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BackgroundThe role of thromboprophylaxis in the post-acute phase of COVID-19 is uncertain due to conflicting results from randomised controlled trials and observational studies. We aimed to determine the effectiveness of post-hospital apixaban in reducing the rate of death and hospital readmission of hospitalised adults with COVID-19. MethodsHEAL COVID is an adaptive randomised open label multicentre platform trial recruiting participants from National Health Service Hospitals in the United Kingdom. Here we report the preliminary results of apixaban comparison of HEAL-COVID. Participants with a hospital admission related to confirmed COVID-19 and an expected date of discharge in the subsequent five days were randomised to either apixaban 2.5 mg twice daily or standard care (no anticoagulation) for 14 days. The primary outcome was hospital free survival at 12 months obtained through routine data sources. The trial was prospectively registered with ISRCTN (15851697) and Clincialtrials.gov (NCT04801940). FindingsBetween 19 May 2021 and 21 November 2022, 402 participants from 109 sites were randomised to apixaban and 399 to standard care. Seven participants withdrew from the apixaban group and one from the standard care group. Analysis was undertaken on an intention-to-treat basis. The apixaban arm was stopped on the recommendation of the oversight committees following an interim analysis due to no indication of benefit. Of the 402 participants randomised to apixaban, 117 experienced death or rehospitalisation during a median follow-up of 344{middle dot}5 days (IQR 125 to 365), and 123 participants receiving standard care experienced death or rehospitalisation during a median follow-up of 349 days (IQR 124 to 365). There was no statistical difference in the rate of death and rehospitalisation (HR: 0{middle dot}96 99%CI 0{middle dot}69-1{middle dot}34; p=0{middle dot}75). Three participants in the apixaban arm experienced clinically significant bleeding during treatment. InterpretationFourteen days of post-hospital anticoagulation with the direct oral anticoagulant apixaban did not reduce the rate of death or rehospitalisation of adults hospitalised with COVID-19. These data do not support the use of prophylactic post-hospital anticoagulation in adults with COVID-19. FundingHEAL-COVID is funded by the National Institute for Health and Care Research [NIHR133788] and the NIHR Cambridge Biomedical Research Centre [BRC-1215-20014*].
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The Australian Capital Territory rapidly responded to an incursion of the SARS-CoV-2 Delta (B.1.617.2) variant on 12 August 2021 with several public health interventions, including a territory-wide lockdown and genomic sequencing. Prior to this date, SARS-CoV-2 had been eliminated locally since July 7, 2020. Sequencing of >75% of cases identified at least 13 independent incursions with onwards spread in the community during the study period, between 12 August and 11 November 2021. Two incursions resulted in the majority of community transmission during this period, with persistent transmission in vulnerable sections of the community. Ultimately, both major incursions were successfully mitigated through public health interventions, including COVID-19 vaccines. In this study we explore the demographic factors that contributed to the spread of these incursions. The high rates of SARS-CoV-2 sequencing in the Australian Capital Territory and the relatively small population size facilitated detailed investigations of the patterns of virus transmission. Genomic sequencing was critical to disentangling complex transmission chains to target interventions appropriately. O_LIDespite a strict lockdown and interstate travel restrictions, the Australian Capital Territory experienced at least 13 incursions of SARS-CoV-2 Delta (B.1.617.2) with onwards spread in the community between 12 August and 11 November 2021. C_LIO_LIThis level of detail was only accessible because of the high rate of SARS-CoV-2 sequencing, with sequencing attempted on 1438/1793 (80%) of cases. C_LIO_LITransmission chains varied in size and duration, with two dominant incursions (ACT.19 and ACT.20) comprising 35% and 53% of all sequenced cases during the study period, respectively. C_LIO_LIThe ACT.20 outbreak persisted longer, due to specific challenges with implementing public health interventions in the affected populations. C_LIO_LIBoth major incursions were successfully curbed through stringent public health measures, including the widespread acceptance of COVID-19 vaccines (>95% of the eligible population by the end of the study period). C_LI
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A comprehensive analysis and characterization of a SARS-CoV-2 infection model that mimics non-severe and severe COVID-19 in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2x103 and 2x104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lungs, liver, and kidney, while lower doses (2x101 and 2x102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this humanized hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in biopsy samples from COVID-19 patients. Finally, the mice that recovered after infection with a low dose of virus also survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human biopsy samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. ImportanceThe pandemic of COVID-19 has reached 112,589,814 cases and caused 2,493,795 deaths worldwide as of February 23, 2021, has raised an urgent need for development of novel drugs and therapeutics to prevent the spread and pathogenesis of SARS-CoV-2. To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 virus to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of anti-viral drugs and therapeutics.
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OBJECTIVE: To determine the effect of an electronic medical record (EMR) nudge at reducing total and inappropriate orders testing for hospital-onset Clostridioides difficile infection (HO-CDI). DESIGN: An interrupted time series analysis of HO-CDI orders 2 years before and 2 years after the implementation of an EMR intervention designed to reduce inappropriate HO-CDI testing. Orders for C. difficile testing were considered inappropriate if the patient had received a laxative or stool softener in the previous 24 hours. SETTING: Four hospitals in an academic healthcare network. PATIENTS: All patients with a C. difficile order after hospital day 3. INTERVENTION: Orders for C. difficile testing in patients administered a laxative or stool softener in <24 hours triggered an EMR alert defaulting to cancellation of the order ("nudge"). RESULTS: Of the 17,694 HO-CDI orders, 7% were inappropriate (8% prentervention vs 6% postintervention; P < .001). Monthly HO-CDI orders decreased by 21% postintervention (level-change rate ratio [RR], 0.79; 95% confidence interval [CI], 0.73-0.86), and the rate continued to decrease (postintervention trend change RR, 0.99; 95% CI, 0.98-1.00). The intervention was not associated with a level change in inappropriate HO-CDI orders (RR, 0.80; 95% CI, 0.61-1.05), but the postintervention inappropriate order rate decreased over time (RR, 0.95; 95% CI, 0.93-0.97). CONCLUSION: An EMR nudge to minimize inappropriate ordering for C. difficile was effective at reducing HO-CDI orders, and likely contributed to decreasing the inappropriate HO-CDI order rate after the intervention.