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.

Global genomic profile of hippocampal endothelial cells by single-nuclei RNA sequencing in female diabetic mice is associated with cognitive dysfunction.

Type II diabetes mellitus (T2D) is a chronic metabolic disease and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males. Therefore, our aim was to evaluate the consequence of T2D on cognitive function and decipher the underlying molecular transcriptomic mechanisms of endothelial cells in an important brain memory center, the hippocampus, using a female murine diabetes model. We assessed cognitive function, metabolic parameters, and then performed hippocampal single-nuclei RNA sequencing (snRNA seq) in adult female db/db and control wild-type (WT) mice. db/db mice exhibited characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared with WT mice. Female db/db mice presented cognitive decline compared with wild-type mice, as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced significant changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization, and cell adhesion, suggesting that diabetes increases endothelial cell permeability. Observed genomic changes also correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. In conclusion, T2D, by transcriptional and posttranscriptional regulation, regulates endothelial cell dysfunction predictive of increased vascular permeability, and negatively impacts cognitive function. Our work has implications for sex-specific molecular therapeutic targets for dementia in females.NEW & NOTEWORTHY Female db/db mice presented cognitive decline as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, or cell adhesion, suggesting increased endothelial permeability. Genomic changes correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia.

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 utility of website-based quality improvement tools for health professionals: a systematic review.

As technology continues to advance, it is important to understand how website-based tools can support quality improvement. Website-based tools refer to resources such as toolkits that users can access and use autonomously through a dedicated website. This review examined how website-based tools can support healthcare professionals with quality improvement, including the optimal processes used to develop tools and the elements of an effective tool. A systematic search of seven databases was conducted to include articles published between January 2012 and January 2024. Articles were included if they were peer reviewed, written in English, based in health settings, and reported the development or evaluation of a quality improvement website-based tool for professionals. A narrative synthesis was conducted using NVivo. Risk of bias was assessed using the Mixed Methods Appraisal Tool. All papers were independently screened and coded by two authors using a six-phase conceptual framework by Braun and Clarke. Eighteen studies met the inclusion criteria. Themes identified were tool development processes, quality improvement mechanisms and barriers and facilitators to tool usage. Digitalizing existing quality improvement processes (n = 7), identifying gaps in practice (n = 6), and contributing to professional development (n = 3) were common quality improvement aims. Tools were associated with the reported enhancement of accuracy and efficiency in clinical tasks, improvement in adherence to guidelines, facilitation of reflective practice, and provision of tailored feedback for continuous quality improvement. Common features were educational resources (n = 7) and assisting the user to assess current practices against standards/recommendations (n = 6), which supported professionals in achieving better clinical outcomes, increased professional satisfaction and streamlined workflow in various settings. Studies reported facilitators to tool usage including relevance to practice, accessibility, and facilitating multidisciplinary action, making these tools practical and time-efficient for healthcare. However, barriers such as being time consuming, irrelevant to practice, difficult to use, and lack of organizational engagement were reported. Almost all tools were co-developed with stakeholders. The co-design approaches varied, reflecting different levels of stakeholder engagement and adoption of co-design methodologies. It is noted that the quality of included studies was low. These findings offer valuable insights for future development of quality improvement website-based tools in healthcare. Recommendations include ensuring tools are co-developed with healthcare professionals, focusing on practical usability and addressing common barriers to enhance engagement and effectiveness in improving healthcare quality. Randomized controlled trials are warranted to provide objective evidence of tool efficacy.

Single Nuclei Transcriptomics Reveals Obesity-Induced Endothelial and Neurovascular Dysfunction: Implications for Cognitive Decline.

Obesity confers risk for cardiovascular disease and vascular dementia. However, genomic alterations modulated by obesity in endothelial cells in the brain and their relationship to other neurovascular unit (NVU) cells are unknown. We performed single nuclei RNA sequencing (snRNAseq) of the NVU (endothelial cells, astrocytes, microglia, and neurons) from the hippocampus of obese (ob/ob) and wild-type (WT) male mice to characterize obesity-induced transcriptomic changes in a key brain memory center and assessed blood-brain barrier permeability (BBB) by gadolinium-enhanced magnetic resonance imaging (MRI). Ob/ob mice displayed obesity, hyperinsulinemia, and impaired glucose tolerance. snRNAseq profiled 14 distinct cell types and 32 clusters within the hippocampus of ob/ob and WT mice and uncovered differentially expressed genes (DEGs) in all NVU cell types, namely, 4462 in neurons, 1386 in astrocytes, 125 in endothelial cells, and 154 in microglia. Gene ontology analysis identified important biological processes such as angiogenesis in endothelial cells and synaptic trafficking in neurons. Cellular pathway analysis included focal adhesion and insulin signaling, which were common to all NVU cell types. Correlation analysis revealed significant positive correlations between endothelial cells and other NVU cell types. Differentially expressed long non-coding RNAs (lncRNAs) were observed in cells of the NVU-affecting pathways such as TNF and mTOR. BBB permeability showed a trend toward increased signal intensity in ob/ob mice. Taken together, our study provides in-depth insight into the molecular mechanisms underlying cognitive dysfunction in obesity and may have implications for therapeutic gene targeting.

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.

Nutrition and physical activity practices in family day care: A cross-sectional survey of Australian family day care educators.

ISSUE ADDRESSED: Munch & Move is a New South Wales (NSW) Ministry of Health program offering family day care (FDC) educators training to support children's healthy behaviours. This study examined educators' nutrition, physical activity and screen time practices and relationships between Munch & Move training and professional development (PD) on these practices. METHODS: NSW FDC educators (n = 186) completed an online survey from July 2020-June 2021. Differences between groups based on Munch & Move training (trained; not trained) and PD (those who completed PD ≥1 time per year; those who completed PD <1 time per year or never) were tested using bivariate analyses. RESULTS: A significantly higher proportion of educators trained in Munch & Move offered information to families regarding food serving sizes, nutrition policies, and children's physical activity and screen time. Over one-third in both groups did not meet the guideline of no screen time for children under 2 years old. Compared with those who completed PD ≥1 time per year, a significantly higher proportion of educators who completed PD <1 time per year or never did not provide families with nutrition guidelines or resources. CONCLUSIONS: Educators trained in Munch & Move, and those who completed PD more frequently, demonstrated better nutrition, physical activity and screen time practices in several areas. SO WHAT?: This study demonstrated benefits of the Munch & Move program, implemented with support from Local Health District health promotion officers, and highlighted key areas for improvement in healthy practices in FDC.

Awareness and use of the Eat Smart Play Smart resources in Out of School Hours Care services: A staff survey in New South Wales, Australia.

ISSUE ADDRESSED: Out of School Hours Care (OSHC) is an important setting to promote healthy eating and physical activity. Between 2017 and 2018, The Eat Smart Play Smart (ESPS) resources were disseminated to OSHC services across New South Wales (NSW), Australia. The aim of this study was to evaluate the awareness and usability of ESPS to support OSHC healthy eating and physical activity practices. METHODS: All NSW OSHC services (approximately 1700) were invited to complete an online survey to assess awareness and use of the ESPS resources (manual and online modules). Data were analysed using SPSS (Version 29). RESULTS: A total of 393 OSHC staff responded to the survey. Most (75%) had used the ESPS resources. Of the 25% who had not used the resources, 63% indicated it was because they did not receive the manual and 52% were not aware of the resources. Of the OSHC services that knew about the resources, 69% indicated that ESPS contributed to their service's ability to meet the Australian National Quality Standards. Respondents identified additional support was required regarding physical activity educational materials and professional learning. Suggestions for improvements included offering content in different formats (e.g., digital). CONCLUSION: This evaluation identified factors influencing the uptake of the ESPS resources and will inform future interventions for OSHC staff to improve knowledge and practices in healthy eating and physical activity promotion. SO WHAT?: Our findings will support the optimisation of ESPS resources and inform future development of future healthy eating and physical activity interventions in the OSHC setting.

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.