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Abstract Aims Use of novel anticoagulation in mechanical circulatory support is controversial. We report the rationale and design of the ApixiVad pilot trial, a pilot study testing the safety of apixaban as an anticoagulant in patients bridged to transplant (BTT) or for destination (DT) with Heartmate 3 (HM3) left ventricular assist device (LVAD). Methods and results Apixaban has been used in small non‐randomized cohorts in LVAD patients and shown to be effective in ex vivo studies. The ApixiVAD study examines apixaban use in a multicentre, international, open‐label, randomized, controlled trial aiming to include 50 BTT or DT HM3 patients with a 1:1 randomization ratio. This event‐driven study has a maximum follow‐up period of 24 months with interim analysis at 6 months. The primary outcome is death, thromboembolic events and major bleeding, including operative bleeding and immediate transplant outcomes. The secondary outcome focuses on patients' quality of life related to anticoagulation. This investigator‐driven pilot study is not powered to determine the non‐inferiority of apixaban. An increase in primary outcome in the apixaban group of 20% will be considered a signal of harm. Conclusions A positive outcome in the ApixiVAD study would provide the basis for future, larger, pivotal anticoagulation trials in LVAD patients.

Background The association between raised pulmonary artery pressures, pulmonary vascular resistance (PVR), and right‐sided heart dysfunction is well recognized. The added value of pulsatile indices, specifically pulmonary arterial compliance (PAC) and characteristic impedance, remains unclear. This study aimed to identify the optimal vascular afterload model for predicting right‐sided heart dysfunction in newly diagnosed pulmonary hypertension (PH). METHODS AND RESULTS This was a prospective cohort study of 86 patients with suspected PH (60±16 years; 66 women) who underwent right‐sided heart catheterization and cardiac magnetic resonance imaging. Right ventricular end‐diastolic volume index (RVEDVi) and right atrial (RA) volume index were measured using cardiac magnetic resonance imaging. Vascular resistance, PAC, and characteristic impedance were measured using pulmonary artery pressure from right‐sided heart catheterization and pulmonary artery flow from cardiac magnetic resonance imaging. Optimal model fit was determined by the lowest Akaike Information Criterion value. A total of 58% of patients had a right ventricular ejection fraction

Abstract The interrelationship between climate change, pollution and the aerobiome (the microbiome of the air) is a complex ecological dynamic with profound implications for human and ecosystem health. This mini‐review explores the multifaceted relationships among these factors. By synthesising existing research and integrating interdisciplinary perspectives, we examine the mechanisms driving interactions within the climate change–pollution–aerobiome nexus. We also explore synergistic and cascading effects and potential impacts on human health (including both communicable and non‐communicable diseases) and that of wider ecosystems. Based on our mini‐review results, climate change influences air pollution and, independently, air pollution affects the composition, diversity and activity of the aerobiome. However, we apply a ‘systems thinking’ approach and create a set of systems diagrams to show that climate change likely influences the aerobiome (including bacteria and fungi) via climate change–pollution interactions in complex ways. Due to the inherent complexity of these systems, we emphasise the importance of holistic and/or interdisciplinary approaches and collaborative efforts in understanding this nexus to safeguard planetary health in an era of rapid environmental change.

Abstract Within the Industry 4.0 landscape, humans collaborate with cyber and physical elements to form human‐cyber‐physical systems (HCPS). These environments are increasingly complex and challenging workspaces due to increasing levels of automation and data availability. An effective system design requires suitable frameworks that consider human activities and needs whilst supporting overall system efficacy. Although several reviews of frameworks for technology were identified, none of these focused on the human in the system (moving towards Industry 5). The critical literature review presented provides a summary of HCPS frameworks, maps the considerations for a human in HCPS, and provides insight for future framework and system development. The challenges, recommendations, and areas for further research are discussed.

Abstract Recent geophysical studies have highlighted the potential utility of integrating both seismic and infrasound data to improve source characterization and event discrimination efforts. However, the influence of each of these data types within an integrated framework is not yet well‐understood by the geophysical community. To help elucidate the role of each data type within a merged structure, we develop a neural network which fuses seismic and infrasound array data via a gated multimodal unit for earthquake‐explosion discrimination within the Korean Peninsula. Model performance is compared before and after adding the infrasound branch. We find that the seismoacoustic model outperforms the seismic model, with the majority of the improvements stemming from the explosions class. The influence of infrasound is quantified by analyzing gated multimodal activations. Results indicate that the model relies comparatively more on the infrasound branch to correct seismic predictions.

Abstract Atherosclerosis is the primary cause of cardiovascular disease, resulting in mortality, elevated healthcare costs, diminished productivity, and reduced quality of life for individuals and their communities. This is exacerbated by the limited understanding of its underlying causes and limitations in current therapeutic interventions, highlighting the need for sophisticated models of atherosclerosis. This review critically evaluates the computational and biological models of atherosclerosis, focusing on the study of hemodynamics in atherosclerotic coronary arteries. Computational models account for the geometrical complexities and hemodynamics of the blood vessels and stenoses, but they fail to capture the complex biological processes involved in atherosclerosis. Different in vitro and in vivo biological models can capture aspects of the biological complexity of healthy and stenosed vessels, but rarely mimic the human anatomy and physiological hemodynamics, and require significantly more time, cost, and resources. Therefore, emerging strategies are examined that integrate computational and biological models, and the potential of advances in imaging, biofabrication, and machine learning is explored in developing more effective models of atherosclerosis.

Abstract Organisms have evolved diverse strategies to manage parasite infections. Broadly, hosts may avoid infection by altering behaviour, resist infection by targeting parasites or tolerate infection by repairing associated damage. The effectiveness of a strategy depends on interactions between, for example, resource availability, parasite traits (virulence, life‐history) and the host itself (nutritional status, immunopathology). To understand how these factors shape host parasite‐mitigation strategies, we developed a mathematical model of within‐host, parasite‐immune dynamics in the context of helminth infections. The model incorporated host nutrition and resource allocation to different mechanisms of immune response: larval parasite prevention; adult parasite clearance; damage repair (tolerance). We also considered a non‐immune strategy: avoidance via anorexia, reducing intake of infective stages. Resources not allocated to immune processes promoted host condition, whereas harm due to parasites and immunopathology diminished it. Maximising condition (a proxy for fitness), we determined optimal host investment for each parasite‐mitigation strategy, singly and combined, across different environmental resource levels and parasite trait values. Which strategy was optimal varied with scenario. Tolerance generally performed well, especially with high resources. Success of the different resistance strategies (larval prevention or adult clearance) tracked relative virulence of larval and adult parasites: slowly maturing, highly damaging larvae favoured prevention; rapidly maturing, less harmful larvae favoured clearance. Anorexia was viable only in the short term, due to reduced host nutrition. Combined strategies always outperformed any lone strategy: these were dominated by tolerance, with some investment in resistance. Choice of parasite mitigation strategy has profound consequences for hosts, impacting their condition, survival and reproductive success. We show that the efficacy of different strategies is highly dependent on timescale, parasite traits and resource availability. Models that integrate such factors can inform the collection and interpretation of empirical data, to understand how those drivers interact to shape host immune responses in natural systems.

Abstract Aims There is limited data describing major adverse kidney events (MAKE) in patients supported with ventricular assist devices (VAD). We aim to describe the association between MAKE and survival, risk factors for MAKE, and renal trajectory in VAD supported patients. Methods and results We conducted a single‐centre retrospective analysis of consecutive VAD implants between 2010 and 2019. Baseline demographics, biochemistry, and adverse events were collected for the duration of VAD support. MAKE was defined as the first event to occur of sustained drop (>50%) in estimated glomerular filtration rate (eGFR), progression to stage V chronic kidney disease, initiation or continuation of renal replacement therapy beyond implant admission or death on renal replacement therapy at any time. One‐hundred and seventy‐three patients were included, median age 56.8 years, 18.5% female, INTERMACS profile 1 or 2 in 75.1%. Thirty‐seven patients experienced MAKE. On multivariate analysis, post‐implant clinical right ventricular failure and the presence of chronic haemolysis, defined by the presence of schistocytes on blood film analysis, were significantly associated with increased risk of MAKE (adjusted odds ratio 9.88, P

Objective The scope of clinical practice of pediatric rheumatology has been difficult to define. The lack of definition prevents an accurate understanding of the knowledge and skills required of practicing pediatric rheumatologists. A practice analysis process was used with the goal of establishing a precise definition of clinical pediatric rheumatology practice. The definition of practice will improve training and the creation of relevant certification examinations. Methods A practice analysis approach used meetings with a representative panel of pediatric rheumatologists to create a practice analysis document (PAD) and a test content outline (TCO). Panel experience, entrustable professional activities, and the current TCO were used to guide the process. Surveys were administered to fellowship program directors (PDs) and a broader group of practicing pediatric rheumatologists to revise and validate the content of the documents. Results A PAD was created, including 14 categories of conditions diagnosed or managed by pediatric rheumatologists and eight domains of practice, with the tasks, knowledge, and skills required to perform these tasks. The survey of PDs (n = 10) indicated that the PAD content is important and useful. A TCO was created and consists of 18 domains used to define content areas to be assessed on certifying examinations. The survey of practicing pediatric rheumatologists (n = 127) indicated that the TCO domains are relevant. Conclusion A practice analysis process produced valuable resources for defining the clinical practice of pediatric rheumatology. The PAD and TCO can be used to develop more specific training curricula and to create relevant certification examinations.

Abstract Climate change and increasing human activities are impacting ecosystems and their biodiversity. Quantitative measurements of essential biodiversity variables (EBV) and essential climate variables are used to monitor biodiversity and carbon dynamics and evaluate policy and management interventions. Ecosystem structure is at the core of EBVs and carbon stock estimation and can help to inform assessments of species and species diversity. Ecosystem structure is also used as an indirect indicator of habitat quality and expected species richness or species community composition. Spaceborne measurements can provide large‐scale insight into monitoring the structural dynamics of ecosystems, but they generally lack consistent, robust, timely and detailed information regarding their full three‐dimensional vegetation structure at local scales. Here we demonstrate the potential of high‐frequency ground‐based laser scanning to systematically monitor structural changes in vegetation. We present a proof‐of‐concept high‐temporal ecosystem structure time series of 5 years in a temperate forest using terrestrial laser scanning (TLS). We also present data from automated high‐temporal laser scanning that can allow upscaling of vegetation structure scanning, overcoming the limitations of a typically opportunistic TLS measurement approach. Automated monitoring will be a critical component to build a network of field monitoring sites that can provide the required calibration data for satellite missions to effectively monitor the structural dynamics of vegetation over large areas. Within this perspective, we reflect on how this network could be designed and discuss implementation pathways.

Heart failure occurs when the heart cannot pump adequate blood to the body, which afflicts over 60 million people worldwide. Its treatment options include physiotherapy, medication, mechanical heart support, heart surgery, or heart transplantation. Ventricular assist devices have direct blood contact while passive ventricular constraint devices have only modest therapeutic efficacy. Current direct cardiac compression devices are either bulky, require noisy driving pneumatic sources, or are unable to mimic the natural heart motion. This study introduces a robotic cardiac compression device made of soft artificial muscle filaments that can simultaneously produce radial, axial, and torsional movements, potentially augmenting the pumping function of a failing heart. An empirical model is developed to describe the device motion and an artificial pericardium is employed to enable uniform force distribution to the heart and real‐time pressure sensing. The proposed device could deliver a stroke volume of 70 mL at 15 beats per minute, or a cardiac output of 1.05 L min−1, and achieve a peak instantaneous flow rate of 2.8 L min−1 and an output pressure of 50 mmHg. The new devices are highly customizable and experimentally validated with fresh porcine heart. They are expected to inspire future development of nonblood‐contacting cardiac assist devices.

Abstract Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas‐entrapping material containing CO in a pre‐clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

Abstract Recent work has demonstrated that many bee species have specific cytochrome P450 enzymes (P450s) that can efficiently detoxify certain insecticides. The presence of these P450s, belonging or closely related to the CYP9Q subfamily (CYP9Q‐related), is generally well conserved across the diversity of bees. However, the alfalfa leafcutter bee, Megachile rotundata, lacks CYP9Q‐related P450s and is 170–2500 times more sensitive to certain insecticides than bee pollinators with these P450s. The extent to which these findings apply to other Megachilidae bee species remains uncertain. To address this knowledge gap, we sequenced the transcriptomes of four Megachile species and leveraged the data obtained, in combination with publicly available genomic data, to investigate the evolution and function of P450s in the Megachilidae. Our analyses reveal that several Megachilidae species, belonging to the Lithurgini, Megachilini and Anthidini tribes, including all species of the Megachile genus investigated, lack CYP9Q‐related genes. In place of these genes Megachile species have evolved phylogenetically distinct CYP9 genes, the CYP9DM lineage. Functional expression of these P450s from M. rotundata reveal they lack the capacity to metabolize the neonicotinoid insecticides thiacloprid and imidacloprid. In contrast, species from the Osmiini and Dioxyini tribes of Megachilidae have CYP9Q‐related P450s belonging to the CYP9BU subfamily that are able to detoxify thiacloprid. These findings provide new insight into the evolution of P450s that act as key determinants of insecticide sensitivity in bees and have important applied implications for pesticide risk assessment.

Abstract Aims The pulmonary artery pulsatility index (PAPi) is a novel haemodynamic marker that has previously been shown to predict right ventricular dysfunction and mortality in patients with pulmonary hypertension and advanced heart failure. Utility of the PAPi in predicting outcomes post‐cardiac transplantation is unknown. The aim of this study was to compare the prognostic significance of PAPi against pulmonary vascular resistance (PVR) for the predication of morbidity and all‐cause mortality post‐transplantation. Methods and results All patients who underwent cardiac transplantation over a 6 year period were studied. Pre‐operative right heart catheter data was obtained. The PAPi was calculated as follows: (systolic pulmonary artery pressure [sPAP] − diastolic pulmonary artery pressure [dPAP])/right atrial (RA) pressure. One hundred fifty‐eight patients with a mean age of 49 ± 14 years were studied (43 with a pre‐transplant left ventricular assist device [LVAD]). Three patients were excluded due to missing data. In the non‐LVAD group, there was no significant difference in PAPi or PVR, nor was there any association with post‐operative outcome (including stratification by natural history sub‐type; all P > 0.05). In the LVAD group, there was no association with PAPi and post‐operative outcome; however, PVR was predictive of post‐operative mortality (mortality: 2.8 ± 1.3 WU vs. alive: 1.7 ± 0.7 WU; P = 0.005). Conclusions The PAPi was not able to discriminate mortality outcomes for patients post‐cardiac transplantation. Pulmonary vascular resistance remains a marker of mortality in an LVAD cohort bridged to transplant (central illustration).

Abstract Background The effect of pulmonary hypertension (PH) on right ventricular (RV) afterload is commonly defined by elevation of pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR). In humans however, one‐third to half of the hydraulic power in the PA is contained in pulsatile components of flow. Pulmonary impedance (Zc) expresses opposition of the PA to pulsatile blood flow. We evaluate pulmonary Zc relationships according to PH classification using a cardiac magnetic resonance (CMR)/right heart catheterization (RHC) method. Methods Prospective study of 70 clinically indicated patients referred for same‐day CMR and RHC [60 ± 16 years; 77% females, 16 mPAP

Abstract Background The NLRP3 inflammasome drives release of pro‐inflammatory cytokines including interleukin (IL)‐1β and IL‐18 and is a potential target for ulcerative colitis (UC). Selnoflast (RO7486967) is an orally active, potent, selective and reversible small molecule NLRP3 inhibitor. We conducted a randomized, placebo‐controlled Phase 1b study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selnoflast. Methods Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL‐1β inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated. Results Selnoflast was well‐tolerated. Plasma concentrations increased rapidly after oral administration, reaching Tmax 1 h post‐dose. Mean plasma concentrations stayed above the IL‐1β IC90 level throughout the dosing interval (mean Ctrough on Day 1 and Day 5: 2.55 μg/mL and 2.66 μg/mL, respectively). At steady state, post‐dose selnoflast concentrations in sigmoid colon (5‐20 μg/g) were above the IC90. Production of IL‐1β was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL‐18 levels. There were no meaningful differences in the expression of an IL‐1‐related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers. Conclusions Selnoflast was safe and well‐tolerated. Selnoflast 450 mg QD achieved plasma and tissue exposure predicted to maintain IL‐1β IC90 over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL‐1β in tissue. Trial registration ISRCTN16847938

Abstract Introduction The Nurture Early for Optimal Nutrition (NEON) study is a multiphase project that aims to optimize feeding, care and dental hygiene practices in South Asian children

Abstract Introduction Novel point‐of‐care assays which measure urine tenofovir (TFV) concentrations may have a role in improving adherence monitoring for people living with HIV (PLHIV) receiving antiretroviral therapy (ART). However, further studies of their diagnostic accuracy, and whether results are associated with viraemia and drug resistance, are needed to guide their use, particularly in the context of the global dolutegravir rollout. Methods We conducted a cross‐sectional evaluation among PLHIV receiving first‐line ART containing tenofovir disoproxil fumarate at enrolment into a randomized trial in two South African public sector clinics. We calculated the diagnostic accuracy of the Abbott point‐of‐care immunoassay to detect urine TFV compared to liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). We evaluated the association between point‐of‐care urine TFV results and self‐reported adherence, viraemia ≥1000 copies/ml and HIV drug resistance, among people receiving either efavirenz or dolutegravir‐based ART. Results Between August 2020 and March 2022, we enrolled 124 participants. The median age was 39 (IQR 34–45) years, 55% were women, 74 (59.7%) were receiving efavirenz and 50 (40.3%) dolutegravir. The sensitivity and specificity of the immunoassay to detect urine TFV ≥1500 ng/ml compared to LC‐MS/MS were 96.1% (95% CI 90.0−98.8) and 95.2% (75.3−100.0), respectively. Urine TFV results were associated with short (p

Abstract Trade‐offs between host resistance to parasites and host growth or reproduction can occur due to allocation of limited available resources between competing demands. To predict potential trade‐offs arising from genetic selection for host resistance, a better understanding of the associated nutritional costs is required. Here, we studied resistance costs by using sheep from lines divergently selected on their resistance to a common blood‐feeding gastro‐intestinal parasite (Haemonchus contortus). First, we assessed the effects of selection for high or low host resistance on condition traits (body weight, back fat, and muscle thickness) and infection traits (parasite fecal egg excretion and loss in blood haematocrit) at various life stages, in particular during the periparturient period when resource allocation to immunity may limit host resistance. Second, we analysed the condition–infection relationship to detect a possible trade‐off, in particular during the periparturient period. We experimentally infected young females in four stages over their first 2 years of life, including twice around parturition (at 1 year and at 2 years of age). Linear mixed‐model analyses revealed a large and consistent between‐line difference in infection traits during growth and outside of the periparturient period, whereas this difference was strongly attenuated during the periparturient period. Despite their different responses to infection, lines had similar body condition traits. Using covariance decomposition, we then found that the phenotypic relationship between infection and condition was dominated by direct infection costs arising from parasite development within the host. Accounting for these within‐individual effects, a cost of resistance on body weight was detected among ewes during their first reproduction. Although this cost and the reproductive constraint on resistance are unlikely to represent a major concern for animal breeding in nutrient‐rich environments, this study provides important new insights regarding the nutritional costs of parasite resistance at different lifestages and how these may affect response to selection.

Abstract It is of increasing importance to understand and predict changes to the systemic and pulmonary circulations in pulmonary hypertension (PH). To do so, it is necessary to describe the circulation in complete quantitative terms. Characteristic impedance (Zc) expresses opposition of the circulation to pulsatile blood flow. Evaluation of systemic and pulmonary Zc relationships according to PH classification has not previously been described. Prospective study of 40 clinically indicated patients referred for CMR and RHC (56 ± 18 years; 70% females, eight mPAP ≤ 25 mmHg, 16 pre‐capillary [Pre‐cPH], eight combined pre‐ and post‐capillary [Cpc‐PH] and eight isolated left‐heart disease [Ipc‐PH]). CMR provided assessment of ascending aortic (Ao) and pulmonary arterial (PA) flow, and RHC, central Ao and PA pressure. Systemic and pulmonary Zc were expressed as the relationship of pressure to flow in the frequency domain. Baseline demographic characteristics were well‐matched across PH subclasses. In those with a mPAP ≤25mHg, systemic Zc and SVR were >2 times higher than pulmonary Zc and PVR. Only Pre‐cPH was associated with inverse pulsatile (systemic Zc 58 [45–69] vs pulmonary Zc 70 [58–85]), but not steady‐state (SVR 1101 [986–1752] vs. PVR 483 [409–557]) relationships. Patients with CpcPH and IpcPH had concordant pulsatile and steady‐state relationships (Graphical Abstract). Measurement of, and the relationship between, systemic and pulmonary Zc in patients according to PH sub‐classification has not previously been described. Systemic Zc was routinely higher than pulmonary Zc, except in patients with newly diagnosed Pre‐cPH, where inverse pulsatile but not steady‐state relationships were observed.

Abstract Aims The CardioMEMS HF System Post‐Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic‐guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. Methods and results COAST is a prospective, international, multicentre, open‐label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic‐guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system‐related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72–88%] than the previous 12 months (0.27 vs. 1.52 events/patient‐year, respectively, P

Abstract Aims This study aimed to describe haemodynamic features of patients with advanced heart failure with preserved ejection fraction (HFpEF) as defined by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Methods and results We used pooled data from two dedicated HFpEF studies with invasive exercise haemodynamic protocols, the REDUCE LAP‐HF (Reduce Elevated Left Atrial Pressure in Patients with Heart Failure) trial and the REDUCE LAP‐HF I trial, and categorized patients according to advanced heart failure (AdHF) criteria. The well‐characterized HFpEF patients were considered advanced if they had persistent New York Heart Association classification of III–IV and heart failure (HF) hospitalization

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by a mutation in the dystrophin gene. In addition to muscle pathology, some patients with DMD will exhibit cognitive impairments with severity being linked to age and type of genetic mutation. Likewise, some studies have shown that mdx mice display impairments in spatial memory compared with wild‐type (WT) controls, while others have not observed any such effect. Most studies have utilized the traditional C57BL/10 (C57) mdx mouse, which exhibits a mild disease phenotype. Recently, the DBA/2J (D2) mdx mouse has emerged as a more severe and perhaps clinically relevant DMD model; however, studies examining cognitive function in these mice are limited. Thus, in this study we examined cognitive function in age‐matched C57 and D2 mdx mice along with their respective WT controls. Our findings show that 8‐ to 12‐week‐old C57 mdx mice did not display any differences in exploration time when challenged with a novel object recognition test. Conversely, age‐matched D2 mdx mice spent less time exploring objects in total as a well as less time exploring the novel object, suggestive of impaired recognition memory. Biochemical analyses of the D2 mdx brain revealed higher soluble amyloid precursor protein β (APPβ) and APP in the prefrontal cortex of mdx mice compared with WT, and lower soluble APPα in the hippocampus, suggestive of a shift towards amyloidogenesis and a similar pathogenesis to Alzheimer's disease. Furthermore, our study demonstrates the utility of the D2 mdx model in studying cognitive impairment.

Abstract Objective To risk‐stratify COVID‐19 patients being considered for discharge from the emergency department (ED). Methods We conducted an observational study to derive and validate a clinical decision rule to identify COVID‐19 patients at risk for hospital admission or death within 72 hours of ED discharge. We used data from 49 sites in the Canadian COVID‐19 Emergency Department Rapid Response Network (CCEDRRN) between March 1, 2020, and September 8, 2021. We randomly assigned hospitals to derivation or validation and prespecified clinical variables as candidate predictors. We used logistic regression to develop the score in a derivation cohort and examined its performance in predicting short‐term adverse outcomes in a validation cohort. Results Of 15,305 eligible patient visits, 535 (3.6%) experienced the outcome. The score included age, sex, pregnancy status, temperature, arrival mode, respiratory rate, and respiratory distress. The area under the curve was 0.70 (95% confidence interval [CI] 0.68–0.73) in derivation and 0.71 (95% CI 0.68–0.73) in combined derivation and validation cohorts. Among those with a score of 3 or less, the risk for the primary outcome was 1.9% or less, and the sensitivity of using 3 as a rule‐out score was 89.3% (95% CI 82.7–94.0). Among those with a score of ≥9, the risk for the primary outcome was as high as 12.2% and the specificity of using 9 as a rule‐in score was 95.6% (95% CI 94.9–96.2). Conclusion The CCEDRRN COVID discharge score can identify patients at risk of short‐term adverse outcomes after ED discharge with variables that are readily available on patient arrival.

Abstract Objectives Patients with laryngeal squamous cell carcinoma (LSCC) often fail radiation therapy (RT), when received as monotherapy or in combination with other treatment modalities. Mechanisms for RT failure are poorly understood. We hypothesized that tumors failing RT would have increased rates of somatic mutations in genes associated with radiation resistance, particularly in genes associated with the NFE2L2 oxidative stress pathway. Using targeted exome sequencing on pretreated LSCC tumors, we retrospectively compared somatic mutation profile with clinical data and response to treatment. Methods Tumors were classified as either radiation‐resistant (RR) or radiation‐sensitive (RS). RR was defined as persistent or recurrent disease within 2 years of receiving full‐dose RT. Early stage (ES) LSCC was defined as Stage I or II tumors without lymph node involvement. Eight genes associated with radiation resistance were prioritized for analysis. RT‐qPCR was performed on five NFE2L2 pathway genes. Results Twenty LSCC tumors were included and classified as either RR (n = 8) or RS (n = 12). No differences in individual rates of somatic mutations by genes associated with radiation resistance were identified. Higher rates of total mutational burden (TMB) and increased alterations associated with the NFE2L2 pathway was observed in RR vs RS tumors (P

Abstract The common chimpanzee Pan troglodytes is the closest extant relative of modern humans and is often used as a model organism to help understand prehistoric human behavior and ecology. Originally presumed herbivorous, chimpanzees have been observed hunting 24 species of birds, ungulates, rodents, and other primates, using an array of techniques from tools to group cooperation. Using the literature on chimpanzee hunting behavior and diet from 13 studies, we aimed to determine the prey preferences of chimpanzees. We extracted data on prey‐specific variables such as targeted species, their body weight, and their abundance within the prey community, and hunter‐specific variables such as hunting method, and chimpanzee group size and sex ratio. We used these data in a generalized linear model to determine what factors drive chimpanzee prey preference. We calculated a Jacobs’ index value for each prey species killed at two sites in Uganda and two sites in Tanzania. Chimpanzees prefer prey with a body weight of 7.6 ± 0.4 kg or less, which corresponds to animals such as juvenile bushbuck (Tragelaphus scriptus) and adult ashy red colobus monkeys (Piliocolobus tephrosceles). Sex ratio in chimpanzee groups is a main driver in developing these preferences, where chimpanzees increasingly prefer prey when in proportionally male‐dominated groups. Prey preference information from chimpanzee research can assist conservation management programs by identifying key prey species to manage, as well as contribute to a better understanding of the evolution of human hunting behavior.

Abstract The squirrel glider (Petaurus norfolcensis) is a threatened, gliding marsupial that persists in fragmented landscapes despite its restricted capacity to cross large gaps. As measures to maintain and/or restore suitable habitat depend on knowledge about the species' ecological requirements, we investigated the area used by squirrel gliders in an urban area near Newcastle, Australia. Using GPS telemetry data and the autocorrelated kernel density estimator, we estimated area used to average 10.8 ha and varied from 4.6 to 15 ha, which is equal to or greater than found in previous studies that spanned longer time periods. This has implications when identifying the minimum patch size necessary for ensuring the long‐term conservation of a squirrel glider population.

Abstract Background and Aim Health‐related quality‐of‐life measurements are important to understand lived experiences of patients who have cirrhosis. These measures also inform economic evaluations by modelling quality‐adjusted life years (QALYs). We aimed to describe health‐related quality of life, specifically multiattribute utility (scale anchors of death = 0.00 and full health = 1.00), across various stages and etiologies of cirrhosis. Methods Face‐to‐face interviews were used to collect Short Form 36 (SF‐36) questionnaire responses from CirCare study participants with cirrhosis (June 2017 to December 2018). The severity of cirrhosis was assessed using the Child‐Pugh score classified as class A (5–6 points), B (7–9), or C (10–15) and by the absence (“compensated”) versus presence (“decompensated”) of cirrhosis‐related complications. Results Patients (n = 562, average 59.8 years [SD = 11.0], male 69.9%) had a range of primary etiologies (alcohol‐related 35.2%, chronic hepatitis C 25.4%, non‐alcoholic fatty liver disease (NAFLD) 25.1%, chronic hepatitis B 5.9%, “other” 8.4%). Significantly lower (all P

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper‐limb sensorimotor impairment. We investigated associations between non‐lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross‐sectional T1‐weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta‐Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA‐UE (Fugl‐Meyer Assessment of Upper Extremity). Robust mixed‐effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni‐corrected, P

Background Most adults presenting with chest pain will not receive a diagnosis and be recorded with unattributed chest pain. The objective was to assess if they have increased risk of cardiovascular disease compared with those with noncoronary chest pain and determine whether investigations and interventions are targeted at those at highest risk. Methods and Results We used records from general practices in England linked to hospitalization and mortality information. The study population included patients aged 18 years or over with a new record of chest pain with a noncoronary cause or unattributed between 2002 and 2018, and no cardiovascular disease recorded up to 6 months (diagnostic window) afterward. We compared risk of a future cardiovascular event by type of chest pain, adjusting for cardiovascular risk factors and alternative explanations for chest pain. We determined prevalence of cardiac diagnostic investigations and preventative medication during the diagnostic window in patients with estimated cardiovascular risk ≥10%. There were 375 240 patients with unattributed chest pain (245 329 noncoronary chest pain). There was an increased risk of cardiovascular events for patients with unattributed chest pain, highest in the first year (hazard ratio, 1.25 [95% CI, 1.21–1.29]), persistent up to 10 years. Patients with unattributed chest pain had consistently increased risk of myocardial infarction over time but no increased risk of stroke. Thirty percent of patients at higher risk were prescribed lipid‐lowering medication. Conclusions Patients presenting to primary care with unattributed chest pain are at increased risk of cardiovascular events. Primary prevention to reduce cardiovascular events appears suboptimal in those at higher risk.

Abstract Predicting the consequences of environmental changes, including human‐mediated climate change on species, requires that we quantify range‐wide patterns of genetic diversity and identify the ecological, environmental, and historical factors that have contributed to it. Here, we generate baseline data on polar bear population structure across most Canadian subpopulations (n = 358) using 13,488 genome‐wide single nucleotide polymorphisms (SNPs) identified with double‐digest restriction site‐associated DNA sequencing (ddRAD). Our ddRAD dataset showed three genetic clusters in the sampled Canadian range, congruent with previous studies based on microsatellites across the same regions; however, due to a lack of sampling in Norwegian Bay, we were unable to confirm the existence of a unique cluster in that subpopulation. These data on the genetic structure of polar bears using SNPs provide a detailed baseline against which future shifts in population structure can be assessed, and opportunities to develop new noninvasive tools for monitoring polar bears across their range.

Abstract Continuous monitoring in the intensive care setting has transformed the capacity to rapidly respond with interventions for patients in extremis. Noninvasive monitoring has generally been limited to transdermal or intravascular systems coupled to transducers including oxygen saturation or pressure. Here it is hypothesized that gastric fluid (GF) and gases, accessible through nasogastric (NG) tubes, commonly found in intensive care settings, can provide continuous access to a broad range of biomarkers. A broad characterization of biomarkers in swine GF coupled to time‐matched serum is conducted . The relationship and kinetics of GF‐derived analyte level dynamics is established by correlating these to serum levels in an acute renal failure and an inducible stress model performed in swine. The ability to monitor ketone levels and an inhaled anaesthetic agent (isoflurane) in vivo is demonstrated with novel NG‐compatible sensor systems in swine. Gastric access remains a main stay in the care of the critically ill patient, and here the potential is established to harness this establishes route for analyte evaluation for clinical management.