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Abstract Background Seizure emergencies (ie, status epilepticus [SE] and cluster seizures [CS]), are common challenging disorders with complex pathophysiology, rapidly progressive drug‐resistant and self‐sustaining character, and high morbidity and mortality. Current treatment approaches are characterized by considerable variations, but official guidelines are lacking. Objectives To establish evidence‐based guidelines and an agreement among board‐certified specialists for the appropriate management of SE and CS in dogs and cats. Animals None. Materials and Methods A panel of 5 specialists was formed to assess and summarize evidence in the peer‐reviewed literature with the aim to establish consensus clinical recommendations. Evidence from veterinary pharmacokinetic studies, basic research, and human medicine also was used to support the panel's recommendations, especially for the interventions where veterinary clinical evidence was lacking. Results The majority of the evidence was on the first‐line management (ie, benzodiazepines and their various administration routes) in both species. Overall, there was less evidence available on the management of emergency seizure disorders in cats in contrast to dogs. Most recommendations made by the panel were supported by a combination of a moderate level of veterinary clinical evidence and pharmacokinetic data as well as studies in humans and basic research studies. Conclusions and Clinical Relevance Successful management of seizure emergencies should include an early, rapid, and stage‐based treatment approach consisting of interventions with moderate to preferably high ACVIM recommendations; management of complications and underlying causes related to seizure emergencies should accompany antiseizure medications.

Background The Society for Cardiovascular Angiography and Interventions proposed a staging system (A–E) to predict prognosis in cardiogenic shock. Herein, we report clinical outcomes of the RECOVER III study for the first time, according to Society for Cardiovascular Angiography and Interventions shock classification. Methods and Results The RECOVER III study is an observational, prospective, multicenter, single‐arm, postapproval study of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support. Patients enrolled in the RECOVER III study were assigned a baseline Society for Cardiovascular Angiography and Interventions shock stage. Staging was then repeated within 24 hours after initiation of Impella. Kaplan‐Meier survival curve analyses were conducted to assess survival across Society for Cardiovascular Angiography and Interventions shock stages at both time points. At baseline assessment, 16.5%, 11.4%, and 72.2% were classified as stage C, D, and E, respectively. At ≤24‐hour assessment, 26.4%, 33.2%, and 40.0% were classified as stage C, D, and E, respectively. Thirty‐day survival among patients with stage C, D, and E shock at baseline was 59.7%, 56.5%, and 42.9%, respectively (P=0.003). Survival among patients with stage C, D, and E shock at ≤24 hours was 65.7%, 52.1%, and 29.5%, respectively (P

Abstract Background The HMGA2:c.83G>A variant was identified in Welsh ponies having pleiotropic effects on height and insulin concentration. Objective Determine whether the HMGA2:c.83G>A variant is associated with decreased height and higher basal insulin concentrations across pony breeds. Animals Two hundred thirty‐six ponies across 6 breeds. Methods Cross‐sectional study. Ponies were genotyped for the HMGA2:c.83G>A variant and phenotyped for height and basal insulin concentrations. Stepwise regression was performed for model analysis using a linear regression model for height and mixed linear model for insulin with farm as a random effect. Coefficient of determination, pairwise comparison of the estimated marginal means and partial correlation coefficients (parcor) were calculated to assess the relationship between HMGA2 genotype and height or insulin. Results Breed and genotype accounted for 90.5% of the variation in height across breeds, and genotype explained 21% to 44% of the variation within breeds. Breed, genotype, cresty neck score, sex, age, and farm accounted for 45.5% of the variation in insulin, with genotype accounting for 7.1%. The HMGA2 A allele frequency was 62% and correlated with both height (parcor = −0.39; P 10 cm shorter than other genotypes. Compared with G/G individuals, A/A and G/A individuals had 4.3 μIU/mL (95% confidence interval [CI]: 1.8‐10.5) and 2.7 μIU/mL (95% CI: 1.4‐5.3) higher basal insulin concentrations, respectively. Conclusions and Clinical Importance These data demonstrate the pleiotropic effects of the HMGA2:c.83G>A variant and its role in identifying ponies at increased risk for insulin dysregulation.

Abstract Bacterial extracellular vesicles (BEVs) contribute to stress responses, quorum sensing, biofilm formation and interspecies and interkingdom communication. However, the factors that regulate their release and heterogeneity are not well understood. We set out to investigate these factors in the common gut commensal Bacteroides thetaiotaomicron by studying BEV release throughout their growth cycle. Utilising a range of methods, we demonstrate that vesicles released at different stages of growth have significantly different composition, with early vesicles enriched in specifically released outer membrane vesicles (OMVs) containing a larger proportion of lipoproteins, while late phase BEVs primarily contain lytic vesicles with enrichment of cytoplasmic proteins. Furthermore, we demonstrate that lipoproteins containing a negatively charged signal peptide are preferentially incorporated in OMVs. We use this observation to predict all Bacteroides thetaiotaomicron OMV enriched lipoproteins and analyse their function. Overall, our findings highlight the need to understand media composition and BEV release dynamics prior to functional characterisation and define the theoretical functional capacity of Bacteroides thetaiotaomicron OMVs.

Abstract Sarcopenia measured through body composition analysis is emerging as an important prognosticator among various malignancies, including oesophageal cancer. Skeletal muscle index (SMI) as determined by the third lumbar vertebrae on cross‐sectional CT images has been demonstrated as a predictor of overall survival in oesophageal cancer, using pre‐defined cut off values for sarcopenia. However, this is largely within the setting of resectable disease. The primary objective of this systematic review and meta‐analysis was to determine the effect of sarcopenia defined by SMI on overall‐survival in patients with unresectable oesophageal cancer. On 30 January 2021, a systematic search of the literature was conducted to identify the role of SMI among patients with unresectable oesophageal cancer, with overall survival as the primary outcome. Databases included MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library. Inclusion criteria included age >18, diagnosis of oesophageal cancer, and non‐operative management. A meta‐analysis was conducted using RevMan 5.4.1 using an inverse variance, random effects model. After the removal of duplicates, 2755 unique search results were obtained. Manual screening of titles and abstracts resulted in 287 full text articles that were reviewed. Of these, five studies met the inclusion criteria with data evaluating the effect of sarcopenia defined by SMI on overall survival. A total of 783 patients, the majority of which were male (n = 638, 81%), with a mean age of 68 ± 2.3 years were included. 641 (82%) patients were diagnosed with squamous cell carcinoma. Sarcopenia, as determined by SMI using pre‐defined cut‐off values, was reported in 517 patients (66%). Meta‐analysis demonstrated decreased overall survival in the sarcopenia group compared with the non‐sarcopenia group (HR = 1.51; 95% CI 1.21–1.89; P = 0.0003; I2 = 0%; Figure 1). No significant publication bias was noted on assessment of funnel plot and Egger's test (P = 0.295). Sarcopenia as defined by SMI is predictive of overall survival among patients with nonoperative oesophageal cancer. Further analysis on the effect of sarcopenia on treatment related adverse effects and complications, particularly related to chemotherapy, radiotherapy, and oesophageal stenting, is needed to identify the degree of prognostication offered by body composition analysis. Studies on the modifiability of sarcopenia will help determine the utility of nutritional interventions.

Abstract Background Expression of the urokinase plasminogen activator receptor (uPAR) is elevated in the airway epithelium in asthma; however, the contribution of uPAR to asthma pathogenesis and scope for therapeutic targeting remains unknown. Objectives To determine (i) the expression profile of uPAR in cultured human bronchial epithelial cells (HBEC) from asthma patients, (ii) the relationship between uPAR and the epithelial barrier, including blocking uPAR functions and (iii) the function of different uPAR isoforms. Methods uPAR levels in HBECs isolated from asthma patients and cells at air liquid interface (ALI) during differentiation were quantified. Transepithelial electrical resistance or electrical cell impedance sensing was used to relate uPAR levels to barrier properties, including effects of uPAR blocking antibodies. The functional effects of gain of function was determined using transcriptomics, in cells over‐expressing membrane (muPAR), soluble cleaved (scuPAR) or soluble spliced (ssuPAR) isoforms. Results Elevated expression of uPAR was a feature of cultured HBECs from asthma patients, suggesting intrinsic alterations in asthma patient cells. Soluble uPAR levels inversely correlated with barrier properties of the HBEC layer in 2D and ALI. Blocking uPAR‐integrin interactions enhanced barrier formation. The gain of function cells showed limited transcriptomic changes. Conclusion This study provides a significant advance in our understanding of the relationship between asthma, uPAR and the epithelial barrier, where elevated circulating uPAR results in a reduced cell barrier, a phenotype prevalent in asthma.

Abstract Bacterial extracellular vesicles (BEVs) are increasingly seen as key signalling mediators between the gut microbiota and the host. Recent studies have provided evidence of BEVs ability to transmigrate across cellular barriers to elicit responses in other tissues, such as the central nervous system (CNS). Here we use a combination of single‐, two‐ and three‐cell culture systems to demonstrate the transmigration of Bacteroides thetaiotaomicron derived BEVs (Bt‐BEVs) across gut epithelium and blood brain barrier (BBB) endothelium, and their subsequent acquisition and downstream effects in neuronal cells. Bt‐BEVs were shown to traffic to the CNS in vivo after intravenous administration to mice, and in multi‐cell in vitro culture systems to transmigrate across gut epithelial and BBB endothelial cell barriers, where they were acquired by both microglia and immature neuronal cells. No significant activation/inflammatory effects were induced in non‐differentiated neurons, in contrast to that observed in microglia cells, although this was notably less than that induced by lipopolysaccharide (LPS). Overall, our findings provide evidence for transmigration of Bt‐BEVs across gut‐epithelial and BBB endothelial cell barriers in vivo and in vitro, and their downstream responses in neural cells. This study sheds light onto how commensal bacteria‐derived BEV transport across the gut‐brain axis and can be exploited for the development of targeted drug delivery.

Abstract INTRODUCTION Although many cognitive measures have been developed to assess cognitive decline due to Alzheimer's disease (AD), there is little consensus on optimal measures, leading to varied assessments across research cohorts and clinical trials making it difficult to pool cognitive measures across studies. METHODS We used a two‐stage approach to harmonize cognitive data across cohorts and derive a cross‐cohort score of cognitive impairment due to AD. First, we pool and harmonize cognitive data from international cohorts of varying size and ethnic diversity. Next, we derived cognitive composites that leverage maximal data from the harmonized dataset. RESULTS We show that our cognitive composites are robust across cohorts and achieve greater or comparable sensitivity to AD‐related cognitive decline compared to the Mini‐Mental State Examination and Preclinical Alzheimer Cognitive Composite. Finally, we used an independent cohort validating both our harmonization approach and composite measures. DISCUSSION Our easy to implement and readily available pipeline offers an approach for researchers to harmonize their cognitive data with large publicly available cohorts, providing a simple way to pool data for the development or validation of findings related to cognitive decline due to AD.

Abstract Objectives To compare long‐term outcomes of laryngeal cancer (LC) in people living with HIV (PLWH) versus uninfected individuals and determine how clinical and viral factors—such as demographics, cancer stage, HIV viral load, and CD4 nadir—contribute to these outcomes. Methods This was a retrospective case–control study of 749 patients seen for LC at a single tertiary care center between 2003 and 2017. Of these, 22 had HIV at the time of LC diagnosis, and they were matched in a 1:4 ratio to uninfected controls based on sex, presence of smoking history, and age at cancer diagnosis. Kaplan–Meier survival curves and Cox proportional hazards models were constructed to identify overall and disease‐free survival differences based on HIV status, as well as other clinical and viral factors. Results Compared to all uninfected individuals, PLWH were diagnosed with LC approximately 6 years younger (p = .013). 1‐, 2‐, and 5‐year overall survival for PLWH were 86.4% (63.4%–95.4%), 77.3% (53.7%–89.9%), and 65.8% (40.8%–82.2%), respectively following LC diagnosis, and HIV was not significantly associated with overall (HR = 3.34 [0.59–18.79]) or disease‐free survival (HR = 2.12 [0.71–6.36]). The incidence rate of locoregional recurrence among PLWH was 541 compared to 371 per 10,000 person‐years in controls, which were not significantly different (p = .420). Furthermore, among PLWH, peak viral load and CD4 nadir were not associated with overall or disease‐free survival. Conclusion While previous work has shown that HIV is associated with elevated risk of LC, survival did not differ significantly between PLWH and uninfected individuals in this study. Level of evidence 3.

Abstract Objectives To explore the impact of various measurements of long‐term health conditions (LTCs) on the resulting prevalence estimates using data from a nationally representative dataset. Methods Children and young people in the Millennium Cohort Study were followed at ages 3, 5, 7, 11, and 14 years (N = 15,631). We estimated the weighted prevalence of LTCs at each time point and examined the degree to which estimates agreed with alternate health indicators (special educational needs and disability [SEND], specific chronic conditions, and common chronicity criteria) using descriptive analyses, Cohen's kappa statistic, and percentage agreement. Results The estimated weighted prevalence of LTCs peaked at 5 years old (20%). Despite high percentage agreement, we observed at best moderate chance‐corrected agreement between the type of LTC and reasons for SEND (kappas from 0.02 to 0.56, percentage agreement from 97% to 99%) or specified chronic conditions (kappas from 0.002 to 0.02, percentage agreement from 73% to 97%). Applying chronicity criteria decreased the estimated weighted prevalence of LTCs (3%). Conclusion How long‐term conditions are defined drastically alters the estimated weighted prevalence of LTCs. Improved clarity and consistency in the definition and measurement of LTCs is urgently needed to underpin policy and commissioning of services.

Abstract The comprehensive evaluation of strategies for decarbonizing large‐scale energy systems requires insights from many different perspectives. In energy systems analysis, optimization models are widely used for this purpose. However, they are limited in incorporating all crucial aspects of such a complex system to be sustainably transformed. Hence, they differ in terms of their spatial, temporal, technological, and economic perspective and either have a narrow focus with high resolution or a broad scope with little detail. Against this background, we introduce the so‐called granularity gaps and discuss two possibilities to address them: increasing the resolutions of the established optimization models, and the different kinds of model coupling. After laying out open challenges, we propose a novel framework to design power systems in particular. Our exemplary concept exploits the capabilities of power system optimization, transmission network simulation, distribution grid planning, and agent‐based simulation. This integrated framework can serve to study the energy transition with greater comprehensibility and may be a blueprint for similar multimodel analyses.

Abstract The processes by which bacteria proactively scavenge essential nutrients in crowded environments such as the gastrointestinal tract are not fully understood. In this context, we observed that bacterial extracellular vesicles (BEVs) produced by the human commensal gut microbe Bacteroides thetaiotaomicron contain multiple high‐affinity vitamin B12 binding proteins suggesting that the vesicles play a role in micronutrient scavenging. Vitamin B12 belongs to the cobamide family of cofactors that regulate microbial communities through their limited bioavailability. We show that B. thetaiotaomicron derived BEVs bind a variety of cobamides and not only deliver them back to the parental bacterium but also sequester the micronutrient from competing bacteria. Additionally, Caco‐2 cells, representing a model intestinal epithelial barrier, acquire cobamide‐bound vesicles and traffic them to lysosomes, thereby mimicking the physiological cobalamin‐specific intrinsic factor‐mediated uptake process. Our findings identify a novel cobamide binding activity associated with BEVs with far‐reaching implications for microbiota and host health.

Abstract Background The pathophysiology of changes in magnetic resonance imaging (MRI) detected after a seizure is not fully understood. Objective To characterize and describe seizure‐induced changes detected by MRI. Animals Eighty‐one client‐owned dogs diagnosed with idiopathic epilepsy. Methods Data collected retrospectively from medical records and included anatomical areas affected, T1‐, T2‐weighted and T2‐FLAIR (fluid‐attenuated inversion recovery) appearance, whether changes were unilateral or bilateral, symmetry, contrast enhancement, mass effect, and, gray and white matter distribution. Diffusion‐ and perfusion weighted maps were evaluated, if available. Results Seizure‐induced changes were T2‐hyperintense with no suppression of signal on FLAIR. Lesions were T1‐isointense (55/81) or hypointense (26/81), local mass effect (23/81) and contrast enhancement (12/81). The majority of changes were bilateral (71/81) and symmetrical (69/71). The most common areas affected were the hippocampus (39/81) cingulate gyrus (33/81), hippocampus and piriform lobes (32/81). Distribution analysis suggested concurrence between cingulate gyrus and pulvinar thalamic nuclei, the cingulate gyrus and parahippocampal gyrus, hippocampus and piriform lobe, and, hippocampus and parahippocampal gyrus. Diffusion (DWI) characteristics were a mixed‐pattern of restricted, facilitated, and normal diffusion. Perfusion (PWI) showed either hypoperfusion (6/9) or hyperperfusion (3/9). Conclusions and Clinical Importance More areas, than previously reported, have been identified that could incur seizure‐induced changes. Similar to human literature, DWI and PWI changes have been identified that could reflect the underlying metabolic and vascular changes.

Abstract Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with a variable clinical course. The lungs are infiltrated by nodules of LAM cells, stromal cells and inflammatory cells, causing lung cysts and respiratory failure. We used immunohistochemical markers in lung biopsy and transplant samples from a national cohort of women with LAM with linked clinical data to understand how LAM nodule cell populations changed with disease progression. Marker distribution was examined qualitatively by dual immunohistochemistry, and markers for LAM cells, fibroblasts, lymphatics, mast cells, proliferation, cathepsin K and mTOR pathway activity were quantitated in LAM nodules and compared with clinical features and prospective lung function loss. The LAM cell marker PNL2 was more extensively expressed in those with higher forced expiratory volume in one second (FEV1), higher diffusion in the lung for carbon monoxide (DLCO) and less extensive disease involvement whilst the converse was true for the protease cathepsin K. Each percentage increase in cathepsin K reactivity was associated with a 0.65% decrease in FEV1 (95% CI −1.11 to −0.18) and a 0.50% decrease in DLCO (95% CI −0.96 to −0.05). Higher reactivity to the mTOR complex 1 activation marker, phospho‐ribosomal protein S6, was associated with a better lung function response to rapamycin (p = 0.0001). We conclude that LAM nodules evolve with disease progression, with LAM cells becoming outnumbered by fibroblasts. Increasing cathepsin K expression is associated with more severe disease and lung function loss. Markers of mTOR activation predict the response to rapamycin, suggesting that more advanced LAM may be less mTOR responsive and treatments specifically targeted towards LAM associated fibroblasts may have roles as adjuncts to mTOR inhibition.

Background and Aim Data on patient needs and access to psychological services in inflammatory bowel disease (IBD) are scarce. This study aimed to describe the levels of distress and the needs, attitudes, and access to psychological services for people within Australia against established Australian IBD Standards. Methods An online cross‐sectional survey was conducted with Australians ≥16 years old recruited via Crohn's & Colitis Australia membership, public and private clinics, and the Royal Flying Doctor Service. K10 was used to measure psychological distress. The Chi‐square test was used to compare those with and without distress on key variables. Results Overall, 731 respondents provided complete data (71.5% female, mean age 46.5 years). Overall, 50% of respondents reported distress; only 15.2% were currently seeing a mental health practitioner; only 16.1% were asked about their mental health by their IBD specialist or IBD nurse; and only 12.2% reported access to a mental health practitioner as part of their IBD service. Those with psychological distress were significantly less satisfied with their IBD care; more commonly hospitalized; had an active disease, fistula or perianal disease, pain, or fatigue; and were receiving steroids, opioids, or antidepressants (all P

Abstract 1. Across Europe, farmland bird populations have continued to decline since the 1970s owing to the intensification of farming practices. Studies of such declines have tended to focus specifically on either the impacts of habitats (nesting and foraging), nest predators or prey availability on bird demographics. The study presented here provides new insights into the relative effects of each of these factors on yellowhammer nest survival. The yellowhammer was selected for this study as it is a UK Red‐Listed bird species whose population is in decline across much of Europe. 2. We use a long‐term dataset of 147 nests, monitored between 1995 and 2007, to provide an insight into how yellowhammer nest survival is influenced by nesting habitat (nest concealment and nest height), foraging habitats (habitat coverage within 100 m of nests), the removal of nest predators (magpie Pica abundance as an inverse measure of avian predator removal through gamekeeping) and food availability (measured with a D‐vac invertebrate suction sampler). 3. Our results indicated that yellowhammer hatching success was negatively related to the coverage of spring agri‐environment scheme habitats, a group which represents invertebrate‐rich agri‐environment habitats, but hatching success increased with nest height. Fledging success was positively related to the coverage of the seed‐rich habitat wild bird seed mixture. The farm‐level abundance of yellowhammer chick‐food invertebrates declined over the study period. 4. Our results highlight the importance of simultaneously considering multiple agents that shape avian breeding success, that is their ability to produce offspring, to inform conservation management. Our key finding for land managers relates to the positive relationship between the proportion of seed rich foraging habitat within the yellowhammer's average foraging range and yellowhammer fledging success, which shows that a habitat intended primarily to provide winter food resources is also important to breeding birds. Chick food abundance in this habitat was, however, similar to broadleaf and cereal crops. We recommend that this habitat should be provided near to potential yellowhammer nesting sites and adjacent to invertebrate‐rich agri‐environment scheme habitats such as beetle banks and conservation headlands to further boost invertebrate resources for a declining farmland bird.

Background The aim of the present work was to study the influence of body position on resting and exercise pulmonary hemodynamics in patients assessed for pulmonary hypertension (PH). Methods and Results Data from 483 patients with suspected PH undergoing right heart catheterization for clinical indications (62% women, age 61±15 years, 246 precapillary PH, 48 postcapillary PH, 106 exercise PH, 83 no PH) were analyzed; 213 patients (main cohort, years 2016–2018) were examined at rest in upright (45°) and supine position, such as under upright exercise. Upright exercise hemodynamics were compared with 270 patients (historical cohort) undergoing supine exercise with the same protocol. Upright versus supine resting data revealed a lower mean pulmonary artery pressure 31±14 versus 32±13 mm Hg, pulmonary artery wedge pressure 11±4 versus 12±5 mm Hg, and cardiac index 2.9±0.7 versus 3.1±0.8 L/min per m2, and higher pulmonary vascular resistance 4.1±3.1 versus 3.9±2.8 Wood P

Abstract The gastrointestinal (GI) tract harbours a complex microbial community, which contributes to its homeostasis. A disrupted microbiome can cause GI‐related diseases, including inflammatory bowel disease (IBD), therefore identifying host‐microbe interactions is crucial for better understanding gut health. Bacterial extracellular vesicles (BEVs), released into the gut lumen, can cross the mucus layer and access underlying immune cells. To study BEV‐host interactions, we examined the influence of BEVs generated by the gut commensal bacterium, Bacteroides thetaiotaomicron, on host immune cells. Single‐cell RNA sequencing data and host‐microbe protein‐protein interaction networks were used to predict the effect of BEVs on dendritic cells, macrophages and monocytes focusing on the Toll‐like receptor (TLR) pathway. We identified biological processes affected in each immune cell type and cell‐type specific processes including myeloid cell differentiation. TLR pathway analysis highlighted that BEV targets differ among cells and between the same cells in healthy versus disease (ulcerative colitis) conditions. The in silico findings were validated in BEV‐monocyte co‐cultures demonstrating the requirement for TLR4 and Toll‐interleukin‐1 receptor domain‐containing adaptor protein (TIRAP) in BEV‐elicited NF‐kB activation. This study demonstrates that both cell‐type and health status influence BEV‐host communication. The results and the pipeline could facilitate BEV‐based therapies for the treatment of IBD.

Abstract Background Previous studies on the relationship between anticholinergic drugs and dementia have reported heterogeneous results. This variability could be due to different anticholinergic scales and differential effects of distinct classes of drugs. Methods Using Cox proportional hazards models, we computed the association between annual anticholinergic burden (AChB) and the risk of dementia in UK Biobank with linked general practitioner prescription records between the years 2000 and 2015 (n = 171,775). Results AChB according to most anticholinergic scales (standardized odds ratio range: 1.027–1.125) and the slope of the AChB trajectory (hazard ratio = 1.094; 95% confidence interval: 1.068–1.119) were predictive of dementia. However, the association between AChB and dementia held only for some classes of drugs, especially antidepressants, antiepileptics, and antidiuretics. Discussion The heterogeneity in previous findings may partially be due to different effects for different classes of drugs. Future studies should establish differences in more detail and further examine the practicality of a general measure of AChB relating to the risk of dementia.

Abstract The whale shark Rhincodon typus is found throughout the world's tropical and warm‐temperate ocean basins. Despite their broad physical distribution, research on the species has been concentrated at a few aggregation sites. Comparing DNA sequences from sharks at different sites can provide a demographically neutral understanding of the whale shark's global ecology. Here, we created genetic profiles for 84 whale sharks from the Saudi Arabian Red Sea and 72 individuals from the coast of Tanzania using a combination of microsatellite and mitochondrial sequences. These two sites, separated by approximately 4500 km (shortest over‐water distance), exhibit markedly different population demographics and behavioral ecologies. Eleven microsatellite DNA markers revealed that the two aggregation sites have similar levels of allelic richness and appear to be derived from the same source population. We sequenced the mitochondrial control region to produce multiple global haplotype networks (based on different alignment methodologies) that were broadly similar to each other in terms of population structure but suggested different demographic histories. Data from both microsatellite and mitochondrial markers demonstrated the stability of genetic diversity within the Saudi Arabian aggregation site throughout the sampling period. These results contrast previously measured declines in diversity at Ningaloo Reef, Western Australia. Mapping the geographic distribution of whale shark lineages provides insight into the species’ connectivity and can be used to direct management efforts at both local and global scales. Similarly, understanding historical fluctuations in whale shark abundance provides a baseline by which to assess current trends. Continued development of new sequencing methods and the incorporation of genomic data could lead to considerable advances in the scientific understanding of whale shark population ecology and corresponding improvements to conservation policy.

Abstract Introduction Patients with chronic foot/ankle pain are often referred for orthopaedic assessment. Psychological vulnerabilities influence pain states (including foot and ankle), therefore this study aimed to establish the prevalence and relative importance of compromised psychological health to perceived foot/ankle pain severity in people referred to an orthopaedic foot and ankle clinic with non‐urgent presentations. Methods Patients with triaged non‐urgent foot/ankle referrals to the Department of Orthopaedics at Gold Coast University Hospital were recruited over a 12‐month period and completed the Manchester‐Oxford Foot and Ankle Questionnaire which was the primary measure. Participants also completed questionnaires assessing their anthropometric, demographic and health characteristics (Self‐Administered Comorbidity Questionnaire) as well as measures of health‐related quality of life (EuroQol‐5‐Dimensions‐5‐Level Questionnaire and EQ Visual Analogue Scale) and psychological health (Center for Epidemiological Studies‐Depression scale, Pain Catastrophizing Scale and Central Sensitization Inventory). Descriptive statistics were used to summarise participant characteristics and a hierarchical multiple linear regression was employed to establish the extent to which psychological variables explain additional variance in foot/ankle pain severity beyond the effects of participant characteristics (age, sex, body mass index (BMI)). Results One hundred and seventy‐two adults were recruited ((64.0% female), median (IQR) age 60.9 (17.7) years and BMI 27.6 (7.5) kg/m2). Specific psychological comorbidities were prevalent including depressive symptoms (48%), central sensitisation (38%) and pain catastrophising (24%). Age, sex and BMI accounted for 11.7% of the variance in MOXFQ‐index and psychological variables accounted for an additional 28.2%. Pain catastrophising was the most significant independent predictor of foot/ankle pain severity (accounting for 14.4% of variance), followed by BMI (10.7%) and depressive symptoms (2.3%). Conclusions This study demonstrated that specific psychological comorbidities and increased BMI are common in this cohort and that these factors are associated with the symptoms for which patients are seeking orthopaedic assessment. This knowledge should prompt clinicians to routinely consider the psychosocial components of patient presentations and develop non‐operative and pre‐operative treatment strategies which consider these factors with the goal of improving overall patient outcomes.

Abstract Background Adverse outcomes arising from foot and ankle surgery, including lack of pain relief, increased disability and perioperative complications are infrequent but inevitable. This mixed‐methods study aims to explore the impact of adverse outcomes on patients following nonemergent foot and ankle surgery. Methods Patients who underwent foot and ankle surgery over a two‐year period were invited to participate in this study if they reported an adverse outcome. Qualitative assessment consisted of individual semi‐structured interviews, designed to explore the decision they made to have surgery and the impact of the outcome after surgery. Quantitative assessment was performed using questionnaires on demographics, current analgesia, foot pain, health‐related quality of life, psychological health, and regret. Results Twelve participants (eight women) consented for inclusion in this study. Current foot pain was high in 10 participants, five met the criteria for central sensitisation syndrome and two had clinically significant pain catastrophising. Most participants regretted their decision to have surgery. The three major themes identified were expectations, communication, and alternatives. Conclusions Self‐reported adverse outcomes following foot and ankle surgery were prevalent and participants in this study consistently complained of persistent pain. Regret was common and reasons cited for their adverse outcomes centred around the feelings of inadequate communication and failure to meet expectations.

Abstract Powdery mildew isa major disease of barley (Hordeum vulgare L.) for which breeders have traditionally relied on dominant, pathogen race‐specific resistance genes for genetic control. Directional selection pressures in extensive monocultures invariably result in such genes being overcome as the pathogen mutates to evade recognition. This has led to a widespread reliance on fungicides and a single broad‐spectrum recessive resistance provided by the mlo gene. The range of resistance genes and alleles found in wild crop relatives and landraces has been reduced in agricultural cultivars through an erosion of genetic diversity during domestication and selective breeding. Three novel major‐effect adult plant resistance (APR) genes from landraces, designated Resistance to Blumeria graminis f. sp. hordei (Rbgh1 to Rbgh3), were identified in the terminal regions of barley chromosomes 5HL, 7HS, and 1HS, respectively. The phenotype of the new APR genes showed neither pronounced penetration resistance, nor the spontaneous necrosis and mesophyll cell death typical of mlo resistance, nor a whole epidermal cell hypersensitive response, typical of race‐specific resistance. Instead, resistance was localized to the site of attempted penetration in an epidermal cell and was associated with cell wall appositions and cytosolic vesicle‐like bodies, and lacked strong induction of reactive oxygen species. The APR genes exhibited differences in vesicle‐like body sizes, their distribution, and the extent of localized 3,3‐diaminobenzidine staining in individual doubled haploid lines. The results revealed a set of unique basal penetration resistance genes that offer opportunities for combining different resistance mechanisms in breeding programs for robust mildew resistance.

Abstract Atmospheric reanalyses are widely used for understanding the past and present climate. They have become increasingly used within the renewable energy sector for assessing wind and solar resources for different regions of the globe in conjunction with observations. Mexico is a country with considerable potential for wind energy production, especially around coastal sites and therefore the characterization of wind resource in these areas of the country is imperative for the most beneficial use of these resources. In this study, we assess how well three global reanalyses, namely ERA‐Interim, ERA5 and MERRA‐2, can reproduce wind observations at a number of key sites across the country. We find that the reanalyses' ability to reproduce these observations is highly variable between different regions in Mexico. Correlation coefficients are around 0.9 in the south of the country where the winds are strongest, but much lower (around 0.5) in Baja California Sur due to the complex coastal topography of the region. ERA5 outperforms ERA‐Interim and MERRA‐2 consistently across the vast majority of sites and so this reanalysis is recommended for local wind power studies. The consistently improved performance compared with ERA‐Interim shows the value of the increased spatial resolution of ERA5. However, in the south and east of Mexico, despite having the highest correlations, ERA5 also has the largest bias, meaning that it underestimates winds consistently across most of the country. Poor correlations between ERA5 and the observations in Veracruz are considered as a case study to understand potential drivers of low wind biases.

Abstract Coronary artery disease (CAD) can adversely affect left ventricular (LV) performance during exercise by impairment of contractile function in the presence of increasing afterload. By performing invasive measures of LV pressure–volume and coronary pressure and flow during exercise, we sought to accurately measure this with comparison to the control group. Sixteen patients, with CCS class >II angina and CAD underwent invasive simultaneous measurement of left ventricular pressure–volume and coronary pressure and flow velocity during cardiac catheterization. Measurements performed at rest were compared with peak exercise using bicycle ergometry. The LV contractile function was measured invasively using the end‐systolic pressure–volume relationship, a load independent marker of contractile function (Ees). Vascular afterload forces were derived from the ratio of LV end‐systolic pressure to stroke volume to generate arterial elastance (Ea). These were combined to assess cardiovascular performance (ventricular‐arterial [VA] coupling ratio [Ea/Ees]). Eleven patients demonstrated flow‐limiting (FL) CAD (hyperemic Pd/Pa

Abstract Introduction This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex‐related difference in N and V pathology. Methods Five thousand and thirty‐two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V). Results Differential protein expression analysis and co‐expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex‐related difference in N and one protein mediated such difference in V damage. Discussion Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex‐specific therapeutic strategies.

Background Up to 30% of patients undergoing transcatheter aortic valve implantation (TAVI) experience minimal symptomatic benefit or die within 1 year, indicating an urgent need for enhanced patient selection. Previous analyses of baseline NT‐proBNP (N‐terminal pro‐brain natriuretic peptide) and TAVI outcomes have assumed a linear relationship, yielding conflicting results. We reexamined the relationship between baseline NT‐proBNP and symptomatic improvement after TAVI. Methods and Results Symptom status, clinical and echocardiographic data, and baseline NT‐proBNP were reviewed from 144 consecutive patients undergoing TAVI for severe symptomatic aortic stenosis. The primary end point was change in New York Heart Association functional class at 1 year. There was a nonlinear, inverted‐U relationship between log‐baseline NT‐proBNP and post‐TAVI change in NYHA class (R2=0.4559). NT‐proBNP thresholds of 10 000 ng/L accurately predicted no symptomatic improvement at 1 year (sensitivity 88%, specificity 83%, positive predictive value 72%, negative predictive value 93%). In adjusted analyses, baseline NT‐proBNP outside this “sweet‐spot” range was the only factor independently associated with poor functional outcome (high: NT‐proBNP >10 000 ng/L, odds ratio [OR], 65; 95% CI, 6–664; low: NT‐proBNP 10 000 ng/L) levels are strongly associated with poor functional outcome, suggesting an alternative cause for symptoms in the former scenario and an irrevocably diseased left ventricle in the latter. Further evaluation of this relationship is warranted.

Abstract Coronavirus disease 2019 is a global pandemic affecting >3 million people in >170 countries, resulting in >200 000 deaths; 35% to 40% of patients and deaths are in the United States. The coronavirus disease 2019 crisis is placing an enormous burden on health care in the United States, including residency and fellowship training programs. The balance between mitigation, training and education, and patient care is the ultimate determinant of the role of cardiology fellows in training during the coronavirus disease 2019 crisis. On March 24, 2020, the Accreditation Council for Graduate Medical Education issued a formal response to the pandemic crisis and described a framework for operation of graduate medical education programs. Guidance for deployment of cardiology fellows in training during the coronavirus disease 2019 crisis is based on the principles of a medical mission, and adherence to preparation, protection, and support of our fellows in training. The purpose of this review is to describe our departmental strategic deployment of cardiology fellows in training using the Accreditation Council for Graduate Medical Education framework for pandemic preparedness.

Objective An aging population requires increased focus on geriatric otolaryngology. Patients aged ≥65 years are not a homogenous population, and important physiologic differences have been documented among the young-old (65-74 years), middle-old (75-84), and old-old (≥85). We aim to analyze differences in dysphagia diagnoses and swallowing-related quality-of-life among these age subgroups. Study Design Retrospective chart review. Setting Tertiary care laryngology clinic. Subjects and Methods We identified chief complaint, diagnosis, and self-reported swallowing handicap (Eating Assessment Tool [EAT-10] score) of all new patients aged ≥65 years presenting to the Johns Hopkins Voice Center between April 2015 and March 2017. Dysphagia diagnoses were classified by physiologic etiology and anatomic source. Diagnostic categories and EAT-10 score were evaluated as functions of patient age and sex. Results Of 839 new patients aged ≥65 years, 109 (13.0%) reported a chief complaint of dysphagia and were included in this study. The most common dysphagia etiologies were neurologic and esophageal. Most common diagnoses were diverticula (15.6%), reflux (13.8%), and radiation induced (8.3%). Diverticula, cricopharyngeal hypertonicity, and radiation-induced changes were associated with higher EAT-10 score ( P < .001). Significant differences by sex were found in anatomic source of dysphagia, as men and women were more likely to present with oropharyngeal and esophageal disease, respectively ( P = .023). Dysphagia etiology and EAT-10 score were similar across age subgroups. Conclusion Important differences among dysphagia diagnosis and EAT-10 score exist among patients aged ≥65 years. Knowledge of these differences may inform diagnostic workup, management, and further investigations in geriatric otolaryngology.