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Do rats run and respond at a higher rate to run during the dark phase when they are typically more active? To answer this question, Long Evans rats were exposed to a response-initiated variable interval 30-s schedule of wheel-running reinforcement during light and dark cycles. Wheel-running and local lever-pressing rates increased modestly during the dark phase. A second experiment examined the potential role of food-anticipatory activity in this effect by delaying postexperimental session feeding by 6 hr. No increase in wheel-running and lever-pressing rates was observed during the dark phase. This suggests that the effect of light/dark cycle on running and responding for the opportunity to run depended upon food-anticipatory activity. (Contains 2 figures and 1 table.)

X-linked isolated lissencephaly sequence and subcortical band heterotopia are allelic human disorders associated with mutations of doublecortin (DCX), giving both familial and sporadic forms. DCX encodes a microtubule-associated protein involved in neuronal migration during brain development. Structural data show that mutations can fall either in surface residues, likely to impair partner interactions, or in buried residues, likely to impair protein stability. Despite the progress in understanding the molecular basis of these disorders, the prognosis value of the location and impact of individual DCX mutations has largely remained unclear. To clarify this point, we investigated a cohort of 180 patients who were referred with the agyria-pachygyria subcortical band heterotopia spectrum. DCX mutations were identified in 136 individuals. Analysis of the parents' DNA revealed the de novo occurrence of DCX mutations in 76 cases [62 of 70 females screened (88.5%) and 14 of 60 males screened (23%)], whereas in the remaining cases, mutations were inherited from asymptomatic (n = 14) or symptomatic mothers (n = 11). This represents 100% of families screened. Female patients with DCX mutation demonstrated three degrees of clinical-radiological severity: a severe form with a thick band (n = 54), a milder form (n = 24) with either an anterior thin or an intermediate thickness band and asymptomatic carrier females (n = 14) with normal magnetic resonance imaging results. A higher proportion of nonsense and frameshift mutations were identified in patients with de novo mutations. An analysis of predicted effects of missense mutations showed that those destabilizing the structure of the protein were often associated with more severe phenotypes. We identified several severe- and mild-effect mutations affecting surface residues and observed that the substituted amino acid is also critical in determining severity. Recurrent mutations representing 34.5% of all DCX mutations often lead to similar phenotypes, for example, either severe in sporadic subcortical band heterotopia owing to Arg186 mutations or milder in familial cases owing to Arg196 mutations. Taken as a whole, these observations demonstrate that DCX-related disorders are clinically heterogeneous, with severe sporadic and milder familial subcortical band heterotopia, each associated with specific DCX mutations. There is a clear influence of the individual mutated residue and the substituted amino acid in determining phenotype severity. [ABSTRACT FROM AUTHOR]

We conducted a prospective Phase II single institution study that combined radiation volume and dose de-intensification in patients with pT0-T3 pN0-N2c p16+ oropharyngeal squamous cell carcinoma (OPSCC) with the goal of maintaining high rates of locoregional control (LRC) while reducing treatment-related toxicity. We provide long-term follow up on the full expansion cohort (n = 150). Eligible patients had pT0-T3 N0-N2c p16+ OPSCC (per AJCC 7th Ed), s/p TORS and neck dissection, with < 5 positive lymph nodes, who met indications for adjuvant radiation (RT) +/- chemotherapy. Adjuvant RT was delivered in 25 fractions over 5 weeks. The primary site was spared in patients with pT1-T2 tumors resected with negative margins and no LVI or PNI. The neck level(s) with confirmed pathologic disease received 50 Gy, while other at-risk ipsilateral nodal regions received 45 Gy. When contralateral neck RT was indicated, the treated volume of the contralateral neck was reduced to mirror the pathologically involved nodal levels in the ipsilateral neck and received 45 Gy. Concurrent chemotherapy was prescribed per NCCN guidelines, but was optionally omitted in patients with ENE ≤ 1 mm. The initial cohort (n = 118) was expanded to 150 patients to gather additional ctHPV DNA data. 150 patients were enrolled between October 2018 and June 2022. Due to one patient withdrawal prior to RT initiation, data from 149 patients treated per protocol were analyzed. Patient characteristics are detailed in Table 1. Median follow-up is 44 months (range 19-63 months). No patients developed local recurrence, but two experienced regional recurrences. One of them developed distant metastatic (DM) disease and then developed bilateral neck recurrence (contralateral untreated surpraclavicular and ipsilateral treated neck) one year later. The second recurred 47 months after completion of RT in the treated contralateral neck, both within and below the 45 Gy volume. The estimated 4-year LRC rate is 97.7% (95% CI = 90-99.5%). Ten patients (6.7%) developed DM and two patients died of DM disease. The TORS bed was spared in 52% of patients; the median dose to the spared primary site was 30.9 Gy (range 16.5 – 46 Gy). The 24 patients with ENE > 1 mm ("high risk" per ECOG 3311) did not experience LRF. At 24 months post-RT, median MDASI-HN scores scaled from 0 to 10 (most severe) were dysphagia-3, xerostomia-3.5, and interference with work-1. Long-term results of our clinical trial of selected p16+ OPSCC patients treated with a combination of radiation dose de-intensification and volume reduction demonstrate high rates of locoregional control, supporting the efficacy of this approach. [ABSTRACT FROM AUTHOR]

Purpose: We quantified the joint evolution of sleep duration and screen time between 2018 and 2022 in a large sample of adolescents from Quebec, Canada, to ascertain changes that occurred during the COVID-19 pandemic., Methods: A natural experiment design was used to compare variations from year to year and in association with the pandemic outbreak. Using structural equation modeling on data collected between 2018 and 2022 among adolescents attending 63 high schools, we analyzed the joint evolution of sleep duration and screen time while adjusting for previous year values, concurrent flourishing score, sex, age, and family level of material deprivation., Results: A total of 28,307 adolescents, aged on average 14.9 years, were included in the analyses. Between 2019 and 2022, sleep duration increased by 9.6 (5.7, 13.5) minutes and screen time by 129.2 (120.5, 138.0) minutes on average. In 2022, the adolescents spent almost equal amounts of time sleeping and using screens. Lower flourishing scores were associated with shorter sleep duration and lengthier screen time. Girls' screen time became similar to boys' over time., Discussion: Adolescents now spend almost equal amounts of time sleeping and using screens, a situation that calls for urgent public health actions. These findings highlight the importance of tracking changes in adolescents' behaviours over time, to design and implement interventions adapted to the changing health needs of different groups., (Copyright © 2024 Society for Adolescent Health and Medicine. All rights reserved.)

Introduction: Venous thromboembolism (VTE) prophylaxis implementation strategies are well-studied in some hospitalized medical and surgical patients. Although VTE is associated with substantial mortality and morbidity in trauma patients, implementation strategies for the prevention of VTE in trauma appear to be based on limited evidence. Therefore, we conducted a systematic review and meta-analysis of published literature on active implementation strategies for VTE prophylaxis administration in hospitalized trauma patients and the impact on VTE events., Methods: A systematic review and meta-analysis was performed in adult hospitalized trauma patients to assess if active VTE prevention implementation strategies change the proportion of patients who received VTE prophylaxis, VTE events, and adverse effects such as bleeding or heparin-induced thrombocytopenia as well as hospital length of stay and the cost of care. An academic medical librarian searched Medline, Scopus, and Web of Science until December 2022., Results: Four studies with a total of 1723 patients in the active implementation strategy group (strategies included education, reminders, human and computer alerts, audit and feedback, preprinted orders, and/or root cause analysis) and 1324 in the no active implementation strategy group (guideline creation and dissemination) were included in the analysis. A higher proportion of patients received VTE prophylaxis with an active implementation strategy (OR=2.94, 95% CI (1.68 to 5.15), p<0.01). No significant difference was found in VTE events. Quality was deemed to be low due to bias and inconsistency of studies., Conclusions: Active implementation strategies appeared to improve the proportion of major trauma patients who received VTE prophylaxis. Further implementation studies are needed in trauma to determine effective, sustainable strategies for VTE prevention and to assess secondary outcomes such as bleeding and costs., Level of Evidence: Systematic review/meta-analysis, level III., Prospero Registration Number: CRD42023390538., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent studies using cell type-specific knockout mouse models have improved our understanding of the pathophysiological relevance of suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) endoplasmic reticulum-associated (ER-associated) degradation (ERAD); however, its importance in humans remains unclear, as no disease variant has been identified. Here, we report the identification of 3 biallelic missense variants of SEL1L and HRD1 (or SYVN1) in 6 children from 3 independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia, and/or ataxia. These SEL1L (p.Gly585Asp, p.Met528Arg) and HRD1 (p.Pro398Leu) variants were hypomorphic and impaired ERAD function at distinct steps of ERAD, including substrate recruitment (SEL1L p.Gly585Asp), SEL1L-HRD1 complex formation (SEL1L p.Met528Arg), and HRD1 activity (HRD1 p.Pro398Leu). Our study not only provides insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establishes the importance of SEL1L-HRD1 ERAD in humans.

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity., Competing Interests: Declaration of interests I.M.W. is an employee of GeneDx, LLC. J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. J.R.L. serves on the Scientific Advisory Board of BG., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Claudin-5 is the most enriched tight junction protein at the blood-brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl- ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood-brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)