study also recognised that previously identified barriers to healthy canteen strategy implementation are ongoing. CONCLUSIONS: The school canteen is an integral part of the school environment and therefore needs whole-of-school support if successful implementation of the Strategy is to occur. SO WHAT: Addressing the barriers and promoting the enablers identified in this study will support better nutrition policy implementation in secondary schools.

Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis.

Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.

Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial.

BACKGROUND: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. OBJECTIVES: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. PATIENTS AND METHODS: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) among adults receiving a 35 mg/kg dose]. RESULTS: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4-11.7). Evaluated doses were ∼35 mg/kg (days 1-14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1-14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. CONCLUSIONS: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.

Physical activity in out of school hours care: an observational study.

BACKGROUND: Opportunities for physical activity within out of school hours care (OSHC) are not well documented in Australia. This study explored factors associated with children (5-12 years) meeting 30 min of moderate to vigorous physical activity (MVPA) while attending OSHC in the afternoon period. METHODS: A cross-sectional study, conducted in 89 OSHC services in New South Wales, Australia, serving 4,408 children. Each service was visited twice between 2018-2019. Physical activity promotion practices were captured via short interviews and System for Observing Staff Promotion of Physical Activity and Nutrition (SOSPAN). Physical activity spaces was measured (m2) and physical activity of 3,614 child days (42% girls), were collected using Acti-Graph accelerometers. Association between program practices and children accumulation of MVPA was tested using mixed effects logistic regression, adjusted by OSHC service and child. RESULTS: Twenty-six percent of children (n = 925) accumulated 30 min or more of MVPA. Factors associated with children reaching MVPA recommendations included: services scheduling greater amounts of child-led free play, both 30-59 min (OR 2.6, 95%CI 1.70, 3.98) and ≥ 60 min (OR 6.4, 95%CI 3.90, 10.49); opportunities for staff-led organised play of ≥ 30 min (OR 2.3, 95%CI 1.47, 3.83); and active games that engaged the majority of children (OR 1.7, 95%CI 1.11, 2.61). Children were less likely to meet MVPA recommendations if services played games with elimination components (OR 0.56, 95%CI 0.37, 0.86). CONCLUSION: Improvements to service-level physical activity promotion practices, specifically the type of physical activity scheduled and the structure of games, may be an effective strategy to increase MVPA of children attending OSHC afterschool in NSW, Australia.

Foods provided to children in family day care: an observational study.

OBJECTIVE: To assess the quality and quantity of foods and beverages provided to children aged 0-5 years in family day care and identify structural and sociodemographic factors associated with the nutritional quality of food provided. DESIGN: A cross-sectional study measured the food and beverages provided to children using weighed food records. The number of serves from different food groups was calculated according to the Australian Guide to Healthy Eating, and a healthy food provision index score was created. Associations between structural and sociodemographic factors and healthy food provision index scores were analysed using linear mixed models. SETTING: Family day care services in two large geographic areas in New South Wales, Australia. PARTICIPANTS: One hundred and four children in thirty-three family day care services. RESULTS: During attendance at childcare, most children met recommended servings of fruit but not dairy, vegetables, lean meat and meat alternatives and wholegrains. Discretionary foods exceeded recommendations. Children's age, socio-economic status and the type of main meal provided were significantly associated with the healthy food provision index score. CONCLUSIONS: Foods provided to children in family day care are aligned with dietary recommendations for fruit but not vegetables, dairy, lean meat and meat alternatives, wholegrains or discretionary foods. Interventions to promote healthy eating are needed to support families and educators to improve the nutritional quality of food provided to children.

Detectable HIV-1 in semen in individuals with very low blood viral loads.

BACKGROUND: Several reports indicate that a portion (5-10%) of men living with HIV-1 intermittently shed HIV-1 RNA into seminal plasma while on long term effective antiretroviral therapy (ART). This is highly suggestive of an HIV-1 reservoir in the male genital tract. However, the status of this reservoir in men living with HIV-1 who are not under treatment is underexplored and has implications for understanding the origins and evolution of the reservoir. FINDING: Forty-three HIV-1 positive, antiretroviral therapy naïve study participants attending a men's health clinic were studied. Semen viral loads and blood viral loads were generally correlated, with semen viral loads generally detected in individuals with blood viral loads > 10,000 cp/ml. However, we found 1 individual with undetectable viral loads (<20cp/ml) and 2 individuals with very low blood viral load (97 and 333cp/ml), but with detectable HIV-1 in semen (485-1157 copies/semen sample). Blood viral loads in the first individual were undetectable when tested three times over the prior 5 years. CONCLUSIONS: Semen HIV-1 viral loads are usually related to blood viral loads, as we confirm. Nonetheless, this was not true in a substantial minority of individuals suggesting unexpectedly high levels of replication in the male genital tract in a few individuals, despite otherwise effective immune control. This may reflect establishment of a local reservoir of HIV-1 populations.

Pediatric Antiretroviral Therapeutic Drug Monitoring: A Five and a Half Year Experience from a South African Tertiary Hospital.

INTRODUCTION: Antiretroviral therapeutic drug monitoring (TDM) is not routinely used in the management of human immunodeficiency virus, but may be useful in pediatric patients who are prone to altered pharmacokinetics. Data on the routine use of antiretroviral TDM in pediatrics are sparse especially data from sub-Saharan Africa. METHODS: We retrospectively reviewed the antiretroviral TDM indications at Tygerberg Children's Hospital, identified pediatric patients who had antiretroviral TDM requests from January 2012 until June 2017 and reviewed their clinical records. RESULTS: Fifty-nine patients were identified who presented with 64 clinical problems for which TDM was requested. TDM was requested for lopinavir, efavirenz and nevirapine in 83% (53/64), 14% (9/64) and 3% (2/64) of clinical problems, respectively. Lopinavir was mostly requested in patients when adherence measures did not correlate with the clinical picture, suspected non-adherence, lopinavir-rifampicin interactions and for neonatal safety monitoring. Efavirenz was requested when toxicity was suspected and nevirapine in patients receiving rifampicin. Lopinavir TDM confirmed non-adherence in 25% (4/16) of cases when adherence measures did not correlate with the clinical picture and in 43% (3/7) of cases when non-adherence was suspected by the clinician. Efavirenz TDM confirmed toxicity in 100% (6/6) of patients. CONCLUSIONS: Lopinavir TDM was mostly requested when adherence measures did not correlate with the clinical picture, when rifampicin was co-administered and for perinatal safety monitoring. Lopinavir TDM excluded pharmacokinetic reasons for failure in patients failing treatment when lopinavir dosing was supervised. Efavirenz TDM was requested for suspected toxicity with a 100% positive predictive value.