Monolithic multiphysics simulation of hypersonic aerothermoelasticity using a hybridized discontinuous Galerkin method

This work presents implementation of a hybridized discontinuous Galerkin (DG) method for robust simulation of the hypersonic aerothermoelastic multiphysics system. Simulation of hypersonic vehicles requires accurate resolution of complex multiphysics interactions including the effects of high-speed turbulent flow, extreme heating, and vehicle deformation due to considerable pressure loads and thermal stresses. However, the state-of-the-art procedures for hypersonic aerothermoelasticity are comprised of low-fidelity approaches and partitioned coupling schemes. These approaches preclude robust design and analysis of hypersonic vehicles for a number of reasons. First, low-fidelity approaches limit their application to simple geometries and lack the ability to capture small scale flow features (e.g. turbulence, shocks, and boundary layers) which greatly degrades modeling robustness and solution accuracy. Second, partitioned coupling approaches can introduce considerable temporal and spatial inaccuracies which are not trivially remedied. In light of these barriers, we propose development of a monolithically-coupled hybridized DG approach to enable robust design and analysis of hypersonic vehicles with arbitrary geometries. Monolithic coupling methods implement a coupled multiphysics system as a single, or monolithic, equation system to be resolved by a single simulation approach. Further, monolithic approaches are free from the physical inaccuracies and instabilities imposed by partitioned approaches and enable time-accurate evolution of the coupled physics system. In this work, a DG method is considered due to its ability to accurately resolve second-order partial differential equations (PDEs) of all classes. We note that the hypersonic aerothermoelastic system is composed of PDEs of all three classes. Hybridized DG methods are specifically considered due to their exceptional computational efficiency compared to traditional DG methods. It is expected that our monolithic hybridized DG implementation of the hypersonic aerothermoelastic system will 1) provide the physical accuracy necessary to capture complex physical features, 2) be free from any spatial and temporal inaccuracies or instabilities inherent to partitioned coupling procedures, 3) represent a transition to high-fidelity simulation methods for hypersonic aerothermoelasticity, and 4) enable efficient analysis of hypersonic aerothermoelastic effects on arbitrary geometries

ENSO-driven interhemispheric Pacific mass transports

Previous studies have shown that ENSO's anomalous equatorial winds, including the observed southward shift of zonal winds that occurs around the event peak, can be reconstructed with the first two Empirical Orthogonal Functions (EOFs) of equatorial region wind stresses. Using a high-resolution ocean general circulation model, we investigate the effect of these two EOFs on changes in warm water volume (WWV), interhemispheric mass transports, and Indonesian Throughflow (ITF). Wind stress anomalies associated with the first EOF produce changes in WWV that are dynamically consistent with the conceptual recharge oscillator paradigm. The ITF is found to heavily damp these WWV changes, reducing their variance by half. Wind stress anomalies associated with the second EOF, which depicts the southward wind shift, are responsible for WWV changes that are of comparable magnitude to those driven by the first mode. The southward wind shift is also responsible for the majority of the observed interhemispheric upper ocean mass exchanges. These winds transfer mass between the Northern and the Southern Hemisphere during El Niño events. Whilst water is transferred in the opposite direction during La Niña events, the magnitude of this exchange is roughly half of that seen during El Niño events. Thus, the discharging of WWV during El Niño events is meridionally asymmetric, while the WWV recharging during a La Niña event is largely symmetric. The inclusion of the southward wind shift is also shown to allow ENSO to exchange mass with much higher latitudes than that allowed by the first EOF alone

The impact of adolescent exposure to medical marijuana laws on high school completion, college enrollment and college degree completion

Background: There is concern that medical marijuana laws (MMLs) could negatively affect adolescents. To better understand these policies, we assess how adolescent exposure to MMLs is related to educational attainment. Methods: Data from the 2000 Census and 2001-2014 American Community Surveys were restricted to individuals who were of high school age (14-18) between 1990 and 2012 (n = 5,483,715). MML exposure was coded as: (i) a dichotomous any MML indicator, and (ii) number of years of high school age exposure. We used logistic regression to model whether MMLs affected: (a) completing high school by age 19; (b) beginning college, irrespective of completion; and (c) obtaining any degree after beginning college. A similar dataset based on the Youth Risk Behavior Survey (YRBS) was also constructed for confirmatory analyses assessing marijuana use. Results: MMLs were associated with a 0.40 percentage point increase in the probability of not earning a high school diploma or GED after completing the 12th grade (from 3.99% to 4.39%). High school MML exposure was also associated with a 1.84 and 0.85 percentage point increase in the probability of college non-enrollment and degree non-completion, respectively (from 31.12% to 32.96% and 45.30% to 46.15%, respectively). Years of MML exposure exhibited a consistent dose response relationship for all outcomes. MMLs were also associated with 0.85 percentage point increase in daily marijuana use among 12th graders (up from 1.26%). Conclusions: Medical marijuana law exposure between age 14 to 18 likely has a delayed effect on use and education that persists over time. (C) 2016 Elsevier Ireland Ltd. All rights reserved

Circulating tumour DNA is a promising biomarker for risk stratification of central chondrosarcoma with IDH1/2 and GNAS mutations

Chondrosarcoma (CS) is a rare tumour type and the most common primary malignant bone cancer in adults. The prognosis, currently based on tumour grade, imaging and anatomical location, is not reliable, and more objective biomarkers are required. We aimed to determine whether the level of circulating tumour DNA (ctDNA) in the blood of CS patients could be used to predict outcome. In this multi-institutional study, we recruited 145 patients with cartilaginous tumours, of which 41 were excluded. ctDNA levels were assessed in 83 of the remaining 104 patients, whose tumours harboured a hotspot mutation in IDH1/2 or GNAS. ctDNA was detected pre-operatively in 31/83 (37%) and in 12/31 (39%) patients postoperatively. We found that detection of ctDNA was more accurate than pathology for identification of high-grade tumours and was associated with a poor prognosis; ctDNA was never associated with CS grade 1/atypical cartilaginous tumours (ACT) in the long bones, in neoplasms sited in the small bones of the hands and feet or in tumours measuring less than 80 mm. Although the results are promising, they are based on a small number of patients, and therefore, introduction of this blood test into clinical practice as a complementary assay to current standard-of-care protocols would allow the assay to be assessed more stringently and developed for a more personalised approach for the treatment of patients with CS

A Qualitative Risk Assessment for Bluetongue Disease and African Horse Sickness: The Risk of Entry and Exposure at a UK Zoo.

Bluetongue virus (BTV) and African horse sickness virus (AHSV) cause economically important diseases that are currently exotic to the United Kingdom (UK), but have significant potential for introduction and onward transmission. Given the susceptibility of animals kept in zoo collections to vector-borne diseases, a qualitative risk assessment for the introduction of BTV and AHSV to ZSL London Zoo was performed. Risk pathways for each virus were identified and assessed using published literature, animal import data and outputs from epidemiological models. Direct imports of infected animals, as well as wind-borne infected Culicoides, were considered as routes of incursion. The proximity of ongoing disease events in mainland Europe and proven capability of transmission to the UK places ZSL London Zoo at higher risk of BTV release and exposure (estimated as low to medium) than AHSV (estimated as very low to low). The recent long-range expansion of AHSV into Thailand from southern Africa highlights the need for vector competence studies of Palearctic Culicoides for AHSV to assess the risk of transmission in this region

Opportunities for improving animal welfare in rodent models of epilepsy and seizures

Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs)

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Clinical features and management of human monkeypox: a retrospective observational study in the UK

Background Cases of human monkeypox are rarely seen outside of west and central Africa. There are few data regarding viral kinetics or the duration of viral shedding and no licensed treatments. Two oral drugs, brincidofovir and tecovirimat, have been approved for treatment of smallpox and have demonstrated efficacy against monkeypox in animals. Our aim was to describe the longitudinal clinical course of monkeypox in a high-income setting, coupled with viral dynamics, and any adverse events related to novel antiviral therapies. Methods In this retrospective observational study, we report the clinical features, longitudinal virological findings, and response to off-label antivirals in seven patients with monkeypox who were diagnosed in the UK between 2018 and 2021, identified through retrospective case-note review. This study included all patients who were managed in dedicated high consequence infectious diseases (HCID) centres in Liverpool, London, and Newcastle, coordinated via a national HCID network. Findings We reviewed all cases since the inception of the HCID (airborne) network between Aug 15, 2018, and Sept 10, 2021, identifying seven patients. Of the seven patients, four were men and three were women. Three acquired monkeypox in the UK: one patient was a health-care worker who acquired the virus nosocomially, and one patient who acquired the virus abroad transmitted it to an adult and child within their household cluster. Notable disease features included viraemia, prolonged monkeypox virus DNA detection in upper respiratory tract swabs, reactive low mood, and one patient had a monkeypox virus PCR-positive deep tissue abscess. Five patients spent more than 3 weeks (range 22–39 days) in isolation due to prolonged PCR positivity. Three patients were treated with brincidofovir (200 mg once a week orally), all of whom developed elevated liver enzymes resulting in cessation of therapy. One patient was treated with tecovirimat (600 mg twice daily for 2 weeks orally), experienced no adverse effects, and had a shorter duration of viral shedding and illness (10 days hospitalisation) compared with the other six patients. One patient experienced a mild relapse 6 weeks after hospital discharge. Interpretation Human monkeypox poses unique challenges, even to well resourced health-care systems with HCID networks. Prolonged upper respiratory tract viral DNA shedding after skin lesion resolution challenged current infection prevention and control guidance. There is an urgent need for prospective studies of antivirals for this disease

Assumption without representation: the unacknowledged abstraction from communities and social goods

We have not clearly acknowledged the abstraction from unpriceable “social goods” (derived from communities) which, different from private and public goods, simply disappear if it is attempted to market them. Separability from markets and economics has not been argued, much less established. Acknowledging communities would reinforce rather than undermine them, and thus facilitate the production of social goods. But it would also help economics by facilitating our understanding of – and response to – financial crises as well as environmental destruction and many social problems, and by reducing the alienation from economics often felt by students and the public

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570