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Objective: The counterintuitive "Union Jack"-inspired turn signals on versions of BMW's Mini vehicles was investigated to reveal potential impacts on human performance. Background: When some Mini drivers indicate a change in direction, they do so with an oppositely oriented arrow. This conflict, between the task-irrelevant spatial shape and task-relevant location of the signal, mimics a "converse" spatial-Stroop effect that, in combination with the ubiquitous use of arrows on road signs, may be confusing. Method: Participants (n = 30) responded—via right and left keypresses—to the directions of road signs and turn signals in both pure and mixed blocks. Reaction times and accuracies were recorded to determine performance in each condition (compatible, neutral, incompatible). Results: Performance suffered when the location and direction of the stimuli did not correspond. When responding to turn signals the cost to performance was especially salient in mixed blocks. Thus, when driving on roads where the meanings of arrows on road signs is important, turn signals pointing in a direction opposite from the directional intention indicated by the signals' location are likely to be confusing. Conclusion: The design of some Mini's "Union Jack" style taillights opposes well-established principles of cognitive functioning, caused confusion in our laboratory study and therefore may be a safety hazard—a possibility that ought to be explored in more realistic (e.g., driving simulator) situations. Application: BMW designers should consider universally adopting the neutral, "horizontal line," illumination style that is currently available in the aftermarket. [ABSTRACT FROM AUTHOR]

Abstract Background The mechanistic pathways that give rise to the extreme symptoms exhibited by rare disease patients are complex, heterogeneous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the underlying causes of diseases rather than merely the presenting symptoms. Moreover, the same dysfunctional series of interrelated symptoms implicated in rare recessive diseases may also lead to milder and potentially preventable symptoms in carriers in the general population. Seizures are a common and extreme phenotype that can result from diverse and often elusive pathways in patients with ultrarare or undiagnosed disorders. Methods In this pilot study, we present an approach to understand the underlying pathways leading to seizures in patients from the Undiagnosed Diseases Network (UDN) by analyzing aggregated genotype and phenotype data from the UK Biobank (UKB). Specifically, we look for enriched phenotypes across UKB participants who harbor rare variants in the same gene known or suspected to be causally implicated in a UDN patient’s recessively manifesting disorder. Analyzing these milder but related associated phenotypes in UKB participants can provide insight into the disease-causing mechanisms at play in rare disease UDN patients. Results We present six vignettes of undiagnosed patients experiencing seizures as part of their recessive genetic condition. For each patient, we analyze a gene of interest: MPO, P2RX7, SQSTM1, COL27A1, PIGQ, or CACNA2D2, and find relevant symptoms associated with UKB participants. We discuss the potential mechanisms by which the digestive, skeletal, circulatory, and immune system abnormalities found in the UKB patients may contribute to the severe presentations exhibited by UDN patients. We find that in our set of rare disease patients, seizures may result from diverse, multi-step pathways that involve multiple body systems. Conclusions Analyses of large-scale population cohorts such as the UKB can be a critical tool to further our understanding of rare diseases in general. Continued research in this area could lead to more precise diagnostics and personalized treatment strategies for patients with rare and undiagnosed conditions.

Background: Former professional collision sport (CS) athletes, particularly American football players, are at risk of developing chronic health conditions; however, little is known about the health outcomes of amateur athletes., Methods: A 60-item health survey examined self-reported symptoms and diagnoses among former Division 1 Collegiate CS athletes and non- or limited-contact sport (non-CS) athletes. Binary logistic regressions tested the association between playing CS and health outcomes., Results: Five hundred and two (6.2%) participants completed the survey: 160 CS athletes (mean age: 59.2, SD = 16.0) and 303 non-CS athletes (mean age: 54.0, SD = 16.9). CS athletes had increased odds of reported cognitive complaints and neuropsychiatric symptoms including memory (P adj < 0.01), attention/concentration (P adj  = 0.01), problem solving/multi-tasking (P adj  = 0.05), language (P adj  = 0.02), anxiety (P adj  = 0.04), impulsivity (P adj  = 0.02), short-fuse/rage/explosivity (P adj < 0.001), and violence/aggression (P adj  = 0.02). CS athletes also reported higher rates of sleep apnea (P adj  = 0.02). There were no group differences in cardiovascular and physical health outcomes., Conclusions: Former CS athletes reported more cognitive and neuropsychiatric complaints. The low response rate is a limitation of this study; however, over 500,000 athletes play college sports each year, thus research on long-term health outcomes in this population is critical.

Background and Objectives: Three phase 3 trials demonstrated the efficacy and safety of atogepant in episodic migraine (EM) and chronic migraine (CM) across 12-week treatment periods. This analysis evaluates improvements in efficacy and functional outcomes in the first 4 weeks of treatment with the oral calcitonin gene-related peptide receptor antagonist, atogepant, for the preventive treatment of migraine., Methods: ADVANCE, ELEVATE, and PROGRESS were phase 3, multicenter, randomized, double-blind, placebo-controlled 12-week trials. ADVANCE and ELEVATE included participants aged 18-80 years with >1 year history of EM and 4-14 monthly migraine days (MMDs). ELEVATE required previous treatment failures to 2-4 classes of oral preventives. PROGRESS included participants aged 18-80 years with >1 year history of CM, ≥15 monthly headache days, and ≥8 MMDs. This analysis reports the atogepant 60 mg once daily (QD) and placebo treatment arms. Outcomes included efficacy endpoints (reporting a migraine day on day 1, change from baseline in weekly migraine days [WMDs] at weeks 1-4, and in MMDs in the first 4 weeks) and functional endpoints evaluated by the Activity Impairment in Migraine-Diary (AIM-D) at weeks 1-4 and the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) at weeks 1-2 and 4., Results: The modified intent-to-treat population included the ADVANCE (atogepant, n = 222; placebo, n = 214), ELEVATE (atogepant, n = 151; placebo, n = 154), and PROGRESS (atogepant, n = 256; placebo, n = 246) studies. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1. The odds ratio compared with placebo was 0.39 (95% CI 0.23-0.67; p = 0.0006) in ADVANCE, 0.53 (95% CI 0.29-0.94, p = 0.031) in ELEVATE, and 0.63 (95% CI 0.43-0.93, p = 0.021) in PROGRESS. Atogepant treatment reduced WMDs at weeks 1-4 and MMDs in the first 4 weeks, and improved AIM-D and EQ-5D-5L at all assessed timepoints for weeks 1-4 compared with placebo., Discussions: Atogepant 60 mg QD demonstrated superiority to placebo in efficacy and functional measures in the first 4 weeks of treatment across 3 preventive studies, 2 in EM and 1 in CM., Trial Registration: ClinicalTrials.gov NCT03777059; NCT04740827; NCT03855137. Submitted: 12/13/2018; 02/02/2021; 02/25/2019. First patient enrolled: 12/14/2018; 03/05/2021; 03/11/2019 clinicaltrials.gov/ct2/show/NCT03777059. clinicaltrials.gov/ct2/show/NCT04740827 clinicaltrials.gov/ct2/show/NCT03855137., Classification of Evidence: This study provides Class II evidence that atogepant 60 mg QD reduces migraine frequency and improves functional outcomes within 4 weeks of initiation in patients with EM and patients with CM.

Background: Ruxolitinib cream has demonstrated anti-inflammatory and antipruritic activity and was well tolerated in a phase 3 study in patients aged 2-11 years with mild to moderate atopic dermatitis (AD)., Objective: This study examined the safety, tolerability, pharmacokinetics, efficacy, and quality of life (QoL) with ruxolitinib cream under maximum-use conditions and with longer-term use., Methods: Eligible patients were aged 2-11 years with moderate to severe AD [Investigator's Global Assessment (IGA) score 3-4], and ≥ 35% affected body surface area (BSA). Patients applied 1.5% ruxolitinib cream twice daily to all baseline-identified lesions during the 4-week maximum-use period, then to active lesions only up to week 52 (patients with ≤ 20% affected BSA from week 8). Safety was assessed by frequency and severity of adverse events. Pharmacokinetic parameters were assessed as secondary endpoints, and efficacy and QoL were exploratory endpoints., Results: Overall, 29 patients (median age 5 years) were enrolled. Treatment-emergent adverse events were reported in 9/29 patients (31.0%); there were no adverse events of special interest (i.e., no serious infections, malignancies, major adverse cardiovascular events, or thromboses) during the study period. Mean steady-state plasma concentration during the maximum-use period was below the known half-maximal inhibitory concentration of Janus kinase-mediated myelosuppression in adults. Reductions in affected BSA and IGA observed at week 4 were sustained with as-needed use through 52 weeks. Improvements in patient-reported outcomes and QoL measures were consistent with efficacy results., Conclusion: These results support the safety of ruxolitinib cream in children (2-11 years) with AD, including those with extensive disease, and are consistent with previous efficacy findings., Gov Identifier: NCT05034822, first registered 30 August 2021., Competing Interests: Declarations. Funding: This study was funded by Incyte Corporation (Wilmington, DE, USA). Competing Interests: LSG has served as an investigator, advisor, and/or speaker for AbbVie, Arcutis, Bristol Myers Squibb, Dermavant, Eli Lilly, Incyte, Ortho Dermatologics, Pfizer, Regeneron, and Sanofi. RB is an advisory board member, consultant, speaker, and/or investigator for and received honoraria and/or grants from AbbVie, Almirall, Amgen, AnaptysBio, Arcutis, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Escalier, Janssen, Kyowa Kirin, LEO Pharma, Nimbus, Pfizer, Regeneron, Sienna, and UCB. He is also an employee and shareholder of Innovaderm Research. SF has received honoraria, clinical research grants, or fees as a consultant, speaker, advisory board member, and/or investigator for AbbVie, Aclaris Therapeutics, Asana BioSciences, AstraZeneca, Athenex, Celgene Corporation, Cutanea Life Sciences, Eli Lilly, Incyte Corporation, Innovaderm Research, Novartis, Pfizer, Promius Pharma, Regeneron, UCB, Valeant Pharmaceuticals North America, and XBiotech. AZ has served as an investigator and/or consultant for AbbVie, Biofrontera, Dermavant, Galderma, Incyte, and UCB. YK, BA, XC, and HK are employees and shareholders of Incyte Corporation. ASP has served as an investigator, consultant, or data safety monitoring board member for AbbVie, Abeona, Apogee, Applied Pharma Research, Arcutis, Aslan, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Galderma, Incyte, Janssen, Johnson and Johnson, Krystal Biotech, LEO, Mitsubishi Tanabe, Nektar, Primus, Procter and Gamble, Regeneron, Sanofi, Seanergy, TWI Biotech, and UCB. ASP is an editorial board member of the American Journal of Clinical Dermatology. ASP was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Availability of Data and Materials: Incyte Corporation (Wilmington, DE, USA) is committed to data sharing that advances science and medicine while protecting patient privacy. Qualified external scientific researchers may request anonymized datasets owned by Incyte for the purpose of conducting legitimate scientific research. Researchers may request anonymized datasets from any interventional study (except Phase 1 studies) for which the product and indication have been approved on or after 1 January 2020 in at least one major market (e.g., US, EU, JPN). Data will be available for request after the primary publication or 2 years after the study has ended. Information on Incyte’s clinical trial data sharing policy and instructions for submitting clinical trial data requests are available at: https://www.incyte.com/Portals/0/Assets/Compliance%20and%20Transparency/clinical-trial-data-sharing.pdf?ver=2020-05-21-132838-960 . Ethics Approval: This study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol was approved by the Advarra Institutional Review Board (Columbia, MD, USA). Consent to Participate: Written informed consent/assent was provided by all patients before enrollment. Consent for Publication: Not applicable. Code Availability: Not applicable. Author Contributions: LSG, RB, BA, HK, and ASP made substantial contributions to the conception and design of the work. LSG, RB, SF, AZ, and ASP all made substantial contributions to the acquisition of data. YK and XC made substantial contributions to the analysis of the data; all authors made substantial contributions to the interpretation of data; all authors drafted the work and revised it critically for important intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved., (© 2025. The Author(s).)

Reference sequences and annotations serve as the foundation for many lines of research today, from organism and sequence identification to providing a core description of the genes, transcripts and proteins found in an organism's genome. Interpretation of data including transcriptomics, proteomics, sequence variation and comparative analyses based on reference gene annotations informs our understanding of gene function and possible disease mechanisms, leading to new biomedical discoveries. The Reference Sequence (RefSeq) resource created at the National Center for Biotechnology Information (NCBI) leverages both automatic processes and expert curation to create a robust set of reference sequences of genomic, transcript and protein data spanning the tree of life. RefSeq continues to refine its annotation and quality control processes and utilize better quality genomes resulting from advances in sequencing technologies as well as RNA-Seq data to produce high-quality annotated genomes, ortholog predictions across more organisms and other products that are easily accessible through multiple NCBI resources. This report summarizes the current status of the eukaryotic, prokaryotic and viral RefSeq resources, with a focus on eukaryotic annotation, the increase in taxonomic representation and the effect it will have on comparative genomics. The RefSeq resource is publicly accessible at https://www.ncbi.nlm.nih.gov/refseq., (Published by Oxford University Press on behalf of Nucleic Acids Research 2024.)

Chronic stress exerts profound effects on mental health, contributing to disorders such as depression, anxiety, and cognitive impairment. This study examines the potential of psilocybin to alleviate behavioral despair and cognitive deficits in a rodent model of chronic stress, focusing on the interplay between the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Endocannabinoid System (ECS). Twenty-two male Wistar rats were divided into control and stress groups. Animals within the stress group were exposed to predator odor and chronic social instability to induce chronic stress, and were either sham treated, or given psilocybin. Behavioral assessments were conducted using the Open Field Test, Sucrose Preference Test, Novel Object Recognition, Elevated Plus Maze, and Forced Swimming Test to evaluate locomotion, anhedonia, memory, anxiety, and behavioral despair, respectively. Blood and brain samples were analyzed for biochemical markers. Results indicated that psilocybin significantly reduced stress-induced behavioral despair and cognitive impairments, likely through ECS-mediated downregulation of the HPA axis. These findings suggest that early intervention with psilocybin has sustained beneficial effects on stress-related behavioral and cognitive disturbances, underscoring its potential as a novel therapeutic approach for stress-related mental health disorders., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Febrile young infants are at risk of invasive bacterial infections (IBIs; bacteremia or bacterial meningitis). American Academy of Pediatrics (AAP) guidelines recommend that when procalcitonin testing is unavailable, C-reactive protein (CRP), absolute neutrophil count (ANC) and temperature should be used to identify low-risk infants. We sought to determine the optimal combination of these inflammatory markers to predict IBI when procalcitonin is unavailable., Methods: This was a secondary analysis of prospectively collected data for all febrile infants aged 60 days or younger evaluated at a tertiary pediatric emergency department (January 2018 to July 2023). Previously healthy term infants aged 8 to 60 days with rectal temperatures of 38.0°C or greater meeting AAP inclusion/exclusion criteria were analyzed. A decision rule was derived by classification and regression tree analysis with 10-fold cross-validation then compared to AAP-recommended thresholds of ANC ≤ 5200/mm3, CRP ≤ 20 mg/L, and temperature ≤ 38.5°C., Results: Among 1987 infants, 38 (1.9%) had IBIs. The AAP-recommended thresholds missed no IBIs (sensitivity: 100.0% [95% CI, 88.6%-100.0%]; negative predictive value (NPV): 100.0% [95% CI, 99.5%-100.0%]; specificity: 50.7% [95% CI, 48.5%-53.0%]). Optimal derived thresholds were CRP ≤ 22.2mg/L, temperature ≤ 39.0°C, and ANC ≤ 4500/mm3; urinalysis and age were not selected. The derived rule also missed no IBIs (sensitivity: 100.0% [95% CI, 88.6%-100.0%]; NPV: 100.0% [95% CI, 99.7%-100.0%]); however, specificity improved to 83.8% (95% CI, 82.1%-85.4%). Area under the receiver operating curve for the cross-validated rule (91.9% [95% CI, 91.1%-92.7%]) was higher than at AAP-recommended thresholds (75.4% (95% CI, 74.3%-76.5%])., Conclusions: The combination of ANC, CRP, and temperature at statistically derived thresholds improved diagnostic accuracy for identifying infants at low risk of IBIs compared to AAP-recommended thresholds., (Copyright © 2025 by the American Academy of Pediatrics.)

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD., Competing Interests: Declaration of interests At the time of this study and its publication, S.W.S. served on the scientific advisory committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations. S.V.M. is an employee of GeneDx, LLC. H.F.P. is on the research advisory boards and speaker bureau for Takeda Pharmaceutical, AvroBio, Amicus Therapeutics, Sanofi, Alexion Therapeutics, Denali Therapeutics, and Acer Therapeutics., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The "female protective effect" in ASD suggests that females may require a higher genetic burden to manifest symptoms similar to those in males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leaves them underrepresented in genome-wide studies. Here, we conducted an X-chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Collection (SSC), and Simons Powering Autism Research (SPARK), alongside 8,981 population controls (43% males). We analyzed 418,652 X chromosome variants, identifying 59 associated with ASD (p values 7.9 × 10 -6 to 1.51 × 10 -5 ), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p = 3.57 × 10 -7 ) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p = 9.47 × 10 -6 ). When mapping genes within 10 kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, and SH3KBP1). FGF13 emerged as an X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation., Competing Interests: Declaration of interests At the time of this study and its publication, S.W.S. served on the scientific advisory committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Sotorasib is approved to be taken as 960 mg orally once daily (8 × 120-mg tablets) for the treatment of KRAS G12C-mutated nonsmall cell lung cancer. Dispersion of tablets in water could be an alternative method for patients who require a liquid formulation due to dysphagia and enteral administration. A clinical study was conducted to assess the pharmacokinetics of 960 mg of sotorasib administered as tablets and as tablets dispersed in water in healthy volunteers. Each subject received 960 mg of sotorasib by mouth, as tablets and as tablets dispersed in water on Days 1 and 4. Sotorasib median time to maximum observed plasma concentration was similar when administered as tablets and as tablets predispersed in water. The geometric least squares mean ratios (water dispersion/tablets) for area under the concentration-time curve from time 0 extrapolated to infinity and maximum observed plasma concentration were 1.049 and 1.080, respectively. Sotorasib 960 mg was well tolerated. Administration of 960 mg of sotorasib as tablets predispersed in water achieved similar systemic exposures to that of sotorasib administered as oral tablets. In vitro evaluations were performed to assess the feasibility of administering sotorasib through an enteral feeding tube. Approximately 98% of sotorasib was recovered, with no new impurities, from enteral feeding tubes. Collectively, these results support that sotorasib can be administered by mouth and via enteral feeding tubes as tablets predispersed in water., (© 2024, The American College of Clinical Pharmacology.)

Background and Aims: Transoral incisionless fundoplication (TIF) is an established safe endoscopic technique for the management of GERD but with variable efficacy. In the past decade, the TIF technology and technique have been optimized and more widely accepted, but data on outcomes outside clinical trials are limited. We tracked patient-reported and clinical outcomes of GERD patients after TIF 2.0., Methods: Patients with body mass index <35 kg/m 2 , hiatal hernia <2 cm, and confirmed GERD with typical or atypical symptoms from 9 academic and community medical centers were enrolled in a prospective registry and underwent TIF 2.0 performed by gastroenterologists and surgeons. The primary outcomes were safety and clinical success (response in 1 subjective and at least 1 of 3 objective secondary end points). Secondary end points were symptom improvement, acid exposure time (AET), esophagitis healing, proton pump inhibitor (PPI) use, and satisfaction. Outcomes were assessed at last follow-up within 12 months., Results: A total of 85 patients underwent TIF 2.0, and 81 were included in the outcomes analysis. Clinical success was achieved in 94%, GERD Health-Related Quality of Life scores improved in 89%, and elevated Reflux Symptom Index score normalized in 85% of patients with elevated baseline. Patient satisfaction improved from 8% to 79% (P < .0001). At baseline, 81% were taking at least daily PPI, and after TIF 2.0, 80% were on no or occasional PPI (P < .0001). Esophageal AET was normal in 72%, greater with an optimized TIF 2.0 valve (defined as >300-degree circumference and >3-cm length; 94% vs 57%; P = .007). There were no TIF 2.0-related serious adverse events., Conclusions: TIF 2.0 is a safe and effective endoscopic outpatient treatment option for selected patients with GERD., Competing Interests: Disclosure The following authors disclosed financial relationships: M. I. Canto: research grant to Johns Hopkins University from EndoGastric Solutions for this investigator-initiated prospective TIF Registry (the sponsor had no influence on the design, conduct, data collection, analysis, interpretation of results, and manuscript preparation), research grants from Pentax Medical Corporation, royalties from UpToDate, and consultant for Castle Biosciences and BlueStar Genomics; P. Janu: consultant for EndoGastric Solutions, Ethicon, Johnson and Johnson, and Olympus; D. L. Diehl: speaker for EndoGastric Solutions; B. Parker: consultant for EndoGastric Solutions; B. K. Abu-Dayyeh: research support from EndoGastric Solutions, Spatz Medical, and ERBE, speaker for Endogastric Solutions, and consultant for Boston Scientific, Olympus, and Medtronic; J. Kolb: consultant for Castle Biosciences and research support from Exact Sciences; M. Murray: consultant for EndoGastric Solutions; R. Sharaiha: consultant for Olympus, Boston Scientific, Cook Medical and Surgical Intuitive and research grants from Boston Scientific and Cook Medical; O. I. Brewer Gutierrez: consultant for EndoGastric Solutions; K. Chang: consultant for and educational grants from Apollo Endosurgery, Cook, Creo, EndoGastric Solutions, Erbe, Medtronic, and Olympus, and member of the EndoGastric Solutions scientific advisory board. All other authors disclosed no financial relationships., (Copyright © 2025 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Food insecurity is a key determinant of not only caregiver's mental health but also children's emotional problems and hyperactivity symptoms. Although substantial studies have explored such a relationship, it is unclear to us whether this relation would vary when considering that caregiver's mental health and aforementioned children's behavioral issues can be the cause and effect of each other. Addressing this research gap is a key to advancing our understanding of how to promote a healthier family dynamic, especially for those facing material needs. This research applies the family stress model to explore how food insecurity affects caregiver psychological distress and child emotional problems and hyperactivity symptoms, while considering the reciprocal relationships between caregiver mental health and these child behavioral issues. Utilizing data from the 2019 Panel Study of Income Dynamic and 2019-2020 Child Development Supplements, this study conducts path analyses applied with propensity score weighting to support causal inference. Results support the family stress model framework, where food insecurity significantly predicts an increase in psychological distress in caregivers, which in turn leads to more severe child emotional problems and hyperactivity symptoms. This study also shows that food insecurity is a risk factor resulting in a reciprocal association between caregiver psychological distress and child emotional problems, where the strength of both directions is similarly harmful to each other. These findings underscore the need to address food insecurity, not only to meet material needs but also to break the harmful cycle of mental health and behavioral issues within families., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due, at least in part, to drug resistance of leukemia stem cells (LSC). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors can eradicate bpCML LSC. In this study, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with combinations of venetoclax/tyrosine kinase inhibitors. Transcriptional analysis of LSC exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to treatment with venetoclax/dasatinib. Pretreatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells to venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment did not affect normal stem cell function, suggesting a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is a LSC-selective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances the response to venetoclax/ dasatinib when targeting LSC, providing a rationale for exploring lysosomal disruption as an adjunctive therapeutic strategy to prolong disease remission.

Advances in understanding of AA have led to the first approved therapies for this disease, and in the past two years, there have been three medicines approved for the treatment of severe alopecia areata. There are numerous clinical trials of novel therapeutics underway across the spectrum of AA., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.LS and VRC07-523LS mAbs for safety and pharmacokinetics in adults., Methods: In this first-in-human phase 1 trial (HVTN 136/HPTN 092), adults without HIV were enrolled at six university-affiliated clinical research sites in the USA. Part A evaluated escalating single intravenous doses or subcutaneous infusion of PGT121.414.LS, in four groups: 3 mg/kg intravenous (treatment group 1; n=3), 10 mg/kg intravenous (treatment group 2; n=4), 30 mg/kg intravenous (treatment group 3; n=3), and 5 mg/kg subcutaneous (treatment group 4; n=3). Part B evaluated repeated sequential intravenous administrations of 20 mg/kg PGT121.414.LS plus 20 mg/kg VRC07-523LS (treatment group 5; n=10) and sequential subcutaneous administrations of 5 mg/kg PGT121.414.LS plus 5 mg/kg VRC07-523LS (treatment group 6; n=10) on days 0, 112, and 224. Participants in treatment groups 1 and 2 were enrolled sequentially, with participants enrolled and randomly assigned to treatment groups 3 and 4 after a review of safety data. Participants in treatment groups 5 and 6 were randomly assigned in blocks after a review of safety data from treatment groups 1-4. The primary endpoints were safety and tolerability of mAbs, serum concentrations and pharmacokinetics of mAbs, and serum neutralising activity, assessed in participants who received all scheduled product administrations. Serum concentrations of each mAb were measured via a multiplex assay, and neutralisation activity against multiple HIV viruses was measured via the TZM-bl assay. Serum concentrations were estimated via an open, two-compartment model with first-order elimination from the central compartment. This study was registered with ClinicalTrials.gov (NCT04212091) and has been completed., Findings: Between Nov 10, 2020, and Oct 5, 2021, we enrolled 33 participants without HIV: median age was 31 years (range 22-48); 19 were assigned female sex at birth and 11 were assigned male sex at birth. Three participants and four participants were sequentially assigned to treatment groups 1 and 2, respectively, and, after safety review, six participants were randomly assigned to treatment groups 3 (n=3) and 4 (n=3); after safety review, 20 participants were randomly assigned to treatment groups 5 (n=10) and 6 (n=10). Intravenous and subcutaneous infusions were safe and well tolerated, without serious adverse events or dose-limiting toxicities. Dose escalation of PGT121.414.LS from 3 mg/kg to 30 mg/kg (intravenous) resulted in a dose-proportional increase in serum concentration of PGT121.414.LS, whether administered alone or in combination with VRC07-523LS. The estimated elimination half-life of PGT121.414.LS was 71 days (95% CI 66-75), three times that of its parental form, PGT121. The estimated subcutaneous (vs intravenous) bioavailability of PGT121.414.LS was 86·1% (95% CI 64·0-95·5). Neutralisation activities were greater in the higher-dose and dual combination intravenous groups than in the subcutaneous administration groups., Interpretation: These findings support further evaluation of PGT121.414.LS in combination with other mAbs for HIV-1 prevention., Funding: US National Institute of Allergy and Infectious Diseases and US National Institutes of Health., Competing Interests: Declaration of interests SRW has received institutional funding from the National Institute of Allergy and Infectious Diseases and US National Institutes of Health (NIH); institutional grants or contracts from Sanofi Pasteur, Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology, and Worcester HIV Vaccine; travel support from Sanofi; has participated on data safety monitoring or advisory boards for Janssen Vaccines (Johnson & Johnson) and BioNTech; and his spouse holds stock or stock options in Regeneron Pharmaceuticals. MEA reports grants to their institution from the Bill & Melinda Gates Foundation, Be Bio, and Moderna; royalties or licences from Elsevier; consulting fees from Seromyx Systems; and monies paid for travel and lectures or presentations from various academic centres and institutions. DHB is a co-inventor on the patent for PGT121.BIJ414.LS. JH, DCM, and KESe report reimbursement for travel from NIH. SE, CBH, MA, YH, JH, LZ, DCM, MP, KESe, and EP-M report grants from NIH. ND-R received funding for travel from CAPRISA. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Long-acting injectable cabotegravir (CAB-LA) for pre-exposure prophylaxis significantly reduced HIV acquisition in HPTN 084. We report on the safety and CAB-LA pharmacokinetics in pregnant women during the blinded period of HPTN 084., Methods: Participants were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Pregnancy testing was performed at each visit; participants with a positive test had study product withheld and were offered open-label TDF/FTC. Pregnancies were confirmed on two tests at least 4 weeks apart. All participants with a positive pregnancy test prior to November 5, 2020 are included in this analysis. Pregnancy incidence, maternal adverse event (AE) incidence, pregnancy outcomes (including composite outcome of spontaneous abortion <20 weeks, intrauterine foetal death or stillbirth ≥20 weeks, premature birth <37 weeks, or small for gestational age) were assessed. The apparent terminal phase half-life (t 1/2app ) of CAB-LA in pregnant women in HPTN 084 was compared to non-pregnant women from the phase 2a HPTN 077 trial. Multivariable models assessed associations with t 1/2app. RESULTS: Fifty-seven pregnancies (30 CAB-LA, 27 TDF/FTC) were confirmed over 3845 person-years [py] (incidence 1.5/100 py, 95% CI 1.1-1.9). CAB-LA group participants had a median 342 days (IQR 192, 497) of CAB-LA exposure prior to pregnancy detection. Grade 2 or higher maternal AE incidence did not differ by study arm (CAB 157, 95% CI 91-271 per 100 py vs. TDF/FTC 217, 95% CI 124-380 per 100 py; p = 0.256). Most pregnancies (81%) resulted in live births (25 CAB-LA, 22 TDF/FTC). Composite poor pregnancy outcomes did not differ significantly by group (CAB 6/30 vs. TDF/FTC 4/27; p = 0.476). No congenital anomalies were observed. The CAB t 1/2app geometric mean was 52.8 days (95% CI 40.7-68.4) in pregnant women compared to 60.3 days (95% CI 47.7-76.3; p = 0.66) in non-pregnant women; neither pregnancy nor body mass index were significantly associated with t 1/2app ., Conclusions: CAB-LA concentrations post-cessation of injections were generally well tolerated in pregnant women. The t 1/2app was comparable between pregnant and non-pregnant women. Ongoing studies will examine the safety and pharmacology of CAB-LA in women who choose to continue CAB-LA through pregnancy and lactation., (© 2025 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: No standardized method has yet been established for evaluating airway mucosal aberrancies associated with chronic obstructive pulmonary disease (COPD) or chronic bronchitis (CB). While goblet cell hyperplasia (GCH) is an established pathognomonic hallmark of the CB disease process, no standardized method exists for acquiring mucosal biopsies and assessing morphologic airway mucosa alterations. Additionally, the impacts from interventions targeting the airway mucosa are not well defined. In this context, a reliable and robust measure for assessing airway mucosa at baseline and subsequent to an intervention is critical for characterizing treatment-related changes., Research Question: Can standardizing airway biopsy tissue collection and histopathological assessment methods generate a robust and repeatable measure to assess airway mucosa tissue characteristics in the setting of COPD/CB?, Study Design & Methods: Initial tissue collection and histological assessment methods were designed by integrating various aspects from previously published evaluations, applied to an initial tissue sample cohort, and then iteratively refined by independent pathologists., Results: A standardized metric for histologic airway mucosa assessments was developed that specified tissue collection methods, including re-sampling airways at multiple time points to enable evaluation of treatment-related effects by incorporating scores for GCH, eosinophilia, and chronic inflammation, and the degree of GCH heterogeneity present within each sample., Conclusion: This multi-center study generated a robust, reproducible approach for assessing airway mucosa aberrancies in the setting of COPD/CB. The iterative approach established consistent tissue specimen recovery and a granular scoring matrix that enabled quantitative scoring of the various tissue findings with substantial histopathologic interrater reliability., Clinical Trial Registration Number: ClinicalTrials.gov; NCT03107494, NCT04677465; URL: www., Clinicaltrials: gov. Australian New Zealand Clinical Trials Registry (ANZCTR); ACTRN12617000330347; URL: anzctr.org.au., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:William Krimsky reports a relationship with Galvanize Therapeutics Inc that includes: employment and equity or stocks. Paul VanderLaan reports a relationship with Galvanize Therapeutics Inc that includes: consulting or advisory. Paul VanderLaan reports a relationship with Intuitive Surgical Inc that includes: consulting or advisory. Paul VanderLaan reports a relationship with Ruby Robotics that includes: consulting or advisory. Paul VanderLaan reports a relationship with Agilent Technologies that includes: consulting or advisory. Paul VanderLaan reports a relationship with Veracyte Inc that includes: consulting or advisory. Jeffrey Iding reports a relationship with Galvanize Therapeutics Inc that includes: consulting or advisory. David Hunter reports a relationship with Galvanize Therapeutics Inc that includes: employment and equity or stocks. Beryl Hatton reports a relationship with Galvanize Therapeutics Inc that includes: employment and equity or stocks. Brett Bannan reports a relationship with Galvanize Therapeutics Inc that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Background: Despite increased recruitment of Latina medical students, the percentage of Latina physicians has remained stagnant, suggesting unique retentive barriers affecting this population. Discriminatory experiences involving bias may contribute to difficulties in the retention and advancement of Latinas in medicine. This qualitative analysis aimed to explore thematic barriers prevalent among Latinas throughout their medical training in the United States., Methods: An anonymous online survey was distributed to Latinas in the continental United States from June 22 to August 12, 2022. Eligibility criteria included self-identifying as Hispanic/Latina, female/woman, and being currently enrolled in or graduated from medical school, residency, or fellowship in the United States in the past 10 years. Content and thematic analyses were done on 602 responses across seven open-ended survey questions., Results: Data were categorized into three main themes: (1) barriers stemming from limited social, cultural, and financial capital; (2) experiences of discrimination, bias, and perceptions of being undervalued; and (3) burdens resulting in notable mental health challenges such as depression and anxiety. Many women questioned their place in medicine throughout training and the value of the sacrifice and trauma endured., Conclusion: This is the first qualitative study evaluating the experiences of Latinas throughout medical training, revealing that they experience disproportionate barriers and discriminatory experiences from both colleagues and patients. Despite calls to enhance institutional climates of diversity, there continues to be an acute need for the reform of medical education to promote an inclusive culture and provide adequate mentorship to marginalized trainees., (© 2025 American Cancer Society.)

Purpose: Sepsis disproportionately affects patients in rural and socially vulnerable communities. A promising strategy to address this disparity is provider-to-provider emergency department (ED)-based telehealth consultation (tele-ED). The objective of this study was to determine if county-level social vulnerability index (SVI) was associated with tele-ED use for sepsis and, if so, which SVI elements were most strongly associated., Methods: We used data from the TELEmedicine as a Virtual Intervention for Sepsis in Rural Emergency Department study. The primary exposures were SVI aggregate and component scores. We used multivariable generalized estimating equations to model the association between SVI and tele-ED use., Findings: Our study cohort included 1191 patients treated in 23 Midwestern rural EDs between August 2016 and June 2019, of whom 326 (27.4%) were treated with tele-ED. Providers in counties with a high SVI were less likely to use tele-ED (adjusted odds ratio [aOR] = 0.51, 95% confidence interval [CI] 0.31‒0.87), an effect principally attributable to the housing type and transportation component of SVI (aOR = 0.44, 95% CI 0.22-0.89). Providers who treated fewer sepsis patients (1‒10 vs. 31+ over study period) and therefore may have been less experienced in sepsis care, were more likely to activate tele-ED (aOR = 3.91, 95% CI 2.08‒7.38)., Conclusions: Tele-ED use for sepsis was lower in socially vulnerable counties and higher among providers who treated fewer sepsis patients. These findings suggest that while tele-ED increases access to specialized care, it may not completely ameliorate sepsis disparities due to its less frequent use in socially vulnerable communities., (© 2024 The Author(s). The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Background: Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction after surgery. Because traditional risk factors do not completely explain variability in risk, this study hypothesized that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV., Methods: Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine (Ann Arbor, Michigan) and Vanderbilt University Medical Center (Nashville, Tennessee) were studied. PONV was defined as nausea or emesis occurring and documented in the postanesthesia care unit. In the discovery phase, genome-wide association studies were performed on each genetic cohort, and the results were meta-analyzed. Next, the polygenic phase assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (c-statistic) and net reclassification index., Results: Of 64,523 total patients, 5,703 developed PONV (8.8%). The study identified 46 genetic variants exceeding the threshold of P < 1 × 10-5, occurring with minor allele frequency greater than 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex (adjusted odds ratio, 1.027 per SD increase in overall genetic risk; 95% CI, 1.001 to 1.053; P = 0.044), a model based on known clinical risks (adjusted odds ratio, 1.029; 95% CI, 1.003 to 1.055; P = 0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (adjusted odds ratio, 1.029; 95% CI, 1.002 to 1.056; P = 0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic, 0.616 compared to 0.613; P = 0.028) and improved net reclassification of 4.6% of cases., Conclusions: Standardized polygenic risk was associated with PONV in all three of the study's models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score greater than 1 SD above the mean has 2 to 3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV or motion sickness (55%), having a history of migraines (17%), or being female (83%) and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Background: Coal mining involves heavy physical demand, which is associated with increased risk of injury and long-term musculoskeletal health disorders and chronic pain. Management of chronic or recurrent pain is in turn associated with prescription opioid use and risk of opioid use disorder (OUD)., Methods: We analyzed clinical data from 5463 coal miners evaluated between 2004 and 2015. Using an iterative text mining procedure, we analyzed structured clinical notes to extract information on occupational histories and clinical data. We evaluated associations along the causal chain using a series of multivariable logistic regression models to determine the relationship between (1) specific mining occupations and history of traumatic injury, (2) history of traumatic injury and current pain, and (3) current pain and current prescription opioid use., Results: Among these mostly-former coal miners (mean age 62.4 years), the average coal mining tenure was 27.3 years; 88.4% reported being previously injured, 92.3% reported suffering from current pain and 39.2% reported current prescription opioid use. Occupations involving the most strenuous mining work were associated with a history of traumatic injury. A history of traumatic injury to body regions of the head/neck/back/spine was associated with current pain involving the head/neck/back/spine (adjusted OR = 5.04; CI 95%: 4.46, 5.70; p < 0.001). In a separate model, reported current pain of the head/neck/back/spine was associated with current prescription opioid use (aOR = 2.66; CI 95%: 2.35, 3.01; p < 0.001)., Conclusions: These miners had a high prevalence of self-reported current pain, and certain specific mining occupations were more strongly associated with a history of injury, pain, and prescription opioid use., (© 2024 The Author(s). American Journal of Industrial Medicine published by Wiley Periodicals LLC.)

Background and Objective: Recommendations of first-line therapies for metastatic hormone-sensitive (mHSPC), nonmetastatic castrate-resistant (M0CRPC), and metastatic castrate-resistant (mCRPC) prostate cancer do not account for cardiotoxicity due to a lack of clear prior evidence. This manuscript assesses cardiotoxicity of these therapies., Methods: We searched Ovid Medline, Elsevier Embase, and the Cochrane Library for randomized clinical trials (RCTs) from database inception to January 14, 2024. Network meta-analyses of first-line mHSPC, M0CRPC, and mCRPC therapies were constructed for the five cardiotoxicity metrics defined by the International Cardio-Oncology Society: heart failure, myocarditis, vascular toxicity, hypertension, and arrhythmias. Additional Bayesian network meta-analyses also accounted for prior treatment history., Key Findings and Limitations: Thirteen RCTs (16 292 patients) were included. For mHSPC, androgen deprivation therapy (ADT) plus docetaxel (DTX) plus abiraterone acetate (AA) with prednisone (P) demonstrated a significant increase in hypertension and arrhythmias versus ADT + DTX (risk ratio [RR] 2.85, 95% confidence interval [CI] 1.67-4.89, and RR 2.01, 95% CI 1.17-3.44, respectively); however, no corresponding differences were observed between ADT + DTX plus darolutamide (DAR) and ADT + DTX (RR 1.55, 95% CI 0.73-3.30, and RR 0.94, 95% CI 0.63-1.40, respectively). For mCRPC assuming a history of mHSPC treatment, ADT + AA + P plus olaparib (OLA) demonstrated a statistically significant decrease in hypertension versus ADT + AA + P (RR 0.20, 95% CI 0.16-0.26). M0CRPC results were unremarkable., Conclusions and Clinical Implications: For mHSPC, ADT + DTX + DAR demonstrates less cardiotoxicity than ADT + DTX + AA + P due to a lower risk of hypertension and arrhythmias from decreased mineralocorticoid excess. In addition, OLA counterintuitively offers decreased hypertension when superimposed on ADT + AA + P for mCRPC treatment after prior androgen deprivation from mHSPC therapy., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The clinical imaging and pathology of a rare case of immature teratoma of the placenta is presented with a discussion of controversies related to classification and clinical suggestions for therapy and follow-up., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Background: Children and adolescents with disabilities (CAD) frequently encounter barriers to participation in physical activity (PA). Schools play a vital role in promoting PA, making it crucial to understand the school-based factors influencing CAD's PA participation., Objective: This qualitative systematic review and meta-synthesis aims to identify and elucidate the school-based factors influencing PA engagement among this population., Methods: A comprehensive search across six databases-Web of Science, PsycINFO, Scopus, SPORTDiscus, and Embase, CNKI-was conducted in August 2023, and subsequently updated in April 2024. English or Chinese peer-reviewed journal articles that contained substantial qualitative data regarding school-based factors affecting PA in CAD were included. The methodological quality of included studies was evaluated utilizing the Critical Appraisal Skills Program Qualitative Checklist. Qualitative data were analyzed through thematic synthesis., Results: A total of 16 studies (12 qualitative studies and 4 mixed-methods studies) were included, all of which were of moderate to high quality. Thematic synthesis identified four major themes: (a) physical environment (provision of facilities, specialized and adapted equipment, space for activities); (b) social environment (peers, school leaders, teachers and other school staff); (c) opportunities for PA (physical education, classroom movement integration, extra-curricular activities); and (d) characteristics of PA (adaption of rules and task difficulty, competition components, diversified activities, fun)., Conclusions: This review reveals the complex interplay of different school-based factors affecting PA participation among CAD. The findings provide valuable insights for educators, policymakers, and health professionals to enhance PA participation in this population., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients post-coronary artery bypass graft (CABG) can re-present with acute coronary syndrome (ACS); however, culprit lesion identification, as well as revascularization, is often challenging. Furthermore, the impact of revascularization in this patient group is relatively unknown., Objectives: The purpose of our study was to evaluate the efficacy of percutaneous coronary intervention (PCI) in patients with previous CABG surgery presenting with ACS., Methods: Using data from the Manitoba Center for Health Policy, we identified patients treated with CABG between April 1979 and March 2018, who subsequently presented with the primary diagnosis of ACS. Patients were divided into four groups: (1) managed medically and not investigated by cardiac catheterization and (2) investigated by cardiac catheterization and treated (2a) medically, (2b) with PCI, and (2c) with redo-CABG. Inverse probability treatment-weighted survival analyses were performed. Ethical approval was obtained from the local research board., Results: Nearly 20% of patients treated with CABG presented with ACS at a median of 7.2 years (age at the time of CABG: 66 years (interquartile range: 58-73 years); 75.6% male). Patients treated with PCI ( N  = 929) demonstrated improved survival compared to the patients investigated by catheterization but treated medically ( N  = 952; hazard ratio 0.87, 95% confidence interval 0.77-0.97, p  = 0.02). Patients who underwent redo CABG ( N  = 171) experienced 13% mortality within the first year, but subsequently, demonstrated a trend toward improved survival., Conclusion: ACS is not uncommon following CABG. Revascularization is associated with prognostic improvement; however, such could be accounted for by inherent group differences, including comorbidities and coronary anatomy These findings should be validated in a prospective randomized study.

Background: Partial-thickness skin wounds are some of the most painful injuries because of large areas of exposed nerve endings. These injuries often require systemic opioid treatment to manage pain adequately. However, the Centers for Disease Control and Prevention reported nearly 17,000 prescription opioid-related deaths in the United States in 2021 alone, highlighting the ongoing need for nonopioid treatment strategies. The authors developed a novel single-application ropivacaine-eluting primary wound dressing that could provide sustained ropivacaine delivery to partial-thickness wounds and assessed its in vivo feasibility for prolonged nonopioid analgesia., Methods: Sustained release of ropivacaine from a poly(lactide-co-caprolactone) matrix was first optimized in vitro using dissolution testing and a Box Behnken design of experiments. The optimized dressing was then tested against a clinical control silicone dressing in a porcine partial-thickness wound study to assess analgesic effect, pharmacokinetics, and wound healing., Results: The ropivacaine-eluting dressing showed a moderate analgesic effect in vivo, where normalized single pinprick scores significantly improved pain over the testing period (4 to 168 hours) (control versus treatment: 232 ± 25% versus 145 ± 16%; P < 0.0003). Ropivacaine blood plasma levels peaked at 8 hours after treatment, with a maximum concentration of 246 ± 74 ng/mL. No significant differences in wound healing were found when compared with control., Conclusion: The ropivacaine-loaded poly(lactide-co-caprolactone)-based wound dressing provided sustained delivery of ropivacaine to partial-thickness skin wounds and enhanced analgesic effect compared with a clinical standard control dressing., Clinical Relevance Statement: This article describes the development and porcine testing of an analgesic wound dressing for management of acute pain in partial-thickness dermal wounds., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Objectives: Cancer diagnosis comes as a shock to many patients, and many of them feel unprepared to handle the complexity of the life-changing event, understand technicalities of the diagnostic reports, and fully engage with the clinical team regarding the personalized clinical decision-making., Materials and Methods: We develop Oncointerpreter.ai an interactive resource to offer personalized summarization of clinical cancer genomic and pathological data, and frame questions or address queries about therapeutic opportunities in near-real time via a graphical interface. It is built on the Mistral-7B and Llama-2 7B large language models trained on a local database trained using a large, curated corpus., Results: We showcase its utility with case studies, where Oncointerpreter.ai extracted key clinical and molecular attributes from deidentified pathology and clinical genomics reports, summarized their contextual significance and answered queries on pertinent treatment options. Oncointerpreter also provided personalized summary of currently active clinical trials that match the patients' disease status, their selection criteria, and geographic locations. Benchmarking and comparative assessment indicated that the model responses were generally consistent, and hallucination, ie, factually incorrect or nonsensical response was rare; treatment- and outcome related queries led to context-aware responses, and response time correlated with verbosity., Discussion: The choice of model and domain-specific training also affected the response quality., Conclusion: Oncointerpreter.ai can aid the existing clinical care with interactive, individualized summarization of diagnostics data to promote informed dialogs with the patients with new cancer diagnoses., Availability: https://github.com/Siris2314/Oncointerpreter., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

With the recent trends toward outpatient shoulder surgery, standardized protocols for perioperative analgesia are critical for reducing length of stay and optimizing outcomes. There are a variety of described anesthetic and analgesic options for shoulder surgery, and the literature is variable regarding optimal choice as patient, provider, and institutional factors often play a role. With general anesthesia alone becoming less utilized, regional methods require critical examination. Knowledge of the differing, and novel, regional anesthetic procedures in conjunction with recent orthopaedic and anesthetic literature is imperative to providing patients with optimal and efficient care., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Background: Children with neuromuscular scoliosis undergoing scoliosis surgery face substantial rates of complications. To mitigate surgical risks such as blood loss in pediatric patients with neuromuscular scoliosis, this study focuses on enabling instrumentation planning for their abnormal vertebral and pelvic anatomy and osteopenia. This study assessed the feasibility of an "ultralow-dose" CT (ULD CT) protocol without sedation in pediatric patients with neuromuscular scoliosis who often have comorbid movement disorders. Our prospective quality improvement study aims: (1) to determine if ULD CT without sedation is feasible in this patient group; (2) to quantify the radiation dose from ULD CT and compare it with preoperative spine radiographs (XR); and (3) to assess if ULD CT allows accurate anatomical assessment and intraoperative navigation given the prevalence of movement disorders., Methods: Children with neuromuscular scoliosis underwent spine XR and ULD CT scans. Chart reviews assessed disease etiology and comorbidities. Radiation dose was quantified through Monte-Carlo simulations giving dose indices and effective dose, with statistical analysis done using a paired student's t -test (α=0.05). CT image quality was assessed for its use in preoperative planning and intraoperative navigation., Results: Fourteen patients (5 males, 9 females, average age 14±3 y) participated. One patient needed sedation due to autism spectrum disorder and global developmental delay. The radiation dose for spine XR was 0.5±0.2 mSv, and ULD CT was 0.6±0.1 mSv. There was no statistically significant difference in radiation doses between methods. All ULD CT scans had adequate quality for preoperative assessment of pedicle diameter and orientation, obstacles impeding pedicle entry, S2 Alar-Iliac screw orientation, and intraoperative navigation., Conclusions: ULD CT without sedation is feasible for children with neuromuscular scoliosis. Radiation doses were comparable to standard radiographs. ULD CT provided accurate anatomical assessments and supported intraoperative navigation, proving beneficial despite movement disorders in these patients., Level of Evidence: Level 2-Development of diagnostic criteria on basis of consecutive patients (with universally applied reference widely accepted standard)., Competing Interests: M.C. is a consultant for OrthoPediatrics Inc. and 7D Surgical Inc. (SeaSpine). The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Earnings and work hours (e.g., weekly work hours) are key determinants of one's mental health. While higher earnings are linked to better mental health due to reduced financial stress, they may come at the cost of longer work hours harmful for mental health. Therefore, balancing work hours with earnings is crucial for mental health. Using the 2015, 2017, and 2019 waves of the Panel Study of Income Dynamics (N = 6,776), this study explores how one's earnings and work hours combine to influence mental health using growth mixture modeling and a negative binomial regression model, with generalized propensity score weighting for causal inference. The findings reveal that working 40 h a week with earnings two to three times the US federal poverty threshold benefits mental health. However, earning more by working 60 h a week does not provide additional mental health benefits. Additionally, individuals with a history of low earnings face a high risk of psychological distress, even as their earnings improve over time. This risk is similar to that experienced by those consistently earning low incomes. Our findings highlight the importance of clarifying work-earning balance for one's mental health as well as identifying people with mental health needs from a longitudinal perspective., Competing Interests: Declaration of competing interest The author(s) declare none., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Aims: Timely transition of care amongst patients with a first diagnosis of cirrhosis in a hospital to an outpatient visit is important. We evaluated rates of outpatient follow-up after a first diagnosis of cirrhosis during an inpatient setting, and its association with subsequent rates of rehospitalisation and mortality., Methods: We conducted a population-based cohort study identifying all hospitalised patients in Sweden diagnosed with cirrhosis between 2002 and 2020 from the Swedish National Patient Register. The primary outcome was any outpatient visit related to cirrhosis within 90 days after hospital discharge. Secondary outcomes were rates of rehospitalisation and mortality within 1 year of discharge in patients receiving outpatient follow-up within 90 days or not. Cox regression was used for all analyses, and incidence rates per 1000 person-years were calculated for mortality and rehospitalisation., Results: Of 8852 patients, 3759 (42%) had outpatient follow-up within 90 days of discharge. Patients who received follow-up within 90 days of discharge were younger, had a higher level of education and were more likely to have liver decompensation or hepatocellular carcinoma compared to those without timely follow-up. We found that follow-up within 90 days was associated with lower rates of all-cause mortality within 1 year (aHR = 0.86, 95%CI = 0.78-0.96) but with no significant impact on rehospitalisations (aHR = 0.97, 95%CI = 0.91-1.03)., Conclusions: In Sweden, 42% of hospitalised patients with newly diagnosed cirrhosis receive outpatient follow-up within 90 days of their hospital discharge. These patients may experience lower mortality but no change in rehospitalisations within 1 year., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Law enforcement workers face a higher risk of cardiovascular disease (CVD), however, employment factors impacting CVD remain systematically understudied, particularly in a national US sample. We describe temporal trends in prevalent CVD including coronary heart disease (CHD), angina, myocardial infarction (MI) and other heart disease; and investigate associations of select employment factors with CVD among law enforcement workers using the National Health Interview Survey (NHIS) from 2006 to 2018., Methods: We analyzed prevalent CVD in law enforcement workers employed in local, state, and federal establishments using the NHIS, a nationally representative sample of US workers. We estimated odds ratios (OR [95% confidence interval, CI]) of CVD in relation to employment factors using survey-weighted multivariable logistic regression models adjusted for sociodemographic and traditional CVD risk factors., Results: Among 2177 law enforcement workers, mean age 46 years, 19% female, prevalence of CVD was higher among disabled (OR = 5.37; 95% CI: 2.53, 11.38 for aggregate CVD outcome) and retired (OR = 2.14; 95% CI: 1.18, 3.88 for aggregate CVD outcome) workers compared to currently employed workers. Workers employed in smaller (1-24 employees) or larger (≥ 500 employees) departments and those with tenure > 20 years also demonstrated higher prevalence odds of select CVD outcomes. Although not statistically significant, higher prevalence odds across CVD outcomes were observed in local government employees, hourly paid workers, and workers with 10-19 years of tenure., Conclusions: Our study highlights that select employment factors, some previously underexplored, may be associated with prevalent CVD in law enforcement workers. Leveraging national surveys and worker cohorts to enhance surveillance of identified groups in this high-risk population could help elucidate the role of employment on CVD development and inform workplace interventions., (© 2024 The Author(s). American Journal of Industrial Medicine published by Wiley Periodicals LLC.)