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Objectives: Our goal was to conduct a hemodynamic analysis of a novel animal model of Fontan physiology. Poor late-term outcomes in Fontan patients are believed to arise from Fontan-induced hemodynamics, but the mechanisms remain poorly understood. Recent advances in surgical experimentation have resulted in the development of a chronic sheep model of Fontan physiology; however, detailed analysis of this model is lacking. Methods: We created a single-stage Fontan model in juvenile sheep with normal biventricular circulation. The superior vena cava was anastomosed to the main pulmonary artery, and the inferior vena cava was connected to the main pulmonary artery using an expanded polytetrafluoroethylene conduit. Longitudinal hemodynamics, including catheterization and magnetic resonance imaging were evaluated. Results: Four out of 12 animals survived, with the longest surviving animal living 3 years after single-stage Fontan. We showed a significant era effect regarding survival (1 out of 8 and subsequently 3 out of 4 animals surviving beyond 2 months) attributed in large part to the procedural learning curve. Key characteristics of Fontan hemodynamics, namely systemic venous hypertension and low normal cardiac output, were observed. However, recapitulation of passive human Fontan hemodynamics is affected by volume loading of the right ventricle given an anatomic difference in sheep azygous venous anatomy draining to the coronary sinus. Conclusions: A significant learning curve exists to ensure long-term survival and future surgical modifications, including banding of the main pulmonary artery and ligation of the azygous to coronary sinus connection are promising strategies to improve the fidelity of model hemodynamics.

Abstract Providing a better understanding of what makes a compound a successful drug candidate is crucial for reducing the high attrition rates in drug discovery. Analyses of the differences between active compounds, clinical candidates and drugs require high-quality datasets. However, most datasets of drug discovery programs are not openly available. This work introduces a dataset of compound-target pairs extracted from the open-source bioactivity database ChEMBL (release 32). Compound-target pairs in the dataset either have at least one measured activity or are part of the manually curated set of known interactions in ChEMBL. Known interactions between drugs or clinical candidates and targets are specifically annotated to facilitate analyses of differences between drugs, clinical candidates, and other active compounds. In total, the dataset comprises 614,594 compound-target pairs, 5,109 (3,932) of which are known interactions between drugs (clinical candidates) and targets. The extraction is performed in an automated manner and fully reproducible. We are providing not only the datasets but also the code to rerun the analyses with other ChEMBL releases.

Abstract Crosslinking mass spectrometry (XL-MS) has the potential to map the interactome of the cell with high resolution and depth of coverage. However, current in vivo XL-MS methods are hampered by crosslinkers that demonstrate low cell permeability and require long reaction times. Consequently, interactome sampling is not high and long incubation times can distort the cell, bringing into question the validity any protein interactions identified by the method. We address these issues with a fast formaldehyde-based fixation method applied prior to the introduction of secondary crosslinkers. Using human A549 cells and a range of reagents, we show that 4% formaldehyde fixation with membrane permeabilization preserves cellular ultrastructure and simultaneously improves reaction conditions for in situ XL-MS. Protein labeling yields can be increased even for nominally membrane-permeable reagents, and surprisingly, high-concentration formaldehyde does not compete with conventional amine-reactive crosslinking reagents. Prefixation with permeabilization uncouples cellular dynamics from crosslinker dynamics, enhancing control over crosslinking yield and permitting the use of any chemical crosslinker.

Abstract The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare (

Abstract Background Human relationships with and connections to nature and the “land” are a commonly accepted Social Determinant of Health. Greater knowledge about these relationships can inform public health policies and interventions focused on health equity among Indigenous populations. Two research questions were explored: (1) what are the experiences of meaningful human-nature relationships among Indigenous youth within central Canada; and (2) how do these relationships function as a determinant of health and wellness within their lives. Methods Drawing from three community-based participatory research (CBPR) projects within two urban centers in Saskatchewan and Manitoba, the integrated qualitative findings presented here involved 92 interviews with 52 Indigenous youth that occurred over a period of nine years (2014–2023). Informed by “two-eyed seeing,” this analysis combined Indigenous Methodologies and a Constructivist Grounded Theory approach. Results Our integrative analysis revealed three cross-cutting themes about meaningful human-nature relationships: (1) promoting cultural belonging and positive identity; (2) connecting to community and family; and (3) supporting spiritual health and relationships. The experiences of young people also emphasized barriers to land and nature access within their local environments. Discussion Policies, practices, and interventions aimed at strengthening urban Indigenous young peoples’ relationships to and connections with nature and the land can have a positive impact on their health and wellness. Public Health systems and healthcare providers can learn about leveraging the health benefits of human-nature relationships at individual and community levels, and this is particularly vital for those working to advance health equity among Indigenous populations.

Abstract Amyloids are associated with over 50 human diseases and have inspired significant effort to identify small molecule remedies. Here, we present an in vivo platform that efficiently yields small molecule inhibitors of amyloid formation. We previously identified small molecules that kill the nematode C. elegans by forming membrane-piercing crystals in the pharynx cuticle, which is rich in amyloid-like material. We show here that many of these molecules are known amyloid-binders whose crystal-formation in the pharynx can be blocked by amyloid-binding dyes. We asked whether this phenomenon could be exploited to identify molecules that interfere with the ability of amyloids to seed higher-order structures. We therefore screened 2560 compounds and found 85 crystal suppressors, 47% of which inhibit amyloid formation. This hit rate far exceeds other screening methodologies. Hence, in vivo screens for suppressors of crystal formation in C. elegans can efficiently reveal small molecules with amyloid-inhibiting potential.

Abstract Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca2+ leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca2+ leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca2+ leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders.

Abstract This paper presents the design and development of a coastal fisheries monitoring system that harnesses artificial intelligence technologies. Application of the system across the Pacific region promises to revolutionize coastal fisheries management. The program is built on a centralized, cloud-based monitoring system to automate data extraction and analysis processes. The system leverages YoloV4, OpenCV, and ResNet101 to extract information from images of fish and invertebrates collected as part of in-country monitoring programs overseen by national fisheries authorities. As of December 2023, the system has facilitated automated identification of over six hundred nearshore finfish species, and automated length and weight measurements of more than 80,000 specimens across the Pacific. The system integrates other key fisheries monitoring data such as catch rates, fishing locations and habitats, volumes, pricing, and market characteristics. The collection of these metrics supports much needed rapid fishery assessments. The system’s co-development with national fisheries authorities and the geographic extent of its application enables capacity development and broader local inclusion of fishing communities in fisheries management. In doing so, the system empowers fishers to work with fisheries authorities to enable data-informed decision-making for more effective adaptive fisheries management. The system overcomes historically entrenched technical and financial barriers in fisheries management in many Pacific island communities.

Abstract Background Arachnoid cysts (AC) are associated with a risk of rupture or haemorrhage following head impact and pose a potential predisposing factor for significant complications of sport-related concussion. Despite a recognised association between ACs and intracranial haemorrhage/cyst rupture, the risk profile of participating in contact sports with AC is not well defined. We report a retrospective case series of players presenting to the Birmingham Sports Concussion Clinic between 2017 and 2023 and underwent MRI head, with a comprehensive review of the prior literature. Results 432 athletes underwent MRI of which 11 were identified to have AC (middle fossa n = 8; posterior fossa n = 2, intraventricular n = 1). Average maximal diameter was 4.1 ± 1.2 cm. 64% had a protracted recovery (≥ 3 months). 9% experienced an AC specific complication (cyst rupture, complete neurological recovery, maximal diameter 6.5 cm, Galassi II, 4 previous concussions). 91% of patients (mean maximal diameter 3.9 ± 1.0 cm) experienced no complications despite multiple previous accumulated sports-related concussions (mean 3.3, range 1–9). Case studies from the literature are summarised (n = 63), with 98% reporting complications, none of which resulted in adverse or unfavourable neurological outcomes. Across prospective and retrospective cohort studies, 1.5% had a structural injury, and (where outcome was reported) all had a favourable outcome. Conclusions AC is an incidental finding in athletes, with the majority in our cohort having sustained serial concussions without AC complication. The single complication within this cohort occurred in the largest AC, and AC size is proposed as a tentative factor associated with increased risk of contact sports participation. Complications of AC appear to be a rare occurrence. This case series and review has not identified evidence to suggest that participation in sports with AC is of significant risk, though individualised assessment and discussion of the potential risks of contact sports participation should be offered.

Abstract HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

Listening to music manipulates attention to be more externally focused, which has the potential to improve muscular efficiency. This study aimed to determine the effect of listening to music on muscle activation during an isometric exercise task, and compare this effect to those of other attentional focus conditions. Apparently healthy subjects (n = ​35; 16 men/19 women) completed an isometric elbow flexion task for 1 ​min in three randomized and counterbalanced conditions: internal focus (INT), external focus with a simple distraction task (EXT), or listening to music (MUS). Muscle activation of the biceps and triceps brachii and heart rate (HR) were recorded throughout the exercise tasks. Ratings of perceived exertion (RPE), affective valence, and motivation were measured at the end of each trial. There was no difference in muscle activation measures among the three conditions. HR during MUS was lower than EXT at 15 ​s ([89.4 ​± ​11.8] beats/min vs. [93.1 ​± ​12.9] beats/min; p ​= ​0.018) and 30 ​s ([90.6 ​± ​12.4] beats/min vs. [94.2 ​± ​12.5] beats/min; p ​= ​0.026), and lower than INT at 60 ​s ([93.3 ​± ​13.3] beats/min vs. [96.7 ​± ​12.0] beats/min; p ​= ​0.016). Overall RPE was higher for INT (13.4 ​± ​2.2) than for MUS ([12.6 ​± ​2.0]; p ​= ​0.020) and EXT ([11.94 ​± ​2.22]; p ​

Abstract Background Administrative healthcare databases, such as Medicare, are increasingly used to identify groups at risk of a crash. However, they only contain information on crash-related injuries, not all crashes. If the driver characteristics associated with crash and crash-related injury differ, conflating the two may result in ineffective or imprecise policy interventions. Methods We linked 10 years (2008–2017) of Medicare claims to New Jersey police crash reports to compare the demographics, clinical diagnoses, and prescription drug dispensings for crash-involved drivers ≥ 68 years with a police-reported crash to those with a claim for a crash-related injury. We calculated standardized mean differences to compare characteristics between groups. Results Crash-involved drivers with a Medicare claim for an injury were more likely than those with a police-reported crash to be female (62.4% vs. 51.8%, standardized mean difference [SMD] = 0.30), had more clinical diagnoses including Alzheimer’s disease and related dementias (13.0% vs. 9.2%, SMD = 0.20) and rheumatoid arthritis/osteoarthritis (69.5% vs 61.4%, SMD = 0.20), and a higher rate of dispensing for opioids (33.8% vs 27.6%, SMD = 0.18) and antiepileptics (12.9% vs 9.6%, SMD = 0.14) prior to the crash. Despite documented inconsistencies in coding practices, findings were robust when restricted to claims indicating the injured party was the driver or was left unspecified. Conclusions To identify effective mechanisms for reducing morbidity and mortality from crashes, researchers should consider augmenting administrative datasets with information from police crash reports, and vice versa. When those data are not available, we caution researchers and policymakers against the tendency to conflate crash and crash-related injury when interpreting their findings.

Abstract Background In Canada, primary care reforms led to the implementation of various team-based care models to improve access and provide more comprehensive care for patients. Despite these advances, ongoing challenges remain. The aim of this scoping review is to explore current understanding of the functioning of these care models as well as the contexts in which they have emerged and their impact on the population, providers and healthcare costs. Methods The Medline and CINAHL databases were consulted. To be included, team-based care models had to be co-located, involve a family physician, specify the other professionals included, and provide information about their organization, their relevance and their impact within a primary care context. Models based on inter-professional intervention programs were excluded. The organization and coordination of services, the emerging contexts and the impact on the population, providers and healthcare costs were analysed. Results A total of 5952 studies were screened after removing duplicates; 15 articles were selected for final analysis. There was considerable variation in the information available as well as the terms used to describe the models. They are operationalized in various ways, generally consistent with the Patient’s Medical Home vision. Except for nurses, the inclusion of other types of professionals is variable and tends to be associated with the specific nature of the services offered. The models primarily focus on individuals with mental health conditions and chronic diseases. They appear to generally satisfy the expectations of the overarching framework of a high-performing team-based primary care model at patient and provider levels. However, economic factors are seldom integrated in their evaluations. Conclusions The studies rarely provide an overarching view that permits an understanding of the specific contexts, service organization, their impacts, and the broader context of implementation, making it difficult to establish universal guidelines for the operationalization of effective models. Negotiating the inherent complexity associated with implementing models requires a collaborative approach between various stakeholders, including patients, to tailor the models to the specific needs and characteristics of populations in given areas, and reflection about the professionals to be included in delivering these services.

Abstract Background N6-methyladenosine (m6A) is the most common internal RNA modification and is involved in regulation of RNA and protein expression. AlkB family member 5 (ALKBH5) is a m6A demethylase. Given the important role of m6A in biological mechanisms, m6A and its regulators, have been implicated in many disease processes, including cancer. However, the contribution of ALKBH5 to invasive breast cancer (BC) remains poorly understood. The aim of this study was to evaluate the clinicopathological value of ALKBH5 in BC. Methods Publicly available data were used to investigate ALKBH5 mRNA alterations, prognostic significance, and association with clinical parameters at the genomic and transcriptomic level. Differentially expressed genes (DEGs) and enriched pathways with low or high ALKBH5 expression were investigated. Immunohistochemistry (IHC) was used to assess ALKBH5 protein expression in a large well-characterised BC series (n = 1327) to determine the clinical significance and association of ALKBH5 expression. Results Reduced ALKBH5 mRNA expression was significantly associated with poor prognosis and unfavourable clinical parameters. ALKBH5 gene harboured few mutations and/or copy number alternations, but low ALKBH5 mRNA expression was seen. Patients with low ALKBH5 mRNA expression had a number of differentially expressed genes and enriched pathways, including the cytokine-cytokine receptor interaction pathway. Low ALKBH5 protein expression was significantly associated with unfavourable clinical parameters associated with tumour progression including larger tumour size and worse Nottingham Prognostic Index group. Conclusion This study implicates ALKBH5 in BC and highlights the need for further functional studies to decipher the role of ALKBH5 and RNA m6A methylation in BC progression.

Abstract Background Equine-assisted services (EAS) involves the use of horses within therapy, learning or horsemanship sessions and has been used with military veterans suffering from post-traumatic stress disorder (PTSD). This study systematically reviewed existing research on the use of EAS in the treatment of PTSD in military veterans and evaluated its effectiveness. Methods A systematic review was performed, in May 2023, with searches and data extraction carried out from three separate databases (PubMed, JSTOR and Science Direct) related to testing the effect of EAS on PTSD outcomes in veterans. A risk of bias assessment of included studies was conducted and meta-analysis of outcomes performed when two or more studies reported the same outcomes. Other effects of EAS on veterans’ health were also discussed. Results A total of 13 studies were identified based on our inclusion and exclusion criteria with 11 originating from the US and the remaining two from Australia and Israel. There were 344 participants amongst all of the studies with a mean age of 47 years and a male:female ratio of 19:6. Eight out of the 13 studies reported PTSD scores, as measured by either PTSD Checklist for DSM-5 (PCL-5) or PCL-Veteran/-Military versions (PCL-V/-M), and results suggested a reduction in PTSD score after EAS treatment of 22.6%. A meta-analysis confirmed that EAS favored a significantly lower PTSD score after treatment, with a mean difference of 12.46, 95% CI [9.03,15.88], p

Abstract Peste des petits ruminants virus (PPRV) is a multi-host pathogen with sheep and goats as main hosts. To investigate the role of cattle in the epidemiology of PPR, we simulated conditions similar to East African zero-grazing husbandry practices in a series of trials with local Zebu cattle (Bos taurus indicus) co-housed with goats (Capra aegagrus hircus). Furthermore, we developed a mathematical model to assess the impact of PPRV-transmission from cattle to goats. Of the 32 cattle intranasally infected with the locally endemic lineage IV strain PPRV/Ethiopia/Habru/2014 none transmitted PPRV to 32 co-housed goats. However, these cattle or cattle co-housed with PPRV-infected goats seroconverted. The results confirm previous studies that cattle currently play a negligible role in PPRV-transmission and small ruminant vaccination is sufficient for eradication. However, the possible emergence of PPRV strains more virulent for cattle may impact eradication. Therefore, continued monitoring of PPRV circulation and evolution is recommended.

An approach to derive the below-bandgap absorption in GaSb/GaAs self-assembled quantum dot devices using room-temperature external quantum efficiency measurement results is presented. Devices with five layers of delta-doped quantum dots placed in the intrinsic, n- and p-regions of a GaAs solar cell are studied. The importance of incorporating an extended Urbach tail absorption in analyzing the absorption strength of quantum dots and the transition states is demonstrated. The theoretically integrated absorbance via quantum dot ground states is calculated as 1.04 × 1015 cm−1s−1, which is in reasonable agreement with the experimentally derived value 8.1 × 1015 cm−1s−1. The wetting layer and quantum dot absorption contributions are separated from the tail absorption and their transition energies are calculated. Using these transition energies and the GaAs energy gap of 1.42 eV, the heavy hole confinement energies for the quantum dots (320 meV) and for the wetting layer (120 meV) are estimated.

Aims: Shoulder arthroplasty is effective in the management of end-stage glenohumeral joint arthritis. However, it is major surgery and patients must balance multiple factors when considering the procedure. An understanding of patients’ decision-making processes may facilitate greater support of those considering shoulder arthroplasty and inform the outcomes of future research. Methods: Participants were recruited from waiting lists of three consultant upper limb surgeons across two NHS hospitals. Semi-structured interviews were conducted with 12 participants who were awaiting elective shoulder arthroplasty. Transcribed interviews were analyzed using a grounded theory approach. Systematic coding was performed; initial codes were categorized and further developed into summary narratives through a process of discussion and refinement. Data collection and analyses continued until thematic saturation was reached. Results: Two overall categories emerged: the motivations to consider surgery, and the information participants used to inform their decision-making. Motivations were, broadly, the relief of pain and the opportunity to get on with life and regain independence. When participants’ symptoms and restrictions prevented them enjoying life to a sufficient extent, this provided the motivation to proceed with surgery. Younger participants tended to focus on maintaining employment and recreational activities, and older patients were eager to make the most of their remaining lifetime. Participants gathered information from a range of sources and were keen to optimize their recovery where possible. An important factor for participants was whether they trusted their surgeon and were prepared to delegate responsibility for elements of their care. Conclusion: Relief of pain and the opportunity to get on with life were the primary reasons to undergo shoulder arthroplasty. Participants highlighted the importance of the patient-surgeon relationship and the need for accurate information in an accessible format which is relevant to people of different ages and functional demands. Cite this article: Bone Jt Open 2024;5(7):543–549.

Abstract Herbivorous insects alter biogeochemical cycling within forests, but the magnitude of these impacts, their global variation, and drivers of this variation remain poorly understood. To address this knowledge gap and help improve biogeochemical models, we established a global network of 74 plots within 40 mature, undisturbed broadleaved forests. We analyzed freshly senesced and green leaves for carbon, nitrogen, phosphorus and silica concentrations, foliar production and herbivory, and stand-level nutrient fluxes. We show more nutrient release by insect herbivores at non-outbreak levels in tropical forests than temperate and boreal forests, that these fluxes increase strongly with mean annual temperature, and that they exceed atmospheric deposition inputs in some localities. Thus, background levels of insect herbivory are sufficiently large to both alter ecosystem element cycling and influence terrestrial carbon cycling. Further, climate can affect interactions between natural populations of plants and herbivores with important consequences for global biogeochemical cycles across broadleaved forests.

Abstract Thermophilization is the directional change in species community composition towards greater relative abundances of species associated with warmer environments. This process is well-documented in temperate and Neotropical plant communities, but it is uncertain whether this phenomenon occurs elsewhere in the tropics. Here we extend the search for thermophilization to equatorial Africa, where lower tree diversity compared to other tropical forest regions and different biogeographic history could affect community responses to climate change. Using re-census data from 17 forest plots in three mountain regions of Africa, we find a consistent pattern of thermophilization in tree communities. Mean rates of thermophilization were +0.0086 °C·y−1 in the Kigezi Highlands (Uganda), +0.0032 °C·y−1 in the Virunga Mountains (Rwanda-Uganda-Democratic Republic of the Congo) and +0.0023 °C·y−1 in the Udzungwa Mountains (Tanzania). Distinct from other forests, both recruitment and mortality were important drivers of thermophilzation in the African plots. The forests studied currently act as a carbon sink, but the consequences of further thermophilization are unclear.

Abstract Various histopathological, clinical and imaging parameters have been evaluated to identify a subset of women diagnosed with lesions with uncertain malignant potential (B3 or BIRADS 3/4A lesions) who could safely be observed rather than being treated with surgical excision, with little impact on clinical practice. The primary reason for surgery is to rule out an upgrade to either ductal carcinoma in situ or invasive breast cancer, which occurs in up to 30% of patients. We hypothesised that the stromal immune microenvironment could indicate the presence of carcinoma associated with a ductal B3 lesion and that this could be detected in biopsies by counting lymphocytes as a predictive biomarker for upgrade. A higher number of lymphocytes in the surrounding specialised stroma was observed in upgraded ductal and papillary B3 lesions than non-upgraded (p

Abstract Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.

Abstract The Structural Genomics Consortium is an international open science research organization with a focus on accelerating early-stage drug discovery, namely hit discovery and optimization. We, as many others, believe that artificial intelligence (AI) is poised to be a main accelerator in the field. The question is then how to best benefit from recent advances in AI and how to generate, format and disseminate data to enable future breakthroughs in AI-guided drug discovery. We present here the recommendations of a working group composed of experts from both the public and private sectors. Robust data management requires precise ontologies and standardized vocabulary while a centralized database architecture across laboratories facilitates data integration into high-value datasets. Lab automation and opening electronic lab notebooks to data mining push the boundaries of data sharing and data modeling. Important considerations for building robust machine-learning models include transparent and reproducible data processing, choosing the most relevant data representation, defining the right training and test sets, and estimating prediction uncertainty. Beyond data-sharing, cloud-based computing can be harnessed to build and disseminate machine-learning models. Important vectors of acceleration for hit and chemical probe discovery will be (1) the real-time integration of experimental data generation and modeling workflows within design-make-test-analyze (DMTA) cycles openly, and at scale and (2) the adoption of a mindset where data scientists and experimentalists work as a unified team, and where data science is incorporated into the experimental design.

Abstract Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar observations in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not others, on glycated haemoglobin (HbA1c). To explore potential effects, we used MR methods to assess effects of accelerometer-derived sleep traits (duration, mid-point least active 5-h, mid-point most active 10-h, sleep fragmentation, and efficiency) on HbA1c/glucose in European adults from the UK Biobank (UKB) (n = 73,797) and the MAGIC consortium (n = 146,806). Cross-trait linkage disequilibrium score regression was applied to determine genetic correlations across accelerometer-derived, self-reported sleep traits, and HbA1c/glucose. We found no causal effect of any accelerometer-derived sleep trait on HbA1c or glucose. Similar MR results for self-reported sleep traits in the UKB sub-sample with accelerometer-derived measures suggested our results were not explained by selection bias. Phenotypic and genetic correlation analyses suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different types of exposure. These findings suggested accelerometer-derived sleep traits do not affect HbA1c. Accelerometer-derived measures of sleep duration and quality might not simply be ‘objective’ measures of self-reported sleep duration and insomnia, but rather captured different sleep characteristics.

Abstract Background Dirofilaria immitis, commonly known as heartworm (HW), is a parasitic nematode transmitted by various mosquito species, leading to heartworm disease (HWD) in dogs. Diagnosis of HW typically involves antigen or microfilariae detection, or visualization of adult worms through imaging or post mortem examination. Polymerase chain reaction (PCR) and micro RNA (miRNA) detection have been explored for HW diagnosis. Methods Three dogs, previously experimentally infected with HW, underwent blood sampling every 4 weeks for 7 months. Samples were assessed for antigen presence after heat treatment, PCR amplification, and microfilaria examination using Giemsa-stained thick smears. Additionally, whole blood aliquots underwent miRNA deep sequencing and bioinformatic analysis. Results Heartworm antigen was detectable after heat treatment at 20 weeks post-inoculation and via PCR at 24 weeks, with microfilariae observed in peripheral blood smears at 28 weeks. However, deep miRNA sequencing revealed that the miRNA candidate sequences are not consistently expressed before 28 weeks of infection. Conclusions While ancillary molecular methods such as PCR and miRNA sequencing may be less effective than antigen detection for detecting immature larval stages in an early stage of infection, our experimental findings demonstrate that circulating miRNAs can still be detected in 28 weeks post-infection. Graphical Abstract

Extracellular enzymes play a key role in mediating organic matter decomposition in soils and the mobility of enzymes is largely controlled by their interaction with soil surfaces. The introduction of pyrogenic products, including biochar produced for the purpose of carbon sequestration or soil health management, may alter the ecological functioning of soil. In this work, we studied the adsorption of four representative soil extracellular enzymes (urease, invertase, α-amylase and protease) to biochar (derived from wood biomass and wheat straw produced at different pyrolysis temperatures, and a wildfire pine char) and soil mixed with biochar. A pH-edge adsorption experiment showed that, for all biochar/enzyme combinations, adsorption of all extracellular enzymes decreased as pH increased from 4 to 9. This pH dependency suggests that electrostatic interaction was the primary adsorption mechanism. Equilibrium enzyme adsorption data was best fit by the Langmuir isotherm and adsorption capacity varied significantly with enzyme type, ranging from 67 to 232 mg·g−1 for urease and 0 to 11 mg·g−1 for the others at pH 5.0. Enzyme adsorption also differed among biochars with or without surface oxidation treatment. Correlations between enzyme adsorption data and biochar properties demonstrated the relevance of enzyme sizes, biochar surface porous structure, and surface chemical functionality in determining biochar adsorption capacity and affinity for enzymes. Soil adsorption experiment showed that biochar addition can enhance or reduce soil adsorption of enzymes, depending on the relative enzyme affinity between the soil and biochar. These findings indicate that pyrogenic organic matter has varying impacts on the mobility of soil extracellular enzymes through direct adsorption and potentially affect the activity and stability of enzymes, and ultimately soil carbon and nutrient cycling.

IntroductionThe translational gap from the discovery of evidence-based solutions to their implementation in healthcare delivery organizations derives from an incorrect assumption that the need for change among executive, administrative, or clinical personnel is the same as the demand for change. For sickle cell disease (SCD), implementation of evidence-based guidelines is often delayed or obstructed due to lack of demand. This challenge allows for the persistence of resource limitations and care delivery models that do not meet the community's unique needs. Agile Storytelling is a process built on the scientific foundations of behavioral economics, complexity science, and network science to create local demand for the implementation of evidence-based solutions.MethodsAgile Storytelling includes a design phase and a testing phase. The design phase converts the evidence-based solution into a minimally viable story of a hero, a villain, struggle, drama, and a resolution. The testing phase evaluates the effectiveness of the story via a series of storytelling sprints in the target local healthcare delivery organization. The efficacy of Agile Storytelling was tested in an iterative n-of-1 case study design.ResultsAgile Storytelling was used in a large, urban, healthcare system within the United States to facilitate implementation of national SCD best-practice guidelines. After repeated failures attempting to use national and local data regarding the high societal need to hire a SCD-specific social worker, an Agile change conductor using Agile Storytelling was able to create demand for the new position within a week. This decision has ultimately improved patient outcomes and led to the adoption of a specialized collaborative care team for SCD within the health network.DiscussionAgile Storytelling can lead to structured, effective, and informed storytelling to create local demand within healthcare delivery organizations.

ABSTRACT Lianas (woody vines and climbing monocots) are increasing in abundance in many tropical forests with uncertain consequences for forest functioning and recovery following disturbances. At a global scale, these increases are likely driven by disturbances and climate change. Yet, our understanding of the environmental variables that drive liana prevalence at regional scales is incomplete and geographically biased towards Latin America. To address this gap, we present a comprehensive study evaluating the combined effects of climate, soil, disturbance and topography on liana prevalence in the Australian Wet Tropics. We established 31 20 × 20 m vegetation plots along an elevation gradient in low disturbance (canopy closure ≥ 75%) and high disturbance (canopy closure ≤ 25%) forest stands. In these plots, all tree and liana (defined as all woody dicot vines and climbing monocots, i.e., rattans) stems ≥ 1 cm DBH were measured and environmental data were collected on climate, soil and topography. Generalised linear models were used with multi‐model averaging to quantify the relative effects of the environmental variables on measures of liana prevalence (liana–tree basal area ratio, woody vine basal area and stem density and rattan stem density). Liana prevalence decreased with elevation but increased with disturbance and mean annual precipitation. The increase in the liana–tree ratio with precipitation was more pronounced for highly disturbed sites. Like other tropical regions, disturbance is an important driver of liana prevalence in Australian rainforests and appears to interact with climate to increase liana–tree ratios. The observed increase in liana–tree ratio with precipitation contrasts findings from elsewhere but is confounded by correlated changes in elevation and temperature, which highlights the importance of regional studies. Our findings show that forests with high disturbance and climatic conditions favourable to lianas are where lianas most likely to outcompete trees and impede forest recovery.

ABSTRACT Brook Trout (Salvelinus fontinalis) populations have experienced marked declines throughout their native range and are presently threatened due to isolation in small habitat fragments, land use changes, and climate change. The existence of numerous, spatially distinct populations poses substantial challenges for monitoring population status (e.g., abundance, recruitment, or occupancy). Genetic monitoring with estimates of effective number of breeders (Nb) provides a potentially powerful metric to complement existing population monitoring, assessment, and prioritization. We estimated Nb for 71 Brook Trout habitat units in mid‐Atlantic region of the United States and obtained a mean Nb of 73.2 (range 6.90–493). Our modeling approach tested whether Nb estimates were sensitive to differences in habitat size, presence of non‐native salmonids, base flow index, temperature, acidic precipitation, and indices of anthropogenic disturbance. We found significant support for three of our hypotheses including the positive influences of available habitat and base flow index and negative effect of temperature. Our results are consistent with presently observed and predicted future impacts of climate change on populations of this cold‐water fish. Importantly, these findings support the use of Nb in population assessments as an index of relative population status.

Abstract Objective Current studies have indicated that diabetes mellitus (DM) is highly prevalent in patients with cancer, but there is little research on consequences on the well‐being of patients during cancer treatment. This analysis evaluates the relationship between DM and patient‐reported outcomes (PRO) in patients with cancer, using a large and well‐characterized cohort. Methods This study utilized the Total Cancer Care protocol at the University of Utah Huntsman Cancer Institute. For this analysis, we integrated data from electronic health records, the Huntsman Cancer Registry, and routinely collected PRO questionnaires. We assessed the association between DM in patients with cancer and PRO scores for anxiety, depression, fatigue, pain interference, and physical function using multiple linear regression and t‐tests. Results The final cohort comprised 3512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n = 1724) were female, with 82.0% (n = 2879) patients reporting PROs at least at one time point. Compared with patients who responded, nonresponders were more often female (p = 0.0035), less frequently non‐Hispanic White (p = 0.0058), and had a higher BMI (p = 0.0759). Patients with cancer and diabetes had worse PRO scores for anxiety (p = 0.0003), depression (p

Abstract In this study, we show that non‐thermal collisions can play a significant role in shaping Europa's exospheric structure. Collisions between radiolytically produced O2 and the O produced via electron impact dissociation of O2 affect the exospheric structure and escape rates. Specifically, O + O2 collisions lead to the production of a non‐thermal O2 population, and increase the O2 escape while decreasing the O escape. These collisions are dependent on three specific physical parameters: (a) the density of O2, (b) the electron impact dissociation rate of O2, and (c) the O + O2 collision cross section. We demonstrate here that O + O2 collisions affect Europa's atmosphere even in the lowest limits considered. Thus, to more accurately determine the influence O + O2 collisions have on Europa's atmosphere in preparation for the forthcoming spacecraft missions, Europa Clipper and the JUpiter ICy moons Explorer (JUICE), these physical parameters need to be better constrained.

Cochlear ribbon synapses between sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) are vulnerable to rapid and primary damage and/or loss due to noise overexposure. Such damaged ribbon synapses can repair spontaneously in mouse and guinea pig. However, the mechanisms for synaptic repair are unclear. Previously, we have demonstrated a critical role for the fractalkine signaling axis (CX3CL1-CX3CR1) in synaptic repair, wherein noise-damaged ribbon synapses are spontaneously repaired in the presence of fractalkine receptor (CX3CR1) expressed by cochlear macrophages. Here, we examined whether local administration of chemokine fractalkine ligand (CX3CL1 or FKN) in the form of a peptide is effective in restoring synapses and hearing loss after noise-induced cochlear synaptopathy (NICS). Specifically, the efficacy of different isoforms of FKN was evaluated for restoration of loss of IHC ribbon synapses and hearing after NICS. A single transtympanic injection of soluble isoform of FKN (sFKN) peptide at 1 day after synaptopathic noise trauma for 2 hours at 93 decibel sound pressure level led to significant recovery of auditory brainstem response (ABR) thresholds, ABR peak I amplitudes and ribbon synapses in FKN knockout mice when compared to mice injected with membrane-bound FKN peptide (mFKN). Likewise, local treatment with sFKN peptide in FKN wild type mice restored synaptopathic noise-damaged ribbon synapses and ABR peak I amplitudes. Mechanistically, FKN regulates macrophage numbers in the damaged cochlea and in the absence of macrophages, sFKN failed to restore loss of synapses and hearing after NICS. Furthermore, sFKN treatment attenuated cochlear inflammation after NICS without altering the expression of CX3CR1. Finally, injected sFKN peptide was detectable inside the cochlea for 24 h localized to the basilar membrane and spiral lamina near the sensory epithelium. These data provide a proof-of-principle that local delivery of an immune factor, sFKN is effective in restoring ribbon synapses and hearing loss after NICS in a macrophage-dependent manner and highlights the potential of sFKN as an immunotherapy for cochlear synaptopathy due to noise.

Hydrothermal liquefaction (HTL) has remarkable potential for efficient conversion of abundant, decentralized organic wastes into renewable fuels. Because waste is a highly distributed resource with context-dependent economic viability, selection of optimal deployment sites is slowed by the need to develop detailed techno-economic analyses (TEA) for the thousands of potential deployment locations, each with their own unique combinates of scale, proximity to infrastructure/markets, and feedstock properties. An economic modeling framework that requires only easily obtainable inputs for assessing economic performance would therefore allow multiplexed analysis of many thousands of cases, whereas traditional TEA would not be possible for more than a handful of cases. Within such a context, the present study uses machine learning to guide development of a TEA and modeling framework which provides accurate cost predictions using three key inputs – feedstock cost, biocrude yield, and process scale – to estimate the minimum fuel selling price (MFSP) that an HTL process can achieve. The structure of the proposed framework is informed and based on empirical observations of cost projections made by a detailed TEA over a wide range of feedstock costs, biocrude yields, and process scales. A machine learning guided process was used to identify, train, and test a series of models using auto-generated data for training and independently reported data for testing. The most accurate model consists of three terms and requires 6 adjustable parameters to predict independently published values of MFSP (N = 28) to within an average value of ± 20.4%. It is demonstrated that the reduced-order model’s predictions fall within 40% of the corresponding published values 95% of the time, and in the worst case, the associated discrepancy is 45.9%, suggesting that the accuracy of the machine learned model is indeed comparable to the TEAs that were used to build it. Moreover, the terms in the model are physically interpretable, conferring greater reliability to the use of its predictions. The model can be used to predict the dependence of MSFP on biocrude yield, scale, and feedstock cost; interestingly, MFSP is insensitive to biocrude yield and/or scale under many situations of interest and identifying the critical value for a given application is crucial to optimizing economic performance. The proposed model can be also extended to evaluate economic performance of newly developed HTL-based processes, including catalytic HTL, and the methodological framework used in this study is deemed appropriate for the development of machine learned TEA models in cases of other similar waste-to-energy technologies.

Background Heart failure (HF) presents a massive burden to health care with a complex pathophysiology that results in HF with reduced left ventricle ejection fraction (EF) or HF with preserved EF. It has been shown that relatively modest changes in protein glycosylation, an essential posttranslational modification, are associated with clinical presentations of HF. We and others previously showed that such aberrant protein glycosylation in animal models can lead to HF. Methods and Results We develop and characterize a novel, tamoxifen‐inducible, cardiomyocyte Mgat1 knockout mouse strain, achieved through deletion of Mgat1, alpha‐1,3‐mannosyl‐glycoproten 2‐beta‐N‐acetlyglucosaminyltransferase, which encodes N‐acetylglucosaminyltransferase I. We investigate the role of hybrid/complex N‐glycosylation in adult HFrEF pathogenesis at the ion channel, cardiomyocyte, tissue, and gross cardiac level. The data demonstrate successful reduction of N‐acetylglucosaminyltransferase I activity and confirm that hybrid/complex N‐glycans modulate gating of cardiomyocyte voltage‐gated calcium channels. A longitudinal study shows that the tamoxifen‐inducible, cardiomyocyte Mgat1 knockout mice present with significantly reduced systolic function by 28 days post induction that progresses into HFrEF by 8 weeks post induction, without significant ventricular dilation or hypertrophy. Further, there was minimal, if any, physiologic or pathophysiologic cardiomyocyte electromechanical remodeling or fibrosis observed before (10–21 days post induction) or after (90–130 days post induction) HFrEF development. Conclusions The tamoxifen‐inducible, cardiomyocyte Mgat1 knockout mouse strain created and characterized here provides a model to describe novel mechanisms and causes responsible for HFrEF onset in the adult, likely occurring primarily through tissue‐level reductions in electromechanical activity in the absence of (or at least before) cardiomyocyte remodeling and fibrosis.

In large areas of the Southern Ocean, iron limits phytoplankton production. Although biologically mediated iron recycling has been studied for the higher trophic-level whales and the lower trophic-level krill, less is known of the numerically abundant seabirds foraging in Antarctic waters. In this study, we estimate the magnitude of iron recycled by two Antarctic breeding seabirds, the Adélie and emperor penguins, across the austral spring and summer in the Prydz Bay region, East Antarctica. Their contribution to iron recycling and associated pathways differs in line with their contrasting life history strategies (summer and winter breeding) and their breeding habitat (land and fast ice). We consider their breeding cycle in relation to their terrestrial activities compared to foraging periods at sea. High iron concentration (~419 mg kg−1) in guano of both penguin species suggests that they are a source of regenerated iron. Breeding emperor penguins supplied an average of 237 μmol iron m−2 day−1 on the fast ice that they breed on that eventually ends in the ocean when the ice melts completely in summer (November–February). During their foraging trips, the adult emperor penguins contribute between 7 × 10−5 and 4 × 10−4 μmol iron m−2 day−1, as their foraging ranges increase over the breeding season. In contrast, breeding Adélie penguins supplied between 254 and 1,243 μmol iron m−2 day−1 whilst at their colony, with a fraction of guano entering the ocean via meltwater flowing into the ocean. The flux decreases to 2 × 10−3 to 6 × 10−2 μmol iron m−2 d−1, whilst they are foraging. Our study finds that penguins redistribute a large flux of iron onto their colonies, which may enter the adjacent water through sea ice melt and facilitated through katabatic winds. Despite their high abundance in Prydz Bay, the contribution of penguins to iron flux during their foraging periods is minor, due to the enormous foraging range being covered. Further research into the bioavailability of iron by marine organisms coupled with parallel measurements of seawater iron concentration and phytoplankton uptake experiments will be invaluable in refining iron budgets in both this region and other hotspots along the Antarctic coast where higher trophic-level animals are abundant.

Summary: Background: Accumulating evidence has highlighted the acute and chronic impact of repetitive subconcussive head impacts (rSHIs) in contact sports. Neurofilament-light (Nf-L), a brain-derived biomarker of neuroaxonal injury, elevates in concert with rSHI. Recently, long-chain ω-3 polyunsaturated fatty acids (LC ω-3 PUFAs) supplementation has been suggested to mitigate brain injury from rSHI as reflected by attenuation of Nf-L concentrations within contact sport athletes. Objective: Using a systematic review with a meta-analysis, we aimed to determine the effect of LC ω-3 PUFA supplementation on Nf-L concentrations in athletes routinely exposed to rSHI. Methods: Electronic databases (PubMed and CINAHL) were searched from inception through January 2024. One-stage meta-analysis of individual participant-level data was used to detect changes in Nf-L concentrations between LC ω-3 PUFA and control/placebo (PL) groups from baseline to midseason (MS) and postseason (PS). Least square means (±SE) for Nf-L change from baseline were compared by treatment group for MS/PS using contrast t tests. Significance was set a priori at adjusted P ≤ 0.05. Results: Of 460 records identified, 3 studies in collegiate American football players (n = 179; LC ω-3 PUFA = 105, PL = 71) were included in the meta-analysis. Compared with PL, the change in Nf-L concentrations was statistically similar at MS [mean difference (MD) = –1.66 ± 0.82 pg·mL–1, adjusted P = 0.09] and significantly lower at PS (MD = –2.23 ± 0.83 pg·mL–1, adjusted P = 0.02) in athletes following LC ω-3 PUFA supplementation. Conclusions: Our findings demonstrate preliminary support for the prophylactic administration of LC ω-3 PUFA in contact sport athletes exposed to rSHI; however, further research is required to determine the effective dosage required.This trial was registered at OSF (DOI: https://doi.org/10.17605/OSF.IO/EY5QW).

IntroductionIdentifying the associations between rural-living or neighborhood disadvantage and neurobiology may clarify rural–urban disparities in older adults with cognitive impairment related to Alzheimer’s disease.MethodsWe examined rural–urban differences and neighborhood disadvantages in brain cortical thickness (CT) measures among 71 rural and 87 urban-dwelling older adults. Analysis of covariance was used to test each FreeSurfer-derived CT measures’ associations with rural–urban living, clinical impairment status, and their interactions. Post-hoc linear regressions were used to test the association between CT measures and neighborhood disadvantage index.ResultsRural-dwelling older adults had thinner cortices in temporal and inferior frontal regions compared to urban participants, especially among clinically normal participants, where the thinner temporal cortex further correlated with higher neighborhood disadvantage. Conversely, rural participants had thicker cortices in superior frontal, parietal and occipital regions.DiscussionOur results suggest a complex interplay between community contexts and neurobiology. For memory-related regions, rural-living and neighborhood disadvantage might be negatively associated with subjects’ brain structures.

Atomic Force Microscopy (AFM) has become the gold standard tool for measuring mechanical properties of biological samples including proteins, single cells and tissues. However, investment in this specialized equipment and gaining expertise in its operation are significant obstacles for non-experts looking to adopt this technique. To address this, we have designed an AFM based mechanical measurement system for measuring cell mechanical properties which is combined with a custom inverted fluorescence microscope which can be used for characterizing mechanosensitive responses. This system, through its ease of use and low setup cost, will promote interdisciplinary research leading to new insights into the role of cell mechanics and mechanosensitive responses in physiology and disease.

Abstract The preservation of genetic variation is fundamental in biodiversity conservation, yet its importance for population viability remains contentious. Mixed‐source reintroductions, where individuals are translocated into a single vacant habitat from multiple genetically divergent and often depauperate populations, provide an opportunity to evaluate how genetic variation and hybridization influence individual and relative population fitness. Population genetic theory predicts that individuals with higher genetic variation and hybrids among populations should have higher fitness. We tested these two hypotheses by analyzing individual and population‐scale data for westslope cutthroat trout (Oncorhynchus clarkii lewisi) in four mixed‐source reintroductions. We observed more hybrid and fewer nonhybrid offspring than expected across four independent mixed‐source reintroductions. We also found clear evidence that heterozygosity influenced individual reproductive and relative population fitness. Overall, we found a strong, positive relationship between genetic variation, hybridization, and transplant fitness, emphasizing the importance of genetic variation and population mixing in conservation.

We ask how statehouse lawmakers in the U.S. understand the connection between the energy transition in transportation and state resources for transport infrastructure and services. We administered a national-level survey of state legislators serving on state transportation committees to gauge perceptions of these key policy gatekeepers about the pressing transportation issues in their state, the policies likely to be legislated, and the extent to which likely policies address important issues. The delegation of investment and funding decisions to state governments make state legislatures a critical conduit for U.S. transportation policy, and committee actors can crucially shape early stages of the agenda setting process. As the transportation sector moves increasingly toward low carbon energy sources, transportation revenues—traditionally derived from taxes on gasoline—are eroded. We explore what policies state legislators could or would adopt to ensure that states, cities, and metro regions have the resources for maintaining and renewing aging transportation infrastructure and to connect transportation funding policy with energy and climate concerns. What level of interest do committee members have in pursuing such policies, and how do they weigh transportation decarbonization alongside competing objectives including environmental protection, economic development, and social equity, and against the perceived priorities of other actors in their orbit, including the committee on which they serve, the legislature as a whole, and constituents in their own district? Our survey results document the relative deprioritization of climate change and decarbonization as policy priorities, which stands in contrast to the relative urgency of these issues for federal and local transportation policymakers. Instead, we find legislators prioritize more short-term, practical issues, like needs to maintain infrastructure, tend to safety, and promote economic growth, as well to provide stable funding for these needs. Lawmakers see policy solutions centered on raising revenue, e.g. electric vehicle registration fees, as most viable. Legislators also believe, we find, that more abstract issues like climate change and decarbonization are of greater importance to themselves than to their constituents. This work informs public policy by collecting new and original data about lawmakers’ knowledge of and opinions about available legislative opportunities to facilitate the energy transition in transportation.

IntroductionThe purpose was to examine the prevalence of low energy availability (LEA), explore dietary behaviors in men collegiate gymnasts (n = 14), and investigate the relationships between energy availability (EA), body composition, and plyometric performance.MethodsBody composition was measured using air displacement plethysmography. Lower- and upper-body peak power (PWRpeak) and modified reactive strength index (RSImod) were calculated from countermovement jump (CMJ) and plyometric push-up (PP) assessments. Energy expenditure was tracked over 3 days, while daily energy and macronutrient intake were recorded. EA was calculated and used to categorize athletes into LEA and non-LEA groups. Pearson correlation coefficients were used to examine relationships between EA, body composition, and performance metrics.Results85.7% of athletes (n = 12) exhibited LEA (20.98 ± 5.2 kcals/kg FFM), with non-LEA athletes (n = 2) marginally surpassing the

Asthma affects 25 million people in the United States, and its prevalence is increasing. Access to care and adherence to prescribed asthma-treatment programs remain the principal formidable challenges for asthma management. Telemedicine offers substantial opportunities for improved asthma care of patients across the full range of socioeconomic strata. Ever-improving digital tools for asthma assessment and treatment are key components of telemedicine platforms for asthma management. These include a variety of remote patient-monitoring devices, digital inhaler systems, and mobile-health applications that facilitate ongoing assessment and adherence to treatment protocols. Digital tools for monitoring treatment focus on tracking medication use, inhalation technique, and physiological markers such as peak-flow rate and pulse-oximetry. Telemedicine visits allow for elements of assessment via video, approximating or duplicating many aspects of in-person visits, such as evaluating a patient's general appearance, breathing effort, and cough. Challenges remain in ensuring equitable access to these technologies, especially in rural and low-income areas, and in maintaining patient privacy and data security in digital platforms.

The global loss of coastal habitats is putting communities at risk of erosion and flooding, as well as impacting ecosystem function, cultural values, biodiversity, and other services. Coastal habitat restoration can provide a nature-based solution to the increasing need for climate adaptation on the coast while recovering lost ecosystems. Despite the benefits of using nature-based coastal protection to manage coastal hazards, there are scientific, socio-political and economic barriers to the broad use of this approach. Understanding the details of these barriers from the perspective of multiple stakeholders is essential to identifying solutions to overcome them. Using a workshop with participants that are key partners and stakeholders (from government, engineering consulting firms, and non-governmental organisations) in the management, design, and delivery of a coastal protection solution we aimed to: (1) gain a better understanding of the barriers faced by multiple stakeholders involved in the implementation of nature-based coastal protection; and (2) identify tangible solutions to these barriers to increase or support implementation, help focus attention on areas for future research, and inform pathways forward for the governance of nature-based coastal protection. We defined 19 barriers to nature-based coastal protection, but the primary ones that are experienced during the delivery of a project are a lack of: education and awareness; community support; necessary expertise and technical guidance; and uncertainty around: the risk reduction that can be achieved; planning and regulatory processes; and ownership of the structure. Two barriers that do not persist during the design stages of a project but are overarching as to whether nature-based coastal protection is considered in the first place, are government support and the availability of funding. The importance of these primary barriers changes depending on the method of nature-based coastal protection. We conclude by identifying both immediate actions and long-term solutions for enabling nature-based coastal protection in response to each of the primary barriers.

Abstract. Background:. Despite the recent emphasis on promoting international collaborations within orthopaedic surgery, criteria for determining the strengths of such partnerships has not been established. The purpose of this study was to evaluate orthopaedic experts' perceptions of the most valuable characteristics of international academic partnerships. Methods:. This study was conducted using a modified Delphi methodology. Experts were identified through the Consortium of Orthopaedic Academic Traumatologists (COACT). Responses were collected from February to September 2022. Three rounds of surveys listing possible topics on a 5-point Likert scale were used to develop consensus among a group of experts. Consensus criteria for topic inclusion in the final scale was determined as a rating of “strongly agree” or “agree” by ≥70% of the participants in the third survey. Results:. The Round 1 survey was distributed to 96 invited participants within the COACT network, of which 50 experts (52.1%) completed the first survey. Consensus was reached on 54 topics organized into the following 5 categories: Research, Advocacy/Leadership, Training/Surgical Skills, Education/Knowledge Exchange, and Sustainability and Safety (RATES Criteria). Conclusions:. Determining the most valuable characteristics of successful international academic partnerships can lead to more sustainable, mutually beneficial collaborations. The criteria identified in this study can provide the foundation for developing new partnerships and assessing existing ones.

Mesenchymal stem/stromal cells (MSCs) are an attractive platform for cell therapy due to their safety profile and unique ability to secrete broad arrays of immunomodulatory and regenerative molecules. Yet, MSCs are well known to require preconditioning or priming to boost their therapeutic efficacy. Current priming methods offer limited control over MSC activation, yield transient effects, and often induce the expression of pro-inflammatory effectors that can potentiate immunogenicity. Here, we describe a genetic priming method that can both selectively and sustainably boost MSC potency via the controlled expression of the inflammatory-stimulus-responsive transcription factor interferon response factor 1 (IRF1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFN-γ). This includes the upregulation of anti-inflammatory effector molecules and the potentiation of MSC capacities to suppress T cell activation. However, we show that IRF1-mediated genetic priming is much more persistent than biochemical priming and can circumvent IFN-γ-dependent expression of immunogenic MHC class II molecules. Together, the ability to sustainably activate and selectively tailor MSC priming responses creates the possibility of programming MSC activation more comprehensively for therapeutic applications.

Background: An increase in opioid-related overdoses, notably from potent synthetic opioids like fentanyl, prompted this consideration of characteristics of emergency department (ED) patients with evidence for illicit fentanyl use or exposure, the correlation with intentional opioid misuse, and subsequent ED management. Methods: A retrospective review was performed of patients presenting to an urban academic medical center ED with evidence for illicit fentanyl use, determined by positive urine drug screens (UDS), from 6/2021 through 11/2021. Participant demographics, comorbidities, ED chief complaint and disposition, and evidence of intentional opioid misuse were considered. Secondary outcomes included provision of buprenorphine/naloxone and/or naloxone kits at discharge, ED recidivism, and six-month mortality. Bivariate comparisons and logistic regression models were performed. Results: Among 409 unique patients, most were white and male with a mean age of 39.4. Approximately half presented with opioid-related complaints. Evidence of intentional opioid misuse was identified in 72.6 % of patients. Black patients had 79 % lower odds of intentional opioid misuse compared to white patients. Regarding ED management, 28.8 % were discharged with buprenorphine/naloxone and 14.0 % with a naloxone kit. Black patients had 63 % lower odds of receiving buprenorphine/naloxone compared to white patients after controlling for covariates. Nearly 6 % of the study population died within six months of the initial ED visit. Conclusion: This fentanyl-focused review describes patient characteristics which largely mirror the epidemiology of the current opioid epidemic; however, despite evidence of objective exposure, it also suggests that Black patients may be less likely to use fentanyl intentionally. It also highlights potential disparities related to ED-based opioid misuse patient management.

Abstract Sustainable reductions in African malaria transmission require innovative tools for mosquito control. One proposal involves the use of low-threshold gene drive in Anopheles vector species, where a ‘causal pathway’ would be initiated by (i) the release of a gene drive system in target mosquito vector species, leading to (ii) its transmission to subsequent generations, (iii) its increase in frequency and spread in target mosquito populations, (iv) its simultaneous propagation of a linked genetic trait aimed at reducing vectorial capacity for Plasmodium, and (v) reduced vectorial capacity for parasites in target mosquito populations as the gene drive system reaches fixation in target mosquito populations, causing (vi) decreased malaria incidence and prevalence. Here the scope, objectives, trial design elements, and approaches to monitoring for initial field releases of such gene dive systems are considered, informed by the successful implementation of field trials of biological control agents, as well as other vector control tools, including insecticides, Wolbachia, larvicides, and attractive-toxic sugar bait systems. Specific research questions to be addressed in initial gene drive field trials are identified, and adaptive trial design is explored as a potentially constructive and flexible approach to facilitate testing of the causal pathway. A fundamental question for decision-makers for the first field trials will be whether there should be a selective focus on earlier points of the pathway, such as genetic efficacy via measurement of the increase in frequency and spread of the gene drive system in target populations, or on wider interrogation of the entire pathway including entomological and epidemiological efficacy. How and when epidemiological efficacy will eventually be assessed will be an essential consideration before decisions on any field trial protocols are finalized and implemented, regardless of whether initial field trials focus exclusively on the measurement of genetic efficacy, or on broader aspects of the causal pathway. Statistical and modelling tools are currently under active development and will inform such decisions on initial trial design, locations, and endpoints. Collectively, the considerations here advance the realization of developer ambitions for the first field trials of low-threshold gene drive for malaria vector control within the next 5 years.

Cryptic species present challenges across many subdisciplines of biology. Not all “cryptic” species, however, are truly cryptic; many are simply underexplored morphologically. We examined this idea for the Antistrophus rufus species complex, which previously contained three species thought to be morphologically cryptic. To determine whether the A. rufus complex are truly cryptic species, we assessed species boundaries of members of the A. rufus species complex using morphological, ecological, and DNA barcode data, and tested whether a set of 50 morphological characters could adequately diagnose these species. We revealed that this complex includes five species, and that there are useful phenotypic diagnostic characters for all members of this species complex. This enabled redescription of four species and the description of Antistrophus laurenae Nastasi, sp. nov., which induces externally inconspicuous galls in stems of Silphium integrifolium Michx., a host not associated with other members of the complex. We use these new diagnostic characters to construct a key to the five species of the rufus complex. We conclude that the A. rufus complex was not a true case of cryptic species. Our Bayesian analysis of DNA barcode data suggests possible cospeciation of members of the rufus complex and their Silphium host plants, but further study is necessary to better understand the evolution of host use in the lineage.