Vascular inflammation and endothelial injury in SARS-CoV-2 infection: the overlooked regulatory cascades implicated by the ACE2 gene cluster.

Coronavirus disease 2019 (COVID-19) has presented physicians with an unprecedented number of challenges and mortality. The basic question is why, in contrast to other 'respiratory' viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in such multi-systemic, life-threatening complications and a severe pulmonary vasculopathy. It is widely known that SARS-CoV-2 uses membrane-bound angiotensin-converting enzyme 2 (ACE2) as a receptor, resulting in internalization of the complex by the host cell. We discuss the evidence that failure to suppress coronaviral replication within 5 days results in sustained downregulation of ACE2 protein expression and that ACE2 is under negative-feedback regulation. We then expose openly available experimental repository data that demonstrate the gene for ACE2 lies in a novel cluster of inter-regulated genes on the X chromosome including PIR encoding pirin (quercetin 2,3-dioxygenase), and VEGFD encoding the predominantly lung-expressed vascular endothelial growth factor D. The five double-elite enhancer/promoters pairs that are known to be operational, and shared read-through lncRNA transcripts, imply that ongoing SARS-CoV-2 infection will reduce host defences to reactive oxygen species, directly generate superoxide O2·- and H2O2 (a ' ROS storm'), and impair pulmonary endothelial homeostasis. Published cellular responses to oxidative stress complete the loop to pathophysiology observed in severe COVID-19. Thus, for patients who fail to rapidly suppress viral replication, the newly appreciated ACE2 co-regulated gene cluster predicts delayed responses that would account for catastrophic deteriorations. We conclude that ACE2 homeostatic drives provide a unified understanding that should help optimize therapeutic approaches during the wait until safe, effective vaccines and antiviral therapies for SARS-CoV-2 are delivered.

Intensive Care Weaning (iCareWean) protocol on weaning from mechanical ventilation: a single-blinded multicentre randomised control trial comparing an open-loop decision support system and routine care, in the general intensive care unit.

INTRODUCTION: Automated systems for ventilator management to date have been either fully heuristic rule-based systems or based on a combination of simple physiological models and rules. These have been shown to reduce the duration of mechanical ventilation in simple to wean patients. At present, there are no published studies that evaluate the effect of systems that use detailed physiological descriptions of the individual patient.The BEACON Caresystem is a model-based decision support system that uses mathematical models of patients' physiology in combination with models of clinical preferences to provide advice on appropriate ventilator settings. An individual physiological description may be particularly advantageous in selecting the appropriate therapy for a complex, heterogeneous, intensive care unit (ICU) patient population. METHODS AND ANALYSIS: Intenive Care weaning (iCareWean) is a single-blinded, multicentre, prospective randomised control trial evaluating management of mechanical ventilation as directed by the BEACON Caresystem compared with that of current care, in the general intensive care setting. The trial will enrol 274 participants across multiple London National Health Service ICUs. The trial will use a primary outcome of duration of mechanical ventilation until successful extubation. ETHICS AND DISSEMINATION: Safety oversight will be under the direction of an independent committee of the study sponsor. Study approval was obtained from the regional ethics committee of the Health Research Authority (HRA), (Research Ethic Committee (REC) reference: 17/LO/0887. Integrated Research Application System (IRAS) reference: 226610. Results will be disseminated through international critical care conference/symposium and publication in peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov under NCT03249623. This research is registered with the National Institute for Health Research under CPMS ID: 34831.

Efficacy and safety of rivaroxaban thromboprophylaxis after arthroplasty of the hip or knee: retrospective cohort study.

Introduction Venous thromboembolism (VTE) is a potentially fatal complication of hip arthroplasty and knee arthroplasty. The National Institute for Health and Care Excellence recommend rivaroxaban for VTE prevention. Amid concerns over bleeding complications, the modified thromboprophylaxis policy of Chelsea and Westminster Hospital (CWH; London, UK) advises enoxaparin given after surgery in the inpatient setting followed by rivaroxaban upon hospital discharge. This retrospective study investigated the efficacy and safety of rivaroxaban in this novel, modified venous-prophylaxis regimen in a surgical orthopaedic cohort at CWH. Methods A total of 479 patients who received modified thromboprophylaxis treatment at CWH after hip arthroplasty or knee arthroplasty between April 2013 and October 2014 formed the study cohort. Seven outcomes based on efficacy and safety while undergoing treatment with rivaroxaban were investigated: symptomatic deep-vein thrombosis (DVT), pulmonary embolism (PE), death, stroke, myocardial infarction (MI), major bleeding episodes (MBEs) and non-major bleeding episodes (NMBEs). Median follow-up was 369 days. Fisher's exact and Mann-Whitney U-tests were adopted to identify associations with these outcomes. Results Prevalence of symptomatic PE, DVT, death, stroke and MI during treatment was zero. One (0.2%) MBE and nine (1.9%) NMBEs occurred. The MBE (a wound haematoma) required a return to theatre for aspiration. Off-treatment VTEs occurred in four (0.8%) patients after completion of a course of rivaroxaban, and were associated with known risk factors. Conclusions Rivaroxaban is an effective and safe anticoagulant for thromboprophylaxis after hip arthroplasty or knee arthroplasty if used in a modified regimen involving enoxaparin administered in the inpatient setting followed by rivaroxaban upon hospital discharge.

Factors at scene and in transfer related to the development of hypothermia in major burns.

There is a paucity of evidence regarding incidence and causes of hypothermia in patients with major burns and its impact on outcomes. This paper identifies contributing factors to hypothermia and its relationship with the severity of physiological scoring systems on admission to a tertiary centre. Patients with burns >20% TBSA admitted between March 2010 and July 2013 comprised this retrospective survey. Data relating to causative factors at time of burn, during transfer, physiological outcome scores (BOBI, SOFA, RTS and APACHE II), length of hospital stay and mortality were collected. SPSS statistical software was used for analysis. The study included 31 patients (medians: age 32 years, burn size 30% TBSA). 13% (n=4) of patients died during hospital admission. 42% (n=13) of patients had a temperature <36.0C on arrival. Temperature on arrival at the burns centre was related to the severity of all physiological scores (p=<0.001). There was no difference between groups in terms of mortality in hospital (p=0.151) or length of hospital stay (p=0.547). Our results show that hypothermia is related to burn severity and patient physiological status. They do not show a relationship between hypothermia and external factors at the time of the burn. This paper prompts further investigation into the prevention of hypothermia in patients with major burns.

Il n'existe que peu de données sur l'incidence et les causes de survenue d'une hypothermie chez les brûlés, ni de son incidence sur le devenir. Cette étude répertorie les facteurs contribuant à l'hypothermie à l'admission dans un centre de référence et sa relation avec les scores de gravité initiaux. Cette étude rétrospective a concerné les patients brûlés sur plus de 20% de SCT admis entre mars 2010 et juillet 2013. Les données concernant les causes d'hypothermie au moment de la brûlure et pendant le transfert, les scores de gravité (BOBI, SOFA, RTS et APACHE II), la durée de séjour et la mortalité ont été relevées. Trente et un dossiers ont été étudiés (âge médian 32 ans, surface brûlée 30%). Quatre (13%) d'ente eux décédés. Treize (42%) avait une température <36°C à l'admission et il existait une corrélation entre la température et les scores de gravité (p<0.001). Il n'y avait pas de différence en termes de mortalité ni de durée de séjour. Cette étude montre que l'hypothermie est corrélée à la gravité de la brûlure et à la gravité générale des patients. On ne retrouve pas de relation entre les facteurs environnementaux au moment de la brûlure et l'hypothermie. Des données supplémentaires sont nécessaires pour la prévention de l'hypothermie liée à la brûlure.

Traumatic brain injury: intensive care management.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. The modern management of severe TBI has fallen into the domain of a multidisciplinary team led by neurointensivists, neuroanaesthetists, and neurosurgeons and is based on the avoidance of secondary injury, maintenance of cerebral perfusion pressure (CPP), and optimization of cerebral oxygenation. In this review, we will discuss the intensive care management of severe TBI with emphasis on the specific measures directed at the control of intracranial pressure and CPP.