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Abstract Background Rib fractures are one of the most common traumatic injuries and may result in significant morbidity and mortality. Despite growing evidence, technological advances and increasing acceptance, surgical stabilization of rib fractures (SSRF) remains not uniformly considered in trauma centers. Indications, contraindications, appropriate timing, surgical approaches and utilized implants are part of an ongoing debate. The present position paper, which is endorsed by the World Society of Emergency Surgery (WSES), and supported by the Chest Wall Injury Society, aims to provide a review of the literature investigating the use of SSRF in rib fracture management to develop graded position statements, providing an updated guide and reference for SSRF. Methods This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of experts then critically revised the manuscript and discussed it in detail, to develop a consensus on the position statements. Results A total of 287 studies (systematic reviews, randomized clinical trial, prospective and retrospective comparative studies, case series, original articles) have been selected from an initial pool of 9928 studies. Thirty-nine graded position statements were put forward to address eight crucial aspects of SSRF: surgical indications, contraindications, optimal timing of surgery, preoperative imaging evaluation, rib fracture sites for surgical fixation, management of concurrent thoracic injuries, surgical approach, stabilization methods and material selection. Conclusion This consensus document addresses the key focus questions on surgical treatment of rib fractures. The expert recommendations clarify current evidences on SSRF indications, timing, operative planning, approaches and techniques, with the aim to guide clinicians in optimizing the management of rib fractures, to improve patient outcomes and direct future research.

The abundance of shark and actinopterygian fossils in the Cretaceous and Paleogene strata of the Atlantic Coastal Plain is well documented; but much remains unknown about the survivorship patterns of these major components of shallow marine faunas in the western Atlantic through the K/Pg mass extinction. To shed light on this subject, we describe an assemblage of new actinopterygian, chondrichthyan, and reptilian microfossils recently recovered from the Maastrichtian Navesink and Maastrichtian–Danian Hornerstown formations at the Jean and Ric Edelman Fossil Park at Rowan University in Mantua Township, New Jersey. The new microfossils clarify extinction patterns across the K/Pg, create temporal and geographic range extensions for several taxa, and expand the known fauna of this regionally-rare and important K/Pg-boundary locality. We report 11 new additions to the vertebrate fauna of Edelman Fossil Park, the first Paleocene record of Saurocephalus lanciformis, the first Cretaceous records of Paralbula marylandica and Palaeogaleus vincenti, and the first recovery of gar and dercetid fish remains from the Paleocene in New Jersey (the last indicating that these fish survived the K/Pg extinction in the western Atlantic). Geographic range extensions include: Notidanodon brotzeni into the Western Hemisphere, Saurocephalus into northeastern North America and Phyllodus paulkatoi to the eastern coast of North America. A dentary of a juvenile alligatorid, Bottosaurus harlani, indicate that the mandible exhibited isometric growth through ontogeny. Our findings generally agree with other studies that these groups were significantly impacted by the extinction event, that extinctions were selective, and recovery was slow. This wealth of novel insights garnered from microfossils in this study highlights their critical importance for elaborating past faunas and illuminating the character of ancient ecosystems. We therefore recommend microsieving as a fruitful method for future faunal studies of shallow-marine strata and predict that such efforts will frequently yield similar important insights.

Abstract Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder resulting from abnormal expansion of an uninterrupted polyglutamine (polyQ) repeat in its disease protein, ataxin-7 (ATXN7). ATXN7 is part of Spt-Ada-Gcn5 acetyltransferase (SAGA), an evolutionarily conserved transcriptional coactivation complex with critical roles in chromatin remodeling, cell signaling, neurodifferentiation, mitochondrial health and autophagy. SCA7 is dominantly inherited and characterized by genetic anticipation and high repeat-length instability. Patients with SCA7 experience progressive ataxia, atrophy, spasticity, and blindness. There is currently no cure for SCA7, and therapies are aimed at alleviating symptoms to increase quality of life. Here, we report novel Drosophila lines of SCA7 with polyQ repeats in wild-type and human disease patient range. We find that ATXN7 expression has age- and polyQ repeat length-dependent reduction in fruit fly survival and retinal instability, concomitant with increased ATXN7 protein aggregation. These new lines will provide important insight on disease progression that can be used in the future to identify therapeutic targets for SCA7 patients.

Abstract There has been an increasing level of recognition of the interaction between cultural mega-events and built heritage in recent years. While research has broadly identified the need to align strategies and visions, as well as involve heritage actors and local communities, there has not been a systematic investigation of the position of industrial heritage within this tableau. This paper examines in depth the European Capital of Culture (ECoC) programme, as it is one of the longest standing Capital of Culture programmes in the world and has a significant record of investment and urban transformation. In this paper, we survey and categorise the inclusion of industrial heritage within the ECoC programme in 36 host cities and regions spread across Europe. This research provides the most comprehensive understanding to date of the specific forms of interaction between industrial heritage and ECoCs to better understand the kinds of relationships that have taken place. We then explore in detail the projects and decisions made in the cases of the 2023 Elefsina, 2017 Pafos and 2008 Liverpool ECoCs.

Abstract Background Occurrences of weight stigma have been documented in prenatal clinical settings from the perspective of pregnant patients, however little is known from the viewpoint of healthcare providers themselves. Reported experiences of weight stigma caused by maternal healthcare providers may be due to negative attitudes towards obesity in pregnancy and a lack of obesity specific education. The objective of this study was to assess weight-related attitudes and assumptions towards obesity in pregnancy among maternal healthcare providers in order to inform future interventions to mitigate weight stigma in prenatal clinical settings. Methods A cross-sectional survey was administered online for maternal healthcare providers in Canada that assessed weight-related attitudes and assumptions towards lifestyle behaviours in pregnancy for patients who have obesity. Participants indicated their level of agreement on a 5-point likert scale, and mean scores were calculated with higher scores indicating poorer attitudes. Participants reported whether they had observed weight stigma occur in clinical settings. Finally, participants were asked whether or not they had received obesity-specific training, and attitude scores were compared between the two groups. Results Seventy-two maternal healthcare providers (midwives, OBGYNs, residents, perinatal nurses, and family physicians) completed the survey, and 79.2% indicated that they had observed pregnant patients with obesity experience weight stigma in a clinical setting. Those who had obesity training perceived that their peers had poorer attitudes (3.7 ± 0.9) than those without training (3.1 ± 0.7; t(70) = 2.23, p = 0.029, Cohen’s d = 0.86). Conclusions Weight stigma occurs in prenatal clinical environments, and this was confirmed by maternal healthcare providers themselves. These findings support advocacy efforts to integrate weight stigma related content and mitigation strategies in medical education for health professionals, including maternal healthcare providers. Future work should include prospective examination of weight related attitudes among maternal healthcare providers and implications of obesity specific education, including strategies on mitigating weight stigma in the delivery of prenatal care.

ABSTRACT Campylobacter infections are a leading cause of bacterial-derived gastroenteritis worldwide with particularly profound impacts on pediatric patients in low- and middle-income countries. It remains unclear how Campylobacter impacts these hosts, though it is becoming increasingly evident that it is a multifactorial process that depends on the host immune response, the gastrointestinal microbiota, various bacterial factors, and host nutritional status. Since these factors likely vary between adult and pediatric patients in different regions of the world, it is important that studies define these attributes in well-characterized clinical cohorts in diverse settings. In this study, we analyzed the fecal microbiota and the metabolomic and micronutrient profiles of asymptomatic and symptomatic pediatric patients in Colombia who were either infected or uninfected with Campylobacter during a case-controlled study on acute diarrheal disease. Here, we report that the microbiome of Campylobacter-infected children only changed in their abundance of Campylobacter spp. despite the inclusion of children with or without diarrhea. In addition to increased Campylobacter, computational models were used to identify fecal metabolites that were associated with Campylobacter infection and found that glucose-6-phosphate and homovanillic acid were the strongest predictors of infection in these pediatric patients, which suggests that colonocyte metabolism is impacted during infection. Despite changes to the fecal metabolome, the concentrations of intestinal minerals and trace elements were not significantly impacted by Campylobacter infection but were elevated in uninfected children with diarrhea.IMPORTANCEGastrointestinal infection with pathogenic Campylobacter species has long been recognized as a significant cause of human morbidity. Recently, it has been observed that pediatric populations in low- and middle-income countries are uniquely impacted by these organisms in that infected children can be persistently colonized, develop enteric dysfunction, and exhibit reduced development and growth. While the association of Campylobacter species with these long-term effects continues to emerge, the impact of infection on the gastrointestinal environment of these children remains uncharacterized. To address this knowledge gap, our group leveraged clinical samples collected during a previous study on gastrointestinal infections in pediatric patients to examine the fecal microbiota, metabolome, and micronutrient profiles of those infected with Campylobacter species and found that the metabolome was impacted in a way that suggests gastrointestinal cell metabolism is affected during infection, which is some of the first data indicating how gastrointestinal health in these patients may be affected.

The identification of females of Agapostemon angelicus Cockerell and A. texanus Cresson has been a longstanding problem, with females of the two species considered morphologically indistinguishable. Prompted by recent collections in Minnesota that unexpectedly revealed the presence of A. angelicus as well as a cryptic form of A. texanus, we reassess the taxonomy of the “doubly punctate” Agapostemon species in both Minnesota and the broader United States. Examination of both new and old specimens has allowed us to identify A. angelicus females morphologically, and we reinstate A. subtilior Cockerell stat. rev. from synonymy with A. texanus. We recognize a number of new synonyms of A. subtilior that were formerly considered synonyms of A. texanus: A. borealis Crawford syn. nov., A. californicus Crawford syn. nov., A. texanus vandykei Cockerell syn. nov., A. californicus psammobius syn. nov., A. angelicus idahoensis syn. nov., and A. californicus clementinus syn. nov. We provide keys and diagnoses to allow for morphological identification of A. angelicus, A. subtilior, and A. texanus. We show that A. texanus s. s. has a relatively restricted range in the prairie region of the United States, with A. subtilior making up the bulk of what was formerly considered A. texanus. We further show that A. angelicus has a more extensive range than previously thought. Additional work remains, as there are a number of gaps in the known ranges of these species and more taxonomic work is required in the A. texanus complex south of the United States.

Policy approaches to the global energy transition often focus on technology-based solutions while ignoring challenges of overall energy demand. A sufficiency-first approach aims to limit superfluous consumption while achieving wellbeing for all. This study focuses on US built environment mechanisms of sufficiency under urban land-use policy. The historical context of US exclusionary and car-oriented planning is reviewed with an order-of-magnitude assessment of the effects on greenhouse gas emissions (GHGE). Using national vehicle-miles traveled (VMT) data derived from mobile device locations (Replica) and validated here with federal data, a hypothetical scenario explores the potential for state urban land-use reforms to enable energy sufficiency. Tenth percentile-VMT (per capita) neighborhoods are defined by state: in 47 states, the typical such neighborhood has less than 33% of its housing units in structures larger than four units. Assuming each state redresses its housing shortage while matching this VMT, 31 Mt CO2e (direct GHGE) and about 38 Mt CO2e (indirect and life-cycle GHGE) would be avoided in 2033. Texas, California, and Florida have the largest absolute emissions reduction opportunity. Urban land-use reforms comprise a logical starting point for a US sufficiency agenda. Key priorities for research, data collection, and technology and policy innovation are proposed. Policy relevance International climate policy is increasingly focused on enabling people to consume less energy: not just technological ‘efficiency’ but ‘sufficiency’ is needed. However, sufficiency has seen little uptake in the US. It may be more relevant to US policymakers if related to the growing momentum for reforming land-use planning and housing policy to address the housing shortage and affordability crisis. This crisis stems in part from the US prevalence of single-family zoning and car-centric planning, rooted in a history of racial segregation; these same laws effectively mandate people to maintain more polluting lifestyles. This study estimates how much climate pollution could be avoided with state-led land-use reform. If states committed to solving the housing shortage while building new housing in neighborhoods where people can drive less, the savings could be comparable with expanding electric vehicle policies. Policymakers and practitioners can enable these reforms while supporting complementary policy goals.

Abstract Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.

Abstract Trigeminal‐specific stimulants have been shown to activate different receptors preferentially and this likely accounts for variation in sensory perception. It is unclear whether trigeminal sensitivity is similar across different transient receptor potential (TRP) receptors or if dysfunction of different receptors results in differing patient symptoms. Therefore, a prospective cohort study was conducted, consisting of trigeminal lateralization testing with three different stimulants (eucalyptol, isothiocyanate, acetic acid), olfaction testing with Sniffin' Sticks, and measurement of various patient‐reported outcome measures (PROMs). A total of 50 participants were enrolled across the olfactory spectrum. Mean TDI score was 27.1 ± 8.3 (range 7.0–39.5) with 38% normosmic and 62% dysosmic. Mean trigeminal lateralization scores out of 20 in the overall cohort were 16.18 (2.78) for eucalyptol, 14.94 (3.49) for mustard oil, and 15.28 (3.68) for vinegar. Eucalyptol showed a significant correlation with threshold scores of Sniffin' Sticks. A significant correlation was found between acetic acid and various PROMs. None of the lateralization scores of the trigeminal stimulants correlated to each other significantly and there was no correlation to age. The lack of correlation suggests that the measured sensitivity of one type of TRP receptor may not translate to similar sensitivity of the other receptors. Additional investigations with TRPV1 and TRPA1 agonists are needed to corroborate our findings.

Abstract Objectives Prior research on olfactory dysfunction in chronic rhinosinusitis (CRS) has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory role. The purpose of this study was to evaluate gene expression in superior turbinate mucosal specimens, comparing normosmic and dysosmic CRS patients without polyps (CRSsNP). Methods Tissue samples were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus surgery. Samples subsequently underwent RNA sequencing and functional analysis to investigate biological pathways associated with differentially expressed genes between dysosmic (n = 7) and normosmic (n = 4) patients. Results Differential gene expression analysis comparing dysosmic and normosmic CRSsNP patients showed upregulation of 563 genes and downregulation of 327 genes. Using stringent criteria for multiple comparisons, one upregulated gene (Immediate Early Response 3 [IER3]) had an false discovery rate (FDR) correction adjusted P value considered statistically significant (P

In the last decade, the detection and attribution science that links climate change to extreme weather and climate events has emerged as a growing field of research with an increasing body of literature. This paper overviews the methods for extreme event attribution (EEA) and discusses the new insights that EEA provides for infrastructure adaptation. We found that EEA can inform stakeholders about current climate risk, support vulnerability-based and hazard-based adaptations, assist in the development of cost-effective adaptation strategies, and enhance justice and equity in the allocation of adaptation resources. As engineering practice shifts from a retrospective approach to a proactive, forward-looking risk management strategy, EEA can be used together with climate projections to enhance the comprehensiveness of decision making, including planning and preparing for unprecedented extreme events. Additionally, attribution assessment can be more useful for adaptation planning when the exposure and vulnerability of communities to past events are analyzed, and future changes in the probability of extreme events are evaluated. Given large uncertainties inherent in event attribution and climate projections, future research should examine the sensitivity of engineering design to climate model uncertainties, and adapt engineering practice, including building codes, to uncertain future conditions. While this study focuses on adaptation planning, EEA can also be a useful tool for informing and enhancing decisions related to climate mitigation.

During the last decades, biochar (BC) has proven to be an innovative candidate in various environmental applications. Nevertheless, the use of biochar in improving soil fertility, immobilizing contaminants and treating wastewater has presented many limitations. Nanomaterial technology has been used to improve the physicochemical properties of biochars, including emerging methods such as chemical precipitation, direct pyrolysis and impregnation of biochars with metals (Fe, Zn, Ce, Cu, Zr, Ti etc) or their oxides. This review discusses recent advancements on the potential, limitations, and prospects of using metal-biochar composites for wastewater treatments and soil remediation. Functionalization of biochar with metal oxides can exacerbate the specific surface area up to 98 %, and diminish the porosity structure up to 89 %. The performance of these metal-biochar composites, which depends on the raw material/precursor of the biochar, the identity of the metal/guest ion, the preparation conditions and the activation method, has shown that the removal rates for inorganic and organic contaminants in the aqueous phase vary from 80.5 to 100 % and from 52.90 to 100 % respectively and that the immobilization rates for heavy metals in soils vary from 16 to 100 %. Remediation mechanisms for various adsorbates in aqueous media and soils generally include electrostatic attraction, oxidation/reduction, complexation and precipitation. Life cycle assessment (LCA), pilot-scale, cost analysis, potential environmental risks, and machine learning modelling studies are found to be lacking for metal-biochar composites and provide areas for future research.

ABSTRACT Thiopseudomonas alkaliphila, an organism recently classified within the Pseudomonadaceae family, has been detected in diverse sources such as human tissues, animal guts, industrial fermenters, and decomposition environments, suggesting a diverse ecological role. However, a large knowledge gap exists in how T. alkaliphila functions. In this comparative genomic analysis, adaptations indicative of habitat specificity among strains and genomic similarity to known opportunistic pathogens are revealed. Genomic investigation reveals a core metabolic utilization of multiple oxidative and non-oxidative catabolic pathways, suggesting adaptability to varied environments and carbon sources. The genomic repertoire of T. alkaliphila includes secondary metabolites, such as antimicrobials and siderophores, indicative of its involvement in microbial competition and resource acquisition. Additionally, the presence of transposases, prophages, plasmids, and Clustered Regularly Interspaced Short Palindromic Repeats-Cas systems in T. alkaliphila genomes suggests mechanisms for horizontal gene transfer and defense against viral predation. This comprehensive genomic analysis expands our understanding on the ecological functions, community interactions, and potential virulence of T. alkaliphila, while emphasizing its adaptability and diverse capabilities across environmental and host-associated ecosystems.IMPORTANCEAs the microbial world continues to be explored, new organisms will emerge with beneficial and/or pathogenetic impact. Thiopseudomonas alkaliphila is a species originally isolated from clinical human tissue and fluid samples but has not been attributed to disease. Since its classification, T. alkaliphila has been found in animal guts, animal waste, decomposing remains, and biogas fermentation reactors. This is the first study to provide an in-depth view of the metabolic potential of publicly available genomes belonging to this species through a comparative genomics and draft pangenome calculation approach. It was found that T. alkaliphila is metabolically versatile and likely adapts to diverse energy sources and environments, which may make it useful for bioremediation and in industrial settings. A range of virulence factors and antibiotic resistances were also detected, suggesting T. alkaliphila may operate as an undescribed opportunistic pathogen.

Little is known about oxygen utilization during infection by bacterial respiratory pathogens. The classical Bordetella species, including B. pertussis, the causal agent of human whooping cough, and B. bronchiseptica, which infects nearly all mammals, are obligate aerobes that use only oxygen as the terminal electron acceptor for electron transport-coupled oxidative phosphorylation. B. bronchiseptica, which occupies many niches, has eight distinct cytochrome oxidase-encoding loci, while B. pertussis, which evolved from a B. bronchiseptica-like ancestor but now survives exclusively in and between human respiratory tracts, has only three functional cytochrome oxidase-encoding loci: cydAB1, ctaCDFGE1, and cyoABCD1. To test the hypothesis that the three cytochrome oxidases encoded within the B. pertussis genome represent the minimum number and class of cytochrome oxidase required for respiratory infection, we compared B. bronchiseptica strains lacking one or more of the eight possible cytochrome oxidases in vitro and in vivo. No individual cytochrome oxidase was required for growth in ambient air, and all three of the cytochrome oxidases conserved in B. pertussis were sufficient for growth in ambient air and low oxygen. Using a high-dose, large-volume persistence model and a low-dose, small-volume establishment of infection model, we found that B. bronchiseptica producing only the three B. pertussis-conserved cytochrome oxidases was indistinguishable from the wild-type strain for infection. We also determined that CyoABCD1 is sufficient to cause the same level of bacterial burden in mice as the wild-type strain and is thus the primary cytochrome oxidase required for murine infection, and that CydAB1 and CtaCDFGE1 fulfill auxiliary roles or are important for aspects of infection we have not assessed, such as transmission. Our results shed light on the environment at the surface of the ciliated epithelium, respiration requirements for bacteria that colonize the respiratory tract, and the evolution of virulence in bacterial pathogens.

Abstract Atmospheric rivers (ARs) deliver significant and essential precipitation to the western United States (US) with consequential interannual variability. The intensity and frequency of ARs strongly influence reservoir levels, mountain snowpack, and groundwater recharge, which are key drivers of water‐resource availability and natural hazards. Between October 2022 and April 2023, western states experienced exceptionally heavy precipitation from several families of powerful ARs. Using observations of surface‐loading deformation from Global Navigation Satellite Systems, we find that terrestrial water‐storage gains exceeded 100% of normal within vital California watersheds. Independent water‐storage solutions derived from different data‐analysis and inversion methods provide an important measure of precision. The sustained storage increases, which we show are closely associated with ARs at daily‐to‐weekly timescales, alleviated both meteorological and hydrological drought conditions in the region, with a lag in hydrological‐drought improvements. Quantifying water‐storage recovery associated with extreme precipitation after drought advances understanding of an increasingly variable hydrologic cycle.

Abstract Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.

AIM: To assess diabetic macular edema (DME) progression during the early phases of the COVID-19 pandemic, when severe societal restrictions raised the concern of possible deterioration of health in patients with systemic conditions, particularly those requiring frequent office visits. METHODS: This is a multicenter retrospective chart review of 370 patients (724 eyes) with an established diagnosis of DME seen on 3 separate visits between January 2019 and July 2021. Period 1 was January 2019 to February 2020 (considered pre-COVID-19), period 2 was March 2020 to December 2020 (considered the height of the pandemic; highest level of pandemic-related clinical and societal regulations) and period 3 was January 2021 to July 2021 (re-adjustment to the new “pandemic norms”). Main outcome measures included visual acuity, body mass index (BMI), blood pressure (BP), hemoglobin A1c (HbA1c), macular thickness, patient adherence to scheduled ophthalmology visits, and DME treatment(s) received at each visit. To facilitate measurement of macular thickness, each macula was divided into 9 Early Treatment Diabetic Retinopathy Study (ETDRS)-defined macular sectors as measured by OCT imaging. RESULTS: There was no change of BMI, systolic BP, and diastolic BP between any of the time periods. HbA1c showed a very small increase from period 1 (7.6%) to period 2 (7.8%, P=0.015) and decreased back to 7.6% at period 3 (P=0.12). Macular thickness decreased for 100% of macular regions. The central macular thickness decreased across all 3 periods from 329.5 to 316.6 μm (P=0.0045). After analysis of multiple variables including HbA1c, BMI, adherence to scheduled appointments, different clinic centers, and treatment interventions, there was no easily identifiable subgroup of patients that experienced the increase in DME. CONCLUSION: DME doesn't worsen during the COVID-19 pandemic, instead sustaining a very small but statistically significant improvement. While identifying a mechanism behind our findings is beyond the scope of this study, potential explanations may include a delay in retinal changes beyond our study period, an unexpected increase in treatment frequency despite pandemic restrictions, and an unanticipated pandemic-related improvement in some lifestyle factors that may have had a positive impact on DME.

Abstract Methods to detect cellular senescence have become increasingly important, even more so in living animals and humans. This cellular state has been found to play fundamental roles in physiological processes as well as functioning detrimentally toward the advent or progression of pathological conditions. Importantly, the study of senescence involvement in these processes in vivo cannot be done without living‐friendly technologies enabling senescence detection. Furthermore, senotherapies or therapies that selectively kill senescent cells have emerged as a new therapeutic strategy for aging and age‐related diseases such as atherosclerosis, cancer, and neurodegenerative disorders and require tools to evaluate their use in vivo. As of now, our in vivo senescence detection toolkit includes genetically engineered reporter mouse models and small molecule imaging probes. Herein, we will focus on the detection of senescence in vivo, including a summary of its challenges, current detection methods and strategies, and a perspective on overcoming the current obstacles.

Background: Conditional survival (CS) analyses provide an estimate of survival accounting for years already survived after treatment. We aim to evaluate the difference between actuarial and conditional survival in patients following lung resection for non–small cell lung cancer (NSCLC). In addition, CS analyses are used to examine whether prognosticators of survival change over time following surgery. Methods: Patients who underwent anatomic lung resection at a single institution for pathologic stage I-IIIA NSCLC between 2010 and 2021 were identified; those who underwent wedge resection for node-negative tumors ≤2 cm were also included. CS estimates were calculated as the probability of remaining disease-free after x years of nonrecurrence (CSx). Kaplan–Meier, log-rank, and Cox proportional hazard methods for examining CS were used for subgroup comparisons and assessing associations with baseline covariates. Results: Overall, 863 patients met the study inclusion criteria, with a median follow-up of 44.1 months. Conditional overall survival (OS) and disease-free survival (DFS) were greater than actuarial rates at all time points after surgery. At the time of resection, male sex (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.03 to 1.72; P = .032), tumor size >3 cm (HR, 1.17; 95% CI, 1.11-1.23; P

Climate change intensifies the frequency and severity of extreme weather events, profoundly altering demographic landscapes globally and within the United States. This study investigates their impact on migration patterns, using propensity score matching and LASSO techniques within a larger regression modeling framework. Here, we analyze historical population trends in relation to climate risk and exposure metrics for various hazards. Our findings reveal nuanced patterns of climate-induced population change, including “risky growth” areas where economic opportunities mitigate climate risks, sustaining growth in the face of observed exposure; “tipping point” areas where the amenities are slowly giving way to the disamenity of escalating hazards; and “Climate abandonment” areas experiencing exacerbated out-migration from climate risks, compounded by other out-migration market factors. Even within a single county, these patterns vary significantly, underscoring the importance of localized analyses. Projecting population impacts due to climate risk to 2055, flood risks are projected to impact the largest percentage of areas (82.6%), followed by heatwaves (47.4%), drought (46.6%), wildfires (32.7%), wildfire smoke (21.7%), and tropical cyclone winds (11.1%). The results underscore the importance of understanding hyperlocal patterns of risk and change in order to better forecast future patterns.

The MOOSE Optimization Module integrates optimization capabilities within the MOOSE framework, enabling efficient and accurate physics-constrained optimization. This module leverages automatic differentiation to compute Jacobians and employs an automatic adjoint formulation for gradient computation, significantly simplifying the implementation of optimization algorithms. The primary goal of this software is to provide a platform where analysts and researchers can rapidly prototype and explore new optimization algorithms tailored to their complex multiphysics problems without requiring them to be computational experts. By handling the aspects of adjoint problem formulation and gradient computation, the module allows users to focus on the optimization problem itself, thereby accelerating the development of more efficient designs and solutions.

The development of MOOSE has kept accelerating since the last release, with over 2,100 pull requests merged over the last 30 months that involved nearly fifty contributors across close to a dozen institutions internationally. The growth in MOOSE's capabilities and downstream applications is reflected in the growth of the community. User support provided on the GitHub discussions forum has steadily increased to nearly 50 daily interactions. New simulation projects, notably to model advanced nuclear reactor and fusion devices, are driving a significant expansion of the capabilities. This paper reports on these developments, with several major released features, new physics modules, and key improvements to the user experience and simulation workflow.

ABSTRACTBordetella species that cause respiratory infections in mammals include B. pertussis, which causes human whooping cough, and B. bronchiseptica, which infects nearly all mammals. Both bacterial species produce filamentous hemagglutinin (FhaB) and adenylate cyclase toxin (ACT), prominent surface-associated and secreted virulence factors that contribute to persistence in the lower respiratory tract by inhibiting clearance by phagocytic cells. FhaB and ACT proteins interact with themselves, each other, and host cells. Using immunoblot analyses, we showed that ACT binds to FhaB on the bacterial surface before it can be detected in culture supernatants. We determined that SphB1, a surface protease identified based on its requirement for FhaB cleavage, is also required for ACT cleavage, and we determined that the presence of ACT blocks SphB1-dependent and -independent cleavage of FhaB, but the presence of FhaB does not affect SphB1-dependent cleavage of ACT. The primary SphB1-dependent cleavage site on ACT is proximal to ACT’s active site, in a region that is critical for ACT activity. We also determined that FhaB-bound ACT on the bacterial surface can intoxicate host cells producing CR3, the receptor for ACT. In addition to increasing our understanding of FhaB, ACT, and FhaB-ACT interactions on the Bordetella surface, our data are consistent with a model in which FhaB functions as a novel toxin delivery system by binding to ACT and allowing its release upon binding of ACT to its receptor, CR3, on phagocytic cells.IMPORTANCEBacteria need to control the variety, abundance, and conformation of proteins on their surface to survive. Members of the Gram-negative bacterial genus Bordetella include B. pertussis, which causes whooping cough in humans, and B. bronchiseptica, which causes respiratory infections in a broad range of mammals. These species produce two prominent virulence factors, the two-partner secretion (TPS) effector FhaB and adenylate cyclase toxin (ACT), that interact with themselves, each other, and host cells. Here, we determined that ACT binds FhaB on the bacterial surface before being detected in culture supernatants and that ACT bound to FhaB can be delivered to eukaryotic cells. Our data are consistent with a model in which FhaB delivers ACT specifically to phagocytic cells. This is the first report of a TPS system facilitating the delivery of a separate polypeptide toxin to target cells and expands our understanding of how TPS systems contribute to bacterial pathogenesis.

Introduction: Duchenne muscular dystrophy (DMD) is a fatal striated muscle degenerative disease. DMD is caused by loss of dystrophin protein, which results in sarcolemmal instability and cycles of myofiber degeneration and regeneration. Pathology is exacerbated by overactivation of infiltrating immune cells and fibroblasts, which leads to chronic inflammation and fibrosis. Mineralocorticoid receptors (MR), a type of nuclear steroid hormone receptors, are potential therapeutic targets for DMD. MR antagonists show clinical efficacy on DMD cardiomyopathy and preclinical efficacy on skeletal muscle in DMD models.Methods: We have previously generated myofiber and myeloid MR knockout mouse models to dissect cell-specific functions of MR within dystrophic muscles. Here, we compared skeletal muscle gene expression from both knockouts to further define cell-type specific signaling downstream from MR.Results: Myeloid MR knockout increased proinflammatory and profibrotic signaling, including numerous myofibroblast signature genes. Tenascin C was the most highly upregulated fibrotic gene in myeloid MR-knockout skeletal muscle and is a component of fibrosis in dystrophic skeletal muscle. Surprisingly, lysyl oxidase (Lox), canonically a collagen crosslinker, was increased in both MR knockouts, but did not localize to fibrotic regions of skeletal muscle. Lox localized within myofibers, including only a region of quadriceps muscles. Lysyl oxidase like 1 (Loxl1), another Lox family member, was increased only in myeloid MR knockout muscle and localized specifically to fibrotic regions.Discussion: This study suggests that MR signaling in the dystrophic muscle microenvironment involves communication between contributing cell types and modulates inflammatory and fibrotic pathways in muscle disease.

Background Implantable loop recorders (ILRs) are increasingly placed for arrhythmia detection. However, historically, ≈75% of ILR alerts are false positives, requiring significant time and effort for adjudication. The LINQII and LUX‐Dx are remotely reprogrammable ILRs with dual‐stage algorithms using artificial intelligence to reduce false positives, but their utility in routine clinical practice has not been studied. Methods and Results We identified patients with the LINQII and LUX‐Dx who were monitored by the Veterans Affairs National Cardiac Device Surveillance Program between March and June 2022. ILR programming was customized on the basis of implant indication. All alerts and every 90‐day scheduled transmissions were manually reviewed. ILRs were remotely reprogrammed, as appropriate, after false‐positive alerts or 2 consecutive same‐type alerts, unless there was ongoing clinical need for that alert. Outcomes were total number of transmissions and false positives. We performed medical record review to determine if patients experienced any adverse clinical events, including hospitalization and mortality. Among 117 LINQII patients, there were 239 total alerts, 43 (18.0%) of which were false positives. Among 105 LUX‐Dx patients, there were 300 total alerts, 115 (38.3%) of which were false positives. LINQIIs were reprogrammed 22 times, resulting in a decrease in median alerts/day from 0.13 to 0.03. LUX‐Dx ILRs were reprogrammed 52 times, resulting in a decrease from 0.15 to 0.01 median alerts/day. There were no adverse clinical events that could have been identified by superior or earlier arrhythmia detection. Conclusions ILRs with artificial intelligence algorithms and remote reprogramming ability are associated with reduced alert burden because of higher true‐positive rates than prior ILRs, without missing potentially consequential arrhythmias.

Abstract Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity contributes to aging and neurodegeneration. However, no study exists on the molecular properties of cell types within human leptomeninges. Here, we provide single nuclei profiling of dissected postmortem leptomeninges from aged individuals. We detect diverse cell types, including unique meningeal endothelial, mural, and fibroblast subtypes. For immune cells, we show that most T cells express CD8 and bear characteristics of tissue-resident memory T cells. We also identify distinct subtypes of border-associated macrophages (BAMs) that display differential gene expressions from microglia and express risk genes for Alzheimer’s Disease (AD), as nominated by genome-wide association studies (GWAS). We discover cell-type-specific differentially expressed genes in individuals with Alzheimer’s dementia, particularly in fibroblasts and BAMs. Indeed, when cultured, leptomeningeal cells display the signature of ex vivo AD fibroblasts upon amyloid-β treatment. We further explore ligand-receptor interactions within the leptomeningeal niche and computationally infer intercellular communications in AD. Thus, our study establishes a molecular map of human leptomeningeal cell types, providing significant insight into the border immune and fibrotic responses in AD.

Introduction: Personal, behavioral, and environmental risk factors are correlated to varying degrees with each other and with the overall likelihood of violent reinjury. When used with fidelity, risk assessment instruments, including the violence reinjury risk assessment instrument (VRRAI), identify domains in which individuals present elevated risk levels to aid in matching services with needs. Less is known about the collinearity among risk factors for violently injured individuals admitted to hospitals. Collinearity between risk factors has ramifications for predictive modeling of violent reinjury risk. The objective of this study was to identify significantly correlated risk factors when the VRRAI was used by hospital-based violence intervention programs (HVIP) for clients. Materials and Methods: Victims of violent injury by modality of firearm, stabbing, and physical assault who were admitted to a level 1 trauma center at a single institution were voluntarily enrolled in a hospital-based violence intervention program (HVIP) between September 2020 and June 2022. Violence intervention specialists (VIS) completed the VRRAI within the first month of participant enrollment. The VRRAI is comprised of 29 binary indicators that may signal elevated risk of violent reinjury. Data from completed assessments were used to apply risk-need-responsivity (RNR) principles along with phi coefficients of key indicators to examine overlap and prevalence in the population. Results: A total of 98 participants were enrolled in the HVIP. The median age was 27 years old and 79 (80.6%) were male, while 66 (67.3%) were non-Hispanic Black or African American, 9 (9.2%) were non-Hispanic White, and 17 (17.3%) identified as Hispanic or Latino. Several statistically significant relationships existed between key risk indicators in the VRRAI. Importantly, a robust relationship was found between the two dynamic risk factors of having heavy connection with gangs and a perception of imminent threat of violence (φc = 0.57, p < 0.01). Conclusion: Data suggest that some variables could be consolidated or removed from the VRRAI to create an even shorter instrument that can be performed more rapidly in the clinical setting. The application of the RNR model illustrates a limited number of dynamic risk factors that could be immediately addressed as part of case management should be prioritized among the questions selected from the VRRAI for inquiry at the intake assessment.

Abstract Evidence on the harms and benefits of social media use is mixed, in part because the effects of social media on well-being depend on a variety of individual difference moderators. Here, we explored potential neural moderators of the link between time spent on social media and subsequent negative affect. We specifically focused on the strength of correlation among brain regions within the frontoparietal system, previously associated with the top-down cognitive control of attention and emotion. Participants (N = 54) underwent a resting state functional magnetic resonance imaging scan. Participants then completed 28 days of ecological momentary assessment and answered questions about social media use and negative affect, twice a day. Participants who spent more than their typical amount of time on social media since the previous time point reported feeling more negative at the present moment. This within-person temporal association between social media use and negative affect was mainly driven by individuals with lower resting state functional connectivity within the frontoparietal system. By contrast, time spent on social media did not predict subsequent affect for individuals with higher frontoparietal functional connectivity. Our results highlight the moderating role of individual functional neural connectivity in the relationship between social media and affect.

Abstract Background The melanocortin 4 antagonist TCMCB07 is safe and effective in reversing cachexia caused by sepsis or cancer in rodents. The safety and pharmacokinetics of TCMCB07 are demonstrated in healthy beagle dogs. Hypothesis/Objectives The objectives of this study were to investigate the safety, peak plasma concentrations, and potential for efficacy of TCMCB07 in pet dogs with naturally occurring cachexia over a 4‐week time period. Animals Fourteen dogs with cachexia of any underlying cause, except cancer of the oral cavity or gastrointestinal tract, were eligible for enrollment with informed client consent. Methods This study was a prospective, 1‐armed open‐label trial. Physical examination, complete blood count, chemistry panel, and owner‐assessed quality of life surveys were checked at weeks 1, 2, and 4. Due to potential for bradycardia and hypotension, Holter monitoring and blood pressure evaluations were scheduled at pre‐enrollment and week 4. Results Fourteen dogs completed the trial. Significant changes detected included increased mean body weight (18.6‐19.5 kg, P

Abstract Background Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal tumor screening (UTS) of newly diagnosed CRC cases is recommended to aid in diagnosis of LS and reduce cancer-related morbidity and mortality. However, not all health systems have adopted UTS processes and implementation may be inconsistent due to system and patient-level complexities. Methods To identify barriers, facilitators, and suggestions for improvements of the UTS process from the patient perspective, we conducted in-depth, semi-structured interviews with patients recently diagnosed with CRC, but not screened for or aware of LS. Patients were recruited from eight regionally diverse US health systems. Interviews were conducted by telephone, 60-minutes, audio-recorded, and transcribed. An inductive, constant comparative analysis approach was employed. Results We completed 75 interviews across the eight systems. Most participants were white (79%), about half (52%) were men, and the mean age was 60 years. Most self-reported either no (60%) or minimal (40%) prior awareness of LS. Overall, 96% of patients stated UTS should be a routine standard of care for CRC tumors, consistently citing four primary motivations for wanting to know their LS status and engage in the process for LS identification: “knowledge is power”; “family knowledge”; “prevention and detection”; and “treatment and surveillance.” Common concerns pertaining to the process of screening for and identifying LS included: creating anticipatory worry for patients, the potential cost and the accuracy of the genetic test, and possibly having one’s health insurance coverage impacted by the LS diagnosis. Patients suggested health systems communicate LS results in-person or by phone from a trained expert in LS; offer proactive verbal and written education about LS, the screening steps, and any follow-up surveillance recommendations; and support patients in communicating their LS screening to any of their blood relatives. Conclusion Our qualitative findings demonstrate patients with CRC have a strong desire for healthcare systems to regularly implement and offer UTS. Patients offer key insights for health systems to guide future implementation and optimization of UTS and other LS screening programs and maximize diagnosis of individuals with LS and improve cancer-related surveillance and outcomes. Trial registration Not available: not a clinical trial.

Scale measuring the construct of “health security in chronic illness” (HSCI) was piloted in Canadian cardiac device patients (N = 176) enrolled in a remote-monitoring study at 2 timepoints. Analysis revealed a 2-factor solution, labeled as “support” and ”certainty”. Patients reported receiving less support over time, but consistent health certainty. Patients with implantable cardioverter defibrillators felt less secure over time and reported lower levels of health security in chronic illness than pacemaker patients. Résumé: Une échelle mesurant le concept de la « sécurité en matière de santé en présence d’une maladie chronique » a fait l’objet d’un projet pilote auprès de patients canadiens porteurs de dispositifs cardiaques (N = 176) inscrits dans une étude de télésurveillance comportant deux évaluations. L’analyse a révélé une solution à deux facteurs, soit le soutien et la certitude. Les patients ont déclaré qu’ils recevaient moins de soutien au fil du temps, mais que la certitude quant à leur santé était constante. Les porteurs d’un défibrillateur cardioverteur implantable se sentaient moins en sécurité au fil du temps et signalaient de plus bas niveaux de sécurité en matière de santé, relativement à leur maladie chronique, que les porteurs d’un stimulateur cardiaque.

Abstract Background COVID‐19 infection delays therapy and in‐person evaluation for oncology patients, but clinic clearance criteria are not clearly defined. Methods We conducted a retrospective review of oncology patients with COVID‐19 at a tertiary care center during the Delta and Omicron waves and compared clearance strategies. Results Median clearance by two consecutive negative tests was 32.0 days (Interquartile Range [IQR] 22.0–42.5, n = 153) and was prolonged in hematologic malignancy versus solid tumors (35.0 days for hematologic malignancy, 27.5 days for solid tumors, p = 0.01) and in patients receiving B‐cell depletion versus other therapies. Median clearance by single negative test was reduced to 23.0 days (IQR 16.0–33.0), with recurrent positive rate 25.4% in hematologic malignancy versus 10.6% in solid tumors (p = 0.02). Clearance by a predefined waiting period required 41 days until an 80% negative rate. Conclusions COVID‐19 clearance remains prolonged in oncology patients. Single‐negative test clearance can balance delays in care with risk of infection in patients with solid tumors.

Abstract Therapeutic options against SARS-CoV-2 are underutilized. Two oral drugs, molnupiravir and paxlovid (nirmatrelvir/ritonavir), have received emergency use authorization. Initial trials suggested greater efficacy of paxlovid, but recent studies indicated comparable potency in older adults. Here, we compare both drugs in two animal models; the Roborovski dwarf hamster model for severe COVID-19-like lung infection and the ferret SARS-CoV-2 transmission model. Dwarf hamsters treated with either drug survive VOC omicron infection with equivalent lung titer reduction. Viral RNA copies in the upper respiratory tract of female ferrets receiving 1.25 mg/kg molnupiravir twice-daily are not significantly reduced, but infectious titers are lowered by >2 log orders and direct-contact transmission is stopped. Female ferrets dosed with 20 or 100 mg/kg nirmatrelvir/ritonavir twice-daily show 1–2 log order reduction of viral RNA copies and infectious titers, which correlates with low nirmatrelvir exposure in nasal turbinates. Virus replication resurges towards nirmatrelvir/ritonavir treatment end and virus transmits efficiently (20 mg/kg group) or partially (100 mg/kg group). Prophylactic treatment with 20 mg/kg nirmatrelvir/ritonavir does not prevent spread from infected ferrets, but prophylactic 5 mg/kg molnupiravir or 100 mg/kg nirmatrelvir/ritonavir block productive transmission. These data confirm reports of similar efficacy in older adults and inform on possible epidemiologic benefit of antiviral treatment.

Abstract Modifying behaviors, such as alcohol consumption, is difficult. Creating psychological distance between unhealthy triggers and one’s present experience can encourage change. Using two multisite, randomized experiments, we examine whether theory-driven strategies to create psychological distance—mindfulness and perspective-taking—can change drinking behaviors among young adults without alcohol dependence via a 28-day smartphone intervention (Study 1, N = 108 participants, 5492 observations; Study 2, N = 218 participants, 9994 observations). Study 2 presents a close replication with a fully remote delivery during the COVID-19 pandemic. During weeks when they received twice-a-day intervention reminders, individuals in the distancing interventions reported drinking less frequently than on control weeks—directionally in Study 1, and significantly in Study 2. Intervention reminders reduced drinking frequency but did not impact amount. We find that smartphone-based mindfulness and perspective-taking interventions, aimed to create psychological distance, can change behavior. This approach requires repeated reminders, which can be delivered via smartphones.

With the advent of Large Language Models (LLMs) like ChatGPT, the integration of Generative Artificial Intelligence (GAI) into clinical medicine is becoming increasingly feasible. This study aimed to evaluate the ability of the freely available ChatGPT-3.5 to generate complex differential diagnoses, comparing its output to case records of the Massachusetts General Hospital published in the New England Journal of Medicine (NEJM). Forty case records were presented to ChatGPT-3.5, prompting it to provide a differential diagnosis and then narrow it down to the most likely diagnosis. The results indicated that the final diagnosis was included in ChatGPT-3.5's original differential list in 42.5% of the cases. After narrowing, ChatGPT correctly determined the final diagnosis in 27.5% of the cases, demonstrating a decrease in accuracy compared to previous studies using common chief complaints. These findings emphasize the necessity for further investigation into the capabilities and limitations of LLMs in clinical scenarios while highlighting the potential role of GAI as an augmented clinical opinion. Anticipating the growth and enhancement of GAI tools like ChatGPT, physicians and other healthcare workers will likely find increasing support in generating differential diagnoses. However, continued exploration and regulation are essential to ensure the safe and effective integration of GAI into healthcare practice. Future studies may seek to compare newer versions of ChatGPT or investigate patient outcomes with physicians integrating this GAI technology. Understanding and expanding GAI's capabilities, particularly in differential diagnosis, may foster innovation and provide additional resources, especially in underserved areas in the medical field.

Herein, we quantitatively analyze the Nd3+ → Cr4+ energy transfer efficiency in the co-doped transparent ceramic YAG host and determine that it can be maintained at less than a 20 % loss of Nd3+ excited states when the Cr4+ absorption coefficient at 1064 nm is less than 1.0 cm−1. Furthermore, we conclude that the energy transfer mechanism can be fully accounted for on the basis of classic Förster-Dexter theory, as the transfer efficiency deduced from the emission kinetics is consistent with that independently determined from the spectroscopic properties of Cr4+ absorption and Nd3+ emission. Systematic studies of trends for Cr3+ → Cr4+ conversion are reported as a function of the oxygen annealing temperature, initial Cr3+ concentration, and incorporation of divalent (Mg2+ and Ca2+) charge compensators. Lastly, no effect of energy migration among the Nd3+ ions was observed.

Abstract Objective: Describe and compare the prevalence of symptomatic and asymptomatic or recently resolved respiratory infections in hospitalized children. Design: Cross-sectional study. Setting: Three hospital primary-to-quaternary care pediatric healthcare system. Patients: People less than 22 years old who underwent admission screening for respiratory viruses using a multitarget polymerase chain reaction (PCR) panel from August 2020 through April 2022. Methods: The symptom status of each patient was recorded by the ordering provider. The prevalence of each virus was described comparing symptomatic and asymptomatic patients. Results for each virus were stratified by age group and trends were examined over time. Results: Of the 32,812 eligible PCR panels collected, 12,965 (39.5%), 18,651 (56.8%), and 1,196 (3.6%) were obtained from patients who were symptomatic, asymptomatic, or had missing or unknown symptom status, respectively. Symptomatic patients were much more likely to test positive for a respiratory virus (67.3% vs 27.0%). The most common viruses detected in asymptomatic patients were rhinovirus/enterovirus (18.0%), SARS-CoV-2 (3.6%), and parainfluenza viruses (2.3%). The odds ratio of testing positive when symptomatic was significantly greater than unity for all viruses but varied by virus and age group. The proportion of positive tests for each virus was dynamic and changed with intermittent epidemics, or viral “waves.” Conclusions: More than one-quarter of children without respiratory symptoms admitted to a pediatric healthcare system had PCR-detectable respiratory viruses. Children with symptoms of a respiratory infection are nevertheless much more likely to have a respiratory virus detected by PCR.

Abstract Background: The interplay between SARS-CoV-2 and contemporaneous bacterial or fungal culture growth may have crucial implications for clinical outcomes of hospitalized patients. This study aimed to quantify the effect of microbiological culture positivity on mortality among hospitalized patients with SARS-CoV-2. Methods: In this retrospective cohort study, we included adult hospitalized patients from OPTUM COVID-19 specific data set, who tested positive for SARS-CoV-2 within 14 days of hospitalization between 01/20/2020 and 01/20/2022. We examined outcomes of individuals with organisms growing on cultures from the bloodstream infections (BSIs), urinary tract, and respiratory tract, and a composite of the three sites. We used propensity score matching on covariates included demographics, comorbidities, and hospitalization clinical parameters. In a sensitivity analysis, we included same covariates but excluded critical care variables such as length of stay, intensive care unit stays, mechanical ventilation, and extracorporeal membrane oxygenation. Results: The cohort included 104,560 SARS-CoV-2 positive adult hospitalized patients across the United States. The unadjusted mortality odds increased significantly with BSIs (98.7%) and with growth on respiratory cultures (RC) (176.6%), but not with growth on urinary cultures (UC). Adjusted analyses showed that BSIs and positive RC independently contribute to mortality, even after accounting for critical care variables. Conclusions: In SARS-CoV-2-positive hospitalized patients, positive bacterial and fungal microbiological cultures, especially BSIs and RC, are associated with an increased risk of mortality even after accounting for critical care variables associated with disease severity. These findings underscore the importance of stringent infection control and the effective management of secondary infections to improve patient outcomes.

Analyzing data from a national deidentified electronic health record-based data set using a matched case–control study design, we found that antibiotic use and severity of illness were independent risk factors for healthcare-associated candidemia in adult patients hospitalized with SARS-CoV-2 infection. Interleukin-6 inhibitor and corticosteroid use were not independent risk factors.

The incidence of upper extremity (UE) injuries in sport, particularly with the shoulder and elbow in baseball/softball players, appears to be increasing yearly, especially in younger age athletes. Improving the objective criteria and testing methods used to determine return to play (RTP) readiness following non-operative or post-operative management of UE injuries is one aspect of the rehabilitation process that may significantly help in reducing reinjury rates. Currently, the majority of clinicians are still using post operative time frame and/or strength/range of motion as their main criteria for clearance to RTP following UE injury. This demonstrates an inadequate reflection of the actual unpredictable, dynamic environment athletes are returning to participate in. In our clinical experiences, objective testing to allow for clearance to sport participation should incorporate neurocognitive and reactive testing to promote improvements in the athlete's ability to dual task and focus/concentrate on the multi-dimensional tasks at hand. We know that neuroplastic changes occur following UE injury resulting in decreased proprioception and increased motor activation with simple UE tasks. Currently the research on UE return to play testing is limited. The purpose of this clinical commentary was to describe the utilization and provide reference values for a series of reactive neurocognitive UE tests, to assist with RTP, in high school and collegiate overhead athletes (baseball and softball) utilizing the Blaze Pod light system. The use of a more dynamic reactive testing battery may decrease the reinjury rates when an athlete is cleared for participation by measuring readiness in chaotic circumstances that are more reflective of the sporting environment the athlete is working to return to resulting in a greater sense of confidence, performance and prevention of reinjuries.

Abstract Biodiversity inventories and monitoring techniques for marine fishes often overlook small (

Abstract Background Identifying key determinants is crucial for improving program implementation and achieving long-term sustainment within healthcare organizations. Organizational-level complexity and heterogeneity across multiple stakeholders can complicate our understanding of program implementation. We describe two data visualization methods used to operationalize implementation success and to consolidate and select implementation factors for further analysis. Methods We used a combination of process mapping and matrix heat mapping to systematically synthesize and visualize qualitative data from 66 stakeholder interviews across nine healthcare organizations, to characterize universal tumor screening programs of all newly diagnosed colorectal and endometrial cancers and understand the influence of contextual factors on implementation. We constructed visual representations of protocols to compare processes and score process optimization components. We also used color-coded matrices to systematically code, summarize, and consolidate contextual data using factors from the Consolidated Framework for Implementation Research (CFIR). Combined scores were visualized in a final data matrix heat map. Results Nineteen process maps were created to visually represent each protocol. Process maps identified the following gaps and inefficiencies: inconsistent execution of the protocol, no routine reflex testing, inconsistent referrals after a positive screen, no evidence of data tracking, and a lack of quality assurance measures. These barriers in patient care helped us define five process optimization components and used these to quantify program optimization on a scale from 0 (no program) to 5 (optimized), representing the degree to which a program is implemented and optimally maintained. Combined scores within the final data matrix heat map revealed patterns of contextual factors across optimized programs, non-optimized programs, and organizations with no program. Conclusions Process mapping provided an efficient method to visually compare processes including patient flow, provider interactions, and process gaps and inefficiencies across sites, thereby measuring implementation success via optimization scores. Matrix heat mapping proved useful for data visualization and consolidation, resulting in a summary matrix for cross-site comparisons and selection of relevant CFIR factors. Combining these tools enabled a systematic and transparent approach to understanding complex organizational heterogeneity prior to formal coincidence analysis, introducing a stepwise approach to data consolidation and factor selection.

Abstract We develop a theory of charge transport along the quantum Hall edge proximitized by a superconductor. We note that generically Andreev reflection of an edge state is suppressed if translation invariance along the edge is preserved. Disorder in a “dirty” superconductor enables the Andreev reflection but makes it random. As a result, the conductance of a proximitized segment is a stochastic quantity with giant sign-alternating fluctuations and zero average. We find the statistical distribution of the conductance and its dependence on electron density, magnetic field, and temperature. Our theory provides an explanation of a recent experiment with a proximitized edge state.

Abstract Background Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA. Results Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA r = 0.82, p

Abstract Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1 nmf164 mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1 nmf164 PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found in Npc1-deficient mice. However, in contrast to Npc1 nmf164 mice, Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC.

Arteries and veins develop different types of occlusive diseases and respond differently to injury. The biological reasons for this discrepancy are not well understood, which is a limiting factor for the development of vein-targeted therapies. This study contrasts human peripheral arteries and veins at the single-cell level, with a focus on cell populations with remodeling potential. Upper arm arteries (brachial) and veins (basilic/cephalic) from 30 organ donors were compared using a combination of bulk and single-cell RNA sequencing, proteomics, flow cytometry, and histology. The cellular atlases of six arteries and veins demonstrated a 7.8× higher proportion of contractile smooth muscle cells (SMCs) in arteries and a trend toward more modulated SMCs. In contrast, veins showed a higher abundance of endothelial cells, pericytes, and macrophages, as well as an increasing trend in fibroblasts. Activated fibroblasts had similar proportions in both types of vessels but with significant differences in gene expression. Modulated SMCs and activated fibroblasts were characterized by the upregulation of MYH10, FN1, COL8A1, and ITGA10. Activated fibroblasts also expressed F2R, POSTN, and COMP and were confirmed by F2R/CD90 flow cytometry. Activated fibroblasts from veins were the top producers of collagens among all fibroblast populations from both types of vessels. Venous fibroblasts were also highly angiogenic, proinflammatory, and hyper-responders to reactive oxygen species. Differences in wall structure further explain the significant contribution of fibroblast populations to remodeling in veins. Fibroblasts are almost exclusively located outside the external elastic lamina in arteries, while widely distributed throughout the venous wall. In line with the above, ECM-targeted proteomics confirmed a higher abundance of fibrillar collagens in veins vs. more basement ECM components in arteries. The distinct cellular compositions and transcriptional programs of reparative populations in arteries and veins may explain differences in acute and chronic wall remodeling between vessels. This information may be relevant for the development of antistenotic therapies.

Peptidylarginine deiminases (PADs or PADIs) catalyze the conversion of positively charged arginine to neutral citrulline, which alters target protein structure and function. Our previous work established that gonadotropin-releasing hormone agonist (GnRHa) stimulates PAD2-catalyzed histone citrullination to epigenetically regulate gonadotropin gene expression in the gonadotrope-derived LβT2 cell line. However, PADs are also found in the cytoplasm. Given this, we used mass spectrometry (MS) to identify additional non-histone proteins that are citrullinated following GnRHa stimulation and characterized the temporal dynamics of this modification. Our results show that actin and tubulin are citrullinated, which led us to hypothesize that GnRHa might induce their citrullination to modulate cytoskeletal dynamics and architecture. The data show that 10 nM GnRHa induces the citrullination of β-actin, with elevated levels occurring at 10 min. The level of β-actin citrullination is reduced in the presence of the pan-PAD inhibitor biphenyl-benzimidazole-Cl-amidine (BB-ClA), which also prevents GnRHa-induced actin reorganization in dispersed murine gonadotrope cells. GnRHa induces the citrullination of β-tubulin, with elevated levels occurring at 30 min, and this response is attenuated in the presence of PAD inhibition. To examine the functional consequence of β-tubulin citrullination, we utilized fluorescently tagged end binding protein 1 (EB1-GFP) to track the growing plus end of microtubules (MT) in real time in transfected LβT2 cells. Time-lapse confocal microscopy of EB1-GFP reveals that the MT average lifetime increases following 30 min of GnRHa treatment, but this increase is attenuated by PAD inhibition. Taken together, our data suggest that GnRHa-induced citrullination alters actin reorganization and MT lifetime in gonadotrope cells.