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IntroductionSleep and epilepsy have an established bidirectional relationship yet only one randomised controlled clinical trial has assessed the effectiveness of behavioural sleep interventions for children with epilepsy. The intervention was successful, but was delivered via face-to-face educational sessions with parents, which are costly and non-scalable to population level. The Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E trial addresses this problem by comparing clinical and cost-effectiveness in children with Rolandic epilepsy between standard care (SC) and SC augmented with a novel, tailored parent-led CASTLE Online Sleep Intervention (COSI) that incorporates evidence-based behavioural components.Methods and analysesCASTLE Sleep-E is a UK-based, multicentre, open-label, active concurrent control, randomised, parallel-group, pragmatic superiority trial. A total of 110 children with Rolandic epilepsy will be recruited in outpatient clinics and allocated 1:1 to SC or SC augmented with COSI (SC+COSI). Primary clinical outcome is parent-reported sleep problem score (Children’s Sleep Habits Questionnaire). Primary health economic outcome is the incremental cost-effectiveness ratio (National Health Service and Personal Social Services perspective, Child Health Utility 9D Instrument). Parents and children (≥7 years) can opt into qualitative interviews and activities to share their experiences and perceptions of trial participation and managing sleep with Rolandic epilepsy.Ethics and disseminationThe CASTLE Sleep-E protocol was approved by the Health Research Authority East Midlands (HRA)–Nottingham 1 Research Ethics Committee (reference: 21/EM/0205). Trial results will be disseminated to scientific audiences, families, professional groups, managers, commissioners and policymakers. Pseudo-anonymised individual patient data will be made available after dissemination on reasonable request.Trial registration numberISRCTN13202325.

Context: Adrenal insufficiency (AI) is associated with reduced life expectancy and increased morbidity even after glucocorticoid replacement therapy. Aim Our aim was to assess the co-morbid burden of AI in a United Kingdom-based population. Methods We retrospectively studied patients diagnosed between 1996 and 2014 (minimum disease duration 12 months) with primary (PAI; n=55 [23 females]; CAH excluded) and secondary AI (SAI; n=79 [29 females]; Cushing’s syndrome and acromegaly excluded) using an electronic patient database (n=352000) in North West England. Patients with AI were identified by diagnostic codes and glucocorticoid prescriptions. Each patient with PAI or SAI was matched to non-AI patients with the same gender and date of birth (control cohort n=35172). Outcome measures were change in weight, prevalence of co-morbid illness (type 2 diabetes [T2D], prediabetes, hypertension, cardiovascular disease [CVD] and osteoporosis) and hospital admissions during the study period. Results In PAI, 91% of patients were treated with hydrocortisone (mean dose 23 ±8 mg) and 9% with prednisolone (mean dose 3 ±2 mg). In SAI, 94% of patients were treated with hydrocortisone (mean dose 18 ±8 mg) and 5% with prednisolone (mean dose 6 ±3 mg). The annual weight change compared to controls was significantly higher in PAI (median 1.16 kg [0.15-2.96], vs -0.01 kg [-0.49 – 0.41]; P=0.001) and SAI (median 0.55 kg [-1.49 – 1.57] vs median -0.47 kg [-0.99 – 0.32]; P=0.045). When comparing the weight at the time of diagnosis to the last available weight in the study period, a higher proportion of patients were within the overweight/obese category (BMI ≥ 25 kg/m2) for PAI (38% [baseline] vs 70% [study end]; P=0.028) but not SAI (85% [baseline] vs 73% [study end]; P=0.327) and controls (65% [baseline] vs 56% [study end]; P=0.218). For PAI, the prevalence of prediabetes (22% vs 10%), T2D (9% vs 5%), hypertension (38% vs 30%) and CVD (9% vs 5%) was significantly (p<0.05) different to controls. For SAI, the prevalence of prediabetes (27% vs 19%), T2D (20% vs 10%), hypertension (68% vs 53%) was significantly different (P<0.05) to controls. There were no differences in the prevalence of CVD between patients with SAI and controls (10% vs 10%; P=0.87). The risk ratio for osteoporosis to controls was 4.00 (P=0.025) for PAI and 4.33 (P=0.018) for SAI. The ratio (to controls) of the number of acute hospital admissions was higher in both PAI (5:1; P=0.011) and SAI (7:1; P=0.017). Conclusion PAI and SAI are both associated with a higher prevalence of co-morbid disease and increased hospital admissions suggesting a greater health burden. The excessive glucocorticoid replacement dose (especially in PAI) may have influenced the adverse metabolic changes observed. Statement of Support ViroPharma, now part of Shire, Lexington, MA, USA provided financial support but were not involved in the study design or interpretation of the data.

Pediatric high-grade gliomas (pHGG) are malignant and usually fatal central nervous system (CNS) WHO Grade 4 tumors. The majority of pHGG consist of diffuse midline gliomas (DMG), H3.3 or H3.1 K27 altered, or diffuse hemispheric gliomas (DHG) (H3.3 G34-mutant). Due to diffuse tumor infiltration of eloquent brain areas, especially for DMG, surgery has often been limited and chemotherapy has not been effective, leaving fractionated radiation to the involved field as the current standard of care. pHGG has only been classified as molecularly distinct from adult HGG since 2012 through Next-Generation sequencing approaches, which have shown pHGG to be epigenetically regulated and specific tumor sub-types to be representative of dysregulated differentiating cells. To translate discovery research into novel therapies, improved pre-clinical models that more adequately represent the tumor biology of pHGG are required. This review will summarize the molecular characteristics of different pHGG sub-types, with a specific focus on histone K27M mutations and the dysregulated gene expression profiles arising from these mutations. Current and emerging pre-clinical models for pHGG will be discussed, including commonly used patient-derived cell lines and in vivo modeling techniques, encompassing patient-derived xenograft murine models and genetically engineered mouse models (GEMMs). Lastly, emerging techniques to model CNS tumors within a human brain environment using brain organoids through co-culture will be explored. As models that more reliably represent pHGG continue to be developed, targetable biological and genetic vulnerabilities in the disease will be more rapidly identified, leading to better treatments and improved clinical outcomes.

Background The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. Methods We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. Results We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. Conclusion Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.

Studies of individual nutrients or foods have revealed much about dietary influences on bone. Multiple food or nutrient approaches, such as dietary pattern analysis, could offer further insight but research is limited and largely confined to older adults. We examined the relationship between dietary patterns, obtained by a posteriori and a priori methods, and bone mineral status (BMS; collective term for bone mineral content (BMC) and bone mineral density (BMD)) in young adults (20–25 years; n 489). Diet was assessed by 7 d diet history and BMD and BMC were determined at the lumbar spine and femoral neck (FN). A posteriori dietary patterns were derived using principal component analysis (PCA) and three a priori dietary quality scores were applied (dietary diversity score (DDS), nutritional risk score and Mediterranean diet score). For the PCA-derived dietary patterns, women in the top compared to the bottom fifth of the ‘Nuts and Meat’ pattern had greater FN BMD by 0·074 g/cm2 (P = 0·049) and FN BMC by 0·40 g (P = 0·034) after adjustment for confounders. Similarly, men in the top compared to the bottom fifth of the ‘Refined’ pattern had lower FN BMC by 0·41 g (P = 0·049). For the a priori DDS, women in the top compared to the bottom third had lower FN BMD by 0·05 g/cm2 after adjustments (P = 0·052), but no other relationships with BMS were identified. In conclusion, adherence to a ‘Nuts and Meat’ dietary pattern may be associated with greater BMS in young women and a ‘Refined’ dietary pattern may be detrimental for bone health in young men.