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Abstract Background Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT). Methods We undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events. Results At two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported. Conclusion Staff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned. Trial Registration ISRCTN13232859 (Registered 16/02/2018).

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.

Concussions in contact sports are challenging for athletes, health professionals and sporting bodies to prevent, detect and manage. Design of interventions for primary prevention, early recognition of concussion and continuing to improve postconcussion management are essential for protecting athletes and promoting brain health. Over the last decade, there have been advancements in video technology for analysing head impact events and improvements in the clinical management of concussions. This study protocol describes how researchers, clinicians and staff from the Australasian National Rugby League (NRL) have brought these advancements together and developed a database of videos with head impact events and clinical outcomes. The intended outputs from this work will enhance the understanding of head impact events in NRL, from biomechanical and gameplay factors to concussion and return to play outcomes. Publishing this protocol increases the transparency of this large-scale effort to better identify head impacts and their relationship to concussions and player movement behaviour to contextualise these variables to generate new knowledge and support the reproducibility of these emerging findings. Between 2017 and 2023, over 5250 head contact cases were recorded in the database, from which >1700 head injury assessments were performed, and >600 concussions were diagnosed. Future studies using these data are planned to inform both primary and secondary injury prevention initiatives, such as risk analysis and prediction of game scenarios that result in concussion, as well as investigation of features and factors that help to inform the duration of recovery and return to play.

Introduction Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC.Methods and analysis In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score

Abstract The hydrological effects of climate change are documented in many regions; however, climate-driven impacts to the source and transport of river nutrients remain poorly understood. Understanding the factors controlling nutrient dynamics across river systems is critical to preserve ecosystem function yet challenging given the complexity of landscape and climate interactions. Here, we harness a large regional dataset of nitrate (NO3 –) yield, concentration, and isotopic composition (δ15N and δ18O) to evaluate the strength of hydroclimate and landscape variables in controlling the seasonal source and transport of NO3 –. We show that hydroclimate strongly influenced the seasonality of river NO3 –, producing distinct, source-dependent NO3 – regimes across rivers from two mountain ranges. Riverine responses to hydroclimate were also constrained by watershed-scale topographic features, demonstrating that while regional climate strongly influences the timing of river NO3 – transport, watershed topography plays a distinct role in mediating the sensitivity of river NO3 – dynamics to future change.

Background and purpose: We previously showed promising primary stability and preservation of bone stock with the ultra-short neck-loading hip implant in total hip arthroplasty (THA). The aim of this study was to evaluate clinical outcome, implant stability, and bone mineral density (BMD). Methods: 50 patients were treated with the ultra-short neck Primoris hip implant at baseline and 48 were available for evaluation at 5-year follow-up. 5 different patient-reported outcome measures (PROMs) including hip-specific scores, disease-specific and generic quality of life outcome measures, and an activity score were used. Furthermore, implant stability using radiostereometric analysis (RSA) and assessment of periprosthetic BMD using dual-energy X-ray absorptiometry (DXA) were applied. Results: By 1-year follow-up, all PROMs showed improvements and remained high at 5-year follow-up. After initial distal translation (subsidence) and negative rotation around the z-axis (varus tilt) the implant showed stable fixation at 5-year follow-up with no further migration beyond 12 months. In the regions of interest (ROI) 3 and 4, BMD remained stable. In ROI 2, further bone loss of 12% was found at 5-year follow-up. Conclusion: Clinical outcome including PROMs was satisfying throughout the 5-year follow-up period. The hip implant remains stable with both bone preservation and loss 5 years after surgery.

IntroductionUnderstanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia.MethodsWe performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures.ResultsData from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, pConclusionIn men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

Background and aims Hypertension is a leading risk factor for cardiovascular disease. Electronic health records (EHRs) are routinely collected throughout a person’s care, recording all aspects of health status, including current and past conditions, prescriptions and test results. EHRs can be used for epidemiological research. However, there are nuances in the way conditions are recorded using clinical coding; it is important to understand the methods which have been applied to define exposures, covariates and outcomes to enable interpretation of study findings. This study aimed to identify codelists used to define hypertension in studies that use EHRs and generate recommended codelists to support reproducibility and consistency.Eligibility criteria Studies included populations with hypertension defined within an EHR between January 2010 and August 2023 and were systematically identified using MEDLINE and Embase. A summary of the most frequently used sources and codes is described. Due to an absence of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) codelists in the literature, a recommended SNOMED CT codelist was developed to aid consistency and standardisation of hypertension research using EHRs.Findings 375 manuscripts met the study criteria and were eligible for inclusion, and 112 (29.9%) reported codelists. The International Classification of Diseases (ICD) was the most frequently used clinical terminology, 59 manuscripts provided ICD 9 codelists (53%) and 58 included ICD 10 codelists (52%). Informed by commonly used ICD and Read codes, usage recommendations were made. We derived SNOMED CT codelists informed by National Institute for Health and Care Excellence guidelines for hypertension management. It is recommended that these codelists be used to identify hypertension in EHRs using SNOMED CT codes.Conclusions Less than one-third of hypertension studies using EHRs included their codelists. Transparent methodology for codelist creation is essential for replication and will aid interpretation of study findings. We created SNOMED CT codelists to support and standardise hypertension definitions in EHR studies.

Autophagy is a catabolic self-degradative pathway that promotes the degradation and recycling of intracellular material through the lysosomal compartment. Although first believed to function in conditions of nutritional stress, autophagy is emerging as a critical cellular pathway, involved in a variety of physiological and pathophysiological processes. Autophagy dysregulation is associated with an increasing number of diseases, including ocular diseases. On one hand, mutations in autophagy-related genes have been linked to cataracts, glaucoma, and corneal dystrophy; on the other hand, alterations in autophagy and lysosomal pathways are a common finding in essentially all diseases of the eye. Moreover, LC3-associated phagocytosis, a form of non-canonical autophagy, is critical in promoting visual cycle function. This review collects the latest understanding of autophagy in the context of the eye. We will review and discuss the respective roles of autophagy in the physiology and/or pathophysiology of each of the ocular tissues, its diurnal/circadian variation, as well as its involvement in diseases of the eye.

This study investigated the extraction and properties of an arabinogalactan polysaccharide from frost grape (FGP) as a potential alternative to gum arabic (GA). Collection date, solvent:feed ratio (S:F), chip size, C-18 filtration, ultrafiltration, freeze drying versus spray drying, methanol pre-extraction, and water absorption were examined. Sugar composition, elemental analysis, dietary fiber content, emulsification activity index (EAI), emulsification stability index (ESI), and viscosity were used to evaluate the extracts. Exudates collected in March from live stems were viscous with high percentage solids and FGP, while May collections were watery with low percentage solids and FGP. Frost grape stems were collected, chipped, and classified by size. The extraction system utilized pressure or vacuum to increase contact between the chips and extraction water. A S:F ratio of ca. 24% gave an excellent yield of FGP. Chips between 1.8 and 3.8 mm gave the highest mass yields. Pre-extracting the chips with methanol and C-18 filtration of the water extract both yielded a lighter product. The EAI for the FGP was higher than that for GA; however, its ESI was lower. Ultrafiltration of the crude extract separated glucose, fructose, and sucrose from the FGP. FGP with glucose, fructose, and sucrose adsorbed water and became darker.

Abstract Predators must contend with numerous challenges to successfully find and subjugate prey. Complex traits related to hunting are partially controlled by a large number of co‐evolved genes, which may be disrupted in hybrids. Accordingly, research on the feeding ecology of animals in hybrid zones has shown that hybrids sometimes exhibit transgressive or novel behaviors, yet for many taxa, empirical studies of predation and diet across hybrid zones are lacking. We undertook the first such field study for a hybrid zone between two snake species, the Mojave rattlesnake (Crotalus scutulatus) and the prairie rattlesnake (Crotalus viridis). Specifically, we leveraged established field methods to quantify the hunting behaviors of animals, their prey communities, and the diet of individuals across the hybrid zone in southwestern New Mexico, USA. We found that, even though hybrids had significantly lower body condition indices than snakes from either parental group, hybrids were generally similar to non‐hybrids in hunting behavior, prey encounter rates, and predatory attack and success. We also found that, compared to C. scutulatus, C. viridis was significantly more active while hunting at night and abandoned ambush sites earlier in the morning, and hybrids tended to be more viridis‐like in this respect. Prey availability was similar across the study sites, including within the hybrid zone, with kangaroo rats (Dipodomys spp.) as the most common small mammal, both in habitat surveys and the frequency of encounters with hunting rattlesnakes. Analysis of prey remains in stomachs and feces also showed broad similarity in diets, with all snakes preying primarily on small mammals and secondarily on lizards. Taken together, our results suggest that the significantly lower body condition of hybrids does not appear to be driven by differences in their hunting behavior or diet and may instead relate to metabolic efficiency or other physiological traits we have not yet identified.

Navy beans are a gluten-free pulse containing great heathy sources for human beings. In this work, we compared the rheological properties of untreated navy bean flour suspensions (UNBFS) and jet-cooked navy bean flour suspensions (JCNBFS). Jet-cooking is a direct-contact heating process employing high-temperature and high-pressure steam for producing food and beverage products. We found that the linear rheological properties of 8% (wt.%) UNBFS exhibited viscoelastic fluid behavior; while 10% (wt.%) UNBFS displayed viscoelastic fluid/solid cross-over behavior; but 12% (wt.%) UNBFS displayed weak viscoelastic solid behavior. Unlike UNBFS, all three (8%, 10%, and 12%) (wt.%) jet-cooked navy bean flour suspensions (JCNBFS) displayed linear rheological properties having viscoelastic solid gel-like behaviors. The rheological properties of JCNBFS were strongly dependent on the concentration of the suspensions. The non-linear viscoelastic properties of the three suspensions of UNBFS exhibited similar viscosity shear thinning behavior. The degree of shear thinning was slightly reduced both at very low and high shear rates. The non-linear rheological properties of the three suspensions of JCNBFS also displayed shear thinning behaviors. The viscosity curves of the JCNBFS were much steeper than those of the UNBFS. This demonstrates that JCNBFS possessed greater shear thinning capacity than UNBFS. Both linear and non-linear rheological property studies for UNBFS and JCNBFS revealed that jet-cooking processing alters the molecular structures of navy bean flours’ starch and proteins, which would influence the navy bean flour suspensions’ properties. The results of this work will be useful to develop new food products from navy beans.

Abstract Boundary conditions for a massless Dirac fermion in 2+1 dimensions where the space is a half-plane are discussed in detail. It is argued that linear boundary conditions that leave the Hamiltonian Hermitian generically break C P and T symmetries as well as Lorentz and conformal symmetry. We show that there is essentially one special case where a single species of fermion has C PT and the full Poincare and conformal symmetry of the boundary. We show that, with doubled fermions, there is a second special case which respects C PT but still violates Lorentz and conformal symmetry. This second special case is essentially the unique boundary condition where the Dirac operator has fermion zero mode edge states. We discuss how the edge states lead to exotic representations of scale, phase and translation symmetries and how imposing a symmetry requirement leads to edge ferromagnetism of the system. We prove that the exotic ferromagnetic representations are indeed carried by the ground states of the system perturbed by a class of interaction Hamiltonians which includes the non-relativistic Coulomb interaction.

Background: Although we had previously reported the cardiac and neurologic outcomes of Chinese and South Asian Ontarians in wave 1 of COVID-19, data on subsequent waves of COVID-19 remain unexamined. This is an extension study of this cohort in waves 2 and 3. Methods: We identified adult Ontarians with a positive COVID-19 polymerase chain reaction test from January 1, 2020 to June 30, 2021, and they were classified as being Chinese or South Asian using a validated surname algorithm; we compared their outcomes of mortality, and cardiac and neurologic complications with those of the general population using multivariable logistic regression models. Results: Compared to the general population (n = 439,977), the Chinese population (n = 15,208) was older (mean age 44.2 vs 40.6 years, P < 0.001) and the South Asian population (n = 46,333) was younger (39.2 years, P < 0.001). The Chinese population had a higher 30-day mortality (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.61) and more hospitalization or emergency department visits (OR, 1.14; 95% CI, 1.09-1.28), with a trend toward a higher incidence of cardiac complications (OR, 1.03; 95% CI, 0.87-1.12) and neurologic complications (OR, 1.23; 95% CI, 0.96-1.58). South Asians had a lower 30-day mortality (OR, 0.88; 95% CI, 0.78-0.98) but a higher incidence of hospitalization or emergency department visits (OR, 1.17; 95% CI, 1.14-1.20) with a trend toward a lower incidence of cardiac complications (OR, 0.76; 95% CI, 0.67-0.87) and neurologic complications (OR, 0.89; 95% CI, 0.73-1.09). There was also a significant difference in these outcomes between wave 1, 2 and 3, with a greater mortality in all groups in waves 2 and 3. Conclusions: Ethnicity continues to be an important determinant of mortality, cardiac and neurologic outcomes, and healthcare use among patients with COVID-19, requiring further studies to understand factors driving these differences. Résumé: Contexte: Nous avons déjà présenté les issues cliniques cardiaques et neurologiques chez les Ontariens de descendance chinoise ou sud-asiatique pour la première vague de la pandémie de COVID-19, mais les données au sujet des vagues ultérieures n’avaient pas encore été analysées. Nous présentons ici une prolongation de cette étude de cohortes pour la seconde et la troisième vague de COVID-19. Méthodologie: Notre analyse porte sur des adultes ontariens ayant obtenu un résultat positif à un test de COVID-19 par réaction en chaîne de la polymérase entre le 1er janvier 2020 et le 30 juin 2021. Un algorithme validé pour l’analyse des noms de famille a été utilisé pour isoler les sujets de descendance chinoise ou sud-asiatique, et leur taux de mortalité de même que les complications cardiaques et neurologiques ont été comparés à ceux de la population générale à l’aide de modèles de régression logistique multivariée. Résultats: En comparaison de la population générale (n = 439 977), les personnes de descendance chinoise (n = 15 208) se sont révélées plus âgées (âge moyen de 44,2 ans contre 40,6 ans, P < 0,001), tandis que les personnes de descendance sud-asiatique (n = 46 333) étaient plus jeunes (39,2 ans, P < 0,001). Dans la population de descendance chinoise, le taux de mortalité après 30 jours était plus élevé (rapport de cotes [RC] de 1,44; intervalle de confiance [IC] à 95 % de 1,28 à 1,61), et davantage d’hospitalisations ou de consultations aux urgences sont survenues (RC de 1,14; IC à 95 % de 1,09 à 1,28). L’incidence de complications cardiaques (RC de 1,03; IC à 95 % de 0,87 à 1,12) et de complications neurologiques (RC de 1,23; IC à 95 % de 0,96 à 1,58) avait également tendance à être plus élevée. Chez les personnes de descendance sud-asiatique, le taux de mortalité après 30 jours était plus faible (RC de 0,88; IC à 95 % de 0,78 à 0,98), mais l’incidence d’hospitalisations ou de consultations aux urgences était plus élevée (RC de 1,17; IC à 95 % de 1,14 à 1,20). Elles présentaient également une tendance vers une plus faible incidence de complications cardiaques (RC de 0,76; IC à 95 % de 0,67 à 0,87) et de complications neurologiques (RC de 0,89; IC à 95 % de 0,73 à 1,09). Des différences significatives ont également été observées pour ces paramètres entre les vagues 1, 2 et 3 de la maladie, et le taux de mortalité était plus élevé pour tous les groupes des vagues 2 et 3. Conclusions: L’origine ethnique demeure un déterminant important de la mortalité, des issues cliniques cardiaques et neurologiques ainsi que de l’utilisation des ressources en santé chez les patients atteints de la COVID-19. D’autres études sont toutefois nécessaires pour mieux comprendre les facteurs qui expliquent ces différences.

Abstract Many animal species exist in fission–fusion societies, where the size and composition of conspecific groups change spatially and temporally. To help investigate such phenomena, social network analysis (SNA) has emerged as a powerful conceptual and analytical framework for assessing patterns of interconnectedness and quantifying group‐level interactions. We leveraged behavioral observations via radiotelemetry and genotypic data from a long‐term (>10 years) study on the pitviper Crotalus atrox (western diamondback rattlesnake) and used SNA to quantify the first robust demonstration of social network structures for any free‐living snake. Group‐level interactions among adults in this population resulted in structurally modular networks (i.e., distinct clusters of interacting individuals) for fidelis use of communal winter dens (denning network), mating behaviors (pairing network), and offspring production (parentage network). Although the structure of each network was similar, the size and composition of groups varied among them. Specifically, adults associated with moderately sized social groups at winter dens but often engaged in reproductive behaviors—both at and away from dens—with different and fewer partners. Additionally, modules formed by individuals in the pairing network were frequently different from those in the parentage network, likely due to multiple mating, long‐term sperm storage by females, and resultant multiple paternity. Further evidence for fission–fusion dynamics exhibited by this population—interactions were rare when snakes were dispersing to and traversing their spring–summer home ranges (to which individuals show high fidelity), despite ample opportunities to associate with numerous conspecifics that had highly overlapping ranges. Taken together, we show that long‐term datasets incorporating SNA with spatial and genetic information provide robust and unique insights to understanding the social structure of cryptic taxa that are understudied.

Introduction In the past 5 years, there have been several advances in the management of inflammatory bowel disease (IBD). We aim for a new guideline to update the most recent guideline published in 2019. We present the prospective operating procedure and technical summary protocol in the manuscript.Methods ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) will be followed in the development of the guideline, approach as laid out in the GRADE handbook, supported by the WHO. The guideline development group is formed by a variety of disciplines, across both primary and secondary care that took part in an online Delphi process and split into key areas. A final consensus list of thematic questions within a ‘patient, intervention, comparison, outcome’ format has been produced and agreed in the final phase of the Delphi process.There will be a detailed technical evidence review with source data including systematic reviews appraised with AMSATAR 2 tool (Assessment of multiple systematic reviews), randomised controlled trial data that will be judged for risk of bias with the Cochrane tool and observational studies for safety concerns assessed through the Robins-I tool. Based on the available evidence, some of the recommendations will be based on GRADE while others will be best practice statements.A full Delphi process will be used to make recommendations using online response systems.This set of procedures has been approved by the Clinical Services and Standards Committee, the British Society of Gastroenterology executive board and aligned with IBD UK standards.

Historically, the role of aggression in the social lives of animals overwhelmingly focused on males. In recent years, however, female–female aggression in vertebrates, particularly lizards, has received increasing attention. This growing body of literature shows both similarities and differences to aggressive behaviours between males. Here, we document female–female aggression in captive Gila monsters (Heloderma suspectum). Based on four unique dyadic trials (eight adult female subjects), we developed a qualitative ethogram. Unexpected and most intriguing were the prevalence and intensity of aggressive acts that included brief and sustained biting, envenomation, and lateral rotation (i.e. rolling of body while holding onto opponent with closed jaws). Given specific behavioural acts (i.e. biting) and the results of bite-force experiments, we postulate that osteoderms (bony deposits in the skin) offer some degree of protection and reduce the likelihood of serious injury during female–female fights. Male–male contests in H. suspectum, in contrast, are more ritualized, and biting is rarely reported. Female–female aggression in other lizards has a role in territoriality, courtship tactics, and nest and offspring guarding. Future behavioural research on aggression in female Gila monsters is warranted to test these and other hypotheses in the laboratory and field.

Since the latter part of 2020, SARS-CoV-2 evolution has been characterised by the emergence of viral variants associated with distinct biological characteristics. While the main research focus has centred on the ability of new variants to increase in frequency and impact the effective reproductive number of the virus, less attention has been placed on their relative ability to establish transmission chains and to spread through a geographic area. Here, we describe a phylogeographic approach to estimate and compare the introduction and dispersal dynamics of the main SARS-CoV-2 variants - Alpha, Iota, Delta, and Omicron - that circulated in the New York City area between 2020 and 2022. Notably, our results indicate that Delta had a lower ability to establish sustained transmission chains in the NYC area and that Omicron (BA.1) was the variant fastest to disseminate across the study area. The analytical approach presented here complements non-spatially-explicit analytical approaches that seek a better understanding of the epidemiological differences that exist among successive SARS-CoV-2 variants of concern.

Abstract Background This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. Methods Placebo‐controlled, parallel group, double‐blind, randomized two‐by‐two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (

Abstract The nutritional integrity of wheat is jeopardized by rapidly rising atmospheric carbon dioxide (CO2) and the associated emergence and enhanced virulence of plant pathogens. To evaluate how disease resistance traits may impact wheat climate resilience, 15 wheat cultivars with varying levels of resistance to Fusarium Head Blight (FHB) were grown at ambient and elevated CO2. Although all wheat cultivars had increased yield when grown at elevated CO2, the nutritional contents of FHB moderately resistant (MR) cultivars were impacted more than susceptible cultivars. At elevated CO2, the MR cultivars had more significant differences in plant growth, grain protein, starch, fructan, and macro and micro-nutrient content compared with susceptible wheat. Furthermore, changes in protein, starch, phosphorus, and magnesium content were correlated with the cultivar FHB resistance rating, with more FHB resistant cultivars having greater changes in nutrient content. This is the first report of a correlation between the degree of plant pathogen resistance and grain nutritional content loss in response to elevated CO2. Our results demonstrate the importance of identifying wheat cultivars that can maintain nutritional integrity and FHB resistance in future atmospheric CO2 conditions.

BackgroundAgeing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia.MethodsWe compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial.ResultsNeither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone.ConclusionThese data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

BackgroundAngiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study.MethodsSarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables.ResultsAllele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo.ConclusionOur results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Bullous pemphigoid is an acquired autoimmune blistering dermatosis that is commonly associated with high morbidity and mortality. New-onset bullous pemphigoid following vaccinations has rarely been reported in the literature. We report two cases of new-onset bullous pemphigoid after COVID-19 vaccination followed by a brief literature review. Twenty-six cases were included in our analysis. Our cases support that new-onset bullous pemphigoid may develop following COVID-19 vaccinations. Entering a period of clinical remission before subsequent COVID-19 vaccinations in addition to close follow-up should be considered to lessen the risk of recurrences or exacerbations.

The MSL Curiosity rover investigated dark, Mn-P-enriched nodules in shallow lacustrine/fluvial sediments at the Groken site in Glen Torridon, Gale Crater, Mars. Applying all relevant information from the rover, the nodules are interpreted as pseudomorphs after original crystals of vivianite, (Fe2+,Mn2+)3(PO4)2·8H2O, that cemented the sediment soon after deposition. The nodules appear to have flat faces and linear boundaries and stand above the surrounding siltstone. ChemCam LIBS (laser-induced breakdown spectrometry) shows that the nodules have MnO abundances approximately twenty times those of the surrounding siltstone matrix, contain little CaO, and have SiO2 and Al2O3 abundances similar to those of the siltstone. A deconvolution of APXS analyses of nodule-bearing targets, interpreted here as representing the nodules’ non-silicate components, shows high concentrations of MnO, P2O5, and FeO and a molar ratio P/Mn = 2. Visible to near-infrared reflectance of the nodules (by ChemCam passive and Mastcam multispectral) is dark and relatively flat, consistent with a mixture of host siltstone, hematite, and a dark spectrally bland material (like pyrolusite, MnO2). A drill sample at the site is shown to contain minimal nodule material, implying that analyses by the CheMin and SAM instruments do not constrain the nodules’ mineralogy or composition. The fact that the nodules contain P and Mn in a small molar integer ratio, P/Mn = 2, suggests that the nodules contained a stoichiometric Mn-phosphate mineral, in which Fe did (i.e., could) not substitute for Mn. The most likely such minerals are laueite and strunzite, Mn2+Fe3+2(PO4)2(OH)2·8H2O and –6H2O, respectively, which occur on Earth as alteration products of other Mn-bearing phosphates including vivianite. Vivianite is a common primary and diagenetic precipitate from low-oxygen, P-enriched waters. Calculated phase equilibria show Mn-bearing vivianite could be replaced by laueite or strunzite and then by hematite plus pyrolusite as the system became more oxidizing and acidic. These data suggest that the nodules originated as vivianite, forming as euhedral crystals in the sediment, enclosing sediment grains as they grew. After formation, the nodules were oxidized—first to laueite/strunzite yielding the diagnostic P/Mn ratio, and then to hematite plus an undefined Mn oxy-hydroxide (like pyrolusite). The limited occurrence of these Mn-Fe-P nodules, both in space and time (i.e., stratigraphic position), suggests a local control on their origin. By terrestrial analogies, it is possible that the nodules precipitated near a spring or seep of Mn-rich water, generated during alteration of olivine in the underlying sediments.

The large-scale generation of vegetable waste in China has become a significant environmental concern. The traditional method of composting results in high nitrogen losses during the process and in the final product. To address this issue and shorten the composting period, this study investigated the effects of bamboo vinegar (BV) and a microbial inoculant (MI) on the physical and chemical properties of the compost and bacterial community composition during the composting process. The results revealed that the addition of BV and BV + MI decreased the time required to reach thermophilic temperatures and conserved nitrogen in the final product. Furthermore, it was found that the dominant nitrifying and denitrifying bacteria, as identified through 16S rDNA analysis, belonged to Nitrosomonas and Proteobacteria, respectively. BV and BV + MI reduced NH3 and N2O emissions, which suggested that BV is a beneficial composting agent that preserves nitrogen during the composting process.

Aims: Hydroxyapatite (HA)-coated collars have been shown to reduce aseptic loosening of massive endoprostheses following primary surgery. Limited information exists about their effectiveness in revision surgery. The aim of this study was to radiologically assess osteointegration to HA-coated collars of cemented massive endoprostheses following revision surgery. Methods: Retrospective review of osseointegration frequency, pattern, and timing to a specific HA-coated collar on massive endoprostheses used in revision surgery at our tertiary referral centre between 2010 to 2017 was undertaken. Osseointegration was radiologically classified on cases with a minimum follow-up of six months. Results: In all, 39 patients underwent radiological review at mean 43.5 months; 22/39 (56.4%) showed no osseointegration to the collar. Revision endoprostheses for aseptic loosening were less likely to show osseointegration compared with other indications for revision. Oncological cases with previous or current infection were more likely to show osseointegration to ≥ 1 collar side than those without evidence of prior infection. Conclusion: This seven-year review identified osseointegration of HA-coated collars after revision surgery is less likely (43.6%, 17/39) than after primary surgery. Young patients who undergo revision surgery following initial oncological indication may benefit the most from this collar design. Use in revision oncological cases with a history of infection may be beneficial. HA-coated collars showed limited benefit for patients undergoing revision for failed arthroplasty with history of infection.

Abstract Facultative parthenogenesis (FP) is widespread in the animal kingdom. In vertebrates it was first described in poultry nearly 70 years ago, and since then reports involving other taxa have increased considerably. In the last two decades, numerous reports of FP have emerged in elasmobranch fishes and squamate reptiles (lizards and snakes), including documentation in wild populations of both clades. When considered in concert with recent evidence of reproductive competence, the accumulating data suggest that the significance of FP in vertebrate evolution has been largely underestimated. Several fundamental questions regarding developmental mechanisms, nonetheless, remain unanswered. Specifically, what is the type of automixis that underlies the production of progeny and how does this impact the genomic diversity of the resulting parthenogens? Here, we addressed these questions through the application of next-generation sequencing to investigate a suspected case of parthenogenesis in a king cobra (Ophiophagus hannah). Our results provide the first evidence of FP in this species, and provide novel evidence that rejects gametic duplication and supports terminal fusion as a mechanism underlying parthenogenesis in snakes. Moreover, we precisely estimated heterozygosity in parthenogenetic offspring and found appreciable retained genetic diversity that suggests that FP in vertebrates has underappreciated evolutionary significance.

Abstract Background The PI 3-kinase (PI3K) pathway has been implicated as a target for melanoma therapy. Methods Given the high degree of genetic heterogeneity in melanoma, we sought to understand the breadth of variation in PI3K signalling in the large NZM panel of early passage cell lines developed from metastatic melanomas. Results We find the vast majority of lines show upregulation of this pathway, and this upregulation is achieved by a wide range of mechanisms. Expression of all class-IA PI3K isoforms was readily detected in these cell lines. A range of genetic changes in different components of the PI3K pathway was seen in different lines. Coding variants or amplification were identified in the PIK3CA gene, and amplification of the PK3CG gene was common. Deletions in the PIK3R1 and PIK3R2 regulatory subunits were also relatively common. Notably, no genetic variants were seen in the PIK3CD gene despite p110δ being expressed in many of the lines. Genetic variants were detected in a number of genes that encode phosphatases regulating the PI3K signalling, with reductions in copy number common in PTEN, INPP4B, INPP5J, PHLLP1 and PHLLP2 genes. While the pan-PI3K inhibitor ZSTK474 attenuated cell growth in all the lines tested, isoform-selective inhibition of p110α and p110δ inhibited cell growth in only a subset of the lines and the inhibition was only partial. This suggests that functional redundancy exists between PI3K isoforms. Furthermore, while ZSTK474 was initially effective in melanoma cells with induced resistance to vemurafenib, a subset of these cell lines concurrently developed partial resistance to PI3K inhibition. Importantly, mTOR-selective or mTOR/PI3K dual inhibitors effectively inhibited cell growth in all the lines, including those already resistant to BRAF inhibitors and ZSTK474. Conclusions Overall, this indicates a high degree of diversity in the way the PI3K pathway is activated in different melanoma cell lines and that mTOR is the most effective point for targeting the growth via the PI3K pathway across all of these cell lines.

Abstract Background Standard prehospital management for Acute respiratory failure (ARF) involves controlled oxygen therapy. Continuous positive airway pressure (CPAP) is a potentially beneficial alternative treatment, however, it is uncertain whether this could improve outcomes and provide value for money. This study aimed to evaluate the cost-effectiveness of prehospital CPAP in ARF. Methods A cost-utility economic evaluation was performed using a probabilistic decision tree model synthesising available evidence. The model consisted of a hypothetical cohort of patients in a representative ambulance service with undifferentiated ARF, receiving standard oxygen therapy or prehospital CPAP. Costs and quality adjusted life years (QALYs) were estimated using methods recommended by NICE. Results In the base case analysis, using CPAP effectiveness estimates form the ACUTE trial, the mean expected costs of standard care and prehospital CPAP were £15,201 and £14,850 respectively and the corresponding mean expected QALYs were 1.190 and 1.128, respectively. The mean ICER estimated as standard oxygen therapy compared to prehospital CPAP was £5685 per QALY which indicated that standard oxygen therapy strategy was likely to be cost-effective at a threshold of £20,000 per QALY (67% probability). The scenario analysis, using effectiveness estimates from an updated meta-analysis, suggested that prehospital CPAP was more effective (mean incremental QALYs of 0.157), but also more expensive (mean incremental costs of £1522), than standard care. The mean ICER, estimated as prehospital CPAP compared to standard care, was £9712 per QALY. At the £20,000 per QALY prehospital CPAP was highly likely to be the most cost-effective strategy (94%). Conclusions Cost-effectiveness of prehospital CPAP depends upon the estimate of effectiveness. When based on a small pragmatic feasibility trial, standard oxygen therapy is cost-effective. When based on meta-analysis of heterogeneous trials, CPAP is cost-effective. Value of information analyses support commissioning of a large pragmatic effectiveness trial, providing feasibility and plausibility conditions are met.

Abstract There are few resources available for assessing historical change in fish trophic dynamics, but specimens held in natural history collections could serve as this resource. In contemporary trophic ecology studies, trophic and source information can be obtained from compound‐specific stable isotope analysis of amino acids of nitrogen (CSIA‐AA‐N). We subjected whole Sebastes ruberrimus and Clupea pallasii to formalin fixation and 70% ethanol preservation. We extracted tissue samples from each fish pre‐fixation, after each chemical change, and then in doubling time for 32–64 days once placed in the final preservative. All samples were subjected to CSIA‐AA‐N, and their glutamic acid and phenylalanine profiles and associated trophic position were examined for differences over time by species. Glutamic acid and phenylalanine values were inconsistent in direction and magnitude, particularly during formalin fixation, but stabilized similarly (in 70% ethanol) among conspecifics. In some cases, the amino acid values of our final samples were significantly different than our initial pre‐preservation samples. Nonetheless, significant differences in glutamic acid, phenylalanine, and estimated trophic position were not detected among samples that were in 70% ethanol for >24 hr. Our results suggest that the relative trophic position of fluid‐preserved specimens can be estimated using CSIA‐AA‐N, and CSIA‐AA‐N estimates for fluid‐preserved specimens should only be reported as relative differences. Timelines of trophic position change can be developed by comparing specimens collected at different points in time, revealing trophic information of the past and cryptic ecosystem responses.

COVID-19 is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and declared by the World Health Organization a global public health emergency. Among the severe outbreaks across South America, Uruguay has become known for curtailing SARS-CoV-2 exceptionally well. To understand the SARS-CoV-2 introductions, local transmissions, and associations with genomic and clinical parameters in Uruguay, we sequenced the viral genomes of 44 outpatients and inpatients in a private healthcare system in its capital, Montevideo, from March to May 2020. We performed a phylogeographic analysis using sequences from our cohort and other studies that indicate a minimum of 23 independent introductions into Uruguay, resulting in five major transmission clusters. Our data suggest that most introductions resulting in chains of transmission originate from other South American countries, with the earliest seeding of the virus in late February 2020, weeks before the borders were closed to all non-citizens and a partial lockdown implemented. Genetic analyses suggest a dominance of S and G clades (G, GH, GR) that make up >90% of the viral strains in our study. In our cohort, lethal outcome of SARS-CoV-2 infection significantly correlated with arterial hypertension, kidney failure, and ICU admission (FDR

With the advent of powerful imaging instruments, the prenatal behaviour of vertebrates has been discovered to be far more complex than previously believed, especially concerning humans, other mammals and birds. Surprisingly, the fetal behaviour of squamate reptiles (lizards, snakes and amphisbaenians), a group of over 11 000 extant species, are largely understudied. Using ultrasonography, 18 late-term pregnant copperhead snakes (Agkistrodon contortrix) from a single population were inspected for fecundity (number of fetuses). Unexpectedly, during the ultrasound procedure that involved 97 fetuses, we observed sinusoidal tail movements in 11 individuals from eight different copperhead mothers. These movements were indistinguishable from caudal luring, a mimetic ambush predatory strategy which is exhibited by newborn copperheads and other snakes. Caudal luring is initiated shortly after birth and is employed to attract susceptible vertebrate prey. Using the same ultrasound equipment and methods, we tested for this behaviour in two species of rattlesnakes (genus Crotalus) not known to caudal lure and none of the late-term fetuses showed any type of tail movements. Prenatal movements in humans and other vertebrates are known to be important for musculoskeletal and sensorimotor development. The fetal behaviours we describe for copperheads, and possibly other snakes, may be similarly important and influence early survival and subsequent fitness.