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Current approaches to preclinical cancer research often fail to consider the impact of ambient oxygen (O2; ~21%) on cancer cells. This is also true for hypoxia studies that typically involves cancer cells previously grown in ambient O2 before subsequent transfer to hypoxia. However, the tumor microenvironment is characterized by significantly lower O2 levels. We have previously demonstrated the impact of ambient O2 on stem cell populations, signaling pathways and resistance to therapy. We developed an experimental approach that allows us to collect and process tumor tissues from transgenic mammary tumor mouse models and ovarian cancer patients under physioxia (3% O2), such that they are never exposed to ambient O2. In this study, our goal was to explore oxygen-dependent signaling pathway alterations and to determine how these pathways are influenced by targeted drugs in the context of physioxia or ambient air (AA). Our studies revealed increased basal phosphorylation levels of EGFR (Y1068) in the tumor cells in AA, relative to physioxia. However, downstream signaling effectors AKT and ERK showed higher phosphorylation levels under physioxia, compared to AA, suggesting that their activation is independent of EGFR signaling. These findings correlate with the decreased sensitivity of the tumor cells under physioxia to target drugs lapatinib and alpelisib. We then sought to examine basal and target drug induced kinome changes in tumor cells under physioxia and AA via Multiplexed Inhibitor Beads (MIBs) kinome assay. This assay revealed significant differences in the kinome of the tumor cells under physioxia compared to AA. Although direct comparison between vehicle and lapatinib treated cells in physioxia and ambient air showed very minimal changes, pairwise comparison between lapatinib treated physioxia cells and vehicle treated AA cells revealed an increase in the activity of PDGFRB in lapatinib treated physioxia cells. Similarly, a receptor tyrosine kinase (RTK) array and western blotting showed increased basal and lapatinib induced phosphorylation of PDGFRB (Y751) under physioxia. Next, we determined the potential role of PDGFRB in downstream signaling pathway activation of AKT and ERK and resistance to lapatinib. We found that sunitinib, a multitarget RTK inhibitor with high affinity for PDGFR effectively decreased PGDFRB activity under physioxia, with a concurrent decrease in the phosphorylation of AKT. Moreover, tumor cells under physioxia were more sensitive to sunitinib treatment, relative to ambient air. Furthermore, a combination of lapatinib and sunitinib rendered tumor cells under physioxia more sensitive to treatment than with lapatinib alone. These findings suggest that ambient and physioxic oxygen tensions differentially impact cancer relevant signaling pathways. Therefore, it may be necessary to carry out preclinical cancer studies in the context of physiologically relevant oxygen tensions to aid translatability. Citation Format: Adedeji K. Adebayo, Brijesh Kumar, Christopher Davis, Steven P. Angus, Harikrishna Nakshatri. Oxygen tension - dependent differences in cancer cell kinome. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4811.

In this paper, we study the factors that influence consumer attitudes toward aquaculture as well as annual expenditure on aquaculture products. Our analysis is composed of two parts. First, we esti...

Societal vulnerability to tropical cyclone (TC) hazards continues to grow among expanding coastal communities. Additionally, climate projections indicate that TCs will likely attain higher intensities, produce greater amounts of rainfall, and contribute to enhanced storm-surge inundation amid a warmer climate. Despite accumulating confidence among the climate projections for TCs, a vital element to the compounding nature of TC hazards remains highly uncertain: how might the frequency of TCs change amid a warmer climate?We posit that the frequency of TCs is inextricably connected to variability among the multi-scale processes that constitute tropical cyclogenesis. Therefore, TC frequency projections should be substantiated with multi-scale assessments that account for convective processes, the evolution of mesoscale precursor disturbances, and large-scale environmental forcing. As a first step towards understanding variability among cyclogenesis events in the context of the Earth’s warming climate system, we present intercomparisons between simulations of cyclogenesis by varying the horizontal grid spacing in an idealized, aquaplanet modeling framework using the Model for Prediction Across Scales-Atmosphere (MPAS-A). Four simulations are constructed—three with quasi-uniform horizontal grid spacings of 60 km, 30 km, and 15 km, and a high-resolution simulation with 3-km horizontal grid spacing in the tropics that smoothly transitions to 15-km grid spacing in the extratropics. Tropical precursor disturbances to cyclogenesis are identified and objectively tracked with the TRACK algorithm.Probability density functions are created for each 6-h time step along the disturbance trajectories to characterize and compare the composite environmental conditions accompanying cyclogenesis as a function of the model grid spacing. Intercomparisons between simulations are further investigated with phase diagrams that depict the composite area- and volume-averaged evolution of thermodynamic and dynamic processes throughout cyclogenesis. Furthermore, shear-relative composite-mean analyses are created to assess structural differences between precursor disturbances to cyclogenesis in the simulations. Collectively, the analyses provide an extensible framework and systematic method to assess multi-scale variability during the cyclogenesis process. We will discuss the implications of our findings in the context of the Earth’s warming climate system and proffer a path towards elucidating TC frequency projections through process-oriented diagnostics that characterize the multi-scale variability inherent to tropical cyclogenesis.

On the 24th November 2021 the sequence of a new SARS CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses., A comprehensive analysis of sera from vaccinees, convalescent patients infected previously by multiple variants and potent monoclonal antibodies from early in the COVID-19 pandemic reveals a substantial overall reduction the ability to neutralize the SARS-CoV-2 Omicron variant, which a third vaccine dose seems to ameliorate. Structural analyses of the Omicron RBD suggest a selective pressure enabling the virus bind ACE2 with increased affinity that is offset by other changes in the receptor binding motif that facilitates immune escape.

Upper extremity injuries are common among the growing population of climbers. Although conditions affecting musculoskeletal structures are the most common causes of symptoms, a comprehensive differential diagnosis is necessary to avoid the misdiagnosis of high-morbidity conditions in this patient population. We present a case of a climber with acute edema, erythema, and pain of the entire right upper extremity. After confirmation of an upper extremity deep vein thrombosis by ultrasound, and in the absence of secondary causes for his thrombotic process, he was diagnosed with effort thrombosis. The patient was treated acutely with anticoagulation, catheter thrombectomy, direct thrombolysis, and balloon angioplasty followed by surgical decompression of the subclavian vein. Owing to the importance of early diagnosis and initiation of treatment, it is critical to keep disorders affecting the upper thoracic vascular structures in consideration.

As Haiti and other nations in the Caribbean and Latin America experience increasing instability, and the United States increases its naval presence in the region, history offers important lessons for future U.S. involvement. An exploration of the tactical innovations of the Marine Corps and of the influence of national history on the Haitian insurgencies during the U.S. occupation of Haiti (1915–34) reveals the significance of history in either achieving or curtailing military goals.

The authors outline a program for understanding the semantics and pragmatics of slur terms, proposing that slurs are mixed expressives that predicate membership in some social group G while simultaneously invoking a complex of historical facts and social attitudes about G. The authors then point to the importance of distinguishing between the potential offensive and derogatory effects of slur terms, with the former deriving from the impact on the listener of the invoked content itself, and the latter deriving from inferences about speaker attitudes and intentions. The authors use the resulting framework to discuss several controversial cases of slurs and slurring: (i) terms targeting political views such as ‘Nazi’ and ‘terf’, and (ii) cases in which non-slurs are used to derogate, as in cases of misgendering. The authors conclude that what counts as a slur is in part dependent on a background system of ideological assumptions, meaning that whether a particular term counts as a slur will depend in part on one’s ideological commitments and assumptions.

Background: Psychologically stressful events can be particularly challenging in the wilderness or extreme environments due to a lack of immediate medical or psychological support. Telemedicine consultations may provide a means to supply medical providers in austere environments with expertise when confronted with these situations. Methods: In this study, we detail a case of psychological care imparted to residents at a remote, arctic research station after they encountered a polar bear. The health care provider at the camp was not a dedicated mental health professional but was able to deliver psychological care with assistance from a trained provider through use of telemedicine. We provide a brief overview of the evidence behind psychological first aid and incident support sessions for the treatment of stress injuries. We also review the evidence for telemedicine for psychological care in wilderness situations and describe its use in this scenario. Results: All station residents were able to resume regular arctic activities. Resident feedback was that the sessions were advantageous. Conclusions: We anticipate the need for psychological care in austere situations to increase in the future, and further training in this field and the advancement of telemedicine consultation will be of benefit to wilderness providers.

Phenomenon: Medical education is better aligning with the needs of health systems. Health systems science competencies, such as high-value care, population health, and systems thinking, are increasingly being integrated into curricula, but not without challenges. One challenge is mixed receptivity by students, the underlying reasons of which have not been extensively explored. In this qualitative study, we explored the research question: "How do students perceive health systems science curricula across all four years, and how do such perceptions inform the reasons for mixed quality ratings?" Approach: Following large-scale health systems science curricular changes in their medical school, we used students' open-ended comments obtained from course evaluations related to 1st-, 2nd-, and 4th-year courses and performed a qualitative thematic analysis to explore students' perceptions. We identified themes, synthesized findings into a conceptual figure, and agreed upon results and quotations. Findings: Five themes were identified: (1) perceived importance and relevance of health systems science education, (2) tension between traditional and evolving health systems science-related professional identity, (3) dissatisfaction with redundancy of topics, (4) competition with basic and clinical science curricula, and, (5) preference for discrete, usable, testable facts over complexity and uncertainty. The relationship between themes is described along a continuum of competing agendas between students' traditional mindset (which focuses on basic/clinical science) and an emerging medical education approach (which focuses on basic, clinical, and health systems science). Insights: Health systems science education can be viewed by learners as peripheral to their future practice and not aligned with a professional identity that places emphasis on basic and clinical science topics. For some students, this traditional identity limits engagement in health systems science curricula. If health systems science is to achieve its full potential in medical education, further work is required to explore the adoption of new perspectives by students and create activities to accelerate the process.

Genome editing technologies allow us to study the metabolic pathways of cells and the contribution of each associated enzyme to various processes, including polyhydroxyalkanoate (PHA) synthesis. These biodegradable polyesters accumulated by a range of bacteria are thermoplastic, elastomeric, and biodegradable, thus have great applicative potential. However, several challenges are associated with PHA production, mainly the cost and shortcomings in their physical properties. The advances in synthetic biology and metabolic engineering provide us with a tool to improve the production process and allow the synthesis of tailor-made PHAs. CRISPR/Cas9 technology represents a new generation of genome editing tools capable of application in nearly all organisms. However, off-target activity is a crucial issue for CRISPR/Cas9 technology, as it can cause genomic instability and disruption of functions of otherwise normal genes. Here, we provide a detailed protocol for scarless deletion of the genes implicated in PHA metabolism of Pseudomonas putida KT2440 using modified CRISPR/Cas9 systems and methodology.

Drug repurposing is promoted as a cost- and time-effective mechanism for providing new medicines. Often, however, there is insufficient consideration by academic researchers of the processes required to ensure that a repurposed drug can be used for a new indication. This may explain the inability of drug repurposing to fulfill its promise. Important aspects, often overlooked, include financial and intellectual property considerations, the clinical and regulatory path, and clinical equipoise, which provides ethical justification for randomized controlled trials. The goal of drug repurposing is to obtain a new regulator-approved label for an existing drug, and so, the trajectory for drug repurposing and traditional drug development is similar. Here, we discuss factors critical for a successful repurposed medicine to help academic investigators better identify drug repurposing opportunities.

BackgroundCOVID-19 is a multi-system disease and patients who survive may experience in-hospital complications. These complications are likely to have important short and long-term consequences for patients, healthcare utilisation, healthcare system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and impact of COVID-19 complications, particularly in those who survive using the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK).MethodsA multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 17th January and 4th August 2020. Complications were defined as organ specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. Outcomes included death, critical care use, and ability to self-care at hospital discharge. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.ResultsOf patients admitted to hospital for management of COVID-19, 49.7% (36 367/73 197) experienced at least one complication. The mean age of our cohort was 71.1 years old (SD 18.7), included more males (56.0%, 41 025/73 ) with 81.0% (59 289/73 197) of patients having at least one comorbidity. Males over 60 were most likely to experience a complication (60 y and over, 54.5% [16 579/30 416] in males and 48.2% [11 707/24 288] in females; Under 60 y, 48.8% [5179/10 609] in males, 36.6% [2814/7689] in females). Renal (24.3%, 17 752/73 197), complex respiratory 18.4% (13 486/73 197), and systemic (16.3%, 11 895/73 197) complications were most frequent. Cardiovascular (12.3%, 8973/73 197), neurological (4.3%, 3115/73 197), and gastrointestinal/liver (0.8%, 7901/73 197) complications were also reported. The presence of any complication was associated with significantly worse survival (adjusted HR 1.74, 95% CI 1.64 to 1.84) and increased admission to critical care (adjusted OR 7.25, 95% CI 6.83 to 7.69). Reduced ability to self-care at discharge was significantly greater in patients who experienced a complication (adjusted OR 2.42, 95% CI 2.31 to 2.54) and was greatest in those who experienced neurological complications (adjusted OR 4.39, 95% CI 3.95 to 4.89). ConclusionsComplications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause significant strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.

Background: Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19. Methods: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded. Findings: We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives. Interpretation: In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist. Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.

Background\ud \ud Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.\ud \ud \ud Methods\ud \ud In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.\ud \ud \ud Findings\ud \ud Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8–32·7) in March 9 to April 26, 2020, to 16·4% (15·0–17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65–0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94–0·95) of the reduction in in-hospital mortality.\ud \ud \ud Interpretation\ud \ud The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.\ud \ud \ud Funding\ud \ud National Institute for Health Research and the Medical Research Council.

BACKGROUND: Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use. METHODS: We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age ( FINDINGS: 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16-49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05-1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08-1·27]; p INTERPRETATION: Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease. FUNDING: National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England.

Introduction Telehealth has the potential to significantly change the specialty of emergency medicine (EM) and has rapidly expanded in EM during the COVID pandemic; however, it is unclear how EM should intersect with telehealth. The field lacks a unified research agenda with priorities for scientific questions on telehealth in EM. Methods Through the 2020 Society for Academic Emergency Medicine's annual consensus conference, experts in EM and telehealth created a research agenda for the topic. The multiyear process used a modified Delphi technique to develop research questions related to telehealth in EM. Research questions were excluded from the final research agenda if they did not meet a threshold of at least 80% of votes indicating "important" or "very important." Results Round 1 of voting included 94 research questions, expanded to 103 questions in round 2 and refined to 36 questions for the final vote. Consensus occurred with a final set of 24 important research questions spanning five breakout group topics. Each breakout group domain was represented in the final set of questions. Examples of the questions include: "Among underserved populations, what are mechanisms by which disparities in emergency care delivery may be exacerbated or ameliorated by telehealth" (health care access) and "In what situations should the quality and safety of telehealth be compared to in-person care and in what situations should it be compared to no care" (quality and safety). Conclusion The primary finding from the process was the breadth of gaps in the evidence for telehealth in EM and telehealth in general. Our consensus process identified priority research questions for the use of and evaluation of telehealth in EM to fill the current knowledge gaps. Support should be provided to answer the research questions to guide the evidenced-based development of telehealth in EM.

Background Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease. Methods This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations. Results Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84–1·07; p=0·35), critical care admission (1·01, 0·87–1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80–1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96–1·32; p=0·14), requirement for oxygen (1·00, 0·89–1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92–1·26; p=0·33). Interpretation NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity. Funding National Institute for Health Research and Medical Research Council.

Diagnostic and therapeutic priorities vary for the 8 types of infection reviewed.

This study evaluates the spatial-temporal patterns in Virginia tornadoes using the National Weather Service Storm Prediction Center’s Severe Weather GIS (SVRGIS) database. In addition to descriptive statistics, the analysis employs Kernel Density Estimation for spatial pattern analysis and space-time cubes to visualize the spatiotemporal frequency of tornadoes and potential trends. Most of the 726 tornadoes between 1960–2019 occurred in Eastern Virginia, along the Piedmont and Coastal Plain. Consistent with other literature, both the number of tornadoes and the tornado days have increased in Virginia. While 80% of the tornadoes occurred during the warm season, tornadoes did occur during each month including two deadly tornadoes in January and February. Over the 60-year period, a total of 28 people were killed in the Commonwealth. Most tornado activity took place in the afternoon and early evening hours drawing attention to the temporal variability of risk and vulnerability. Spatial analysis results identify significant, non-random clusters of tornado activity and increasing temporal frequency. While this study improves weather-related literacy and addresses a need in the Commonwealth, more research is necessary to further evaluate the synoptic and mesoscale mechanisms of Virginia tornadoes.

Graphical abstract, Highlights • Abnormal right coronary artery origin and course are demonstrated by FE. • Color flow Doppler is essential for visualizing fetal coronary artery anatomy. • Color-compare images help identify coronary artery origin and course.

This article examines three multilingual lyrics from the Middle Ages in which linguistic difference is employed as a strategy for defining the relationship between language and poetic form. Two poems by twelfth-century troubadours, “Eras quan vey,” a descort in five languages by Raimbaut de Vaqueiras, and “Lo ferm voler,” a sestina by Arnaut Daniel, are read as experimental compositions that promote the function of lyric forms to provide stability to the vernacular in a fluid oral context by communicating meaning in nondiscursive ways. The influence of these works—and also thirteenth-century Occitan grammars by Raimon Vidal and Uc Faidit—may be detected in a later multilingual poem by Dante Alighieri, “Aï faus ris,” which alternates among French, Latin, and Italian according to an intricate formal structure. While previous studies have argued that this fascinating poem strives to synthesize different languages to produce a perfect poetic idiom, this article contends that “Aï faus ris” in fact performs the limitations of human language and the inevitability of linguistic difference, advocating instead for the conceptual harmony of lyric form as an aesthetic vehicle.

Background: Direct-to-consumer virtual visits are increasingly popular across both for-profit and nonprofit healthcare systems. Introduction: Virtual visits offer a convenient affordable w...

Introduction Liver fibrosis and cirrhosis are late complications in Fontan palliation. Liver biopsy is the gold standard. The goal of this study is to correlate transjugular liver biopsy (TJLB) in the setting of Fontan palliation with noninvasive testing and hemodynamics. Methods Between August 2014 and July 2017, 49 Fontan patients underwent TJLB. All the patients had hemodynamic evaluation, 28 patients had MRE (magnetic resonance elastography) and 40 patients had cardiopulmonary exercise test. Histologic liver fibrosis was quantitated using traditional histologic scoring systems and a modified Ishak congestive hepatic fibrosis score. Results Median age 17.8 years, median time since Fontan 15.2 years. Primary diagnosis and Fontan type were variables, but predominantly LV morphology (30/49), lateral tunnel Fontan (29/49), originally fenestrated (37/49), and 11/49 had a pacemaker. Histologic fibrosis correlated with MRE (R = 0.62, P ≤ .001). Histologic fibrosis and MRE correlated with Fontan pressure (R = 0.38, P = .008 & R = 0.59, P ≤ .001). Morphology of the single ventricle did not correlate with liver fibrosis. The presence of a fenestration resulted in a higher cardiac index (P = .026) but did not resulted in lower liver fibrosis (P = .64). Conclusion Noninvasive tests, such as MRE, may be suitable for longitudinal follow-up in patients with single ventricle physiology. Our data suggest that there is reasonable correlation of MRE liver stiffness with biopsy scoring systems and Fontan pressures. We demonstrated the feasibility of TJLB in the setting of Fontan palliation and demonstrated its correlation with noninvasive measures particularly MRE. We recommend selective use of TJLB when MRE score is >5 KPa or when there are other clinical signs of cirrhosis.

Bronchiectasis and bronchiolectasis are defined as irreversible airways dilation of the central and peripheral bronchi, respectively. Bronchiectasis is a common finding on thin-section (

The study of the fossil record is fundamental to understand the evolution of traits. Because fossil remains are often fragmented and/or deformed by taphonomic processes, a preliminary realignment of their constituent parts is often necessary to properly interpret their shapes. In virtual anthropology, these procedures are carried out using digital models of the remains. We present a new semi-automatic alignment R software, Digital Tool for Alignment (DTA), which uses the shape information contained in a reference sample to find the best alignment solution for the disarticulated regions. We tested DTA on three different case-studies: (1) a sample of 14 primate species including both male and female individuals, (2) a simulated, disarticulated skull of Homo sapiens, and (3) a real disarticulated human fossil specimen, Amud 1 (Homo neanderthalensis). In the first case study, we simulated disarticulation directly on digital models of the primate skulls and tested alignment quality as a function of phylogenetic proximity, sex, and body size. In the second, we compared DTA to manual alignments conducted for the same digital models. Finally, we performed DTA on a real-world case study. We found that phylogenetic proximity provides is the most important factor for alignment efficiency. However, sex and allometric effects might also be important and should therefore be taken into account at selecting reference models for alignments. DTA performs at least as well as manual alignments. Yet, as compared to manual procedures, it is faster, requires no prior anatomical knowledge and expertise and allows indefinite manipulation of the fossil items. Anat Rec, 302:1104-1115, 2019. © 2019 Wiley Periodicals, Inc.

Substance use disorders (SUD) often co-occur with other mental disorders such as major depression (MD). Our previous findings revealed sex-dependent changes in extracellular levels of glutamate (Glu) and glutamine (Gln) in the nucleus accumbens (NAc) in Long–Evans rats that were exposed to 21 days of chronic social defeat stress (CSDS), which models MD. The current study investigated the role of a Gln transporter called sodium-coupled neutral amino acid transporter subtype 1/2 (SNAT 1/2), phosphate-activated glutaminase (PAG), and astrocytic glutamate transporter-1 (GLT-1) on CSDS animals exposed to cocaine. Before cocaine exposure, CSDS males already showed decreased levels of SNAT 1/2 in the NAc and prefrontal cortex (PFC) compared to non-CSDS controls. The reduction in SNAT 1/2 levels was associated with an increase in Gln localization in the mitochondrial outer membrane in accumbal glutamatergic nerve terminals projecting from the PFC. CSDS females showed increased GLT-1 levels in the NAc and PFC compared to non-CSDS controls. Both acute and repeated cocaine exposure attenuated locomotor responses in CSDS males but increased those in CSDS females. Cocaine reduced SNAT 1/2 levels in the NAc but increased them in the PFC in CSDS males. Additionally, both PAG and GLT-1 levels were increased in the PFC in CSDS males. On the other hand, cocaine reduced SNAT 1/2 and GLT-1 levels in the NAc and PFC in CSDS females. Our results show that CSDS altered locomotor responses upon cocaine exposure in a sex-dependent manner that may be mediated by molecules associated with the Glu-Gln transfer.

Study Objective: To determine whether deployment of an integrated virtual sepsis surveillance program could improve time to antibiotics and mortality in a longitudinal cohort of non-present on admi...

Background\ud \ud Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.\ud \ud \ud Methods\ud \ud We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).\ud \ud \ud Findings\ud \ud 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model.\ud \ud \ud Interpretation\ud \ud The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.\ud \ud \ud Funding\ud \ud National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.

Background: Sugar accumulation is critically important in determining sugar crop productivity. However, improvement in sugar content has been stagnant among sugar crops for decades. Sorghum, especially sweet sorghum with high biomass, has shown great potential for biofuel. In this study, sorghum was investigated as a C4 diploid model for crops with more complicated genomes such as maize and sugarcane. To enhance sugar accumulation, the sucrose isomerase (SI) gene, driven by stem-specific promoters (A2 or LSG) with a vacuole-targeted signal peptide, was transformed into the sorghum inbred line (Tx430).Results: The study demonstrated that transgenic lines of grain sorghum, containing 50-60% isomaltulose, accumulated sevenfold (804 mM) more total sugar than the control Tx430 did (118 mM) in stalks. Subsequently, the elite engineered lines (A5, and LSG9) were crossed with sweet sorghum (R9188, and Rio). Total sugar contents (over 750 mM), were significantly higher in F1, and F2 progenies than the control Rio (480 mM). The sugar contents of the engineered lines (over 750 mM), including T0, T1, F1, and F2, are higher than that of the field-grown sugarcane (normal range 600-700 mmol/L). Additionally, physiological characterization demonstrated that the superior progenies had notably higher rates of photosynthesis, sucrose transport, and sink strength than the controls.Conclusions: The genetic engineering approach has significantly enhanced total sugar content in grain sorghum (T0, and T1) and hybrid sorghum (F1, and F2), demonstrating that sorghum can accumulate sugar contents as high or higher than sugarcane. This research puts sorghum in the spotlight and frontier as a biofuel crop, particularly as it is a shorter duration crop. The substantial increase in sugar content would lead to enormous financial benefits for industrial utilization. This study could have a substantial impact on renewable bioenergy. More importantly, our results demonstrated that the phenotype of high sugar accumulation is inheritable and shed light on improvement for other sugar crops.

Background Frostbite is a thermal injury caused when tissue is exposed to sub-zero temperatures (in degrees Celsius) long enough for ice crystals to form in the affected tissue. Depending on the degree of tissue damage, thrombosis, ischaemia, necrosis (tissue death), gangrene and ultimately amputation may occur. Several interventions for frostbite injuries have been proposed, such as hyperbaric oxygen therapy, sympathectomy (nerve block), thrombolytic (blood-thinning) therapy and vasodilating agents such as iloprost, reserpine, pentoxifylline and buflomedil, but the benefits and harms of these interventions are unclear. Objectives To assess the benefits and harms of the different management options for frostbite injuries. Search methods On 25 February 2020, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase (OvidSP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index-Science (CPCI-S), as well as trials registers. Shortly before publication, we searched Clinicaltrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, OpenGrey and GreyLit (9 November 2020) again. We investigated references from relevant articles, and corresponded with a trial author. Selection criteria We included randomised controlled trials (RCTs) that compared any medical intervention, e.g. pharmacological therapy, topical treatments or rewarming techniques, for frostbite injuries to another treatment, placebo or no treatment. Data collection and analysis Two authors independently extracted data. We used Review Manager 5 for statistical analysis of dichotomous data with risk ratio (RR) with 95% confidence intervals (CIs). We used the Cochrane 'Risk of bias' tool to assess bias in the included trial. We assessed incidence of amputations, rates of serious and non-serious adverse events, acute pain, chronic pain, ability to perform activities of daily living, quality of life, withdrawal rate from medical therapy due to adverse events, occupational effects and mortality. We used GRADE to assess the quality of the evidence. Main results We included one, open-label randomised trial involving 47 participants with severe frostbite injuries. We judged this trial to be at high risk of bias for performance bias, and uncertain risk for attrition bias; all other risk of bias domains we judged as low. All participants underwent rapid rewarming, received 250 mg of aspirin and 400 mg intravascular (IV) buflomedil (since withdrawn from practice), and were then randomised to one of three treatment groups for the following eight days. Group 1 received additional IV buflomedil 400 mg for one hour per day. Group 2 received the prostacyclin, iloprost, 0.5 ng to 2 ng/kg/min IV for six hours per day. Group 3 received IV iloprost 2 ng/kg/min for six hours per day plus fibrinolysis with 100 mg recombinant tissue plasminogen activator (rtPA) for the first day only. The results suggest that iloprost and iloprost plus rtPA may reduce the rate of amputations in people with severe frostbite compared to buflomedil alone, RR 0.05 (95% CI 0.00 to 0.78; P = 0.03; very low-quality evidence) and RR 0.31 (95% CI 0.10 to 0.94; P = 0.04; very low-quality evidence), respectively. Iloprost may be as effective as iloprost plus rtPA at reducing the amputation rate, RR 0.14 (95% CI 0.01 to 2.56; P = 0.19; very low-quality evidence). There were no reported deaths or withdrawals due to adverse events in any of the groups; we assessed evidence for both outcomes as being of very low quality. Adverse events (including flushing, nausea, palpitations and vomiting) were common, but not reported separately by comparator arm (very low-quality evidence). The included study did not measure the outcomes of acute pain, chronic pain, ability to perform activities of daily living, quality of life or occupational effects. Authors' conclusions There is a paucity of evidence regarding interventions for frostbite injuries. Very low-quality evidence from a single small trial indicates that iloprost, and iloprost plus rtPA, in combination with buflomedil may reduce the need for amputation in people with severe frostbite compared to buflomedil alone. However, buflomedil has been withdrawn from use. High quality randomised trials are needed to establish firm evidence for the treatment of frostbite injuries.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non–idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17–2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

The Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for the prevention and management of tick-borne illness (TBI). Recommendations are graded based on quality of supporting evidence according to criteria put forth by the American College of Chest Physicians. The guidelines include a brief review of the clinical presentation, epidemiology, prevention, and management of TBI in the United States, with a primary focus on interventions that are appropriate for resource-limited settings. Strong recommendations are provided for the use of DEET, picaridin, and permethrin; tick checks; washing and drying clothing at high temperatures; mechanical tick removal within 36 h of attachment; single-dose doxycycline for high-risk Lyme disease exposures versus "watchful waiting;" evacuation from backcountry settings for symptomatic tick exposures; and TBI education programs. Weak recommendations are provided for the use of light-colored clothing; insect repellents other than DEET, picaridin, and permethrin; and showering after exposure to tick habitat. Weak recommendations are also provided against passive methods of tick removal, including the use of systemic and local treatments. There was insufficient evidence to support the use of long-sleeved clothing and the avoidance of tick habitat such as long grasses and leaf litter. Although there was sound evidence supporting Lyme disease vaccination, a grade was not offered as the vaccine is not currently available for use in the United States.

OBJECTIVES Increased use of three-dimensional (3D) imaging data has led to a need for methods capable of capturing rich shape descriptions. Semi-landmarks have been demonstrated to increase shape information but placement in 3D can be time consuming, computationally expensive, or may introduce artifacts. This study implements and compares three strategies to more densely sample a 3D image surface. MATERIALS AND METHODS Three dense sampling strategies: patch, patch-thin-plate spline (TPS), and pseudo-landmark sampling, are implemented to analyze skulls from three species of great apes. To evaluate the shape information added by each strategy, the semi or pseudo-landmarks are used to estimate a transform between an individual and the population average template. The average mean root squared error between the transformed mesh and the template is used to quantify the success of the transform. RESULTS The landmark sets generated by each method result in estimates of the template that on average were comparable or exceeded the accuracy of using manual landmarks alone. The patch method demonstrates the most sensitivity to noise and missing data, resulting in outliers with large deviations in the mean shape estimates. Patch-TPS and pseudo-landmarking provide more robust performance in the presence of noise and variability in the dataset. CONCLUSIONS Each landmarking strategy was capable of producing shape estimations of the population average templates that were generally comparable to manual landmarks alone while greatly increasing the density of the shape information. This study highlights the potential trade-offs between correspondence of the semi-landmark points, consistent point spacing, sample coverage, repeatability, and computational time.