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Social media creates the possibility for rapid, viral spread of content, but how many posts actually reach millions? And is misinformation special in how it propagates? We answer these questions by analyzing the virality of and exposure to information on Facebook during the U.S. 2020 presidential election. We examine the diffusion trees of the approximately 1 B posts that were re-shared at least once by U.S.-based adults from July 1, 2020, to February 1, 2021. We differentiate misinformation from non-misinformation posts to show that (1) misinformation diffused more slowly, relying on a small number of active users that spread misinformation via long chains of peer-to-peer diffusion that reached millions; non-misinformation spread primarily through one-to-many affordances (mainly, Pages); (2) the relative importance of peer-to-peer spread for misinformation was likely due to an enforcement gap in content moderation policies designed to target mostly Pages and Groups; and (3) periods of aggressive content moderation proximate to the election coincide with dramatic drops in the spread and reach of misinformation and (to a lesser extent) political content.

Abstract Introduction Translating evidence-based practices into real-world healthcare settings is challenging, particularly in the rapidly evolving field of genomics. A pragmatic two-arm cluster-randomized clinical trial (Hide and Seek Project – HaSP) tested two implementation approaches for improving hereditary cancer referral practices with one key distinction: implementation strategies that were designed 1) explicitly using psychological theory, or 2) using healthcare professional intuition. This mixed-methods process evaluation aimed to provide insights into how and why change occurred by examining contextual determinants, identifying mechanisms of action, and exploring the role of theory. Methods Post-implementation interviews were conducted with Implementation Leads and clinicians from participating HaSP sites. Transcripts were analysed using a mixed inductive and deductive approach, guided by the updated Consolidated Framework for Implementation Research (2.0). Findings were triangulated with other HaSP process evaluation data sources, including HaSP focus group observations, HaSP research team focus groups, MDT observations, and Implementation Lead project logs. Logic models and case studies were developed to articulate causal processes underlying strategy effectiveness and conditions necessary for implementation success. Results Eighteen participants from seven HaSP sites were interviewed. Qualitative analysis identified themes related to Lynch syndrome complexity, pandemic disruptions, operational challenges, information technology constraints, multidisciplinary collaboration, cultural determinants, attitudes towards change, the value of theory, adaptations, and implementation support. Within these themes, a total of 39 contextual determinants were identified, with barriers and facilitators spanning 18 CFIR constructs across five domains. Logic models and case studies highlighted a number of mechanisms of action, producing variable clinical outcomes. Process evaluation findings, interpreted together with HaSP trial outcomes, indicate that theory-based implementation strategies may better support Lynch syndrome detection practices compared to intuition-based strategies. Conclusions The information gained from this process evaluation deepens understanding of the factors influencing the success of hospital-specific implementation strategies within the HaSP framework. Potential pathways for optimising the effectiveness of the overall HaSP implementation approach have been identified. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12618001072202. Registered 27 June 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375348&isReview=true .

Abstract Background Indocyanine green angiography (ICGA) is the gold standard to diagnose, evaluate and follow up choroidal inflammation. It allows clinicians to precisely determine the type and extension of choroidal vasculitis in the two main choroidal structures, the choriocapillaris and the choroidal stroma. The presence of choroidal vasculitis is often overlooked by the physician who often does not include ICGA in the investigation of posterior uveitis. Purpose To describe choroidal vasculitis by analysing its ICGA signs in order to investigate and follow choroiditis and determine the pathophysiological mechanisms of inflammation of choroidal vessels. Methods The tutorial is presenting the normal findings in a non-inflamed choroid and the semiology of diverse choroidal vasculitis conditions, followed by practical illustrations using typical cases. Results The two identified patterns of choroidal vasculitis corresponded on one side to choriocapillaritis appearing as areas of hypofluorescence depicting the involvement and extension of choriocapillaris inflammatory non-perfusion. The vasculitis of the choriocapillaris goes from limited and reversible when distal endcapillary vessels are involved such as in Multiple Evanescent White Dot Syndrome (MEWDS) to more severe involvement in Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE), Multifocal Choroiditis (MFC) or Serpiginous Choroiditis (SC) with more pronounced non-perfusion causing scars if not treated diligently. On the other side, stromal choroidal vasculitis is characterised by leaking hyperfluorescent vessels that appear fuzzy and at the origin of late diffuse choroidal hyperfluorescence. Conclusion Choroidal vasculitis is present in almost all patients with inflammatory choroidal involvement, occlusive in case of choriocapillaritis and leaky in stromal choroiditis causing vessel hyperfluorescence, fuzziness of the choroidal vessels and late diffuse stromal hyperfluorescence on ICGA. Systemic vasculitis entities produce occlusive vasculitis of large choroidal vessels.

Abstract Background Timely and effective pre-hospital management of penetrating neck injuries (PNI) is critical to improve patient outcomes. Pre-hospital interventions in patients with PNI can be especially challenging due to the anatomical injury site coupled with a resource-limited environment. Nationally, in the United Kingdom, no consensus statement or expert agreed guidance exists on how to best manage PNI in the pre-hospital setting. Method We conducted a national modified e-Delphi study with subject matter experts (SMEs) from multiple professional specialities with experience in the management of PNI. Pre-identified SMEs were contacted and consented prior to participation allowing for a remotely conducted Delphi using REDCap and Microsoft Teams. In Round 1, statements drawn from the literature base were distributed to all SMEs. Round 2 comprised a facilitated and structured discussion of the statements and then an online survey provided final ratification in Round 3. Of the participating SMEs consensus was set a priori at 70%. Results Of the 67 pre-identified SMEs, 28 participated, resulting in a response rate of 42%. From the first two rounds, 19 statements were derived with every statement achieving consensus in Round 3. Subsequently, an algorithm for the pre-hospital management of PNI was developed and agreed with SME consensus. Conclusion Curation of national consensus statements from SMEs aims to provide principles and guidance for PNI management in a complicated patient group where pre-hospital evidence is lacking. Multi-professional national consensus on the best approach to manage these injuries alongside a novel PNI management algorithm aims to optimise time critical care and by extension improve patient outcomes.

Abstract Digital health tools are emerging as a promising solution for optimizing Deep Brain Stimulation (DBS) therapy for neurodegenerative diseases such as Parkinson’s Disease (PD), addressing challenges of therapy maintenance, care access, and discrete assessments. Wearable technology and mobile health platforms can offer remote monitoring capabilities, allowing for real-time virtual programming with optimization of patients’ therapy, use of digital biomarkers that can help identify the onset, symptoms, medication-related fluctuations and side-effects, and response to DBS treatment. Through an investigational remote monitoring application (RM app) integrating patient-reported outcomes (PROs) and objective data using wearables, we aimed to develop an accessible, data-driven digital tool to monitor patient symptoms and deliver low-burden and easy-to-access DBS therapy. The platform is designed to be compatible with several consumer-grade wearables and ensures patient data privacy and security. We conducted a feasibility study to test the tool’s effectiveness in a large-scale DBS study, where subjects received a home-monitoring kit consisting of an iPhone and Apple Watch, pre-configured with the RM app to enable remote data collection. Compliance in this paper is defined as adherence to the RM app and Apple watch usage. Analysis of 67 subjects from the study demonstrated an average compliance rate of 63.3% for daily check-ins, 85.5% for monthly surveys and 61.9% for passive data with an average of 55 days of post-implant data. The study highlights the feasibility of frequent monitoring in the early post-implant period that could lead to optimal outcomes for patients. The platform developed can further optimize study execution and be extended to other chronic conditions treated with neuromodulation implants such as depression and pain.

Austenitization is significant for understanding the microstructure and residual stress evolution in additive manufacturing of non-austenitic steels. However, the accurate modeling of austenite transformation of additively manufactured parts is rarely reported. In this work, a new kinetic model is proposed to describe the diffusional austenitization of additively manufactured 17-4 PH martensitic stainless steel. The proposed kinetic model is based on the classic Johnson-Mehl-Avrami-Kolmogorov (JMAK) theory, and incorporates a new austenite grain growth model that accounts for the maximum austenite grain size and the effective driving force for growth. Experimental results obtained through dilatometry show that the proposed kinetic model is able to fit and predict the austenite transformation curves across a wide range of heating rates. This model accurately predicts the saturated austenite fraction by maximum austenite grain size and facilitates the understanding of the effect of heating rate on diffusional austenite transformation behavior. The findings imply that the drag force restricting the maximum austenite grain size originates from the initial martensitic microstructure. The transition from the diffusional austenitization to massive or displacive phase transformation at the heating rate of 100 °C/s is identified for additively manufactured 17-4 PH martensitic stainless steel.

Abstract The provision of social care for people in prison in England has historically been lacking. Seeking to address this, the 2014 Care Act clarified that local authorities are responsible for identifying, assessing and meeting prisoners’ social care needs. Against this background, in 2020 we undertook a survey to explore the emerging services for this group. Eighty-six (57%) local authorities responded. A mixed methods approach was taken. Numerical data were analysed through descriptive statistics with comparisons made to the previous survey. An inductive approach to thematic analysis was used to analyse the free text responses. The findings revealed some improvements since the 2015/16 surveys, including the wider introduction of self-referral systems, the success of peer supporters in identifying people in need of social care and greater multi-disciplinary working. However, other issues remained stubbornly persistent, including a dearth of systematic processes to identify those needing social care on release from prison, a lack of timely information sharing and disputes over the sending and receiving authorities’ responsibilities. There were also particular concerns about the shortage of appropriate accommodation for people leaving prison. Perhaps the most striking finding, however, was how little most authorities knew about this population. Building on discussions in previous papers, we explore three ways in which arrangements could be strengthened for this group: the collection of better data, the wider use of release on temporary licence and the greater employment of technology in planning people’s release.

Abstract Background The COVID-19 pandemic accelerated the adoption of remote care, or telemedicine, in many clinical areas including maternity care. One component of remote care, the use of self-monitoring of blood pressure in pregnancy, could form a key component in post-pandemic care pathways. The BUMP trials evaluated a self-monitoring of blood pressure intervention in addition to usual care, testing whether it improved detection or control of hypertension for pregnant people at risk of hypertension or with hypertension during pregnancy. This paper reports the qualitative evaluation which aimed to understand how the intervention worked, the perspectives of participants in the trials, and, crucially, those who declined to participate. Methods The BUMP trials were conducted between November 2018 and May 2020. Thirty-nine in-depth qualitative interviews were carried out with a diverse sample of pregnant women invited to participate in the BUMP trials across five maternity units in England. Results Self-monitoring of blood pressure in the BUMP trials was reassuring, acceptable, and convenient and sometimes alerted women to raised BP. While empowering, taking a series of self-monitored readings also introduced uncertainty and new responsibility. Some declined to participate due to a range of concerns. In the intervention arm, the performance of the BUMP intervention may have been impacted by women’s selective or delayed reporting of raised readings and repeated testing in pursuit of normal BP readings. In the usual care arm, more women were already self-monitoring their blood pressure than expected. Conclusions The BUMP trials did not find that among pregnant individuals at higher risk of preeclampsia, blood pressure self-monitoring with telemonitoring led to significantly earlier clinic-based detection of hypertension nor improved management of blood pressure. The findings from this study help us understand the role that self-monitoring of blood pressure can play in maternity care pathways. As maternity services consider the balance between face-to-face and remote consultations in the aftermath of the COVID-19 pandemic, these findings contribute to the evidence base needed to identify optimal, effective, and equitable approaches to self-monitoring of blood pressure.

Abstract Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 ligases with diverse sets of substrates.

Abstract Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we perform single-nucleus RNA-seq (snRNA-seq) on left atrial (LA) samples from patients with AF and controls. From more than 175,000 nuclei we find that only cardiomyocytes (CMs) and macrophages (MΦs) have a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was overexpressed in CMs among patients with AF and localized to the intercalated disks. Further, in both knockdown and overexpression experiments we identify a potent role for ATRNL1 in cell stress response, and in the modulation of the cardiac action potential. Finally, we detect an unexpected expression pattern for a leading AF candidate gene, KCNN3. In sum, we uncover a role for ATRNL1 which may serve as potential therapeutic target for this common arrhythmia.

Abstract Background Hypertensive disorders of pregnancy affect around 10% of pregnancies and remain a major cause of maternal and foetal morbidity and mortality. Trials have shown that self-monitoring blood pressure during pregnancy is safe, but self-monitoring alone does not improve blood pressure control or pregnancy outcomes. This study aimed to develop and optimise a multicomponent intervention to support blood pressure monitoring, hypertension management and urine testing within current care pathways. Methods Relevant literature, input from patient and public contributors (PPI) and stakeholder groups, and the researcher’s previous experience were used to develop an initial intervention. Think-aloud interviews and focus groups with women from diverse backgrounds with lived experience of hypertension in pregnancy and healthcare professionals provided feedback on the intervention prototype (n = 29). The MRC Framework for Developing Complex Interventions guided the processes to optimise the intervention’s acceptability and maximise engagement. A detailed tabulation of participants’ views and logic models was produced using the COM-B model of Behaviour Change. Results The prototype intervention was acceptable and viable to both pregnant women with experience of hypertensive pregnancy and healthcare professionals. Emerging themes centred on how the intervention could be optimised within current National Health Service care pathways and the lives of pregnant women to support behaviour change. Key target behaviours to support the intervention included increasing understanding of blood pressure management, engagement with the intervention, monitoring blood pressure and urine and taking appropriate actions based on those readings. This informed the development of recommendations involving clear action timelines for women and evidence-based guidance to support decision-making by healthcare professionals. The findings were used to produce the multi-component My Pregnancy Care intervention, consisting of a smartphone application and an information leaflet to support blood pressure self-monitoring and proteinuria self-testing, self-management of antihypertensive medication and smartphone application use. Conclusions This research provided comprehensive insight into the needs of pregnant women with hypertension and their healthcare teams regarding self-monitoring and management of blood pressure. This supported the development of a tailored multi-component digital intervention that addresses barriers to blood pressure self-management by being user-friendly, persuasive and acceptable. It is hoped that the intervention will support the monitoring and management process, collaboration between healthcare professionals and women, clinical action and improved clinical outcomes.

Abstract Background Prenatal care is a critical component of maternal and child health, providing essential preventive, diagnostic, and therapeutic services to pregnant women. Adequate antenatal care has been linked to reduced maternal and infant mortality and improved birth outcomes. Despite its importance, disparities in antenatal care coverage persist globally, including Sierra Leone, with significant implications for maternal and child health. This study examined the trends and inequalities in antenatal care utilisation in Sierra Leone. Methods We used data from the 2008, 2013, and 2019 Sierra Leone Demographic and Health Surveys. Simple inequality measures (Difference and Ratio) and complex measures (Population Attributable Risk and Population Attributable Fraction) were computed using the World Health Organization’s Health Equity Assessment Toolkit software. Inequality in antenatal care was calculated on six stratefiers: age groups for women, birth order, educational levels, economic status, residential areas, and sub-national province. Results There was a significant increase in adequate antenatal care coverage from 2008 (15.2%) to 2013 (36.5%) but a decrease in 2019 (22.1%). The inequality in age increased over time from a Difference of 2.7 percentage points in 2008 to a Difference of 5.3 percentage points in 2019, indicating age-related inequalities. The Population Attributable Fraction decreased from 2.7% in 2008 to zero in 2013, indicating no further improvement in the national average of adequate antenatal care coverage can be achieved in the absence of age-related inequalities. However, it increased to 7.7% in 2019, indicating that the national average of adequate antenatal care coverage would have increased by 7.7% in the absence of age-related inequalities. The birth order inequality increased from a Difference of − 5.2 percentage points in 2008 to 2.6 percentage points in 2019. The Population Attributable Fraction was zero in 2008 and 3.4% in 2019, showing that the national average of adequate antenatal care coverage would have increased by 3.4% if there was no parity-based inequality. Inequality in economic status decreased from 32.1 percentage points in 2008 (Difference = 32.1) to 2.8 percentage points in 2019 (Difference = 2.8). The Population Attributable Fraction revealed that the national average could have been 164.4% higher in 2008 and 20.8% higher in 2013; however, it was zero in 2019, indicating that no further improvement can be achieved in the national average if there was no inequality related to economic status. Inequality for education decreased from 49.9 percentage points in 2008 (Difference = 49.9) to 11.0 percentage points in 2019 (Difference = 11.0). Inequality decreased from a Difference of 20.8 percentage points in 2008 to a Difference of 1.7 percentage points in 2019 for place of residence inequality, showing a reduction in inequality. Provincial inequality decreased from a Difference of 33.9 percentage points in 2008 to 8.5 percentage points in 2019. Conclusion While there have been notable improvements in antenatal care coverage in Sierra Leone, adequate antenatal care coverage is still below the WHO target of 78% in 2016, and significant inequalities persist. Addressing these inequalities requires a multifaceted approach considering demographic, economic, educational, and geographic indicators considered in this study. Sustained efforts and targeted interventions are critical by the Sierra Leone government to ensure that all women, regardless of their background, have access to essential antenatal care services up to at least eight visits.

Mohan Prasath Mani,1,2 Hemanth Ponnambalath Mohanadas,3 Ahmad Athif Mohd Faudzi,4,5 Ahmad Fauzi Ismail,6 Nick Tucker,7 Shahrol Mohamaddan,8 Manikandan Ayyar,9 Tamilselvam Palanisamy,1 Rajasekar Rathanasamy,10 Saravana Kumar Jaganathan11– 13 1Department of Mechanical Engineering, SNS College of Technology, Coimbatore, TN, India; 2School of Biomedical Engineering and Health Sciences, Faculty of Engineering, Universiti Teknologi Malaysia, Skudai, JB, Malaysia; 3Device Development Group, New Product Research and Development, Abbott Diabetes Care, Alameda, CA, USA; 4School of Electrical Engineering, Faculty of Engineering, UniversitiTeknologi Malaysia, Skudai, JB, Malaysia; 5Centre for Artificial Intelligence and Robotics, Universiti Teknologi Malaysia, Kuala Lumpur, SG, Malaysia; 6Advanced Membrane Technology Research Centre (AMTEC), School of Chemical and Energy Engineering, Universiti Teknologi Malaysia, Skudai, JB, Malaysia; 7School of Engineering and Physical Sciences, College of Health and Sciences, University of Lincoln, Lincoln, LS, UK; 8Innovative Global ProgramCollege of Engineering Shibaura Institute of Technology Tokyo, Tokyo, Japan; 9Department of Chemistry, Centre for Materials Chemistry, Karapagam Acdemy of Higher Education, Coimbatore, TN, India; 10Department of Mechanical Engineering, Kongu Engineering College, Perunduari, TN, India; 11Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; 12School of Engineering & Technology, Duy Tan University, Da Nang, Vietnam; 13Biomaterials and Tissue Engineering, School of Engineering and Physical Sciences, College of Health and Sciences, University of Lincoln, Lincoln, LS, UKCorrespondence: Saravana Kumar Jaganathan, Institute of Research and Development, Duy Tan University, Da Nang, Vietnam, Email jaganathansaravanakumar@dtu.edu.vn; sjaganathan@lincoln.ac.ukPurpose: Wound patches are essential for wound healing, yet developing patches with enhanced mechanical and biological properties remains challenging. This study aimed to enhance the mechanical and biological properties of polyurethane (PU) by incorporating magnesium chloride (MgCl2) into the patch.Methodology: The composite patch was fabricated using the electrospinning technique, producing nanofibers from a mixture of PU and MgCl2 solutions. The electrospun PU/MgCl2 was then evaluated for various physico-chemical characteristics and biological properties to determine its suitability for wound healing applications.Results: Tensile strength testing showed that the mechanical properties of the composite patch (10.98 ± 0.18) were significantly improved compared to pristine PU (6.66 ± 0.44). Field scanning electron microscopy (FESEM) revealed that the electrospun nanofiber patch had a smooth, randomly oriented non-woven structure (PU – 830 ± 145 nm and PU/MgCl2 – 508 ± 151 nm). Fourier infrared spectroscopy (FTIR) confirmed magnesium chloride’s presence in the polyurethane matrix via strong hydrogen bond formation. Blood compatibility studies using coagulation assays, including activated partial thromboplastin time (APTT), prothrombin time (PT), and hemolysis assays, demonstrated improved blood compatibility of the composite patch (APTT – 174 ± 0.5 s, PT – 91 ± 0.8s, and Hemolytic percentage – 1.78%) compared to pristine PU (APTT – 152 ± 1.2s, PT – 73 ± 1.7s, and Hemolytic percentage – 2.55%). Antimicrobial testing showed an enhanced zone of inhibition (Staphylococcus aureus – 21.5 ± 0.5 mm and Escherichia coli – 27.5 ± 2.5 mm) compared to the control, while cell viability assays confirmed the non-cytotoxic nature of the developed patches on fibroblast cells.Conclusion: The study concludes that adding MgCl2 to PU significantly improves the mechanical, biological, and biocompatibility properties of the patch. This composite patch shows potential for future wound healing applications, with further studies needed to validate its efficacy in-vivo.Keywords: wound dressings, polyurethane, MgCl2, biomaterial, nanofibers

We performed nanopore-based metagenomic screening on 885 ticks collected from 6 locations in Mongolia and divided the results into 68 samples: 23 individual samples and 45 pools of 2–12 tick samples each. We detected bacterial and parasitic pathogens Anaplasma ovis, Babesia microti, Coxiella burnetii, Borrelia miyamotoi, Francisella tularensis subsp. holarctica and novicida, Spiroplasma ixodetis, Theileria equi, and Rickettsia spp., including R. raoultii, R. slovaca, and R. canadensis. We identified the viral pathogens Crimean-Congo hemorrhagic fever virus (2.9%), recently described Alongshan virus (ALSV) (2.9%), and Beiji nairovirus (5.8%). We assembled ALSV genomes, and maximum-likelihood analyses revealed clustering with viruses reported in humans and ticks from China. For ALSV, we identified surface glycoprotein markers associated with isolates from Asia viruses hosted by Ixodes persulcatus ticks. We also detected 20 virus species of unknown public health impact, including a near-complete Yanggou tick virus genome. Our findings demonstrate that nanopore sequencing can aid in detecting endemic and emerging tickborne pathogens.

Abstract Biofilms are mucilaginous-organic layers produced by microbial activity including viruses. Growing biofilms form microbial mats which enhance sediment stability by binding particles with extracellular polymeric substances and promoting growth through nutrient cycling and organic matter accumulation. They preferentially develop at the sediment-water interface of both marine and non-marine environments, and upon the growing surfaces of modern tufa and travertine. In this context, however, little is known about the factors, environmental or anthropogenic, which affect viral communities in freshwater spring settings. To explore this issue, geochemical and metagenomic data were subjected to multidimensional analyses (Principal Component Analysis, Classical Multidimensional Scaling, Partial Least Squares analysis and cluster analysis based on beta-diversity), and these show that viral composition is specific and dependent on environment. Indeed, waters precipitating tufa and travertine do vary in their geochemistry with their viruses showing distinct variability between sites. These differences between virus groups allow the formulation of a viral proxy, based on the Caudoviricetes/Megaviricetes ratio established on the most abundant groups of viruses. This ratio may be potentially used in analysing ancient DNA preserved in carbonate formations as an additional source of information on the microbiological community during sedimentation.

ABSTRACT: The primary objective of this cross-sectional observational study was to determine whether bulk tank milk quality, udder health, udder hygiene, and milk production outcomes were associated with facility type on organic dairies. A secondary objective was to identify other management-related risk factors associated with bulk tank milk quality, udder health, udder hygiene, and milk production on organic dairy herds in Vermont. We aimed to enroll 40 farms, to compare herds using the 2 most common systems (freestalls, tiestalls) for housing organic dairy cattle in the state with those using a bedded pack during the nongrazing season (typically November–May). Two general styles of bedded packs were observed: cultivated bedded packs and untilled deep-bedded packs. Due to the limited number of herds using bedded packs to house lactating dairy cattle in Vermont, we combined untilled and cultivated bedded packs to describe udder hygiene, milk quality, and udder health on these loose-housing systems deeply bedded with organic material. The study was completed on 21 farms (5 bedded packs, 6 freestalls, 10 tiestalls) before interruption due to the COVID-19 pandemic. Data captured from DHIA records from the test closest to the date of the farm visit included average SCS, standardized 150-d milk (pounds), percentage of cows with current high SCS (SCS ≥4.0), percentage of cows with newly elevated SCS (previous SCS

We developed a new rule-based, cellular-automaton algorithm for predicting the hazard extent, sediment transport, and topographic change associated with the runout of a landslide. This algorithm, which we call MassWastingRunout (MWR), is coded in Python and implemented as a component for the package Landlab. MWR combines the functionality of simple runout algorithms used in landscape evolution and watershed sediment yield models with the predictive detail typical of runout models used for landslide inundation hazard mapping. An initial digital elevation model (DEM), a regolith depth map, and the location polygon of the landslide source area are the only inputs required to run MWR to model the entire runout process. Runout relies on the principle of mass conservation and a set of topographic rules and empirical formulas that govern erosion and deposition. For the purpose of facilitating rapid calibration to a site, MWR includes a calibration utility that uses an adaptive Bayesian Markov chain Monte Carlo algorithm to automatically calibrate the model to match observed runout extent, deposition, and erosion. Additionally, the calibration utility produces empirical probability density functions of each calibration parameter that can be used to inform probabilistic implementation of MWR. Here we use a series of synthetic terrains to demonstrate basic model response to topographic convergence and slope, test calibrated model performance relative to several observed landslides, and briefly demonstrate how MWR can be used to develop a probabilistic runout hazard map. A calibrated runout model may allow for region-specific and more insightful predictions of landslide impact on landscape morphology and watershed-scale sediment dynamics and should be further investigated in future modeling studies.

Summary: Background: Symptom fluctuations within and between individuals with long COVID are widely reported, but the extent to which severity varies following different types of activity and levels of exertion, and the timing of symptoms and recovery, have not previously been quantified. We aimed to characterise timing, severity, and nature of symptom fluctuations in response to effortful physical, social and cognitive activities, using Ecological Momentary Assessments. Methods: We recorded activity, effort, and severity of 8 core symptoms every 3 h for up to 24 days, in cohorts from both clinic and community settings. Symptom severities were jointly modelled using autoregressive and moving average processes. Findings: Consent was received from 376 participants providing ≥1 week's measurements (273 clinic-based, 103 community-based). Severity of all symptoms was elevated 30 min after all categories of activity. Increased effort was associated with increased symptom severity. Fatigue severity scores increased by 1.8/10 (95% CI: 1.6–1.9) following the highest physical exertions and by 1.5 (1.4–1.7) following cognitive efforts. There was evidence of only mild delayed fatigue 3 h (0.3, 0.2–0.5) or one day later (0.2, 0.0– 0.5). Fatigue severity increased as the day progressed (1.4, 1.0–1.7), and cognitive dysfunction was 0.2 lower at weekends (0.1–0.3). Interpretation: Cognitive, social, self-care and physical activities all triggered increased severity across every symptom, consistent with associated common pathways as potential therapeutic targets. Clear patterns of symptom fluctuations emerged that support more targeted self-management. Funding: National Institute for Health and Care Research.

Abstract Background Articular cartilage degeneration can result from injury, age, or arthritis, causing significant joint pain and disability without surgical intervention. Currently, the only FDA cell-based therapy for articular cartilage injury is Autologous Chondrocyte Implantation (ACI); however, this procedure is costly, time-intensive, and requires multiple treatments. Mesenchymal stromal cells (MSCs) are an attractive alternative autologous therapy due to their availability and ability to robustly differentiate into chondrocytes for transplantation with good safety profiles. However, treatment outcomes are variable due to donor-to-donor variability as well as intrapopulation heterogeneity and unstandardized MSC manufacturing protocols. Process improvements that reduce cell heterogeneity while increasing donor cell numbers with improved chondrogenic potential during expansion culture are needed to realize the full potential of MSC therapy. Methods In this study, we investigated the potential of MSC metabolic modulation during expansion to enhance their chondrogenic commitment by varying the nutrient composition, including glucose, pyruvate, glutamine, and ascorbic acid in culture media. We tested the effect of metabolic modulation in short-term (one passage) and long-term (up to seven passages). We measured metabolic state, cell size, population doubling time, and senescence and employed novel tools including micro-magnetic resonance relaxometry (µMRR) relaxation time (T2) to characterize the effects of AA on improved MSC expansion and chondrogenic potential. Results Our data show that the addition of 1 mM L-ascorbic acid-2-phosphate (AA) to cultures for one passage during MSC expansion prior to initiation of differentiation improves chondrogenic differentiation. We further demonstrate that AA treatment reduced the proportion of senescent cells and cell heterogeneity also allowing for long-term expansion that led to a > 300-fold increase in yield of MSCs with enhanced chondrogenic potential compared to untreated cells. AA-treated MSCs with improved chondrogenic potential showed a robust shift in metabolic profile to OXPHOS and higher µMRR T2 values, identifying critical quality attributes that could be implemented in MSC manufacturing for articular cartilage repair. Conclusions Our results suggest an improved MSC manufacturing process that can enhance chondrogenic potential by targeting MSC metabolism and integrating process analytic tools during expansion.

Abstract Background Youth (ages 14–24) in Nigeria have disproportionately high rates of new HIV infection. Pre-exposure prophylaxis could substantially reduce new infections among youth but has not been scaled up. This cross-sectional study aimed to assess Pre-exposure prophylaxis awareness, willingness to use, and prior use of Pre-exposure prophylaxis among youth in Nigeria. Methods This is a secondary analysis of cross-sectional data from a quasi-experimental pilot study (clinical trial NCT04070287). The analysis focused on Pre-exposure prophylaxis awareness, willingness to use, and prior use among 324 youth recruited between September 2019 to March 2020. Descriptive statistics were calculated as frequencies and percentages for categorical variables and means and standard deviations for continuous variables. Results Of the 324 participants, the mean age and standard deviation were 21.17 (± 2.20) years. The majority were 20–24 years old (75.9%) and male (57.7%). Only 30.7% used condoms consistently over three months. Regarding Pre-exposure prophylaxis awareness and willingness, 62.6% had never heard of Pre-exposure prophylaxis, and 158 (50.1%) reported willingness to use Pre-exposure prophylaxis. Only 10 (3.2%) reported having used Pre-exposure prophylaxis. Conclusion Nigerian youth have low awareness of and prior use of Pre-exposure prophylaxis. Given the gap between prior use and willingness to use Pre-exposure prophylaxis, our findings suggest missed opportunities to prevent new HIV infections among youth in Nigeria. Efforts to increase awareness and uptake of Pre-exposure prophylaxis among this population should consider youth-led Pre-exposure prophylaxis outreach efforts and effectively communicate the benefits of Pre-exposure prophylaxis to this population. Trial Registration NCT04070287, the Date of registration of the trial is 20-07-2019.

Purpose – Facility management (FM) in healthcare is an organisational function that provides non-medical activities, ensuring operational functionality of critical health infrastructure. FM leaders are under pressure to implement the digital transformation, confronted with a highly complex and challenging operational environment. However, the current scope and understanding of the digital transformation in FM is rather limited, with a strong focus on technology. This perspective is inadequate to realise a digital transformation in healthcare organisations and requires a new framework. To ensure the practical applicability, a clearer depiction on how FM practitioners in the field, currently understand the digital transformation, is necessary. Design/methodology/approach – A sequential exploratory mixed-methods design was chosen with a qualitative data collection and quantitative data analysis phase. A total of 23 semi-structured research interviews with professionals from FM in healthcare in Switzerland were carried out. Topic modeling was used to analyse, identify and cluster topics. Findings – In total, nine distinct digital transformation topics were generated: ‘addressing future organisational and people needs’, ‘end-user-oriented processes’, ‘digitalisation management vs. digital tools’, ‘major organisational change’, ‘information exchange and work culture’, ‘digital systems’, ‘pressure’, ‘company-wide strategy’ and ‘management support and communication involving non-medical support services’. The findings indicate that FM practitioners perceive the digital transformation beyond the purely technological viewpoint, although they lack the know-how and instruments necessary to implement the digital transformation. Originality/value – This study employs an innovative research design, resulting in foundational insights on how FM in healthcare perceives the digital transformation. As such, the study expands the notion on what the digital transformation means for the FM field.

Abstract Background The evolution of extracellular matrix is tightly linked to the evolution of organogenesis in metazoans. Tenascins are extracellular matrix glycoproteins of chordates that participate in integrin-signaling and morphogenetic events. Single tenascins are encoded by invertebrate chordates, and multiple tenascin paralogs are found in vertebrates (designated tenascin-C, tenascin-R, tenascin-W and tenascin-X) yet, overall, the evolution of this family has remained unclear. Results This study examines the genomes of hemichordates, cephalochordates, tunicates, agnathans, cartilaginous fishes, lobe-finned fishes, ray-finned fishes and representative tetrapods to identify predicted tenascin proteins. We comprehensively assess their evolutionary relationships by sequence conservation, molecular phylogeny and examination of conservation of synteny of the encoding genes. The resulting new evolutionary model posits the origin of tenascin in an ancestral chordate, with tenascin-C-like and tenascin-R-like paralogs emerging after a whole genome duplication event in an ancestral vertebrate. Tenascin-X appeared following a second round of whole genome duplication in an ancestral gnathostome, most likely from duplication of the gene encoding the tenascin-R homolog. The fourth gene, encoding tenascin-W (also known as tenascin-N), apparently arose from a local duplication of tenascin-R. Conclusions The diversity of tenascin paralogs observed in agnathans and gnathostomes has evolved through selective retention of novel genes that arose from a combination of whole genome and local duplication events. The evolutionary appearance of specific tenascin paralogs coincides with the appearance of vertebrate-specific cell and tissue types where the paralogs are abundantly expressed, such as the endocranium and facial skeleton (tenascin-C), an expanded central nervous system (tenascin-R), and bone (tenascin-W).

Abstract Image segmentation of the liver is an important step in treatment planning for liver cancer. However, manual segmentation at a large scale is not practical, leading to increasing reliance on deep learning models to automatically segment the liver. This manuscript develops a generalizable deep learning model to segment the liver on T1-weighted MR images. In particular, three distinct deep learning architectures (nnUNet, PocketNet, Swin UNETR) were considered using data gathered from six geographically different institutions. A total of 819 T1-weighted MR images were gathered from both public and internal sources. Our experiments compared each architecture’s testing performance when trained both intra-institutionally and inter-institutionally. Models trained using nnUNet and its PocketNet variant achieved mean Dice-Sorensen similarity coefficients>0.9 on both intra- and inter-institutional test set data. The performance of these models suggests that nnUNet and PocketNet liver segmentation models trained on a large and diverse collection of T1-weighted MR images would on average achieve good intra-institutional segmentation performance.

Abstract Benign prostatic hyperplasia (BPH) is a prevalent age-related condition often characterized by debilitating urinary symptoms. Its etiology is believed to stem from hormonal imbalance, particularly an elevated estradiol-to-testosterone ratio and chronic inflammation. Our previous studies using a mouse steroid hormone imbalance model identified a specific increase in macrophages that migrated and accumulated in the prostate lumen where they differentiated into lipid-laden foam cells in mice implanted with testosterone and estradiol pellets, but not in sham animals. The current study focused on further characterizing the cellular heterogeneity of the prostate in this model as well as identifying the specific transcriptomic signature of the recruited foam cells. Moreover, we aimed to identify epithelia-derived signals that drive macrophage infiltration and luminal translocation. Male C57BL/6J mice were implanted with slow-release testosterone and estradiol pellets (T + E2) or sham surgery was performed and the ventral prostates were harvested two weeks later for scRNA-seq analysis. We identified Ear2 + and Cd72 + macrophages that were elevated in response to steroid hormone imbalance, whereas a Mrc1 + resident macrophage population did not change. In addition, an Spp1 + foam cell cluster was almost exclusively found in T + E2 mice. Further markers of foam cells were also identified, including Gpnmb and Trem2, and GPNMB was confirmed as a novel histological marker with immunohistochemistry. Foam cells were also shown to express known pathological factors Vegf, Tgfb1, Ccl6, Cxcl16 and Mmp12. Intriguingly, a screen for chemokines identified the upregulation of epithelia-derived Cxcl17, a known monocyte attractant, in T + E2 prostates suggesting that it might be responsible for the elevated macrophage number as well as their translocation to the lumen. Our study identified macrophage subsets that responded to steroid hormone imbalance as well as further confirmed a potential pathological role of luminal foam cells in the prostate. These results underscore a potential pathological role of the identified prostate foam cells and suggests CXCL17-mediated macrophage migration as a critical initiating event.

Abstract Wildlife tagging provides critical insights into animal movement ecology, physiology, and behavior amid global ecosystem changes. However, the stress induced by capture, handling, and tagging can impact post-release locomotion and activity and, consequently, the interpretation of study results. Here, we analyze post-tagging effects on 1585 individuals of 42 terrestrial mammal species using collar-collected GPS and accelerometer data. Species-specific displacements and overall dynamic body acceleration, as a proxy for activity, were assessed over 20 days post-release to quantify disturbance intensity, recovery duration, and speed. Differences were evaluated, considering species-specific traits and the human footprint of the study region. Over 70% of the analyzed species exhibited significant behavioral changes following collaring events. Herbivores traveled farther with variable activity reactions, while omnivores and carnivores were initially less active and mobile. Recovery duration proved brief, with alterations diminishing within 4–7 tracking days for most species. Herbivores, particularly males, showed quicker displacement recovery (4 days) but slower activity recovery (7 days). Individuals in high human footprint areas displayed faster recovery, indicating adaptation to human disturbance. Our findings emphasize the necessity of extending tracking periods beyond 1 week and particular caution in remote study areas or herbivore-focused research, specifically in smaller mammals.

Abstract Atomistic simulations are crucial for predicting material properties and understanding phase stability, essential for materials selection and development. However, the high computational cost of density functional theory calculations challenges the design of materials with complex structures and composition. This study introduces new data acquisition strategies using Bayesian-Gaussian optimization that efficiently integrate the geometry of the convex hull to optimize the yield of batch experiments. We developed uncertainty-based acquisition functions to prioritize the computation tasks of configurations of multi-component alloys, enhancing our ability to identify the ground-state line. Our methods were validated across diverse materials systems including Co-Ni alloys, Zr-O compounds, Ni-Al-Cr ternary alloys, and a planar defect system in intermetallic (Ni1−x , Co x )3Al. Compared to traditional genetic algorithms, our strategies reduce training parameters and user interaction, cutting the number of experiments needed to accurately determine the ground-state line by over 30%. These approaches can be expanded to multi-component systems and integrated with cost functions to further optimize experimental designs.

Abstract Although continuum-scale segregation is a well-documented behavior in multi-species materials, detailed site-specific behavior remains largely unexplored. This is partially due to the complexity of analyzing materials at the requisite time and length scales for describing segregation with full atomic accuracy. Here, we better evaluate the segregation behavior of disordered grain boundary (GB) atomic environments through leveraging a set of Strain Functional Descriptors (SFDs) to generate an atomic descriptor (i.e., fingerprint). Using this atomic fingerprint, we resolve key relationships between atomic structure and segregation energy. Machine learning (ML) techniques are utilized in concert with this SFD fingerprint to elucidate complex relationships relating segregation potential to changes in specific features of the local Gaussian density captured by the SFDs. Finally, we identify relationships that indicate both individual and joint structure-property correlations. Linking atomic segregation energy to key structural features demonstrates the value of higher-order descriptors for uncovering complex structure-property relationships at an atomic scale.

Abstract Background Children’s physical inactivity is a persisting international public health concern. While there is a large body of literature examining physical activity interventions for children, the unique physical activity context of low-density communities in rural areas and smaller urban centres remains largely underexplored. With an influx of families migrating to rural communities and small towns, evaluations of health promotion efforts that support physical activity are needed to ensure they are meeting the needs of the growing populations in these settings. The aim of this community-based research was to explore service providers’ and parents’ perspectives on physical activity opportunities available in their community and recommendations toward the development and implementation of efficacious physical activity programming for children in rural communities and smaller urban centres. Methods Three in-person community forums with recreation service providers (n = 37 participants) and 1 online community forum with the parents of school-aged children (n = 9 participants) were hosted. An online survey and Mentimeter activity were conducted prior to the community forums to gather participants’ views on the barriers and facilitators to physical activities and suggestions for activity-promoting programs. The service provider and parent discussions were audio-recorded, transcribed verbatim, and analyzed following a deductive approach guided by Hseih and Shannon’s (2005) procedure for direct content analysis. A code list developed from the responses to the pre-forum survey and Mentimeter activity was used to guide the analysis and category development. Results Seven distinct categories related to the existing physical activity opportunities and recommendations for programs in rural communities and smaller urban centres were identified during the analysis: (1) Recovery from Pandemic-Related Measures, (2) Knowledge and Access to Programs, (3) Availability, (4) Personnel Support, (5) Quality of Programs and Facilities, (6) Expenses and Subsidies, and (7) Inclusivity and Preferences. Conclusion To improve the health and well-being of children who reside in low-density areas, the results of this study highlight service provider and parent recommendations when developing and implementing community-based physical activity programs and interventions in rural and smaller urban settings, including skill development programs, non-competitive activity options, maximizing existing spaces for activities, and financial support.

OBJECTIVES: Quick returns (

Abstract Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy’s side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on “health-span” rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on “dementia worry” strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than “magic bullet”) clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

Abstract While quiescent galaxies have comparable amounts of cool gas in their outer circumgalactic medium (CGM) compared to star-forming galaxies, they have significantly less interstellar gas. However, open questions remain on the processes causing galaxies to stop forming stars and stay quiescent. Theories suggest dynamical interactions with the hot corona prevent cool gas from reaching the galaxy, therefore predicting the inner regions of quiescent galaxy CGMs are devoid of cool gas. However, there is a lack of understanding of the inner regions of CGMs due to the lack of spatial information in quasar-sightline methods. We present integral-field spectroscopy probing 10–20 kpc (2.4–4.8 Re) around a massive quiescent galaxy using a gravitationally lensed star-forming galaxy. We detect absorption from Magnesium (MgII) implying large amounts of cool atomic gas (108.4–109.3 M⊙ with T~104 Kelvin), in comparable amounts to star-forming galaxies. Lens modeling of Hubble imaging also reveals a diffuse asymmetric component of significant mass consistent with the spatial extent of the MgII absorption, and offset from the galaxy light profile. This study demonstrates the power of galaxy-scale gravitational lenses to not only probe the gas around galaxies, but to also independently probe the mass of the CGM due to it’s gravitational effect.

Introduction: Medical and nonmedical ketamine use is increasing in the United States. This will likely lead to an increase in emergency department (ED) visits in individuals experiencing associated side effects. Physicians will need to be able to effectively recognize and manage ketamine-related complications. Case Report: A 31-year-old male with a three-year history of inhalational, intramuscular, and intravenous nonmedical ketamine use presented to the ED twice within a week with symptoms of severe atraumatic back pain, abdominal pain, and dyspepsia. A comprehensive workup, including advanced imaging, was unrevealing for identifiable causes, and the patient was discharged with instructions for primary care follow-up for further evaluation. The patient used information shared on Reddit, an online forum and social network, to identify that the cause of his pain was related to chronic ketamine use. Subsequently, upon discontinuation of ketamine, the pain improved in 24 hours. The patient self-navigated to addiction treatment. Conclusion: Emergency physicians should consider sequelae of chronic ketamine use as a possible cause for gastrointestinal and urologic symptoms in the ED. In addition to thorough examination and assessment for other acute medical problems, patients should be offered education, symptomatic treatment, and linkage to harm reduction and substance use disorder treatment services.

Abstract Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration.

Abstract Immunohistochemistry is a crucial method for detecting specific proteins within tissue samples, yet constrained to one biomarker per tissue section. Multiplexed immunofluorescence, while allowing simultaneous visualization of multiple proteins, faces limitations in the number of simultaneous fluorescent labels due to spectral overlap. Although cyclic immunofluorescence techniques have successfully broadened antibody staining capacities in a single tissue sample, they are plagued by time-consuming and labor-intensive procedures, sample degradation risks, and inability to scale beyond thin sections. In this study, we introduce the use of 3D confocal Fluorescence Lifetime Imaging Microscopy as a high-throughput, multiplexed immunofluorescence platform that can differentiate 11 or more biomarkers in 3D tissue volumes. Leveraging both spectral and lifetime information, this approach allows for practical spatial biology in thin sections that can readily scale to larger volumes of tissue. We believe that this highly multiplexed and versatile biomarker imaging platform will significantly expedite cancer research and enable new translational approaches in the future.

Background Access to language assistance is a patient's right under federal law. Despite this, underuse of language services persists. Objective The aim of this study was to explore the interest in obtaining bilingual certification and to describe perspectives on language services by resident physicians. Methods Between May and August 2021, we conducted a cross-sectional survey of residents at a public, urban hospital serving mostly patients with limited English proficiency (LEP). We assessed resident perspectives on language services, exposure to language-related trainings, non-English language (NEL) skills, and interest in bilingual certification. Results A total of 214 residents of 289 completed the survey (a 74% response rate). Of the 95 residents who used their NEL for patient care, 65 (68%) would be interested in bilingual certification. Sixty-nine (33%), 65 (31%), and 95 (45%) residents disagreed or strongly disagreed with being satisfied with the language services available, convenience, and sufficient equipment, respectively. Furthermore, 28 (13%) disagreed or strongly disagreed that they could achieve bi-directional communication with LEP patients. Conclusions Over a quarter of the residents expressed interest in bilingual certification and were likely to pass the certification exam. Many reported using their own NEL skills without certification and held negative views on services and trainings.

While the exercise-induced responses of circulated biomarkers related to inflammation and brain health are well documented in humans, little is known about the effect of menopausal status on these responses. This study compared the responses of inflammatory cytokines and brain-derived neurotrophic factor (BDNF) to high-intensity exercise between pre- and postmenopausal middle-aged females. Eight premenopausal (44 ± 3 years) and seven postmenopausal (57 ± 2 years) females performed a high-intensity interval training (HIIT) session consisting of 10 × 1 min running intervals (90% maximum heart rate) separated by 1 min passive recovery intervals. Blood samples were collected at baseline (fasted), pre-exercise (postprandial), and at 0, 30, and 90 min post-HIIT and analyzed for interleukin (IL-6) and 10 (IL-10), tumour necrosis factor-alpha (TNF-α), and BDNF. IL-6 significantly increased from pre-exercise to 0 min post-HIIT in postmenopausal (+40%, p = 0.01) and to 30 min post-HIIT in premenopausal females (+60%, p = 0.02). IL-6 remained elevated at 90 min post-HIIT in premenopausal (+104%, p = 0.05) and to a higher degree in postmenopausal females (+385%, p < 0.001). IL-10 showed no response. TNF-α increased from pre- to 0 min post-HIIT (+10%, p = 0.05), then decreased to below pre-exercise at 30 min (−10%, p = 0.02) and 90 min (−5%, p = 0.04) in both groups. BDNF increased immediately post-HIIT in premenopausal (+60%, p < 0.001) but not postmenopausal females. The differences in IL-6 and BDNF responses to HIIT between pre- and postmenopausal females provide evidence of the role of female reproductive hormones in the regulation of these exercise-induced responses.

Abstract Background The black/white heart disease mortality disparity began increasing in the early 1980’s, coincident with the switch from sucrose to high-fructose-corn-syrup/(HFCS) in the US food supply. There has been more fructose in HFCS than generally-recognized-as-safe/GRAS, which has contributed to unprecedented excess-free-fructose/(unpaired-fructose) in foods/beverages. Average- per-capita excess-free-fructose, from HFCS, began exceeding dosages/(5-10 g) that trigger fructose-malabsorption in the early 1980’s. Fructose malabsorption contributes to gut-dysbiosis and gut-in-situ-fructosylation of dietary peptides/incretins/(GLP-1/GIP) which forms atherosclerotic advanced-glycation-end-products. Both dysregulate gut endocrine function and are risk factors for cardiovascular disease/(CVD). Limited research shows that African Americans have higher fructose malabsorption prevalence than others. CVD risk begins early in life. Methods Coronary-Artery-Risk-Development-in-Adults/(CARDIA) study data beginning in 1985–86 with 2186 Black and 2277 White participants, aged 18–30 y, were used to test the hypothesis that HFCS sweetened beverage intake increases CVD risk/incidence, more among Black than White young adults, and at lower intakes; while orange juice-a low excess-free-fructose juice with comparable total sugars and total fructose, but a 1:1 fructose-to-glucose-ratio, i.e., low excess-free-fructose, does not. Cox proportional hazards models were used to calculate hazard ratios. Results HFCS sweetened beverage intake was associated with higher CVD risk (HR = 1.7) than smoking (HR = 1.6). CVD risk was higher at lower HFCS sweetened beverage intake among Black than White participants. Intake, as low as 3 times/wk, was associated with twice the CVD risk vs. less frequent/never, among Black participants only (HR 2.1, 95% CI 1.2–3.7; P = 0.013). Probability of an ordered relationship approached significance. Among Black participants, CVD incidence jumped 62% from 59.8/1000, among ≤ 2-times/wk, to 96.9/1000 among 3–6 times/wk consumers. Among White participants, CVD incidence increased from 37.6/1000, among ≤ 1.5-times/wk, to 41.1/1000, among 2 times/wk–once/d – a 9% increase. Hypertension was highest among Black daily HFCS sweetened beverage consumers. Conclusion The ubiquitous presence of HFCS over-the-past-40 years, at higher fructose-to-glucose ratios than generally-recognized-as-safe, may have contributed to CVD racial disparities, due to higher fructose-malabsorption prevalence among Black individuals, unpaired/excess-free-fructose induced gut dysbiosis and gut fructosylation of dietary peptides/incretins (GLP-1/GIP). These disturbances contribute to atherosclerotic plaque; promote incretin insufficiency/dysregulation/altered satiety/dysglycemia; decrease protective microbiota metabolites; and increase hypertension, CVD morbidity and mortality.

Abstract Background Early childhood educators play a critical role in promoting physical activity and reducing sedentary time in childcare centres. However, early childhood educators receive limited specialised pre- and in-service learning opportunities relating to these behaviours and may lack the capacity to effectively engage children in healthy movement behaviours. This study aimed to examine the efficacy of an e-Learning course on increasing early childhood educators’ physical activity and sedentary behaviour-related capacities. Methods A two-group parallel randomized controlled trial was conducted with early childhood educators in Canada (Mage = 41.78, 97% female). Participants randomized to the intervention group were asked to complete a physical activity and sedentary behaviour e-Learning course within a 4-week period. Participants randomized to the waitlist control condition were assigned to a waitlist to receive the intervention after the testing period. Participants reported on their self-efficacy, knowledge, intentions, and perceived behavioural control relating to physical activity and sedentary behaviours at baseline, post-intervention, and 3 months follow-up. Linear mixed effects models were estimated to determine difference in changes in outcomes from baseline to post-intervention, and follow-up. Results A total of 209 early childhood educators participated in the study (intervention n = 98; control n = 111). The TEACH e-Learning course was found to be efficacious at improving all of the examined outcomes, with standardized effect sizes ranging from d = 0.58 to d = 0.65 for self-efficacy outcomes, d = 0.66 to d = 1.20 for knowledge outcomes, d = 0.50 to d = 0.65 for intention outcomes, and d = 0.33 to d = 0.69 for perceived behavioural control outcomes post-intervention. The intervention effects were sustained at follow-up for all outcomes apart from perceived behavioural control to limit screen time. Additionally, the magnitude of the effect for knowledge outcomes decreased at follow-up, with standardized effect sizes ranging from d = 0.49 to d = 0.67. Conclusions The e-Learning course was highly successful at improving early childhood educators’ capacity pertaining to physical activity and sedentary behaviours. Providing training content through e-Learning may be an efficacious approach to providing continual professional learning opportunities relating to physical activity and sedentary time to early childhood educators on a large scale.

Abstract Background The protein C system regulates blood coagulation, inflammation, and vascular integrity. AB002 is an injectable protein C activating enzyme under investigation to safely prevent and treat thrombosis. In preclinical models, AB002 is antithrombotic, cytoprotective, and anti-inflammatory. Since prophylactic use of heparin is contraindicated during hemodialysis in some end-stage renal disease (ESRD) patients, we propose using AB002 as a short-acting alternative to safely limit blood loss due to clotting in the dialysis circuit. Methods This phase 2, randomized, double-blind, placebo-controlled, single-dose study evaluates the safety and tolerability of AB002 administered into the hemodialysis line of ESRD patients during hemodialysis at one study center in the United States (ClinicalTrials.gov: NCT03963895). In this study, 36 patients were sequentially enrolled into two cohorts and randomized to AB002 or placebo in a 2:1 ratio. In cohort 1, patients received 1.5 µg/kg AB002 (n = 12) or placebo (n = 6); in cohort 2, patients received 3 µg/kg AB002 (n = 12) or placebo (n = 6). Patients underwent five heparin-free hemodialysis sessions over 10 days and were dosed with AB002 or placebo during session four. Results Here we show that AB002 is safe and well-tolerated in ESRD patients, with no treatment-related adverse events. Clinically relevant bleeding did not occur in any patient, and the time to hemostasis at the vascular access sites is not affected by AB002. Conclusions As far as we are aware, this proof-of-concept study is the first clinical trial assessing the therapeutic potential of protein C activation. The results herein support additional investigation of AB002 to safely prevent and treat thrombosis in at-risk populations.

Abstract Background In 2021, more than two-thirds of the world’s children lived in a conflict-affected country. In 2022, 13 million Ukrainians were forced to flee their homes after Russia’s full-scale invasion. Hope Groups are a 12-session psychosocial, mental health, and parenting support intervention designed to strengthen parents, caregivers, and children affected by war and crisis. The primary objective of this study is to evaluate the effectiveness of Hope Groups among Ukrainians affected by war, compared to a wait-list control group. This protocol describes a promising decentralized intervention delivery model and an innovative research design, which estimates the causal effect of Hope Groups while prioritizing prompt delivery of beneficial services to war-affected participants. Methods This protocol describes a pragmatic cluster randomized controlled trial (RCT) among Ukrainians externally displaced, internally displaced within Ukraine, and living at home in war-affected areas. This study consists of 90 clusters with 4–7 participants per cluster, totaling approximately n = 450 participants. Intervention clusters will receive 12-session Hope Groups led by peer facilitators, and control clusters will be wait-listed to receive the intervention after the RCT concludes. Clusters will be matched on the facilitator performing recruitment and intervention delivery. Primary outcomes are caregiver mental health, violence against children, and positive parenting practices. Secondary outcomes include prevention of violence against women and caregiver and child well-being. Outcomes will be based on caregiver report and collected at baseline and endline (1-week post-intervention). Follow-up data will be collected among the intervention group at 6–8 weeks post-intervention, with aims for quasi-experimental follow-ups after 6 and 12 months, pending war circumstances and funding. Analyses will utilize matching techniques, Bayesian interim analyses, and multi-level modeling to estimate the causal effect of Hope Groups in comparison to wait-list controls. Discussion This study is the first known randomized trial of a psychosocial, mental health, and parenting intervention among Ukrainians affected by war. If results demonstrate effectiveness, Hope Groups hold the potential to be adapted and scaled to other populations affected by war and crisis worldwide. Additionally, methodologies described in this protocol could be utilized in crisis-setting research to simultaneously prioritize the estimation of causal effects and prompt delivery of beneficial interventions to crisis-affected populations. Trial registration This trial was registered on Open Science Framework on November 9, 2023. Registration: OSF.IO/UVJ67 .

Disbudding prevents horn growth in calves through thermal or chemical cauterization and causes damage that is painful for weeks following the procedure. Current pain management strategies are only effective from 1 to 2 h (local anesthetic) to 1 to 3 d (nonsteroidal anti-inflammatory drugs). A potential practical solution for addressing longer-term pain may be to administer ethanol as a cornual nerve block. When administered at a high concentration, ethanol damages the functionality of peripheral nerves, promoting localized long-lasting analgesia. It is also thought to be painful, thus ethanol may be combined with lidocaine, as a mixed solution or administered beforehand. We tested the use of an ethanol cornual nerve block for anesthesia around the horn bud in 2 pilot studies. We used different concentrations and amounts of ethanol (100% and 70%) in combination with different ratios of lidocaine in our attempt to identify an effective block. In pilot 1, 14 nondisbudded calves were administered 2 to 4 mL of 100% ethanol below the bony ridge on each side of the head to block the cornual nerve at 3 to 10 d of age (n = 28 horn buds) and observed for 5 wk. The duration of loss of sensation was evaluated using pinprick tests 10 min, 1, 3, and 7 d after the block, and then weekly thereafter until 35 d or full sensation had returned. Pinprick tests consisted of lightly pressing a needle in 10 evenly spaced locations around the base of the horn bud (0 responses = no sensation, 1–5 responses = partial sensation, 6–10 responses = full sensation). Pilot 2 looked at the 24 h after the injection and consisted of 9 nondisbudded calves (5 mL of 2:1, 70% ethanol and 2% lidocaine per horn bud) and 6 disbudded individuals (5 mL of 100% ethanol, 70% ethanol, or 2% lidocaine per horn bud). All treatments were administered at the calf level. Anesthesia was checked 10 min after the injection and 4 or 16 h later. In pilot 1, on the day of the ethanol injection (0 d), there was no sensation in 85% of horn buds. Sensation began to return as early as 1 d after blocking, with only 50%, 21%, and 3% of horn buds having no sensation at 1, 7, and 35 d, respectively. Partial sensation was present in 25%, 17%, and 10% of horn buds at these time points. In pilot 2, 27.8% of horn buds in the nondisbudded group had no sensation, whereas 33.3% had partial sensation 10 min after the injection. In the disbudded calves 10 min after the injection, 100% of horn buds from the 100% ethanol group had partial sensation and 100% of horn buds administered 70% ethanol had full sensation. Four or sixteen hours later, 100% of horn buds had full sensation. Together, in these pilot studies, ethanol provided inconsistent anesthesia when used for a cornual nerve block.

Disbudding damages the germinal horn bud cells and prevents subsequent horn growth in young calves. Hot-iron cautery or caustic paste are the most common disbudding techniques and are unequivocally painful procedures. An important technique in controlling the acute pain experienced during disbudding is the cornual nerve block (CNB) that uses a local anesthetic agent and targets a branch of the trigeminal cranial nerve, the zygomaticotemporal nerve, as it travels along the temporal groove of the skull. Though CNB have been used since 1932, practitioners have reported variability in achieving full desensitization of the horn bud region since its inception. This failure may have led to the establishment of variations in the CNB technique, without consensus on a reliable and repeatable approach. Reasons for CNB failures may include technical errors by the practitioner, such as an injection into subcutaneous or deep muscle bodies; biologically important path variations in the zygomaticotemporal nerve and its cornual branches; and secondary innervation of the horn bud region, particularly the cornual branches of the infratrochlear nerve. Further investigation into documenting and understanding CNB failure and alternatives, such as regional perfusion, is warranted.

Abstract Correct regulation of intercellular communication is a fundamental requirement for cell differentiation. In Arabidopsis thaliana, the female germline differentiates from a single somatic ovule cell that becomes encased in β−1,3-glucan, a water insoluble polysaccharide implicated in limiting pathogen invasion, regulating intercellular trafficking in roots, and promoting pollen development. Whether β−1,3-glucan facilitates germline isolation and development has remained contentious, since limited evidence is available to support a functional role. Here, transcriptional profiling of adjoining germline and somatic cells revealed differences in gene expression related to β−1,3-glucan metabolism and signalling through intercellular channels (plasmodesmata). Dominant expression of a β−1,3-glucanase in the female germline transiently perturbed β−1,3-glucan deposits, allowed intercellular movement of tracer molecules, and led to changes in germline gene expression and histone marks, eventually leading to termination of germline development. Our findings indicate that germline β−1,3-glucan fulfils a functional role in the ovule by insulating the primary germline cell, and thereby determines the success of downstream female gametogenesis.

Abstract Adult vertebrate cartilage is usually quiescent. Some vertebrates possess ocular scleral skeletons composed of cartilage or bone. The morphological characteristics of the spotted wolffish (Anarhichas minor) scleral skeleton have not been described. Here we assessed the scleral skeletons of cultured spotted wolffish, a globally threatened marine species. The healthy spotted wolffish we assessed had scleral skeletons with a low percentage of cells staining for the chondrogenesis marker sex-determining region Y-box (Sox) 9, but harboured a population of intraocular cells that co-express immunoglobulin M (IgM) and Sox9. Scleral skeletons of spotted wolffish with grossly observable eye abnormalities displayed a high degree of perochondrial activation as evidenced by cellular morphology and expression of proliferating cell nuclear antigen (PCNA) and phosphotyrosine. Cells staining for cluster of differentiation (CD) 45 and IgM accumulated around sites of active chondrogenesis, which contained cells that strongly expressed Sox9. The level of scleral chondrogenesis and the numbers of scleral cartilage PCNA positive cells increased with the temperature of the water in which spotted wolffish were cultured. Our results provide new knowledge of differing Sox9 spatial tissue expression patterns during chondrogenesis in normal control and ocular insult paradigms. Our work also provides evidence that spotted wolffish possess an inherent scleral chondrogenesis response that may be sensitive to temperature. This work also advances the fundamental knowledge of teleost ocular skeletal systems.

Purpose: To evaluate the maximal load to failure, cyclic displacement, stiffness, and modes of failure of onlay subpectoral biceps tenodesis with an intramedullary unicortical metal button (MB) versus an inlay, all-suture Caspari-Weber (CW) technique. Methods: Sixteen matched paired human cadaveric proximal humeri were randomly allocated for subpectoral BT with either CW or MB using a high-strength suture (N = 16; 8 male, 8 female, mean age = 82.5 years, range 62-99 years). Specimens were tested on a servohydraulic mechanical testing apparatus under cyclic load for 1,000 cycles and then loaded to failure. Maximal load to failure, displacement, construct stiffness, and mode of failure were compared. Results: There was no significant difference between groups when comparing construct stiffness, creep displacement, or displacement at ultimate load. The maximal load to failure for the CW technique was greater than the unicortical MB (588.36 ± 149.06 N vs 375.83 ± 131.4 N, P = .014). Conclusions: In this study, the all-suture CW biceps tenodesis technique had a greater maximal load to failure than the onlay unicortical MB technique while having similar construct displacement and stiffness. The CW subpectoral biceps tenodesis may offer a lower cost alternative with a mechanically robust fixation when performing an open subpectoral biceps tenodesis. Clinical Relevance: This cadaveric biomechanical study can help guide surgeons when selecting a fixation technique for biceps tenodesis.

Functionally graded materials are an emergent method for designing components with programmable site-specific material properties. These materials are typically fabricated using metal additive manufacturing tools by simultaneously feeding multiple wire and/or powder feedstocks at various rates to achieve spatial composition change. The wire-powder-directed energy deposition (WP-DED) technique is of particular interest for many functionally graded material applications by balancing the low raw materials cost of wire with the high resolution of powder. However, feeding wire and powder are inherently different processes since all extruded wire enters the melt pool, while much of the blown powder is scattered, which makes determining the composition of the build challenging. In this study, we devise a simple area-based measurement method for estimating the composition of WP-DED structures. WP-DED single beads are printed using 309L stainless steel wire and commercially pure Fe powder at five wire feed rates (0.5, 0.75, 1.00, 1.25, 1.50 mm/mm) and five powder feed rates (2, 4, 6, 8, 10 rpm). Characteristic defects including interface gaps and macrosegregation (lack of mixing) tendencies are examined. High powder feed rates (8, 10 rpm) result in interface gaps at all wire feed rates, but smooth deposition and complete mixing is achieved at low powder feed rates, particularly with lower wire feed rates as well. The area-based composition measurement method is within ±20% of energy dispersive x-ray spectroscopy measurements for all samples, showing its effectiveness as a rapid composition estimate for WP-DED materials development.

Objective: We aimed to determine the relationship between socioeconomic and psychological factors and overall cardiovascular health (CVH), as defined by the American Heart Association's Life's Essential 8 (LE8), among young adults in Puerto Rico. Methods: Participants were 2156 young adults, between the ages of 18–29 years, enrolled in the PR-OUTLOOK study. The analysis included survey, laboratory, and physical measurement data collected from September 2020 to November 2023. Assessed socioeconomic indicators included food insecurity, housing instability, economic insecurity, and subjective social standing. Evaluated psychological factors comprised symptoms of depression, anxiety, post-traumatic stress, and overall perceived stress. LE8 scores were calculated and classified as suboptimal (poor/intermediate range) vs. ideal CVH. Logistic regression models estimated associations between each socioeconomic and psychological measure and suboptimal CVH, and dominance analysis assessed the importance of each measure. Results: Participants' mean age was 22.6 (SD = 3.1), 60.9 % were female, about one-third (34.2 %) had high school education or less, and over one-third had public or no health insurance (38.4 %). Participants reporting socioeconomic adversity (i.e., high food insecurity, housing instability and economic insecurity, and low subjective social standing) and elevated psychological symptoms (i.e., symptoms of anxiety, depression, post-traumatic stress, and overall perceived stress) had lower CVH scores. However, in the adjusted analysis, only lower subjective social standing (OR = 1.38, 95 % CI = 1.13–1.69) and elevated symptoms of anxiety (OR = 1.63, 95 % CI = 1.25–2.13) and depression (OR = 1.30, 95 % CI = 1.03–1.65) emerged as the primary contributors to suboptimal CVH (vs. ideal). Conclusion: Efforts to preserve and enhance CVH among young Puerto Ricans on the island should target these factors.

Male infertility has been a primary cause of global infertility, affecting 8–12% of couples worldwide. Previous studies have shown that semen quality decreases with advanced aging with an increased presence of inflammatory cells. In this study, we examined changes in the epigenome across a diverse cohort that includes both fertile and infertile men. We also compare the age-associated changes in semen to those observed in buccal swabs in order to characterize differences in epigenetic aging across diverse tissues. We found that variations in the semen methylome associated with aging are linked to inflammatory genes. Many age-associated sites are demethylated with advanced aging and are associated with the activation of inflammatory pathways. By contrast, we do not observe age-associated changes in inflammatory genes in buccal swab methylomes, which instead are characterized by changes to bivalent promoters. Our findings highlight the potential of epigenetic markers as indicators of male reproductive health.

IntroductionMany designathons, hackathons, and similar participatory events suffer from minimal training and support after the events. Responding to this need, we organized a health innovation bootcamp: an intensive, team-based apprenticeship training with research and entrepreneurial rigor among young people in Nigeria to develop HIV self-testing (HIVST) delivery strategies for Nigerian youth. The purpose of this paper was to describe an innovation bootcamp that aimed to develop HIVST delivery strategies for Nigerian youth.MethodsThe four-week, in-person innovation bootcamp, informed by youth participatory action research and comprised a series of workshops, took place in Lagos, Nigeria. The goal was to build research and entrepreneurial capacities among young people to develop and implement HIVST strategies. A qualitative content analysis informed by an adapted World Health Organization’s HIVST delivery framework explored key elements of the proposed HIVST service delivery strategies developed at the bootcamp.ResultsTwenty participants, aged 18–24 years, from five teams completed the innovation bootcamp. The five teams developed HIV service delivery strategies that included an element of repacking HIVST kits to make them more appealing to young people. Other strategies that emerged included leveraging community engagement platforms (e.g., vocational skills training and youth community events) to promote HIVST, and the use of reward-referral system to encourage HIVST uptake among young people. All strategies included ways to ensure privacy protection for recipients of the HIVST delivery package.ConclusionThis study demonstrated the feasibility and acceptability of the health innovation bootcamp model to create HIVST designed for and led by young people. This suggests a way to build capacity after participatory events to sustain youth-led research, which could have implications for post-designathon training.