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Distinguishing proton-coupled electron transfer (PCET) from uncoupled electron transfer (ET) in proteins can be challenging. A recent investigation [J. C. Koone, M. Simmang, D. L. Saenger, M. L. Hunsicker-Wang and B. F. Shaw, J. Am. Chem. Soc. , 145 , 16488-16497] reported that protein charge ladders and capillary electrophoresis can distinguish between single ET, PCET, and two-proton coupled ET (2PCET) by directly measuring the change in protein net charge upon reduction/oxidation (Δ Z ET ). The current study used similar methods to assess PCET in zinc-free, "double copper" superoxide dismutase-1 (4Cu-SOD1), where one copper is bound at the copper site of each monomer and one copper is bound at the bridging zinc site, resulting in a quasi-type III Cu center. At pH 7.4, the net charge ( Z ) of the 4Cu-SOD1 dimer was unaffected by reduction of all four Cu 2+ ions, i.e. , Δ Z 4ET = -0.09 ± 0.05 per dimer (-0.02 ± 0.01 per copper atom). These values suggest that PCET is taking place at all four Cu atoms of the homodimer. Molecular dynamics and Poisson-Boltzmann calculations suggest that a metal-coordinating histidine at the zinc site (His71) is the proton acceptor. These data show how ligands of a naturally occurring zinc site can help facilitate PCET when the right redox metal is bound.

Stable isotope data have made pivotal contributions to nearly every discipline of the physical and natural sciences. As the generation and application of stable isotope data continues to grow exponentially, so does the need for a unifying data repository to improve accessibility and promote collaborative engagement. This paper provides an overview of the design, development, and implementation of IsoBank (www.isobank.org), a community-driven initiative to create an open-access repository for stable isotope data implemented online in 2021. A central goal of IsoBank is to provide a web-accessible database supporting interdisciplinary stable isotope research and educational opportunities. To achieve this goal, we convened a multi-disciplinary group of over 40 analytical experts, stable isotope researchers, database managers, and web developers to collaboratively design the database. This paper outlines the main features of IsoBank and provides a focused description of the core metadata structure. We present plans for future database and tool development and engagement across the scientific community. These efforts will help facilitate interdisciplinary collaboration among the many users of stable isotopic data while also offering useful data resources and standardization of metadata reporting across eco-geoinformatics landscapes., Competing Interests: The authors declare no competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Objectives: Post-marketing surveillance of sotrovimab's effect during implementation in the Canadian population is limited., Methods: The study used a propensity score-matched retrospective cohort design. Follow-up began between the periods of December 15, 2021 and April 30 2022. The study assessed any severe outcome defined as all-cause hospital admission or mortality within 30 days of a confirmed COVID-19-positive test. Covariate-adjusted odds ratios between sotrovimab treatment and the severe outcome was conducted using logistic regression., Results: There were 22,289 individuals meeting the treatment criteria for sotrovimab. There were 1603 treated and 6299 untreated individuals included in the analysis. The outcome occurrence in the study was 5.49% (treated) and 4.21% (untreated), with a median time from diagnosis to treatment of 1.00 days (interquartile range 2.00 days). In the propensity-matched cohort, sotrovimab was not associated with lower odds of a severe outcome (odds ratio 1.20, 95% confidence interval 0.91-1.58), adjusting for confounding variables., Conclusions: After adjusting for confounding variables, sotrovimab treatment was not associated with lower odds of a severe outcome within 30-days of COVID-19-positive date., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Minimum spanning trees and forests are powerful sparsification techniques that remove cycles from weighted graphs to minimize total edge weight while preserving node reachability, with applications in computer science, network science, and graph theory. Despite their utility and ubiquity, they have several limitations, including that they are only defined for undirected networks, they significantly alter dynamics on networks, and they do not generally preserve important network features such as shortest distances, shortest path distribution, and community structure. In contrast, distance backbones, which are subgraphs formed by all edges that obey a generalized triangle inequality, are well defined in directed and undirected graphs and preserve those and other important network features. The backbone of a graph is defined with respect to a specified path-length operator that aggregates weights along a path to define its length, thereby associating a cost to indirect connections. The backbone is the union of all shortest paths between each pair of nodes according to the specified operator. One such operator, the max function, computes the length of a path as the largest weight of the edges that compose it (a weakest link criterion). It is the only operator that yields an algebraic structure for computing shortest paths that is consistent with De Morgan's laws. Applying this operator yields the ultrametric backbone of a graph in that (semi-triangular) edges whose weights are larger than the length of an indirect path connecting the same nodes (i.e. those that break the generalized triangle inequality based on max as a path-length operator) are removed. We show that the ultrametric backbone is the union of minimum spanning forests in undirected graphs and provides a new generalization of minimum spanning trees to directed graphs that, unlike minimum equivalent graphs and minimum spanning arborescences, preserves all max - min shortest paths and De Morgan's law consistency., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Published by IOP Publishing Ltd.)

Freshwater mussels (order: Unionida) are highly imperiled globally and are increasingly the focus of captive propagation efforts to protect and restore wild populations. The Upper Tennessee River Basin (UTRB) in Virginia is a freshwater biodiversity hotspot hosting at least 45 of North America's ~300 species of freshwater mussels, including 21 threatened and endangered species listed under the U.S. Endangered Species Act. Recent studies have documented that viruses and other microbes have contributed to freshwater mussel population declines in the UTRB. We conducted a multi-year longitudinal study of captive-reared hatchery mussels released to restoration sites throughout the UTRB to evaluate their viromes and compare them to captive hatchery environments. We documented 681 viruses from 27 families. The hatchery mussels had significantly less viruses than those deployed to wild sites, with only 20 viruses unique to the hatchery mussels. After the hatchery mussels were released into the wild, their number of viruses initially spiked and then increased steadily over time, with 451 viruses in total unique to the mussels in the wild. We found Clinch densovirus 1 (CDNV-1), a virus previously associated with mass mortality events in the Clinch River, in all samples, but the wild site mussels consistently had significantly higher CDNV-1 levels than those held in the hatchery. Our data document substantial differences between the viruses in the mussels in the hatchery and wild environments and rapid virome shifts after the mussels are released to the wild sites. These findings indicate that mussel release programs might benefit from acclimatization periods or other measures to mitigate the potential negative effects of rapid exposure to infectious agents found in natural environments.

Adults with Down syndrome (DS) have unique health care needs with evidence-based care guidelines to address these. Yet, the 2020 adult guidelines were unstudied; we aimed to assess adherence to these guidelines. We reviewed clinical and demographic data from medical charts of 327 adults with DS who were seen in the MGH DSP. We calculated adherence to care guidelines and analyzed correlations between both demographic traits and clinical results. Mean adherence rate to each of the nine adult guidelines was 67.3%. Adherence rates that were below our mean adherence rate included colonoscopy (42.9%), iron (41.9%), audiology specialist (35.8%), and audiogram (35.2%). We found four significant correlations: assigned females at birth had a significantly higher body mass index (BMI) than assigned males at birth (p < 0.001), Hispanic patients had a significantly higher BMI than other patients (p = 0.015), Hispanic patients had a significantly higher rate of diabetes than other patients (p = 0.036), and Black patients had a significantly lower rate of hypothyroidism than other patients (p = 0.004). We assessed the adherence rates to adult DS guidelines and highlighted disparities in healthcare for patients with DS to inform clinicians on how to improve care for patients with DS., (© 2024 Wiley Periodicals LLC.)

The histone variant H3.3 acts in coordination with histone posttranslational modifications and other chromatin features to facilitate appropriate transcription. Canonical histone H3 and histone variant H3.3 are post-translationally modified with the genomic distribution of these marks denoting different features and with more recent evidence suggesting that these modifications may influence transcription. While the majority of posttranslational modifications occur on histone tails, there are defined modifications within the globular domain, such as acetylation of H3K122/H3.3K122. To understand the function of the residue H3.3K122 in transcriptional regulation, we attempted to generate H3.3K122A mouse embryonic stem (mES) cells but were unsuccessful. Through multi-omic profiling of mutant cell lines harboring two or three of four H3.3 targeted alleles, we have uncovered that H3.3K122A is neomorphic and results in lethality. This is surprising as prior studies demonstrate H3.3-null mES cells are viable and pluripotent, albeit with reduced differentiation capacity. Together, these studies have uncovered a novel dependence of a globular domain residue of H3.3 for viability and broadened our understanding of how histone variants contribute to transcription regulation and pluripotency in mES cells.

Background: Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex ® , a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI., Methods: Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests., Results: GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus., Conclusions: The use of an FDA-approved CBD (Epidiolex ® ) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation., (© 2024. The Author(s).)

Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how Protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘J.M.S., D.A.C., J.C.K.E., and L.W. are employees of Schrödinger; B.H. is a consultant for and is on the Scientific Advisory Board of Schrödinger, Inc.; R.A.F. has a significant financial stake in, is a consultant for, and is on the Scientific Advisory Board of Schrödinger, Inc. H.A., S.M.G., R.G., S.G., L.D.M., J.C.M., R.B.D., D.G.R., A.S., T.W., and A.B. are employees of AstraZeneca’., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Flow diversion (FD: flow diversion, flow diverter) is an endovascular treatment for many intracranial aneurysm types; however, limited reports have explored the use of FDs in bifurcation aneurysm management. We analyzed the safety and efficacy of FD for the management of intracranial bifurcation aneurysms., Methods: A systematic review identified original research articles that used FD for treating intracranial bifurcation aneurysms. Articles with >4 patients that reported outcomes on the use of FDs for the management of bifurcation aneurysms along the anterior communicating artery (AComA), internal carotid artery terminus (ICAt), basilar apex (BA), or middle cerebral artery bifurcation (MCAb) were included. Meta-analysis was performed using a random effects model., Results: 19 studies were included with 522 patients harboring 534 bifurcation aneurysms (mean size 9 mm, 78% unruptured). Complete aneurysmal occlusion rate was 68% (95% CI 58.7% to 76.1%, I 2 =67%) at mean angiographic follow-up of 16 months. Subgroup analysis of FD as a standalone treatment estimated a complete occlusion rate of 69% (95% CI 50% to 83%, I 2 =38%). The total complication rate was 22% (95% CI 16.7% to 28.6%, I 2 =51%), largely due to an ischemic complication rate of 16% (95% CI 10.8% to 21.9%, I 2 =55%). The etiologies of ischemic complications were largely due to jailed artery hypoperfusion (47%) and in-stent thrombosis (38%). 7% of patients suffered permanent symptomatic complications (95% CI 4.5% to 9.8%, I 2 =6%)., Conclusion: FD treatment of bifurcation aneurysms has a modest efficacy and relatively unfavorable safety profile. Proceduralists may consider reserving FD as a treatment option if no other surgical or endovascular therapy is deemed feasible., Competing Interests: Competing interests: MB is a consultant for Cerenovus, consultant for Integra, and a member of the advisory board for Stryker. GT is a consultant for Dynamed and a Steering Committee member for Medtronic. GT is an Associate Editor for Journal of Neurointerventional Surgery. All other authors have no conflicts of interest to report., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Elephant ear plants are popular ornamental plants renowned for their large foliage. These plants have been implicated in various inadvertent and deliberate ingestions. The leaves and roots of these plants contain raphides, which are needle-shaped calcium oxalate crystals. Ingestion of these crystals results in a localized inflammatory response, typically manifesting as irritation, edema, hypersalivation, and dysphagia. Herein, we describe a case of an older gentleman who presented to our institution following intentional ingestion of the leaves and roots of an elephant ear plant. This report describes the clinical manifestations secondary to the toxicities related to the ingestion of this plant and displays the successful conservative management approach employed following multiple diagnostic studies., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Malone et al.)

Background: A recent meta-analysis revealed that vagally mediated heart rate variability (vmHRV; a biomarker of emotion regulation capacity) significantly decreases in the luteal phase of the menstrual cycle. As two follow-up studies suggest, these vmHRV decreases are driven primarily by increased luteal progesterone (P4). However, analyses also revealed significant interindividual differences in vmHRV reactivity to the cycle, which is in line with longstanding evidence for interindividual differences in mood sensitivity to the cycle. The present study begins to investigate whether these interindividual differences in vmHRV cyclicity can explain who is at higher risk of showing premenstrual emotional changes. We expected a greater degree of midluteal vmHRV decrease to be predictive of a greater premenstrual increase in negative affect., Methods: We conducted an observational study with a naturally cycling community sample (N = 31, M = 26.03 years). Over a span of six weeks, participants completed (a) daily ratings of negative affect and (b) counterbalanced lab visits in their ovulatory, midluteal, and perimenstrual phases. Lab visits were scheduled based on positive ovulation tests and included assessments of baseline vmHRV and salivary ovarian steroid levels., Results: In line with previous research, multilevel models suggest that most of the sample shows ovulatory-to-midluteal vmHRV decreases which, however, were not associated with premenstrual emotional changes. Interestingly, it was only the subgroup with luteal increases in vmHRV whose negative affect markedly worsened premenstrually and improved postmenstrually., Conclusion: The present study begins to investigate cyclical changes in vmHRV as a potential biomarker of mood sensitivity to the menstrual cycle. The results demonstrate a higher level of complexity in these associations than initially expected, given that only atypical midluteal increases in vmHRV are associated with greater premenstrual negative affect. Potential underlying mechanisms are discussed, among those the possibility that luteal vmHRV increases index compensatory efforts to regulate emotion in those with greater premenstrual negative affect. However, future studies with larger and clinical samples and more granular vmHRV assessments should build on these findings and further explore associations between vmHRV cyclicity and menstrually related mood changes., (© 2024. The Author(s).)

One in three children in the United States is exposed to insecure housing conditions, including unaffordable, inconsistent, and unsafe housing. These exposures have detrimental impacts on youth mental health. Delineating the neurobehavioral pathways linking exposure to housing insecurity with children's mental health has the potential to inform interventions and policy. However, in approaching this work, carefully considering the lived experiences of youth and families is essential to translating scientific discovery to improve health outcomes in an equitable and representative way. In the current paper, we provide an introduction to the range of stressful experiences that children may face when exposed to insecure housing conditions. Next, we highlight findings from the early-life stress literature regarding the potential neurobehavioral consequences of insecure housing, focusing on how unpredictability is associated with the neural circuitry supporting cognitive and emotional development. We then delineate how community-engaged research (CEnR) approaches have been leveraged to understand the effects of housing insecurity on mental health, and we propose future research directions that integrate developmental neuroscience research and CEnR approaches to maximize the impact of this work. We conclude by outlining practice and policy recommendations that aim to improve the mental health of children exposed to insecure housing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The cytokine TSLP promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown., Objectives: This study investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss., Methods: RNA-sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single-cell RNA-sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro., Results: This study found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single-cell RNA-sequencing revealed that TSLP recruited distinct T-cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro., Conclusions: This study proposes that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The combination of CO 2 -selective ionic liquids (ILs) with block copolymers, such as Pebax 1657, has demonstrated an enhancement of the gas separation capabilities of polymeric membranes. In the current work, the development of composite membranes by applying a thin, concentrated selective layer made of Pebax/imidazolium-based ionic liquids (ILs) is presented. The objective of the experiments was to determine the optimized IL loading and investigate how the alteration of the anion impacts the properties of the membranes. Two membrane configurations have been studied: coated flat sheet membranes, supported on a porous poly(ether sulfone) (PES) layer, as well as composite hollow fiber membranes, supported on commercial polypropylene (PP) hollow fibers. Coated hollow fiber composites were fabricated using a continuous coating method, offering a straightforward scalability in the manufacturing process. The determined mechanical pressure stability of hollow fiber composites reached up to 5 bar, indicating their potential for various industrial gas separation applications. It was found that the Pebax 1657-based coating containing 40 wt % [C 6 mim][NTf 2 ] yielded membranes with the best gas separation properties, for both the coated flat sheet and the hollow fiber configurations. The CO 2 permeance of hollow fibers reached 23.29 GPU, whereas the CO 2 /N 2 ideal selectivity stood at 8.7, suggesting the necessity of the further enhancement of the coating technique, which can be achieved, for example, through application of multiple coatings. Nonetheless, the superior ideal selectivity of the CO 2 /CO separation, reaching 12.44, gave a promising outlook for further novel membrane applications, which involve the separation of the aforementioned gases., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background/aaims: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F , NYX and TRPM1 . High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression., Methods: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F , NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated., Results: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F , NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F , NYX and TRPM1 , respectively., Conclusions: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Among extant species, the ability to sample the extremes of body size-one of the most useful predictors of an individual's ecology-is highly unlikely. This improbability is further exaggerated when sampling the already incomplete fossil record. We quantify the likelihood of sampling the uppermost limits of body size in the fossil record using Tyrannosaurus rex Osborn, 1905 as a model, selected for its comparatively well-understood life history parameters. We computationally generate a population of 140 million T. rex (based on prior estimates), modelling variation about the growth curve both with and without sexual dimorphism (the former modelled after Alligator mississippiensis ), and building in sampling limitations related to species survivorship and taphonomic bias, derived from fossil data. The 99th percentile of body mass in T. rex has likely already been sampled, but it will probably be millennia before much larger giants (99.99th percentile) are sampled at present collecting rates. Biomechanical and ecological limitations notwithstanding, we estimate that the absolute largest T. rex may have been 70% more massive than the currently largest known specimen (~15,000 vs. ~8800 kg). Body size comparisons of fossil species should be based on ontogenetically controlled statistical parameters, rather than simply comparing the largest known individuals whose recovery is highly subject to sampling intensity., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Objective: The northeastern state of Rhode Island (RI) has a Vaccinate Before You Graduate (VBYG) program that supplements the traditional primary care infrastructure by providing vaccines to adolescents while they are in school, with no out-of-pocket expenses. We analyzed data from RI's immunization registry to evaluate whether VBYG also reduces disparities in adolescent immunization rates., Methods: We identified adolescent and catch-up vaccines administered in RI to people who were aged 11-18 at any point during the 5-year study period of 2019-2023, and conducted bivariate and multivariate analyses of vaccine administration data by setting (VBYG clinics, community health centers [CHCs], all other primary care practices [oPCPs], other school-based clinics, and other sites) and adolescent demographics (racial and ethnic identity, insurance status, sex, and age at time of vaccine)., Results: Of over 387,000 routine vaccines administered during the study period, 3.3 % were administered by a VBYG clinic despite significant declines during school closures associated with the early COVID-19 pandemic. VBYG-administered doses went to slightly older youth, and a higher proportion were catch-up doses (25.7 % versus 14.1 % for CHC doses and 6.5 % for oPCP). Youths received an average of 2.71 vaccines in VBYG clinics compared to 1.77 from oPCPs and 2.08 from CHCs. A higher proportion of vaccines administered by VBYG went to adolescents of color and those without private insurance than those administered by oPCPs., Conclusions: VBYG provides a model to other jurisdictions of a vaccine safety net for adolescents who may not otherwise receive recommended vaccines before exiting the school system., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from Vibrio cholerae : this is one of the strongest protein-carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB 5 ), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (O δ- H → F δ- ) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB 5 with native GM1, the GM1 carbohydrate epitope, and meta -mononitrophenyl-α-galactoside (MNPG) revealed a trend that fully supports the importance of this key interaction. These NMR data suggest that F-GM1 binds in a closely similar conformation as native GM1. Crystallographic analyses of the complex also confirm that the OH → F bioisosteric exchange at C2 of the terminal galactose induces a ring conformation that eliminates key hydrogen bonds: these interactions are compensated for by inter- and intramolecular fluorine-specific interactions., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Culture-positive (CP) and culture-negative (CN) periprosthetic joint infections (PJI) remain a crucial area of research; however, current studies comparing these infections rely on unstandardized outcome reporting tools. Our study aimed to compare the outcomes of two-stage revision of CP and CN PJI using the standardized Musculoskeletal Infection Society (MSIS) outcome reporting tool. We retrospectively reviewed 138 patients who were diagnosed with PJI and indicated for two-stage revision total knee arthroplasty (rTKA). The majority of patients in both CP and CN cohorts achieved infection control without the need for reoperation (54.1% and 62.5%, respectively). There was a significant difference in the overall distribution of MSIS outcomes ( p = 0.043), with a significantly greater rate of CN patients falling into Tier 1 (infection control without the use of suppressive antibiotics) (52.5% versus 29.6%, p = 0.011). There was also a significant difference in the distribution of septic versus aseptic reoperations after 2nd stage ( p = 0.013), with more CP reoperations being septic and more CN reoperations being aseptic. The duration from first to second stage was significantly shorter in the CN cohort ( p = 0.002). While overall infection control was similar between cohorts, these data suggest that the outcomes of two-stage rTKA are favorable in cases of CN PJI.

Although gender differences in the prevalence of substance use disorders (SUD) have been well-characterized, little is known about when gender differences emerge along the continuum of substance use. Understanding the contribution of gender to risk at key transition points across this continuum is needed to identify potential mechanisms underlying gender differences and to inform improved gender-responsive interventions. To characterize gender differences in the progression of cannabis, cocaine, and heroin use, the current study used data from the United States-based 2015-2019 National Survey on Drug Use and Health to quantify gender differences in: (1) perceived access to drugs, (2) lifetime drug use among individuals with at least some access, and (3) past-year SUD among those who had ever used each drug. Logistic regressions were conducted for each drug to examine gender differences across all three stages, controlling for sociodemographic factors and survey year. Compared to women, men had higher odds of reporting access to and lifetime use of all three drug types. Men also had higher odds of past-year cannabis and cocaine use disorders compared to women. Results suggest gender differences emerge in the earliest stage of drug use (access) and may accumulate across the stages of use. The magnitude of gender differences varied across stages, with the largest differences observed for odds of drug initiation among those with perceived access to each drug. Longitudinal data will be needed to confirm these findings and to provide insight into potential contributors to gender-specific risk and intervention targets across the continuum of drug use severity., Competing Interests: Declaration of competing interest The authors have no conflicts of interest pertinent to this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Domestic dogs ( Canis lupus familiaris ) live with humans, frequently contact other animals and may serve as intermediary hosts for the transmission of viruses. Free-roaming dogs, which account for over 70% of the world's domestic dog population, may pose a particularly high risk in this regard. We conducted an epidemiological study of dog viromes in three locations in Uganda, representing low, medium and high rates of contact with wildlife, ranging from dogs owned specifically for traditional hunting in a biodiversity and disease 'hotspot' to pets in an affluent suburb. We quantified rates of contact between dogs and wildlife through owner interviews and conducted canine veterinary health assessments. We then applied broad-spectrum viral metagenomics to blood plasma samples, from which we identified 46 viruses, 44 of which were previously undescribed, in three viral families, Sedoreoviridae , Parvoviridae and Anelloviridae . All 46 viruses (100 %) occurred in the high-contact population of dogs compared to 63 % and 39 % in the medium- and low-contact populations, respectively. Viral prevalence ranged from 2.1 % to 92.0 % among viruses and was highest, on average, in the high-contact population (22.3 %), followed by the medium-contact (12.3 %) and low-contact (4.8 %) populations. Viral richness (number of viruses per dog) ranged from 0 to 27 and was markedly higher, on average, in the high-contact population (10.2) than in the medium-contact (5.7) or low-contact (2.3) populations. Viral richness was strongly positively correlated with the number of times per year that a dog was fed wildlife and negatively correlated with the body condition score, body temperature and packed cell volume. Viral abundance (cumulative normalized metagenomic read density) varied 124-fold among dogs and was, on average, 4.1-fold higher and 2.4-fold higher in the high-contact population of dogs than in the low-contact or medium-contact populations, respectively. Viral abundance was also strongly positively correlated with the number of times per year that a dog was fed wildlife, negatively correlated with packed cell volume and positively correlated with white blood cell count. These trends were driven by nine viruses in the family Anelloviridae , genus Thetatorquevirus , and by one novel virus in the family Sedoreoviridae , genus Orbivirus . The genus Orbivirus contains zoonotic viruses and viruses that dogs can acquire through ingestion of infected meat. Overall, our findings show that viral prevalence, richness and abundance increased across a gradient of contact between dogs and wildlife and that the health status of the dog modified viral infection. Other ecological, geographic and social factors may also have contributed to these trends. Our finding of a novel orbivirus in dogs with high wildlife contact supports the idea that free-roaming dogs may serve as intermediary hosts for viruses of medical importance to humans and other animals.

Cell-state density characterizes the distribution of cells along phenotypic landscapes and is crucial for unraveling the mechanisms that drive diverse biological processes. Here, we present Mellon, an algorithm for estimation of cell-state densities from high-dimensional representations of single-cell data. We demonstrate Mellon's efficacy by dissecting the density landscape of differentiating systems, revealing a consistent pattern of high-density regions corresponding to major cell types intertwined with low-density, rare transitory states. We present evidence implicating enhancer priming and the activation of master regulators in emergence of these transitory states. Mellon offers the flexibility to perform temporal interpolation of time-series data, providing a detailed view of cell-state dynamics during developmental processes. Mellon facilitates density estimation across various single-cell data modalities, scaling linearly with the number of cells. Our work underscores the importance of cell-state density in understanding the differentiation processes, and the potential of Mellon to provide insights into mechanisms guiding biological trajectories., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Conflict-affected youth are at risk for poor psychological and social outcomes, yet few receive mental health services. Strategies to expand access and sustain evidence-based interventions (EBIs) across novel delivery platforms must be tested. The present study was a hybrid type II implementation-effectiveness trial using a cluster randomized design. The primary goal was to evaluate feasibility and impact of using the collaborative team approach to deliver the Youth Readiness Intervention (YRI), an EBI, integrated into a youth entrepreneurship program (ENTR) with quality control in post-conflict Sierra Leone., Method: Youth were screened and randomly assigned to control, ENTR, or combined YRI and ENTR (YRI+ENTR). Implementation outcomes were dissemination and implementation indicators, competence, and fidelity. Effectiveness outcomes were emotion regulation, psychological distress, and interpersonal functioning. Secondary outcomes were third-party reporter assessments of youth functioning and behavior., Results: Data were collected and analyzed from 1,151 youth participants and 528 third-party reporters. Scores on implementation constructs, competence, and fidelity demonstrated acceptable intervention response and quality. YRI+ENTR participants showed overall improvements in depression (β = -.081, 95% CI -0.124 to -0.038, d = -0.154) and anxiety (β = -.043, 95% CI -0.091 to -0.005, d = 0.082) symptoms compared with control participants. Community leaders indicated that YRI+ENTR participants demonstrated improvements in overall work or training performance compared with control participants (β = -.114, 95% CI 0.004 to 0.232, d = 0.374)., Conclusion: Integration of EBIs such as the YRI into youth employment programs has the potential to address limited reach of EBIs in conflict and post-conflict settings. A collaborative team implementation approach can facilitate integration and fidelity., Plain Language Summary: In a Hybrid Type-II Implementation-Effectiveness trial conducted in Sierra Leone, researchers tested a Collaborative Team Approach (CTA) for delivering an evidence-based mental health intervention, the Youth Readiness Intervention (YRI), within a youth entrepreneurship program. A total of 1,151 youth participated in the study, with outcomes measured on youth mental health indicators of emotional regulation, psychological distress, and interpersonal functioning, as well as implementation indicators, competence, and fidelity. Results demonstrated that the integrated YRI and entrepreneurship program led to significant improvements in depression and anxiety symptoms compared to the control group. Community leaders also noted enhanced overall performance in YRI participants, suggesting that integrating evidence-based interventions into youth employment programs can effectively address mental health challenges in low-resource regions., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. One or more of the authors of this paper received support from a program designed to increase minority representation in science., Clinical Trial Registration Information: Youth FORWARD Phase 2 YRI and EPP Study; https://clinicaltrials.gov/; NCT03542500., Study Preregistration Information: Youth Functioning and Organizational Success for West African Regional Development (Youth FORWARD): Study Protocol; https://doi.org/10.1176/appi.ps.202000009., (Copyright © 2024. Published by Elsevier Inc.)

The onset of the COVID-19 pandemic saw a significant surge in the utilization of telemental health (TMH) services. This narrative review aimed to investigate the efficacy of TMH for serious mood disorders prior to the COVID-19 pandemic. A search across databases was conducted for randomized controlled trials focusing on TMH interventions for mood disorders, encompassing major depressive disorder (MDD) and bipolar disorder (BD). Study and patient characteristics, interventions, and outcomes were extracted. From a pool of 2611 papers initially identified, 17 met the inclusion criteria: 14 focused on MDD, while 4 addressed BD. Among these, 6 papers directly compared TMH interventions to in-person of same treatment, revealing improved access to care and higher rates of appointment follow-up with TMH. Additionally, 6 papers comparing TMH to treatment as usual demonstrated improvements in mood outcomes. Conversely, 3 papers comparing different TMH interventions found no discernible differences in outcomes. Notably, 3 studies evaluated TMH as an adjunct to usual care, all reporting enhancements in depression outcomes. Overall, preliminary evidence suggests that prior to COVID-19, TMH interventions for serious mood disorders facilitated improved access to care and follow-up, with comparable clinical outcomes to traditional in-person interventions. The discussion addresses limitations and provides recommendations for future research in this domain., (© 2024. The Author(s).)

Rationale: Premenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD., Aims: The goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers., Methods: Participants were females age 18-50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity., Results: The sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p's>0.05)., Conclusion: Serum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD., Competing Interests: Declaration of Competing Interest ALM holds a provisional patent on the anti-inflammatory effects of allopregnanolone and related neurosteroids, and has current and previous funding from Sage Therapeutics related to the anti-inflammatory actions of allopregnanolone. LH has consulted for PureTech Health and Flo Health. JLP has research funding from NIMH and Janssen Pharmaceuticals; served as a consultant to SAGE Therapeutics, Biogen, Merck, Brii Biologics, Pure Tech, Dionysus Health, and Flo Health; speaker for employees of Karuna Therapeutics; founder’s stock in Dionysus Health; two patents: “Epigenetic Biomarkers of Postpartum Depression” and “Epigenetic Biomarkers of PMDD and SSRI Response.” LMO reports no conflicts of interest, but has research funding from NIMH and NICHD and receives royalties and editorial fees from APA Publishing, Elsevier, and UpToDate., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here, we focused on Alcaligenes faecalis , a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes reepithelialization of diabetic keratinocytes, a process that is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

Whole-genome bisulfite sequencing (BS-Seq) measures cytosine methylation changes at single-base resolution and can be used to profile cell-free DNA (cfDNA). In plasma, ultrashort single-stranded cfDNA (uscfDNA, ∼50 nt) has been identified together with 167 bp double-stranded mononucleosomal cell-free DNA (mncfDNA). However, the methylation profile of uscfDNA has not been described. Conventional BS-Seq workflows may not be helpful because bisulfite conversion degrades larger DNA into smaller fragments, leading to erroneous categorization as uscfDNA. We describe the '5mCAdpBS-Seq' workflow in which pre-methylated 5mC (5-methylcytosine) single-stranded adapters are ligated to heat-denatured cfDNA before bisulfite conversion. This method retains only DNA fragments that are unaltered by bisulfite treatment, resulting in less biased uscfDNA methylation analysis. Using 5mCAdpBS-Seq, uscfDNA had lower levels of DNA methylation (∼15%) compared to mncfDNA and was enriched in promoters and CpG islands. Hypomethylated uscfDNA fragments were enriched in upstream transcription start sites (TSSs), and the intensity of enrichment was correlated with expressed genes of hemopoietic cells. Using tissue-of-origin deconvolution, we inferred that uscfDNA is derived primarily from eosinophils, neutrophils, and monocytes. As proof-of-principle, we show that characteristics of the methylation profile of uscfDNA can distinguish non-small cell lung carcinoma from non-cancer samples. The 5mCAdpBS-Seq workflow is recommended for any cfDNA methylation-based investigations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Cholesterol-dependent cytolysins (CDCs) comprise a large family of pore-forming toxins produced by Gram-positive bacteria, which are used to attack eukaryotic cells. Here, we functionally characterize a family of 2-component CDC-like (CDCL) toxins produced by the Gram-negative Bacteroidota that form pores by a mechanism only described for the mammalian complement membrane attack complex (MAC). We further show that the Bacteroides CDCLs are not eukaryotic cell toxins like the CDCs, but instead bind to and are proteolytically activated on the surface of closely related species, resulting in pore formation and cell death. The CDCL-producing Bacteroides is protected from the effects of its own CDCL by the presence of a surface lipoprotein that blocks CDCL pore formation. These studies suggest a prevalent mode of bacterial antagonism by a family of two-component CDCLs that function like mammalian MAC and that are wide-spread in the gut microbiota of diverse human populations., (© 2024. The Author(s).)

Inspired by the specificity of α-(2,9)-sialyl epitopes in bacterial capsular polysaccharides (CPS), a doubly fluorinated disaccharide has been validated as a vaccine lead against Neisseria meningitidis serogroups C and/or B. Emulating the importance of fluorine in drug discovery, this molecular editing approach serves a multitude of purposes, which range from controlling α-selective chemical sialylation to mitigating competing elimination. Conjugation of the disialoside with two carrier proteins (CRM197 and PorA) enabled a semisynthetic vaccine to be generated; this was then investigated in six groups of six mice. The individual levels of antibodies formed were compared and classified as highly glycan-specific and protective. All glycoconjugates induced a stable and long-term IgG response and binding to the native CPS epitope was achieved. The generated antibodies were protective against MenC and/or MenB; this was validated in vitro by SBA and OPKA assays. By merging the fluorinated glycan epitope of MenC with an outer cell membrane protein of MenB, a bivalent vaccine against both serogroups was created. It is envisaged that validation of this synthetic, fluorinated disialoside bioisostere as a potent antigen will open new therapeutic avenues.

Background: Past research has illuminated pivotal roles of dopamine D 3 receptors (D 3 R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear., Methods: We employed Cre-LoxP techniques to selectively delete D 3 R from presynaptic dopamine neurons or postsynaptic dopamine D 1 receptor (D 1 R)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D 3 R in cocaine and opioid actions., Results: Our results revealed D 3 R expression in ∼25% of midbrain dopamine neurons and ∼70% of D 1 R-expressing neurons in the nucleus accumbens. While dopamine D 2 receptors (D 2 R) were expressed in ∼80% dopamine neurons, we found no D 2 R and D 3 R colocalization among these cells. Selective deletion of D 3 R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D 3 R from D 1 R-expressing neurons attenuated locomotor responses to D 1 -like and D 2 -like agonists. Strikingly, deletion of D 3 R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D 3 R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D 3 R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D 1 R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia., Conclusions: We dissected presynaptic versus postsynaptic D 3 R function in the mesolimbic dopamine system. D 2 R and D 3 R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D 3 R are critically involved in the actions of opioids but not cocaine., (Published by Elsevier Inc.)

Background: A minority of naturally cycling individuals experience clinically significant affective changes across the menstrual cycle. However, few studies have examined cognitive and behavioral constructs that may maintain or worsen these changes. Several small studies link rumination with premenstrual negative affect, with authors concluding that a tendency to ruminate amplifies and perpetuates hormone-sensitive affective symptoms. Replication in larger samples is needed to confirm the validity of rumination as a treatment target., Method: 190 cycling individuals ( M = 30.82 years; 61.1% Caucasian) were recruited for moderate perceived stress, a risk factor for cyclical symptoms. They completed the Rumination Response Scale at baseline, then reported daily affective and physical symptoms across 1-6 cycles. Multilevel growth models tested trait rumination as a predictor of baseline levels, luteal increases, and follicular decreases in symptoms., Results: The degree of affective cyclicity was normally distributed across a substantial range, supporting feasibility of hypothesis tests and validating the concept of dimensional hormone sensitivity. Contrary to prediction, higher brooding did not predict levels or cyclical changes of any symptom. In a subsample selected for luteal increases in negative affect, brooding predicted higher baseline negative affect but still did not predict affective cyclicity., Conclusions: An individual's trait-like propensity to engage in rumination may not be a valid treatment target in premenstrual mood disorders. State-like changes in rumination should still be further explored, and well-powered prospective studies should explore other cognitive and behavioral factors to inform development of targeted psychological treatments for patients with cyclical affective symptoms.

Background: Self-stigma of seeking psychological help is a critical factor prohibiting individuals from seeking eating disorder (ED) treatment, but has been widely unexplored in racial/ethnic and sexual minority (SM) samples. The current study examined differences in ED pathology and self-stigma of help-seeking at the intersection of race and gender within a cisgender SM sample., Methods: Cisgender SM participants ( n  = 354) identifying as Black, Indigenous, or People of Color (BIPOC; 52%), Asian American and Pacific Islander (AAPI; 24%), or White (24%) were recruited through Prolific Academic. One-way analyses of variance were used to examine differences in the Self-Stigma of Seeking Help Scale (SSOSH) and Eating Pathology Symptom Inventory (EPSI) subscales among men and women in each group. Pearson's correlations explored associations between SSOSH and EPSI subscales within each subgroup., Results: Findings indicated significant between-group differences on the SSOSH and the EPSI subscales of Body Dissatisfaction, Purging, and Excessive Exercise. SSOSH was significantly positively correlated with Body Dissatisfaction in the White SM cis-women group and Binge Eating in the BIPOC SM cis-men group., Conclusions: Results demonstrate unique, intersectional between-group differences in ED pathology and self-stigma among SM individuals. Further research on the impact of intersectionality on these constructs within larger samples is warranted.

Objective: To investigate the perspectives of pediatric otolaryngologists on the impact of the coronavirus disease 2019 (COVID-19) pandemic on their research., Methods: Two surveys were sent to members of the American Society of Pediatric Otolaryngology (ASPO) in 2019 and 2021 to assess research perspectives before and during the COVID-19 pandemic. The surveys contained questions about research engagement, barriers, time allocation, and shifts in research focus., Results: The COVID-19 pandemic reshaped research within pediatric otolaryngology, with a mixed impact on the amount of time allocated to research endeavors. Almost half of respondents reported a change in research focus to COVID-19-related studies. Protected time and funding were significant pre-pandemic barriers, whereas reduced staff, collaboration opportunities, and enrollment limitations emerged as key pandemic-related obstacles. A personal commitment to research was most strongly correlated with time spent on this endeavor. During the pandemic, women were less likely to report an increase in research activity when compared to men, possibly due to a disproportionate burden of caregiving on women during school closures and stay-at-home orders., Conclusion: Overall, the pandemic prompted both increases and decreases in research time allocation, depending on individual circumstances and priorities. Despite new challenges, pediatric otolaryngologists remain committed to research and have continued to remain productive., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kfoury et al.)

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults., Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science., Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions., Clinical Trials.gov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brett Anderson reported receiving direct support for work not related to RECOVER work/publications from Genentech and the National Institute of Allergy and Immunology. Walter Dehority reported receiving grant support from Merck and participating in research for the Moderna COVID-19 pediatric vaccine trial and the Pfizer Paxlovid trial. Alex Fiks reported receiving support from NJM insurance and personal consulting fees not related to this paper from Rutgers University and the American Academy of Pediatrics. Ashraf Harahsheh reported serving as a scientific advisory board member unrelated to this paper for OP2 DRUGS. Lawrence Kleinman reported serving as an unpaid member of the Board of Directors for the DARTNet Institute, as a principle investigator at Quality Matters, Inc., and as the Vice Chair for the Borough of Metuchen Board of Health. Dr. Kleinman also reported grant support for work not related to RECOVER work/publications from NIH, HRSA, and the Robert Wood Johnson Foundation. Dr. Kleinman also reported minority individual stock ownership in Apple Computer, Sanofi SA, Experion, GlaxoSmithKline, Magyar Bank, Regeneron Pharmaceuticals, JP Morgan Chase, and Amgen Inc. Torri Metz reported participating as a Principle Investigator in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She is also a principle investigator for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Joshua Milner reported serving as a member of the Scientific Advisory Board for Blueprint Medicines, in a capacity unrelated to RECOVER work/publications. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Gross et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In March 2020, the World Health Organization declared COVID-19 a pandemic, which ultimately led to many meat processors temporarily shutting down or reducing processing capacity. This backlog in processing capacity forced many feedlots to retain cattle for longer periods of time and assume the risk of major market fluctuations. The aim of this study was to understand how a dietary insult affects meat quality and muscle metabolism in market-ready steers (590 kg). Sixteen market-ready (590 kg) commercial Angus crossbred steers were subjected to a maintenance diet of either forage or grain for 60 d. Longissimus lumborum (LL) muscle samples were collected immediately postmortem and processed for characteristics reflecting the underlying muscle fiber type and energy state of the tissue. Despite cattle being subjected to a 60-d feeding period, there were no detectable differences ( P  > 0.05) in carcass characteristics, color of lean, or ultimate pH (pH u ). Moreover, our data show that muscle plasticity is rather resilient, as reflected by lack of significance ( P  > 0.05) in oxidative and glycolytic enzymes, myosin heavy chain isoforms (MyHC), myoglobin, and mitochondrial DNA (mtDNA) contents. These data show that market-ready steers are capable of withstanding a low-input feeding strategy up to 60 d without dramatically impacting underlying muscle characteristics and meat quality development., Competing Interests: There is no conflict of interest for all authors that could be perceived as prejudicing the impartiality of the research reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Despite advances in clinical science, the burden of mental health problems among youth is not improving. To tackle this burden, clinical science with youth needs methods that include youth and family perspectives on context and public health. In this paper, we illustrate how community-engaged research (CEnR) methods center these perspectives. Although CEnR methods are well-established in other disciplines (e.g. social work, community psychology), they are underutilized in clinical science with youth. This is due in part to misperceptions of CEnR as resource-intensive, overly contextualized, incompatible with experimentally controlled modes of inquiry, or irrelevant to understanding youth mental health. By contrast, CEnR methods can provide real-world impact, contextualized clinical solutions, and sustainable outcomes. A key advantage of CEnR strategies is their flexibility-they fall across a continuum that centers community engagement as a core principle, and thus can be infused in a variety of research efforts, even those that center experimental control (e.g. randomized controlled trials). This paper provides a brief overview of this continuum of strategies and its application to youth-focused clinical science. We then discuss future directions of CEnR in clinical science with youth, as well as structural changes needed to advance this work. The goals of this paper are to help demystify CEnR and encourage clinical scientists to consider adopting methods that better consider context and intentionally engage the communities that our work seeks to serve.

We present a new highly interdisciplinary project-based course in computer aided drug discovery (CADD). This course was developed in response to a call for alternative pedagogical approaches during the COVID-19 pandemic, which caused the cancellation of a face-to-face summer research program sponsored by the Louisiana Biomedical Research Network (LBRN). The course integrates guided research and educational experiences for chemistry, biology, and computer science students. We implement research-based methods with publicly available tools in bioinformatics and molecular modeling to identify and prioritize promising antiviral drug candidates for COVID-19. The purpose of this course is three-fold: I. Implement an active learning and inclusive pedagogy that fosters student engagement and research mindset; II. Develop student interdisciplinary research skills that are highly beneficial in a broader scientific context; III. Demonstrate that pedagogical shifts (initially incurred during the COVID-19 pandemic) can furnish longer-term instructional benefits. The course, which has now been successfully taught a total of five times, incorporates four modules, including lectures/discussions, live demos, inquiry-based assignments, and science communication., (© 2024 The Authors. Biochemistry and Molecular Biology Education published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to compare 3-year overall survival after simultaneous portal (PVE) and hepatic vein (HVE) embolization versus PVE alone in patients undergoing liver resection for primary and secondary cancers of the liver., Methods: In this multicentre retrospective study, all DRAGON 0 centres provided 3-year follow-up data for all patients who had PVE/HVE or PVE, and were included in DRAGON 0 between 2016 and 2019. Kaplan-Meier analysis was undertaken to assess 3-year overall and recurrence/progression-free survival. Factors affecting survival were evaluated using univariable and multivariable Cox regression analyses., Results: In total, 199 patients were included from 7 centres, of whom 39 underwent PVE/HVE and 160 PVE alone. Groups differed in median age (P = 0.008). As reported previously, PVE/HVE resulted in a significantly higher resection rate than PVE alone (92 versus 68%; P = 0.007). Three-year overall survival was significantly higher in the PVE/HVE group (median survival not reached after 36 months versus 20 months after PVE; P = 0.004). Univariable and multivariable analyses identified PVE/HVE as an independent predictor of survival (univariable HR 0.46, 95% c.i. 0.27 to 0.76; P = 0.003)., Conclusion: Overall survival after PVE/HVE is substantially longer than that after PVE alone in patients with primary and secondary liver tumours., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Conflicting data exist regarding increased perioperative VTE risk while on feminizing hormone therapy. The effect has been poorly studied within the transgender population. Acute perioperative cessation of feminizing hormone therapy often leads to unpleasant side effects and exacerbates gender dysphoria in the perioperative period. We seek to identify the VTE incidence in patients undergoing facial feminization while continuing HRT throughout the time of surgery., Methods: A 38-year retrospective cohort study within a two-surgeon practice (D.K.O. and J.C.D.) was designed to evaluate postoperative VTE in patients continuing hormone therapy. The primary outcome variable was identified as suffering a VTE postoperatively., Results: 1,715 patients underwent facial feminization surgery within our search window. 953 patients met final inclusion criteria. 1 patient (0.10%) was diagnosed with a VTE postoperatively, comparable to reported literature rates for similar cosmetic and orthognathic procedures. The average Caprini score of all patients was 3.1±1.0 and the average case length was 491.9±111.0 minutes. Subgroup analysis of patients before and after internal practice changes identified 714 (77.7%) patients continuing full dose hormonal therapy perioperatively, 197 (20.7%) patients undergoing hormonal dose reduction to 25-50% perioperatively, and 8 patients who were either not taking hormonal therapy or stopped in the perioperative period. There was no significant difference in VTE incidence between the 3 subgroups (p > 0.99)., Conclusions: Perioperative use of feminizing hormonal therapy does not increase risk for perioperative VTE in patients undergoing facial feminization surgery. Therefore, it is reasonable to continue these medications through the time of surgery., Competing Interests: Financial Disclosure Statement: The authors for this article have no commercial associations or financial conflicts of interest to disclose. No funding was received for this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.)

Abstract: Procedural anxiety and pain negatively affect surgical outcomes and the patient experience during awake, invasive procedures (AIPs). This systematic review aims to evaluate the effect of using virtual reality (VR) to enhance the intraprocedural patient experience during AIPs. PRISMA, Cochrane, and SWiM Reporting Items guidelines were followed. PubMed, EMBASE, CENTRAL, and medRxiv databases were systematically searched for randomised controlled trials (RCTs) investigating the use of immersive VR headsets to enhance the patient experience in adults undergoing AIPs. Sixteen studies were included. The VR and control groups comprised 685 and 677 patients, respectively. Patients underwent endoscopic procedures in 9 studies ("endoscopic") and interventions that involved a skin incision in 7 studies ("incision"). Eleven (of 13) studies demonstrated a favourable effect on procedural anxiety with VR use compared with standard intraprocedural care (85% [95% CI: 46%-100%], P = 0.011). Ten (of 13) studies demonstrated a favourable effect on pain with VR use (77% [95% CI: 38%-100%], P = 0.046). Seven (of 9) studies demonstrated a favourable VR effect on patient satisfaction (78% (95% CI: 44%-100%), P = 0.070). The effect of VR on physiological markers of anxiety and pain and requirements for additional pro re nata (PRN) analgesia and sedation were not clear. No significant differences in patient experience were identified between the "incision" and "endoscopic" subgroups. This review demonstrates that VR can feasibly be used to enhance the patient experience during AIPs by attenuating subjective perceptions of procedural anxiety and pain. However, further RCTs are required to elucidate the effect of VR on more objective measures of the patient experience., (Copyright © 2023 International Association for the Study of Pain.)