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This study explores the participation patterns and demographic characteristics of young citizen scientists engaged in online citizen science through the Zooniverse platform. By analysing log data from 242 participants and survey responses from 64 individuals, the research sheds light on the contributions and behaviours of these young volunteers. Key findings highlight the significant engagement of young participants, each contributing to various projects and demonstrating consistent activity on the platform. Surprisingly, demographic factors like age and gender showed no significant association with participation levels. However, confidence in using the platform positively correlated with increased engagement, emphasising the role of self-efficacy in fostering participation. Additionally, systematic participation was linked to higher project contributions, underscoring the importance of structured engagement. The study highlights the need for targeted strategies to empower young individuals to contribute meaningfully to scientific research while promoting inclusivity and engagement across diverse demographics.

Abstract Background The experiences of GPs in Australia highlight key considerations regarding workload demands, remuneration incentives and the practical implications of working in regions with high ethnic density. This exploration helps to understand the elements that influence GPs delivery of care, particular for refugee women who exhibit disproportionately higher rates of chronic pain. This qualitative study explored the experiences of GPs providing care for refugee women living with chronic pain. Methods Semi-structured interviews were undertaken with 10 GPs (9 female and 1 male) practicing across metropolitan Melbourne, Australia. GPs were recruited via purposive sampling and a snowballing strategy. Participants work experience ranged from one to 32 years. Audio recordings of the interviews were transcribed verbatim and stored in qualitative data Nvivo 12 software for coding. Transcripts of interviews were analysed thematically using a phenomenological approach. Results Three overarching themes were identified: (1) meeting the needs of refugee women living with chronic pain; (2) the role of the GP; and (3) the challenges of the health care system. These themes reflected the complexity of consultations which arose, in part, from factors such as trust, the competencies of clinician’s and the limitations posed by time, funding and interpreter use. Conclusion GPs acknowledged the uniqueness of refugee women’s chronic pain needs and whilst doctors welcomed care, many were often challenged by the complex nature of consultations. Those that worked in settings that aligned with refugee women’s needs highlighted the importance of cultivating culturally safe clinical environments and listening to their patients’ stories. However, system level challenges such as time, funding and resource constraints created significant challenges for GPs. Exploring GPs experiences allows for a better understanding of how vectors of disadvantage intersect in health care and highlights the need to better support doctors to improve health care provision for refugee women living with chronic pain.

Abstract DNA characterisation in people with tuberculosis (TB) is critical for diagnostic and microbiome evaluations. However, extracellular DNA, more frequent in people on chemotherapy, confounds results. We evaluated whether nucleic acid dyes [propidium monoazide (PMA), PEMAX] and DNaseI could reduce this. PCR [16S Mycobacterium tuberculosis complex (Mtb) qPCR, Xpert MTB/RIF] was done on dilution series of untreated and treated (PMA, PEMAX, DNaseI) Mtb. Separately, 16S rRNA gene qPCR and sequencing were done on untreated and treated sputa before (Cohort A: 11 TB-negatives, 9 TB-positives; Cohort B: 19 TB-positives, PEMAX only) and 24-weeks after chemotherapy (Cohort B). PMA and PEMAX reduced PCR-detected Mtb DNA for dilution series and Cohort A sputum versus untreated controls, suggesting non-intact Mtb is present before treatment-start. PEMAX enabled sequencing-based Mycobacterium-detection in 7/12 (58%) TB-positive sputa where no such reads otherwise occurred. In Cohort A, PMA- and PEMAX-treated versus untreated sputa had decreased α- and increased β-diversities. In Cohort B, β-diversity differences between timepoints were only detected with PEMAX. DNaseI had negligible effects. PMA and PEMAX (but not DNaseI) reduced extracellular DNA in PCR and improved pathogen detection by sequencing. PEMAX additionally detected chemotherapy-associated taxonomic changes that would otherwise be missed. Dyes enhance microbiome evaluations especially during chemotherapy.

Abstract The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p

Abstract We introduce a proof-of-concept extended reality (XR) environment for discussing cancer, presenting genomic information from multiple tumour sites in the context of 3D tumour models generated from CT scans. This tool enhances multidisciplinary discussions. Clinicians and cancer researchers explored its use in oncology, sharing perspectives on XR’s potential for use in molecular tumour boards, clinician-patient communication, and education. XR serves as a universal language, fostering collaborative decision-making in oncology.

The purpose of this study was to compare ankle stability and dynamic single-leg balance between jumping athletes and non-athletes, and to examine the correlation between ankle stability and dynamic single-leg balance. Thirty-eight jumping athletes and thirty-seven non-athletes participated in this study. The Cumberland Ankle Instability Tool (CAIT) was used to assess ankle stability. The Y-Balance Test (YBT) was used to examine single-leg balance in the anterior (AN), posteromedial (PM), and posterolateral (PL) directions. The results show that 42.11% of jumping athletes and 21.62% of non-athletes exhibited chronic ankle instability (CAI) in their examined leg. In addition, jumping athletes exhibited significantly worse ankle stability than non-athletes (p = 0.038). The two groups showed no significant difference in the YBT scores in all directions (p = 0.113 AN, 0.567 PM, 0.542 PL). Very low correlations were found between the CAIT and the YBT scores in all directions (r < 0.107). In conclusion, single-leg jumping athletes experienced a higher prevalence of CAI and significantly worse ankle stability than non-athletes. However, the results of the YBT did not correlate strongly with the CAIT scores, suggesting an inability to predict dynamic single-leg balance deficits based on perceived ankle stability alone in this population.

Abstract Mollusca is a morphologically diverse phylum, exhibiting an immense variety of calcium carbonate structures. Proteomic studies of adult shells often report high levels of rapidly-evolving, ‘novel’ shell matrix proteins (SMPs), which are hypothesized to drive shell diversification. However, relatively little is known about the phylogenetic distribution of SMPs, or about the function of individual SMPs in shell construction. To understand how SMPs contribute to shell diversification a thorough characterization of SMPs is required. Here, we build tools and a foundational understanding of SMPs in the marine gastropod species Crepidula fornicata and Crepidula atrasolea because they are genetically-enabled mollusc model organisms. First, we established a staging system of shell development in C. atrasolea for the first time. Next, we leveraged previous findings in C. fornicata combined with phylogenomic analyses of 95 metazoan species to determine the evolutionary lineage of its adult SMP repertoire. We found that 55% of C. fornicata’s SMPs belong to molluscan orthogroups, with 27% restricted to Gastropoda, and only 5% restricted at the species level. The low percentage of species-restricted SMPs underscores the importance of broad-taxon sampling and orthology inference approaches when determining homology of SMPs. From our transcriptome analysis, we found that the majority of C. fornicata SMPs that were found conserved in C. atrasolea were expressed in both larval and adult stages. We then selected a subset of SMPs of varying evolutionary ages for spatial-temporal analysis using in situ hybridization chain reaction (HCR) during larval shell development in C. atrasolea. Out of the 18 SMPs analyzed, 12 were detected in the larval shell field. These results suggest overlapping larval vs. adult SMP repertoires. Using multiplexed HCR, we observed five SMP expression patterns and three distinct cell populations within the shell field. These patterns support the idea that modular expression of SMPs could facilitate divergence of shell morphological characteristics. Collectively, these data establish an evolutionary and developmental framework in Crepidula that enables future comparisons of molluscan biomineralization to reveal mechanisms of shell diversification.

Background: The effect of some methods of time-restricted eating (TRE) on obesity has been investigated before, however its short term effect on obesity indices and physiological responses to exercise is not clear yet. This study aimed to evaluate the effect of TRE on anthropometric indices, as well as, resting and post-exercise responses of cortisol and erythrocyte sedimentation rate (ESR). Methods: Sixteen healthy men aged 17-29 years with body mass index (BMI) of 17.2-33.5 kg/m2 were voluntarily enrolled in this study. TRE was followed for two weeks; during this period of time, no food was consumed from 8 am to 4 pm, although water intake was allowed. Body weight, height, and waist were measured before and after TRE. Blood samples were provided before and after TRE following 10-11 hours of fasting, and after eating breakfast together with YoYo exercise test on the same day. Results: BMI and waist-to-height ratio (WHtR) decreased following two weeks of TRE. Also, a significant reduction in resting cortisol and an increase in resting ESR were noticed. After TRE, acute exercise and intake of breakfast, an increase in erythrocyte sedimentation rate (ESR) and reduction in cortisol were observed. Conclusion: Although two weeks TRE improved anthropometric indicators and resting cortisol as an anti-inflammatory response, ESR increased at rest and in response to acute exercise and intake of breakfast.

Abstract Background Although natural rubber latex remains dominant as the primary manufacturing material for male condoms synthetic materials first introduced in the early 1990s address many of the limitations of latex including the risk of allergies. Polyurethane elastomers allow condoms to be made significantly thinner to provide greater sensitivity and encourage greater use of condoms for contraception and STI prophylaxis. The primary objective of this Study was to evaluate the breakage, slippage and acceptability of two ultra-thin polyurethane condoms against a thin control latex male condom, designated latex C, in a randomized, cross over, masked, non-inferiority study. The condom designated Polyurethane A was designed for markets where 52/53 mm wide latex condoms are preferred whereas the condom designated Polyurethane B was designed for markets where the smaller 49 mm wide latex condom is preferred. Methods The Study was designed to meet the requirements specified in ISO 29943–1: 2017 and FDA guidelines for clinical studies on synthetic condoms. It was conducted by two Essential Access Health centres, one in Northern California and the other in Southern California. Sexually active heterosexual couples (300) aged between 18 and 45 years were recruited to use three sets of five condoms in a block randomized order, recording breakage, slippage and acceptability after each use. A total of 252 couples contributed 2405 evaluable condom uses per protocol for the Condom A versus Latex C comparison (1193 Polyurethane A plus 1212 Latex C), and 247 couples provided 2335 evaluable condom uses per protocol for the Condom B versus Latex C comparison (1142 Polyurethane B plus 1193 Latex C). Only condoms used for vaginal intercourse were included in the analysis. Findings Although the total failure rates (breakage and slippage) for the polyurethane condoms were higher than for the control Latex C condom, all condoms performed extremely well with low failure rates compared to similar condom studies. Condom Polyurethane A met the noninferiority requirements specified in ISO 23409:2011 relative to Latex C, the control NR latex condom, in the full Study population. While condom Polyurethane B did not meet the noninferiority requirement for the full Study population, it did meet the noninferiority requirement when analysis was restricted to the intended population (men with penis lengths ≤ 170 mm). Trial registration The Study is registered with ClinicalTrials.gov, NCT04622306, Protocol Reference SAGCS 2, initial release date 11/02/2020.

Abstract Objectives This study aims to compare the efficacy of remote versus in-person training strategies to teach ultrasound guided knee arthrocentesis using formalin embalmed cadavers. Methods 30 first-year medical student participants were randomly assigned to remote or in-person training groups. Pre- and post- training surveys were used to evaluate participant’s self-confidence in their ability to perform the procedure. Participants were asked to watch a 30-minute training video and then attend a skills training workshop. The workshops consisted of 20 min of hands-on instruction followed by a skills assessment. Results Following training, participant self-confidence increased significantly across all survey items in both groups (p = 0.0001). No significant changes in participant self-confidence were detected between the groups. Skills and knowledge-related metrics did not differ significantly between the groups with the exception of the “knowledge of instruments” variable. Conclusions Our data suggests that remote ultrasound-guided procedure training, although logistically complex, is a viable alternative to traditional in-person learning techniques even for a notoriously hands on skill like ultrasound guided knee arthrocentesis. Novice first-year medical student operators in the remote-training group were able to significantly increase their confidence and demonstrate competency in a manner statistically indistinguishable from those trained in-person. These results support the pedagogical validity of using remote training to teach ultrasound guided procedures which could have implications in rural and global health initiatives where educational resources are more limited.

MuscleX is an integrated, open-source computer software suite for data reduction of X-ray fiber diffraction patterns from striated muscle and other fibrous systems. It is written in Python and runs on Linux, Microsoft Windows or macOS. Most modules can be run either from a graphical user interface or in a `headless mode' from the command line, suitable for incorporation into beamline control systems. Here, we provide an overview of the general structure of the MuscleX software package and describe the specific features of the individual modules as well as examples of applications.

Abstract Background Tuberculosis (TB), a major cause of disease and antimicrobial resistance, is spread via aerosols. Aerosols have diagnostic potential and airborne-microbes other than Mycobacterium tuberculosis complex (MTBC) may influence transmission. We evaluated whether PneumoniaCheck (PMC), a commercial aerosol collection device, captures MTBC and the aeromicrobiome of people with TB. Methods PMC was done in sputum culture-positive people (≥ 30 forced coughs each, n = 16) pre-treatment and PMC air reservoir (bag, corresponding to upper airways) and filter (lower airways) washes underwent Xpert MTB/RIF Ultra (Ultra) and 16S rRNA gene sequencing (sequencing also done on sputum). In a subset (n = 6), PMC microbiota (bag, filter) was compared to oral washes and bronchoalveolar lavage fluid (BALF). Findings 54% (7/13) bags and 46% (6/14) filters were Ultra-positive. Sequencing read counts and microbial diversity did not differ across bags, filters, and sputum. However, microbial composition in bags (Sphingobium-, Corynebacterium-, Novosphingobium-enriched) and filters (Mycobacterium-, Sphingobium-, Corynebacterium-enriched) each differed vs. sputum. Furthermore, sequencing only detected Mycobacterium in bags and filters but not sputum. In the subset, bag and filter microbial diversity did not differ vs. oral washes or BALF but microbial composition differed. Bags vs. BALF were Sphingobium-enriched and Mycobacterium-, Streptococcus-, and Anaerosinus-depleted (Anaerosinus also depleted in filters vs. BALF). Compared to BALF, none of the aerosol-enriched taxa were enriched in oral washes or sputum. Interpretation PMC captures aerosols with Ultra-detectable MTBC and MTBC is more detectable in aerosols than sputum by sequencing. The aeromicrobiome is distinct from sputum, oral washes and BALF and contains differentially-enriched lower respiratory tract microbes.

Abstract Background In Australia, university clinical programs rely heavily on external healthcare professionals to provide a range of authentic clinical training and professional development opportunities for students. There is, however, a limited understanding of the factors that motivate these professionals to be educators and whether this varies across different healthcare disciplines within Australia. As the demand for clinical placements continues to increase, it is critical for the ongoing success of these programs that universities identify both the barriers associated with teaching and the benefits that enhance job satisfaction. Methods A two-part questionnaire was emailed to 849 external healthcare educators teaching predominantly in Medicine, Medical Imaging, and Optometry programs at Deakin University. Part-one surveyed the socio-demographics, perceived benefits, and barriers to teaching, plus the utilisation of entitlements offered by the university. Part-two was modelled on Dybowski and Harendza’s validated Physician Teaching Motivation Questionnaire (PTMQ) and adapted to an Australian audience. Results Overall, 776 out of the 849 questionnaires were considered in the final participant pool. The response rate for part-one was 19.7% (n = 153/776) and 18.3% (n = 142/776) for part-two. Across all professions, altruism was the primary source of motivation for teaching in Deakin University’s healthcare programs. Medical Imaging educators placed a higher value on career-related teaching aspects compared to those in Medicine and Optometry (p

Abstract Background Forests are significant terrestrial biomes for carbon storage, and annual carbon accumulation of forest biomass contributes offsets affecting net greenhouse gases in the atmosphere. The immediate loss of stored carbon through fire on forest lands reduces the annual offsets provided by forests. As such, the United States reporting includes annual estimates of direct fire emissions in conjunction with the overall forest stock and change estimates as a part of national greenhouse gas inventories within the United Nations Framework Convention on Climate Change. Forest fire emissions reported for the United States, such as the 129 Tg CO2 reported for 2022, are based on the Wildland Fire Emissions Inventory System (WFEIS). Current WFEIS estimates are included in the Inventory of U.S. Greenhouse Gas Emissions and Sinks: 1990–2022 published in 2024 by the United States Environmental Protection Agency. Here, we describe WFEIS the fire emissions inventory system we used to address current information needs, and an analysis to confirm compatibility of carbon mass between estimated forest fire emissions and carbon in forest stocks. Results The summaries of emissions from forests are consistent with previous reports that show rates and interannual variability in emissions and forest land area burned are generally greater in recent years relative to the 1990s. Both emissions and interannual variability are greater in the western United States. The years with the highest CO2 emissions from forest fires on the 48 conterminous states plus Alaska were 2004, 2005, and 2015. In some years, Alaska emissions exceed those of the 48 conterminous states, such as in 2022, for example. Comparison of forest fire emission to forest carbon stocks indicate there is unlikely any serious disconnect between inventory and fire emissions estimates. Conclusions The WFEIS system is a user-driven approach made available via a web browser. Model results are compatible with the scope and reporting needs of the annual national greenhouse gas inventories.

Abstract Background Wood carbon fractions (CFs)—the proportion of dry woody biomass comprised of elemental carbon (C)—are a key component of forest C estimation protocols and studies. Traditionally, a wood CF of 50% has been assumed in forest C estimation protocols, but recent studies have specifically quantified differences in wood CFs across several different forest biomes and taxonomic divisions, negating the need for generic wood CF assumptions. The Intergovernmental Panel on Climate Change (IPCC), in its 2006 “Guidelines for National Greenhouse Gas Inventories”, published its own multitiered system of protocols for estimating forest C stocks, which included wood CFs that (1) were based on the best available literature (at the time) and (2) represented a significant improvement over the generic 50% wood CF assumption. However, a considerable number of new studies on wood CFs have been published since 2006, providing more accurate, robust, and spatially- and taxonomically- specific wood CFs for use in forest C estimation. Main text We argue that the IPCC’s recommended wood CFs and those in many other forest C estimation models and protocols (1) differ substantially from, and are less robust than, wood CFs derived from recently published data-rich studies; and (2) may lead to nontrivial errors in forest C estimates, particularly for countries that rely heavily on Tier 1 forest C methods and protocols (e.g., countries of the Global South with large expanses of tropical forests). Based on previous studies on this topic, we propose an alternative set of refined wood CFs for use in multiscale forest C estimation, and propose a novel decision-making framework for integrating species- and location-specific wood CFs into forest C estimation models. Conclusion The refined wood CFs that we present in this commentary may be used by the IPCC to update its recommended wood CFs for use in forest C estimation. Additionally, we propose a novel decision-making framework for integrating data-driven wood CFs into a wider suite of multitiered forest C estimation protocols, models, and studies.

Abstract Converging evidence indicates that extra-embryonic yolk sac is the source of both macrophages and endothelial cells in adult mouse tissues. Prevailing views are that these embryonically derived cells are maintained after birth by proliferative self-renewal in their differentiated states. Here we identify clonogenic endothelial-macrophage (EndoMac) progenitor cells in the adventitia of embryonic and postnatal mouse aorta, that are independent of Flt3-mediated bone marrow hematopoiesis and derive from an early embryonic CX3CR1+ and CSF1R+ source. These bipotent progenitors are proliferative and vasculogenic, contributing to adventitial neovascularization and formation of perfused blood vessels after transfer into ischemic tissue. We establish a regulatory role for angiotensin II, which enhances their clonogenic and differentiation properties and rapidly stimulates their proliferative expansion in vivo. Our findings demonstrate that embryonically derived EndoMac progenitors participate in local vasculogenic responses in the aortic wall by contributing to the expansion of endothelial cells and macrophages postnatally.

Abstract Background Implementation of the World Health Organization (WHO) recommended Advanced HIV Disease screening package, remains poor in most settings with limited resources. More than 50% of newly diagnosed-HIV clients are missed on screening as a result of implementation barriers. It is important to mitigate the existing barriers and leverage enablers’ inorder to maximize uptake of the advanced HIV disease screening. This study aimed to identify strategies for scaling up implementation of advanced HIV disease screening among newly HIV-diagnosed clients in pre-ART phase using a Consolidated Framework for Implementation Research-Expert Recommendation for Implementing Change (CFIR-ERIC) guiding tool. Methods A qualitative study was conducted at Rumphi district hospital in Malawi (August – September, 2023). Two sessions of Focus group discussions (FDGs) involving key stakeholders were facilitated to identify specific strategies following the initial study on exploration of barriers and facilitators of advanced HIV disease screening package. Participants comprised healthcare providers, purposively selected from key hospital departments. A deductive approach was used to analyze FDG transcripts where emerging themes were mapped with ERIC list of strategies. CFIR-ERIC Matching tool version 1.0, was used to generate an output of the most to least expert-endorsed Level 1 and Level 2 strategies. Findings About 25 key healthcare workers participated in FDGs. Overall, 6 Level 1 strategies (≥ 50% expert endorsement score) and 4 Level 2 strategies (≥ 20%, ≤ 49% expert endorsement score) were identified, targeting barriers associated with availability of resources, intervention complexity, access to knowledge and information, communication; and implementation leads. Most of the reported strategies were cross-cutting and aimed at enhancing clinical knowledge of the intervention (distributing training materials, educational meetings), developing stakeholders’ interrelations (network weaving) as well as improving clinical workflow (environmental restructuring). Use of evaluative and iterative strategies such as monthly data collection for evaluation were also recommended as part of continuous improvement while an AHD coordinator was recommended to be formally appointed inorder to spearhead coordination of AHD screening services. Conclusion Through the involvement of key stakeholders and the use of CFIR-ERIC matching tool, this study has identified cross-cutting strategies that if well implemented, can help to mitigate contextual barriers and leverage enablers for an improved delivery of AHD screening package.

Abstract Background Despite surgical and pharmacological interventions, endometriosis can recur. Reliable information regarding risk of recurrence following a first diagnosis is scant. The aim of this study was to examine clinical and survey data in the setting of disease recurrence to identify predictors of risk of endometriosis recurrence. Methods This observational study reviewed data from 794 patients having surgery for pelvic pain or endometriosis. Patients were stratified into two analytic groups based on self-reported or surgically confirmed recurrent endometriosis. Statistical analyses included univariate, followed by multivariate logistic regression to identify risk factors of recurrence, with least absolute shrinkage and selection operator (Lasso) regularisation. Risk-calibrated Supersparse Linear Integer Models (RiskSLIM) and survival analyses (with Lasso) were undertaken to identify predictive features of recurrence. Results Several significant features were repeatedly identified in association with recurrence, including adhesions, high rASRM score, deep disease, bowel lesions, adenomyosis, emergency room attendance for pelvic pain, younger age at menarche, higher gravidity, high blood pressure and older age. In the surgically confirmed group, with a score of 5, the RiskSLIM method was able to predict the risk of recurrence (compared to a single diagnosis) at 95.3% and included adenomyosis and adhesions in the model. Survival analysis further highlighted bowel lesions, adhesions and adenomyosis. Conclusions Following an initial diagnosis of endometriosis, clinical decision-making regarding disease management should take into consideration the presence of bowel lesions, adhesions and adenomyosis, which increase the risk of endometriosis recurrence.

Abstract Background Primary care is often described as slow to change. But conceptualized through complexity theory, primary care is continually changing in unpredictable, non-linear ways through self-organization processes. Self-organization has proven hard to study directly. We aimed to develop a methodology to study self-organization and describe how a primary care clinic self-organizes over time. Methodology We completed a virtual case study of an urban primary care clinic from May-Nov 2021, applying methodological insights from actor-network theory to examine the complexity theory concept of self-organization. We chose to focus our attention on self-organization activities that alter organizational routines. Data included fieldnotes of observed team meetings, document collection, interviews with clinic members, and notes from brief weekly discussions to detect actions to change clinical and administrative routines. Adapting schema analysis, we described changes to different organizational routines chronologically, then explored intersecting changes. We sought feedback on results from the participating clinic. Findings Re-establishing equilibrium remained challenging well into the COVID-19 pandemic. The primary care clinic continued to self-organize in response to changing health policies, unintended consequences of earlier adaptations, staff changes, and clinical care initiatives. Physical space, technologies, external and internal policies, guidelines, and clinic members all influenced self-organization. Changing one created ripple effects, sometimes generating new, unanticipated problems. Member checking confirmed we captured most of the changes to organizational routines during the case study period. Conclusions Through insights from actor-network theory, applied to studying actions taken that alter organizational routines, it is possible to operationalize the theoretical construct of self-organization. Our methodology illuminates the primary care clinic as a continually changing entity with co-existing and intersecting processes of self-organization in response to varied change pressures.

Abstract This study is the first to investigate the presence and movement of the novel Liberibacter species ‘Candidatus Liberibacter brunswickensis’ (CLbr) in eggplant, Solanum melongena. The psyllid, Acizzia solanicola can transmit CLbr to eggplant and CLbr can be acquired by CLbr-negative A. solanicola individuals from CLbr-positive eggplants. In planta, CLbr can replicate, move and persist. Investigation into the early development of eggplants showed that CLbr titres had increased at the inoculation site at 14 days post inoculation access period (DPIAP). CLbr had become systemic in the majority of plants tested by 28 DPIAP. The highest bacterial titres were recorded at 35 DPIAP in all samples of the inoculated leaf, the roots, stems and the midrib and petiole samples of the newest leaf (the top leaf). This finding strongly suggests that CLbr movement in planta follows the source to sink relationship as previously described for ‘Ca. Liberibacter asiaticus’ (CLas) and ‘Ca. Liberibacter solanacearum’ (CLso). No symptoms consistent with Liberibacter-associated diseases were noted for plants colonised by CLbr during this study, consistent with the hypothesis that CLbr does not cause disease of eggplant during the early stages of host colonisation. In addition, no significant differences in biomass were found between eggplant colonised with CLbr, compared to those that were exposed to CLbr-negative A. solanicola, and to control plants.

Neuronal activity consumes cellular energy and generates carbon dioxide (CO2). To counter this metabolic challenge, synaptic signalling communicates with nearby microvasculature to increase local blood flow. Is this process solely based on feedforward synaptic signalling, or is the generated CO2 also involved? This question was addressed in mice in a new Nature Communications publication by Tournissac and colleagues where they showed that neurovascular coupling is not affected by exogenous CO2 or its associated acidification.

Summary: Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID. Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.). Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events. Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions. Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.

Abstract Background Stroke affects long-term physical and cognitive function; many survivors report unmet health needs, such as pain or depression. A hospital-led follow-up service designed to address ongoing health problems may avoid unplanned readmissions and improve quality of life. Methods This paper outlines the protocol for a registry-based, randomised controlled trial with allocation concealment of participants and outcome assessors. Based on an intention-to-treat analysis, we will evaluate the feasibility, acceptability, potential effectiveness and cost implications of a new tailored, codesigned, hospital-led follow-up service for people within 6–12 months of stroke. Participants (n = 100) from the Australian Stroke Clinical Registry who report extreme health problems on the EuroQol EQ-5D-3L survey between 90 and 180 days after stroke will be randomly assigned (1:1) to intervention (follow-up service) or control (usual care) groups. All participants will be independently assessed at baseline and 12–14-week post-randomisation. Primary outcomes for feasibility are the proportion of participants completing the trial and for intervention participants the proportion that received follow-up services. Acceptability is satisfaction of clinicians and participants involved in the intervention. Secondary outcomes include effectiveness: change in extreme health problems (EQ-5D-3L), unmet needs (Longer-term Unmet Needs questionnaire), unplanned presentations and hospital readmission, functional independence (modified Rankin Scale) and cost implications estimated from self-reported health service utilisation and productivity (e.g. workforce participation). To inform future research or implementation, the design contains a process evaluation including clinical protocol fidelity and an economic evaluation. Discussion The results of this study will provide improved knowledge of service design and implementation barriers and facilitators and associated costs and resource implications to inform a future fully powered effectiveness trial of the intervention. Trial registration ACTRN12622001015730pr. Trial sponsor Florey Institute of Neuroscience and Mental Health, 245 Burgundy Street, Heidelberg, VIC, 3084, PH: +61 3 9035 7032

The effects of the antioxidant, butylated hydroxytoluene (BHT), and the metal chelator, ethylenediaminetetraacetic acid (EDTA) in combination with cedarwood oil (CWO) were investigated for wood preservation against subterranean termites as well as two species of white-rot decay fungi and two species of brown-rot decay fungi. Vacuum pressure impregnation was used to treat wood blocks. Resistance of the treated wood test blocks was evaluated using a no-choice bioassay for termites and a soil bottle assay wood decay fungi. Eight treatments were tested: H2O only; BHT only; EDTA only; BHT with EDTA; CWO only; CWO with EDTA; CWO with BHT; and CWO with BHT plus EDTA. For termites, the lowest percentage wood mass losses were for the EDTA, BHT, CWO, and CWO/EDTA treatments, all of which were statistically equivalent. Correspondingly, these treatments all had the highest termite mortalities at 100%. The four species of decay fungi were affected differently by the wood treatments; however, overall CWO and EDTA gave the best protection against wood mass loss. The addition of BHT did not decrease mass loss.

Abstract Background Retained surgical items (RSI) are preventable events that pose a significant risk to patient safety. Current strategies for preventing RSIs rely heavily on manual instrument counting methods, which are prone to human error. This study evaluates the feasibility and performance of a deep learning-based computer vision model for automated surgical tool detection and counting. Methods A novel dataset of 1,004 images containing 13,213 surgical tools across 11 categories was developed. The dataset was split into training, validation, and test sets at a 60:20:20 ratio. An artificial intelligence (AI) model was trained on the dataset, and the model’s performance was evaluated using standard object detection metrics, including precision and recall. To simulate a real-world surgical setting, model performance was also evaluated in a dynamic surgical video of instruments being moved in real-time. Results The model demonstrated high precision (98.5%) and recall (99.9%) in distinguishing surgical tools from the background. It also exhibited excellent performance in differentiating between various surgical tools, with precision ranging from 94.0 to 100% and recall ranging from 97.1 to 100% across 11 tool categories. The model maintained strong performance on a subset of test images containing overlapping tools (precision range: 89.6–100%, and recall range 97.2–98.2%). In a real-time surgical video analysis, the model maintained a correct surgical tool count in all non-transition frames, with a median inference speed of 40.4 frames per second (interquartile range: 4.9). Conclusion This study demonstrates that using a deep learning-based computer vision model for automated surgical tool detection and counting is feasible. The model’s high precision and real-time inference capabilities highlight its potential to serve as an AI safeguard to potentially improve patient safety and reduce manual burden on surgical staff. Further validation in clinical settings is warranted.

Introduction: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with renal involvement primarily affects the renal cortex and presents with key histopathologic findings of a pauci-immune necrotizing and crescentic glomerulonephritis. Infrequently reported and poorly characterized is renal medullary angiitis (RMA), a pathologic variant of AAV primarily involving the renal medulla. This study seeks to describe the presentation and treatment outcomes of RMA. Methods: In this single-center cohort, renal pathology samples classified as AAV with renal involvement underwent secondary review to determine if they met histopathologic criteria for RMA. Demographic, clinical, and laboratory data were obtained via electronic medical record review. Descriptive statistical analysis was performed on key variables. Results: Of the 136 kidney biopsy samples classified as AAV with renal involvement, histopathologic features of RMA were present in 13 cases. The mean (SD) age at the time of RMA diagnosis was 65 (19) years, and 54% were female. Most cases presented with extrarenal manifestations of disease. Initial median (IQR) estimated glomerular filtration rate and proteinuria on presentation were 16 (10–19) mL/min/1.73 m2 and 1,100 (687–2,437) mg, respectively. The primary histologic features were high degrees of interstitial inflammation comprised leukocytes, neutrophils, plasma cells, and eosinophils along with either interstitial hemorrhage or necrosis. All patients were treated with glucocorticoids in combination with either cyclophosphamide, rituximab, or mycophenolate. All patients achieved disease remission. During a median (IQR) follow-up of 42 (14–68) months, 1 patient reached ESKD and 1 patient died. Conclusions: In this single-center case series, we identified the presence of RMA in 9.5% of AAV samples that underwent secondary review. RMA presented with severe impairment in renal function and multisystem disease. Standard of care immunosuppression for AAV was effective for remission induction in RMA. It remains unclear whether standard prognostication tools are useful in this population.

Abstract The purpose of this study was to examine how demographics, etiology, and clinical examination findings are related to visual outcomes in subjects with open globe injury (OGI) across a large and generalizable sample. A retrospective cohort analysis was performed using data collected from the electronic medical records of four tertiary university centers for subjects with OGI presenting from 2018 to 2021. Demographic information, injury mechanisms, clinical exam findings, visual acuity (VA) at presentation and most recent follow-up were recorded. In subjects with bilateral OGIs, only right eyes were included. A modified ocular trauma score (OTS) using presenting VA, the presence of perforating injury, OGI, and afferent pupillary defect was calculated. The risk of subjects’ demographic characteristics, ocular trauma etiology, clinical findings and modified OTS on the presence of monocular blindness at follow-up were assessed using univariable and multivariable regression models. 1426 eyes were identified. The mean age was 48.3 years (SD: ± 22.4 years) and the majority of subjects were men (N = 1069, 75.0%). Univariable analysis demonstrated that subjects of Black race were 66% (OR: 1.66 [1.25–2.20]; P

Abstract Division and differentiation events by which cell populations with specific functions are generated often take place as part of a developmental programme, which can be represented by a sequence of compartments. A compartment is the set of cells with common characteristics; sharing, for instance, a spatial location or a phenotype. Differentiation events are transitions from one compartment to the next. Cells may also die or divide. We consider three different types of division events: (i) where both daughter cells inherit the mother’s phenotype (self-renewal), (ii) where only one of the daughters changes phenotype (asymmetric division), and (iii) where both daughters change phenotype (symmetric division). The self-renewal probability in each compartment determines whether the progeny of a single cell, moving through the sequence of compartments, is finite or grows without bound. We analyse the progeny stochastic dynamics with probability generating functions. In the case of self-renewal, by following one of the daughters after any division event, we may construct lifelines containing only one cell at any time. We analyse the number of divisions along such lines, and the compartment where lines terminate with a death event. Analysis and numerical simulations are applied to a five-compartment model of the gradual differentiation of hematopoietic stem cells and to a model of thymocyte development: from pre-double positive to single positive (SP) cells with a bifurcation to either SP4 or SP8 in the last compartment of the sequence.

Abstract Background Clinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades. Methods Twenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades. Results High-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037). Conclusions Both high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades. Trial registration ClinicalTrials.gov, NCT03741426 . Registered on 13 November 2018. Relevance statement The newly developed T2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses. Graphical Abstract

Abstract Background Evaluations of continuing professional development programs typically focus on short-term knowledge and skill acquisition. There is a need for more comprehensive program evaluation methods that assess a broader range of impacts and can elicit how and why these outcomes occurred. We conducted a qualitative study to investigate the impacts of a multidisciplinary, online health professional postgraduate degree and to gain insights into the factors that led to these impacts. Methods Participants were graduates of the University of Melbourne’s Master of Cancer Sciences who could participate in an online interview. Semi-structured, qualitative interviews were conducted exploring a broad range of impacts, including changes in professional practice and career trajectory since graduation, and how the degree influenced these impacts. Data were analysed inductively. Results Fifteen participants (female: 80%, 31–50 years old: 67%) from a range of professions were interviewed. A number of major themes were uncovered. Impacts on career trajectory included expanded career horizons (e.g. increased role diversity and complexity), and increased confidence in their professional identity. Impacts on professional practice included individual improvements in patient care and research, as well as changes in organisational practice. Factors identified as leading to these impacts were: (i) active, interactive and interprofessional learning; (ii) networking, informal mentoring, and role-modelling; and (iii) support at multiple levels. Conclusion This study provides preliminary evidence of the positive impact of a Master of Cancer Sciences on graduate career trajectory and professional practice. In addition, the inductive methodology enabled identification of the curricular features (both planned and emergent) that influenced these impacts, facilitating potential transferability of learnings to other teaching programs.

Abstract The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.

Background: Proximal humerus fractures are a common injury, predominantly affecting older adults. This study aimed to develop risk-prediction models for prolonged length of hospital stay (LOS), serious adverse complications, and readmission within 30 days of surgically treated proximal humerus fractures using machine learning (ML) techniques. Methods: Adult patients (age >18) who underwent open reduction internal fixation (ORIF), hemiarthroplasty, or total shoulder arthroplasty for proximal humerus fracture between 2016 and 2021 were included. Preoperative demographic and clinical variables were collected for all patients and used to establish ML-based algorithms. The model with optimal performance was selected according to area under the curve (AUC) on the receiver operating curve (ROC) curve and overall accuracy, and the specific predictive features most important to model derivation were identified. Results: A total of 7473 patients were included (72.1% male, mean age 66.2 ± 13.7 years). Models produced via gradient boosting performed best for predicting prolonged LOS and complications. The model predicting prolonged LOS demonstrated good discrimination and performance, as indicated by (Mean: 0.700, SE: 0.017), recall (Mean: 0.551, SE: 0.017), accuracy (Mean: 0.717, SE: 0.010), F1-score (Mean: 0.616, SE: 0.014), AUC (Mean: 0.779, SE: 0.010), and Brier score (Mean: 0.283, SE: 0.010) Preoperative hematocrit, preoperative platelet count, and patient age were considered the strongest predictive features. The model predicting serious adverse complications exhibited comparable discrimination [precision (Mean: 0.226, SE: 0.024), recall (Mean: 0.697, SE: 0.048), accuracy (Mean: 0.811, SE: 0.010), F1-score (Mean: 0.341, SE: 0.031)] and superior performance relative to the LOS model [AUC (Mean: 0.806, SE: 0.024), Brier score (Mean: 0.189, SE: 0.010), noting preoperative hematocrit, operative time, and patient age to be most influential. However, the 30-day readmission model achieved the weakest relative performance, displaying low measures of precision (Mean: 0.070, SE: 0.012) and recall (Mean: 0.389, SE: 0.053), despite good accuracy (Mean: 0.791, SE: 0.009). Conclusion: Predictive models constructed using ML techniques demonstrated favorable discrimination and satisfactory-to-excellent performance in forecasting prolonged LOS and serious adverse complications occurring within 30 days of surgical intervention for proximal humerus fracture. Modifiable preoperative factors such as hematocrit and platelet count were identified as significant predictive features, suggesting that clinicians could address these factors during preoperative patient optimization to enhance outcomes. Overall, these findings highlight the potential for ML techniques to enhance preoperative management, facilitate shared decision-making, and enable more effective and personalized orthopedic care by exploring alternative approaches to risk stratification.

Background Foodborne and waterborne illnesses affect over four million Canadians annually and pose a preventable burden on the nation’s healthcare system. Climate change can increase the risk of such illnesses by increasing the likelihood of exposure to contaminants. As climate change progresses, it is imperative to better understand its impact on the dissemination of foodborne and waterborne contaminants throughout the food system. Currently, there is limited, synthesised evidence for how future changes in Canada’s climate may affect the risk of contamination of preharvest foods. The aim of this research is to collate and describe available information on effects of climate variables on biological and chemical contamination of preharvest foods in Canada. This information will contribute to improved understanding of climate change impacts and potential adaptation and mitigation strategies to increase climate resiliency in Canada’s food system.Methods A preliminary search of MEDLINE, Web of Science and Google was conducted to verify the absence of existing reviews and to inform the development of this review protocol. Information will be identified by searching four academic databases: MEDLINE via Ovid, AGRICultural OnLine Access (AGRICOLA), CAB International and Web of Science. This search will be supplemented by a targeted grey literature search. The search strategy includes index terms and keywords for Canada-relevant foodborne and waterborne pathogens and chemical contaminants, preharvest foods and climate change. Search results will be managed using Covidence during all phases of the review, conducted by two independent reviewers. Data will be extracted, synthesised and presented using graphical and tabular formats.This scoping review protocol describes the process for retrieving a comprehensive set of evidence for how climate change variables may increase risk of biological or chemical contamination of preharvest foods in Canada. This review will provide decision-makers with a detailed understanding of climate variable-preharvest food-contaminant combinations using the best available evidence.Ethics and dissemination Ethical considerations are not applicable to this protocol as scoping reviews conduct secondary data analysis that synthesises data from publicly available sources. The results from this review will be disseminated through a peer-reviewed publication and conference presentation.

Introduction: We sought to describe emergency department (ED) buprenorphine treatment variability among EDs with varying operational characteristics. Methods: We performed a retrospective cohort study of adult patients with opioid use disorder discharged from 12 hospital-based EDs within a large healthcare system as a secondary data analysis of a quality improvement study. Primary outcome of interest was buprenorphine treatment rate. We described treatment rates between EDs, categorized by tertile of operational characteristics including annual census, hospital and intensive care unit (ICU) admission rates, ED length of stay (LOS), and boarding time. Secondary outcomes were ED LOS and 30-day return rates. Results: There were 7,469 unique ED encounters for patients with opioid use disorder between January 2020–May 2021, of whom 759 (10.2%) were treated with buprenorphine. Buprenorphine treatment rates were higher in larger EDs and those with higher hospital and ICU admission rates. Emergency department LOS and 30-day ED return rate did not have consistent associations with buprenorphine treatment. Conclusion: Rates of treatment with ED buprenorphine vary according to the operational characteristics of department. We did not observe a consistent negative relationship between buprenorphine treatment and operational metrics, as many feared. Additional funding and targeted resource allocation should be prioritized by departmental leaders to improve access to this evidence-based and life-saving intervention.

Abstract Background Perennial ryegrass (Lolium perenne) in New Zealand pastures is typically infected with the mutualist Epichloë fungal endophyte. This endophyte assists the plant in resisting biotic and abiotic stresses, but the standard strain of endophyte is toxic to livestock. Elite ryegrasses with selected endophytes have been developed to provide protective properties to the grass plant and lessen or eliminate the negative impacts on livestock. Methods Using immunology and molecular techniques, the presence of endophyte infection and endophyte strain in ryegrass tillers was determined for 24 dairy pastures sampled for up to 7 years in regions of the North and South Islands. Results In general, infection levels were high and showed small increases over time. Some pastures failed to reach 70% infection. The sown, selected endophytes were the dominant endophyte strains present and these were stable over time. Standard endophyte was the primary nonsown endophyte, and while generally low and so of little importance, it increased over time and for some pastures, this would have been detrimental to livestock. Pasture establishment technique influenced the level of contamination. Conclusions Results reinforce the importance of following best practice procedures in the seed industry and on‐farm. Researchers should monitor trials for contaminating nonsown standard endophyte.

Abstract Pyrethroid bednets treated with the synergist piperonyl butoxide (PBO) offer the possibility of improved vector control in mosquito populations with metabolic resistance. In 2017–2019, we conducted a large-scale, cluster-randomised trial (LLINEUP) to evaluate long-lasting insecticidal nets (LLINs) treated with a pyrethroid insecticide plus PBO (PBO LLINs), as compared to conventional, pyrethroid-only LLINs across 104 health sub-districts (HSDs) in Uganda. In LLINEUP, and similar trials in Tanzania, PBO LLINs were found to provide greater protection against malaria than conventional LLINs, reducing parasitaemia and vector density. In the LLINEUP trial, we conducted cross-sectional household entomological surveys at baseline and then every 6 months for two years, which we use here to investigate longitudinal changes in mosquito infection rate and genetic markers of resistance. Overall, 5395 female Anopheles mosquitoes were collected from 5046 households. The proportion of mosquitoes infected (PCR-positive) with Plasmodium falciparum did not change significantly over time, while infection with non-falciparum malaria decreased in An. gambiae s.s., but not An. funestus. The frequency of genetic markers associated with pyrethroid resistance increased significantly over time, but the rate of change was not different between the two LLIN types. The knock-down resistance (kdr) mutation Vgsc-995S declined over time as Vgsc-995F, the alternative resistance mutation at this codon, increased. Vgsc-995F appears to be spreading into Uganda. Distribution of LLINs in Uganda was previously found to be associated with reductions in parasite prevalence and vector density, but here we show that the proportion of infective mosquitoes remained stable across both PBO and non-PBO LLINs, suggesting that the potential for transmission persisted. The increased frequency of markers of pyrethroid resistance indicates that LLIN distribution favoured the evolution of resistance within local vectors and highlights the potential benefits of resistance management strategies. Trial registration: This study is registered with ISRCTN, ISRCTN17516395. Registered 14 February 2017, http://www.isrctn.com/ISRCTN17516395 .

Abstract Background Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). Methods Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. Results At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25–5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48–9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03–8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02–5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57–5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23–5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46–9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76–7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07–3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10–4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15–8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. Conclusion Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.

Abstract Background Well-built housing limits mosquito entry and can reduce malaria transmission. The association between community-level housing and malaria burden in Uganda was assessed using data from randomly selected households near 64 health facilities in 32 districts. Methods Houses were classified as ‘improved’ (synthetic walls and roofs, eaves closed or absent) or ‘less-improved’ (all other construction). Associations between housing and parasitaemia were made using mixed effects logistic regression (individual-level) and multivariable fractional response logistic regression (community-level), and between housing and malaria incidence using multivariable Poisson regression. Results Between November 2021 and March 2022, 4.893 children aged 2–10 years were enrolled from 3.518 houses; of these, 1.389 (39.5%) were classified as improved. Children living in improved houses had 58% lower odds (adjusted odds ratio = 0.42, 95% CI 0.33–0.53, p 67% of houses improved had a 63% lower parasite prevalence (adjusted prevalence ratio 0.37, 95% CI 0.19–0.70, p

Abstract One Health is a recognition of the shared environment inhabited by humans, animals and plants, and the impact of their interactions on the health of all organisms. The COVID-19 pandemic highlighted the need for a framework of pathogen surveillance in a tractable One Health paradigm to allow timely detection and response to threats to human and animal health. We present case studies centered around the recent global approach to tackle antimicrobial resistance and the current interest in wastewater testing, with the concept of “one sample many analyses” to be further explored as the most appropriate means of initiating this endeavor.

Abstract Traumatic Brain Injury (TBI) induces neuroinflammatory response that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist, used to treat drug addiction. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI seizures can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and/or seizures post-TBI. TBI was induced by a modified Marmarou Weight-Drop (WD) method on 4-week-old C57BL/6J male mice. Mice were placed in two groups: non-telemetry assessing the acute effects or in telemetry monitoring for interictal events and spontaneous seizures both following TBI and naltrexone. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation, neurodegeneration and fiber track integrity at 8 days and 3 months post-TBI. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. Our results show an increase in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. Video-EEG revealed increased interictal events in TBI mice, with 71% mice developing post-traumatic seizures (PTS). Naltrexone treatment ameliorated neuroinflammation, neurodegeneration, reduced interictal events and prevented seizures in all TBI mice, which makes naltrexone a promising candidate against PTS, TBI-associated neuroinflammation and epileptogenesis in a WD model of TBI.

Abstract Background Cystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination. Methods Wildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Viral plaque assays and qPCR were used to assess viral levels in CNS. Immune cell infiltration into the CNS and immune cell activation were determined by flow cytometry and 10X genomics chromium 3’ single cell RNA sequencing (scRNA-seq). Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and axonal damage assessed by immunohistochemical staining for SMI-32. Remyelination was evaluated by electron microscopy (EM) and calculation of g-ratios. Results JHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with increased axonal damage and demyelination associated with impaired remyelination. Single-cell RNA-seq of CD45 + cells enriched from spinal cords of infected Cst7-/- and control mice revealed enhanced expression of transcripts encoding T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) and perforin (Prf1) transcripts in CD8 + T cells from Cst7-/- mice compared to controls. Conclusions Cystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the idea that cystatin F influences expression of proinflammatory gene expression impacting neuroinflammation, T cell activation and/or glia cell responses ultimately impacting neuroinflammation and neurologic disease.

Abstract Greater exposure to stressors over the life course is believed to promote striatum-dependent over hippocampus-dependent learning and memory processes under stressful conditions. However, little research in this context has actually assessed lifetime stressor exposure and, moreover, it remains unknown whether greater cumulative lifetime stressor exposure exerts comparable effects on striatum-dependent learning and hippocampus-dependent learning in non-stressful contexts. To investigate this issue, we used the Stress and Adversity Inventory for Adults (Adult STRAIN) and Multicued Search Task to investigate the relation between cumulative lifetime stressor exposure and striatum-dependent stimulus–response learning and hippocampus-dependent contextual learning under non-stressful conditions among healthcare professionals (N = 205; 157 females, 48 males; Age: M = 34.23, SD 9.3, range 20–59 years). Individuals with moderate, but not low, cumulative lifetime stressor exposure exhibited impaired learning for stimulus–response associations. In contrast, learning for context associations was unrelated to participants' lifetime stressor exposure profiles. These results thus provide first evidence that cumulative lifetime stressor exposure may have negative consequences on human striatum-dependent stimulus–response learning under non-stressful environmental conditions.

Abstract We aimed to characterize the cognitive profile of post-acute COVID-19 syndrome (PACS) patients with cognitive complaints, exploring the influence of biological and psychological factors. Participants with confirmed SARS-CoV-2 infection and cognitive complaints ≥ 8 weeks post-acute phase were included. A comprehensive neuropsychological battery (NPS) and health questionnaires were administered at inclusion and at 1, 3 and 6 months. Blood samples were collected at each visit, MRI scan at baseline and at 6 months, and, optionally, cerebrospinal fluid. Cognitive features were analyzed in relation to clinical, neuroimaging, and biochemical markers at inclusion and follow-up. Forty-nine participants, with a mean time from symptom onset of 10.4 months, showed attention-executive function (69%) and verbal memory (39%) impairment. Apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%) were prevalent. Visual memory (8%) correlated with total gray matter (GM) and subcortical GM volume. Neuronal damage and inflammation markers were within normal limits. Over time, cognitive test scores, depression, apathy, anxiety scores, MRI indexes, and fluid biomarkers remained stable, although fewer participants (50% vs. 75.5%; p = 0.012) exhibited abnormal cognitive evaluations at follow-up. Altered attention/executive and verbal memory, common in PACS, persisted in most subjects without association with structural abnormalities, elevated cytokines, or neuronal damage markers.

Abstract Many tropical landscapes have experienced the loss of traditional cultivation practices as they have transitioned to other land use systems. The Tanintharyi Region of southern Myanmar is a landscape experiencing a rapid land use regime shift from traditional subsistence farming to permanent cash crop agriculture. Despite previous research in this region on the expansion of large‐scale agribusiness, such as oil palm and rubber plantations, little is known about how the small‐scale shifting cultivation system practiced by the local Karen ethnic people in Tanintharyi has changed over recent decades or the underlying reasons for this transition. Our study explores this transition process and its drivers from a social and land system change perspective in four villages of Bokpyin Township in Tanintharyi. We investigated the drivers of land cover and land use change by collecting information through focus groups and individual interviews with community members who previously practised shifting cultivation. We also quantified the overall change in land cover and land use through remote sensing analysis of Landsat 8 (2020) and declassified KH‐9 satellite imagery (1976). Prior to a period of civil war in the 1980s, cultivators used a traditional ‘slash‐and‐burn’ agricultural system for subsistence use. The present land use system is dominated by permanent betel nut cultivation, which represents the primary income source for farming households. The reported drivers of the transition to cash crop farming are greater income potential and livelihood security, risk of losing fallow land due to the needs for new cultivation areas for in‐migration and new centralized land use policies and administration after the national ceasefire agreement in 2012. The documented change in land use systems has been paired with a concurrent net loss of forest that, given the conflicted governance within the landscape, seems likely to continue without additional land use planning efforts. Our study contributes to an increased understanding of changes in shifting cultivation systems that are being documented globally. Furthermore, our example of combining qualitative interviews with analysis of historical satellite imagery to detect and explain land use regime shifts can serve as a model for future work in different landscapes. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Background Low skeletal muscle mass (LSMM) and/or, function associated with an increased risk of treatment‐related toxicities and inferior overall survival (OS) among adults with solid malignancies. However, the association between LSMM and treatment‐related toxicities among adults with haematologic malignancies remains unclear. Methods Using a pre‐published protocol (CRD42020197814), we searched seven bibliographic databases from inception to 08/2021 for studies reporting the impact of LSMM among adults ≥18 years with a known haematologic malignancy. The primary outcome of interest was OS, and secondary outcomes included progression free survival (PFS) and non‐relapse mortality (NRM). These effect sizes were quantified in terms of hazards ratio (HR) along with 95% confidence interval (CI) and pooled across studies using a DerSimonian–Laird random‐effects model. Heterogeneity was assessed using the Cochran's Q and the I2 statistic. All hypothesis testing was two‐sided with an alpha of 0.05. Results Of 3791 studies screened, we identified 20 studies involving 3468 patients with a mean age of 60 years; 44% were female and the most common malignancy was diffuse large B‐cell lymphoma (42%). Most studies measured muscle mass using single slice computed tomography imaging at the L3 level. The presence of LSMM was associated with worse OS (pooled HR = 1.81, 95% CI = 1.48–2.22, P

Abstract Introduction Traditional methods for assessing movement quality rely on subjective standardized scales and clinical expertise. This limitation creates challenges for assessing patients with spinocerebellar ataxia (SCA), in whom changes in mobility can be subtle and varied. We hypothesized that a machine learning analytic system might complement traditional clinician-rated measures of gait. Our objective was to use a video-based assessment of gait dispersion to compare the effects of troriluzole with placebo on gait quality in adults with SCA. Methods Participants with SCA underwent gait assessment in a phase 3, double-blind, placebo-controlled trial of troriluzole (NCT03701399). Videos were processed through a deep learning pose extraction algorithm, followed by the estimation of a novel gait stability measure, the Pose Dispersion Index, quantifying the frame-by-frame symmetry, balance, and stability during natural and tandem walk tasks. The effects of troriluzole treatment were assessed in mixed linear models, participant-level grouping, and treatment group-by-visit week interaction adjusted for age, sex, baseline modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA), and time since diagnosis. Results From 218 randomized participants, 67 and 56 participants had interpretable videos of a tandem and natural walk attempt, respectively. At Week 48, individuals assigned to troriluzole exhibited significant (p = 0.010) improvement in tandem walk Pose Dispersion Index versus placebo {adjusted interaction coefficient: 0.584 [95% confidence interval (CI) 0.137 to 1.031]}. A similar, nonsignificant trend was observed in the natural walk assessment [coefficient: 1.198 (95% CI − 1.067 to 3.462)]. Further, lower baseline Pose Dispersion Index during the natural walk was significantly (p = 0.041) associated with a higher risk of subsequent falls [adjusted Poisson coefficient: − 0.356 [95% CI − 0.697 to − 0.014)]. Conclusion Using this novel approach, troriluzole-treated subjects demonstrated improvement in gait as compared to placebo for the tandem walk. Machine learning applied to video-captured gait parameters can complement clinician-reported motor assessment in adults with SCA. The Pose Dispersion Index may enhance assessment in future research. Trial Registration—ClinicalTrials.gov Identifier NCT03701399.

Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress β-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Abstract The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.