Admission avoidance in acute epistaxis: A prospective national audit during the initial peak of the COVID-19 pandemic.

OBJECTIVES: To report changes in practice brought about by COVID-19 and the implementation of new guidelines, and to explore factors relating to unscheduled re-presentations for patients discharged from the emergency department (ED). DESIGN: Prospective multicentre national audit over 12 weeks from 6th April 2020. SETTING: UK secondary care ENT departments. PARTICIPANTS: Adult patients with acute epistaxis. MAIN OUTCOME MEASURES: Re-presentation within 10 days for patients discharged from the ED. RESULTS: Eighty three centres from all four UK nations submitted 2631 valid cases. The majority of cases were ED referrals (89.7%, n = 2358/2631). 54.6% were discharged from the ED following ENT review (n = 1267/2322), of whom 19.5% re-presented within 10 days (n = 245/1259) and 6.8% were ultimately admitted (n = 86/1259). 46.7% of patients had a non-dissolvable pack inserted by ED prior to referral to ENT (n = 1099/2355). The discharge rates for ED patients and their subsequent re-presentation rates were as follows: non-dissolvable packs, 29.5% discharged (n = 332/1125), 18.2% re-presented (n = 60/330); dissolvable products, 71.1% discharged (n = 488/686), 21.8% re-presented (n = 106/486); cautery only, 89.2% discharged (n = 247/277), 20.0% re-presented (n = 49/245); and no intranasal intervention, 85.5% discharged (n = 200/234), 15.2% re-presented (n = 30/198). Univariable logistic regression showed that not being packed by ED, antiplatelet medications, failed cautery and recent epistaxis treatment were significant predictors of re-presentation within 10 days. CONCLUSIONS: Management of acute epistaxis was notably affected during the initial peak of the pandemic, with a shift towards reduced admissions. This national audit highlights that many patients who may previously have been admitted to hospital may be safely discharged from the ED following acute epistaxis.

Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets.

Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host's immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB-the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years-reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in M. tb.

Development of an External Control Arm Using Electronic Health Record-Based Real-World Data to Evaluate the Efficacy of COVID-19 Treatment.

To protect people from severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, tremendous research efforts have been made toward coronavirus disease 19 (COVID-19) treatment development. Externally controlled trials (ECTs) may help reduce their development time. To evaluate whether ECT using real-world data (RWD) of patients with COVID-19 is feasible enough to be used for regulatory decision making, we built an external control arm (ECA) based on RWD as a control arm of a previously conducted randomized controlled trial (RCT), and compared it to the control arm of the RCT. The electronic health record (EHR)-based COVID-19 cohort dataset was used as RWD, and three Adaptive COVID-19 Treatment Trial (ACTT) datasets were used as RCTs. Among the RWD datasets, eligible patients were evaluated as a pool of external control subjects of the ACTT-1, ACTT-2, and ACTT-3 trials, respectively. The ECAs were built using propensity score matching, and the balance of age, sex, and baseline clinical status ordinal scale as covariates between the treatment arms of Asian patients in each ACTT and the pools of external control subjects was assessed before and after 1:1 matching. There was no statistically significant difference in time to recovery between ECAs and the control arms of each ACTT. Among the covariates, the baseline status ordinal score had the greatest influence on the building of ECA. This study demonstrates that ECA based on EHR data of COVID-19 patients could sufficiently replace the control arm of an RCT, and it is expected to help develop new treatments faster in emergency situations, such as the COVID-19 pandemic.

Effectiveness of Remdesivir Treatment Protocols Among Patients Hospitalized with COVID-19: A Target Trial Emulation.

BACKGROUND: Remdesivir is recommended for certain hospitalized patients with COVID-19. However, these recommendations are based on evidence from small randomized trials, early observational studies, or expert opinion. Further investigation is needed to better inform treatment guidelines with regard to the effectiveness of remdesivir among these patients. METHODS: We emulated a randomized target trial using chargemaster data from 333 US hospitals from 1 May 2020 to 31 December 2021. We compared three treatment protocols: remdesivir within 2 days of hospital admission, no remdesivir within the first 2 days of admission, and no remdesivir ever. We used baseline comorbidities recorded from encounters up to 12 months before admission and identified the use of in-hospital medications, procedures, and oxygen supplementation from charges. We estimated the cumulative incidence of mortality or mechanical ventilation/extracorporeal membrane oxygenation with an inverse probability of censoring weighted estimator. We conducted analyses in the total population as well as in subgroups stratified by level of oxygen supplementation. RESULTS: A total of 274,319 adult patients met the eligibility criteria for the study. Thirty-day in-hospital mortality risk differences for patients adhering to the early remdesivir protocol were -3.1% (95% confidence interval = -3.5%, -2.7%) compared to no early remdesivir and -3.7% (95% confidence interval -4.2%, -3.2%) compared to never remdesivir, with the strongest effect in patients needing high-flow oxygen. For mechanical ventilation/extracorporeal membrane oxygenation, risk differences were minimal. CONCLUSIONS: We estimate that, among hospitalized patients with COVID-19, remdesivir treatment within 2 days of admission reduced 30-day in-hospital mortality, particularly for patients receiving supplemental oxygen on the day of admission.

The worldwide coronavirus disease 2019 outbreak: Advice and recommendation on radiology management and infection control from makeshift hospitals in Wuhan.

ABSTRACT: To describe and advise on management protocols and infection-protection experience of the radiology department in makeshift hospitals in Wuhan during the coronavirus disease 2019 (COVID-19) outbreak.Based on the literature review and the experience in the frontline, we retrospectively reviewed the configuration of the radiology department, human resource, personal protection, examination procedures for patients confirmed with COVID-19 in Wuhan fangcang shelter hospital.From February 11, 2020 to March 10, 2020, 2730 and 510 CT examinations were performed in the Hanjiang shelter hospital and Hanyang Sports School shelter hospital, respectively, including initial examinations and re-examinations. The maximum number of daily CT examinations reached 289. The CT scanned a patient approximately once every 13 mins.Fangcang shelter radiology department could be powerful components of both global and national responses to the COVID-19 pandemic.

Tailoring lipid management interventions to reduce inequalities in cardiovascular disease risk management in primary care for deprived communities in Northern England: a mixed-methods intervention development protocol.

INTRODUCTION: Hyperlipidaemia contributes a significant proportion of modifiable cardiovascular disease (CVD) risk, which is a condition that disproportionally affects disadvantaged socioeconomic communities, with death rates in the most deprived areas being four times higher than those in the least deprived. With the national CVD Prevention programme being delivered to minimise risk factors, no evidence is available on what has been implemented in primary care for deprived populations. This study describes the protocol for the development of a tailored intervention aiming to optimise lipid management in primary care settings to help reduce inequalities in CVD risks and improve outcomes in deprived communities. METHODS AND ANALYSIS: A mixed-methods approach will be employed consisting of four work packages: (1) rapid review and logic model; (2) assessment and comparison of CVD risk management for deprived with non-deprived populations in Northern England to England overall; (3) interviews with health professionals; and (4) intervention development. A systematic search and narrative synthesis will be undertaken to identify evidence-based interventions and targeted outcomes in deprived areas. General practice-level data will be assessed to establish the profile of lipid management, compared with the regional and national levels. Health professionals involved in the organisation and delivery of routine lipid management to deprived populations will be interviewed to understand the implementation and delivery of current lipid management and associated challenges. The prototype intervention will be informed by the evidence generated from workpackages 1-3, which will be reviewed and assessed using the nominal group technique to reach consensus. Training and skills development materials will also be developed as needed. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Faculty of Medical Sciences Research Ethics Committee at Newcastle University, UK. Findings will be disseminated to the participating sites, participants, commissioners, and in peer-reviewed journals and academic conferences.

Shanghai expert consensus on clinical protocol for traditional Chinese medicine treatment of COVID-19 among the elderly population (second edition).

This document is the revised edition of the previously issued Shanghai Expert Consensus on Clinical Protocol for Traditional Chinese Medicine Treatment of COVID-19 among the Elderly Population. Based on the clinical experience and the Protocol for Diagnosis and Treatment of COVID-19 (Trial 9th Edition), this revised edition provides treatment approaches and recommendations to proactively cope with Omicron variant and increase the therapeutic efficacy for coronavirus disease 2019 among the elderly population in Shanghai, China.

Enteral Nutrition Overview.

Enteral nutrition (EN) provides critical macro and micronutrients to individuals who cannot maintain sufficient oral intake to meet their nutritional needs. EN is most commonly required for neurological conditions that impair swallow function, such as stroke, amytrophic lateral sclerosis, and Parkinson's disease. An inability to swallow due to mechanical ventilation and altered mental status are also common conditions that necessitate the use of EN. EN can be short or long term and delivered gastrically or post-pylorically. The expected duration and site of feeding determine the type of feeding tube used. Many commercial EN formulas are available. In addition to standard formulations, disease specific, peptide-based, and blenderized formulas are also available. Several other factors should be considered when providing EN, including timing and rate of initiation, advancement regimen, feeding modality, and risk of complications. Careful and comprehensive assessment of the patient will help to ensure that nutritionally complete and clinically appropriate EN is delivered safely.

Efficacy and safety of antimicrobial stewardship prospective audit and feedback in patients hospitalized with COVID-19: A protocol for a pragmatic clinical trial.

BACKGROUND: The use of broad-spectrum antibiotics is widespread in patients with COVID-19 despite a low prevalence of bacterial co-infection, raising concerns for the accelerated development of antimicrobial resistance. Antimicrobial stewardship (AMS) is vital but there are limited randomized clinical trial data supporting AMS interventions such as prospective audit and feedback (PAF). High quality data to demonstrate safety and efficacy of AMS PAF in hospitalized COVID-19 patients are needed. METHODS AND DESIGN: This is a prospective, multi-center, non-inferiority, pragmatic randomized clinical trial evaluating AMS PAF intervention plus standard of care (SOC) versus SOC alone. We include patients with microbiologically confirmed SARS-CoV-2 infection requiring hospital admission for severe COVID-19 pneumonia. Eligible ward beds and critical care unit beds will be randomized prior to study commencement at each participating site by computer-generated allocation sequence stratified by intensive care unit versus conventional ward in a 1:1 fashion. PAF intervention consists of real time review of antibacterial prescriptions and immediate written and verbal feedback to attending teams, performed by site-based AMS teams comprised of an AMS pharmacist and physician. The primary outcome is clinical status at post-admission day 15 measured using a 7-point ordinal scale. Patients will be followed for secondary outcomes out to 30 days. A total of 530 patients are needed to show a statistically significant non-inferiority, with 80% power and 2.5% one-sided alpha assuming standard deviation of 2 and the non-inferiority margin of 0.5. DISCUSSION: This study protocol presents a pragmatic clinical trial design with small unit cluster randomization for AMS intervention in hospitalized COVID-19 that will provide high-level evidence and may be adopted in other clinical situations. TRIAL REGISTRATION: This study is being performed at the University of Alberta and is registered at ClinicalTrials.gov (NCT04896866) on May 17, 2021.

Accelerating development of new shorter TB treatment regimens in anticipation of a resurgence of multi-drug resistant TB due to the COVID-19 pandemic.

The WHO 2020 global TB Report estimates that in 2019 there were an estimated 500,000 cases of multi-drug resistant TB (MDR-TB) of which only 186,772 MDR-TB cases were diagnosed, and positive treatment outcomes were achieved in 57% of them. These data highlight the need for accelerating and improving MDR-TB screening, diagnostic, treatment and patient follow-up services. The last decade has seen three new TB drugs being licensed; bedaquiline, delamanid and pretomanid, and combinations these new, existing and repurposed drugs are leading to improved cure rates. The all oral six month WHO regimen for MDR-TB is more tolerable, has higher treatment success rates and lower mortality. However, the unprecedented ongoing COVID-19 pandemic is having major direct and indirect negative impacts on health services overall, including national TB programs and TB services. This adds further to longstanding challenges for tackling MDR-TB such as cost, rollout of diagnostics and drugs, and implementation of latest WHO guidelines for MDR-TB. In light of COVID-19 disruption of TB services, it is anticipated the numbers of MDR-TB cases will rise in 2021 and 2022 and will affect treatment outcomes further. Investing more in development of new TB drugs and shorter MDR-TB treatment regimens is required in anticipation of emerging drug resistance to new TB drug regimens. There is an urgent need for protecting current investments in TB services, sustaining gains being made in TB control and accelerating roll out of TB diagnostic and treatment services.

Implementation of platform trials in the COVID-19 pandemic: A rapid review.

MOTIVATION: Platform designs - master protocols that allow for new treatment arms to be added over time - have gained considerable attention in recent years. Between 2001 and 2019, 16 platform trials were initiated globally. The COVID-19 pandemic seems to have provided a new motivation for these designs. We conducted a rapid review to quantify and describe platform trials used in COVID-19. METHODS: We cross-referenced PubMed, ClinicalTrials.gov, and the Cytel COVID-19 Clinical Trials Tracker to identify platform trials, defined by their stated ability to add future arms. RESULTS: We identified 58 COVID-19 platform trials globally registered between January 2020 and May 2021. According to trial registries, 16 trials have added new therapies (median 3, IQR 4) and 11 have dropped arms (median 3, IQR 2.5). About 50% of trials publicly share their protocol, and 31 trials (53%) intend to share trial data. Forty-nine trials (84%) explicitly report adaptive features, and 21 trials (36%) state Bayesian methods. CONCLUSIONS: During the pandemic, there has been a surge in the number of platform trials compared to historical use. While transparency in statistical methods and clarity of data sharing policies needs improvement, platform trials appear particularly well-suited for rapid evidence generation. Trials secured funding quickly and many succeeded in adding new therapies in a short time period, thus demonstrating the potential for these trial designs to be implemented beyond the pandemic. The evidence gathered here may provide ample insight to further inform operational, statistical, and regulatory aspects of future platform trial conduct.

Surveying the local public health response to COVID-19 in Canada: Study protocol.

BACKGROUND: Public health services and systems research is under-developed in Canada and this is particularly the case with respect to research on local public health unit operational functioning and capacity. The purpose of this paper is to report on a study that will collect retrospective information on the local public health response to COVID-19 throughout Canada between 2020 and 2021. METHODS/DESIGN: The goal of the study is to develop and implement a study framework that will collect retrospective information on the local public health system response to the COVID-19 pandemic in Canada. This study will involve administering a mixed-method survey to Medical Health Officers/Medical Officers of Health in every local and regional public health unit across the country, followed by a process of coding and grouping these responses in a consistent and comparable way. Coded responses will be assessed for patterns of divergent or convergent roles and approaches of local public health across the country with respect to interventions in their response to COVID-19. The Framework Method of thematic analysis will be applied to assess the qualitative answers to the open-ended questions that speak to public health policy features. DISCUSSION: The strengths of the study protocol include the engagement of Medical Health Officers/Medical Officers of Health as research partners and a robust integrated knowledge translation approach to further public health services and systems research in Canada.

Efficacy and Safety of Washed Microbiota Transplantation to Treat Patients with Mild-to-Severe COVID-19 and Suspected of Having Gut Microbiota Dysbiosis: Study Protocol for a Randomized Controlled Trial.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is often accompanied by gastrointestinal symptoms, which are related to gut microbiota dysbiosis (GMD). Whether washed microbiota transplantation (WMT) is an effective treatment for COVID-19 patients suspected of having GMD by restoring the gut microbiota is unknown. This study is designed to explore the efficacy and safety of WMT in COVID-19 patients suspected of having GMD. METHODS: This is a randomized, multicenter, single-blind prospective study. COVID-19 patients suspected of having GMD will be randomly divided to receive routine treatment only or to receive routine treatment and WMT. The frequency of WMT will be once a day for three consecutive days. Laboratory and imaging examinations will be performed at admission, 1 and 2 weeks after treatment, and on the day of discharge. Then a telephone follow-up will be conducted at 1st week, 2nd week, and 6th month after discharge. The clinical efficacy and safety of WMT in COVD-19 patients suspected of having GMD and the effects of WMT on the organ function, homeostasis, inflammatory response, intestinal mucosal barrier function, and immunity of the patients will be evaluated. RESULTS: By following the proposed protocol, WMT is expected to be efficacious and safe for the treatment of COVID-19 patients suspected of having GMD, and the therapeutic effect is expected to be associated with improvement of the intestinal mucosal barrier function, inflammatory response, and immunity. CONCLUSION: The findings from this study may offer a new approach for the prevention and treatment of COVID-19 patients suspected of having GMD.

Complex Pathophysiological Mechanisms and the Propose of the Three-Dimensional Schedule For Future COVID-19 Treatment.

At present, the global COVID-19 epidemic is still in a state of anxiety, and increasing the cure rate of critically ill patients is an important means to defeat the virus. From an immune perspective, ARDS driven by an inflammatory storm is still the direct cause of death in severe COVID-19 patients. Although some experience has been gained in the treatment of COVID-19, and intensive COVID-19 vaccination has been carried out recently, it is still effective to save lives to develop more effective programs to alleviate the inflammatory storm and ARDS in patients with SARS-CoV-2 or emerging variants of SARS-CoV-2. In reorganizing the ARDS-related inflammatory storm formation program in COVID-19 patients, we highlighted the importance of the vicious circle of inflammatory cytokines and inflammatory cell death, which is aggravated by blood circulation to form multi-system inflammation. Summarizes the interlocking and crisscrossing of inflammatory response and inflammatory cell death mechanisms including NETs, pyrolysis, apoptosis and PANoptosis in severe COVID-19. More importantly, in response to the inflammatory storm formation program we described, and on the premise of following ethical and clinical experimental norms, we propose a three-dimensional integrated program for future research based on boosting antiviral immune response at the initial stage, inhibiting inflammatory cytokine signaling at the exacerbation stage and inhibiting cell death before it's worse to prevent and alleviate ARDS.

Competitive sport after SARS-CoV-2 infection in children.

BACKGROUND: With the gradual resumption of sports activities after the lock-down period for coronavirus pandemic, a new problem is emerging: Allow all athletes to be able to return to compete after SARS-CoV-2 infection in total safety. Several protocols have been proposed for healed athletes but all of them have been formulated for the adult population. The aim of the present study is to evaluate the adequacy of Italian practical recommendations for return-to-paly, in order to exclude cardiorespiratory complications due to COVID-19 in children and adolescents. METHODS: Between April 2020 and January 2021 the Italian Sports Medical Federation formulated cardiorespiratory protocols to be applied to athletes recovered from SARS-CoV-2 infection. The protocols take into account the severity of the infection. Protocols include lung function tests, cardiopulmonary exercise test, echocardiographic evaluation, blood chemistry tests. RESULTS: From September 2020 to February 2021, 45 children and adolescents (aged from 9 to 18 years; male = 26) with previous SARS-CoV-2 infection were evaluated according to the protocols in force for adult. 55.5% of the subjects (N = 25) reported an asymptomatic infection; 44.5% reported a mild symptomatic infection. Results of lung function test have exceeded the limit of 80% of the theoretical value in all patients. The cardiorespiratory capacity of all patients was within normal limits (average value of maximal oxigen uptake 41 ml/kg/min). No arrhythmic events or reduction in the ejection fraction were highlighted. CONCLUSION: The data obtained showed that, in the pediatric population, mild coronavirus infection does not cause cardiorespiratory complications in the short and medium term. Return to play after Coronavirus infection seems to be safe but it will be necessary to continue with the data analysis in order to modulate and optimize the protocols especially in the pediatric field.

Low mortality from COVID-19 at a nursing facility in France following a combined preventive and active treatment protocol.

BACKGROUND: The aim of this study was to retrospectively describe the evolution of symptoms, infections, and mortality at a nursing facility in France that had implemented a protocol for the prevention and treatment of COVID-19. METHODS: A database was created on 21 March 2020 to store all information related to residents, including co-morbidities, as well as COVID-19 symptoms, incidence, and mortality. Residents followed a COVID-19 protocol, consisting of preventive (administering vitamins and zinc, social distancing, and temperature checks) and active (antibiotics, anticoagulants, and corticosteroids) measures. RT-PCR and serology testing were performed on residents. A new coefficient, named the Zemgor coefficient, was calculated as the haemoglobin-to-albumin ratio at 2 time points 15 days apart, to monitor hypoxemia. RESULTS: In January 2020, the nursing facility housed 192 residents, 75 men and 117 women, aged 80±11. One or more co-morbidities were present in 94% of residents, with the most common being dementia. The COVID-19 protocol provided 61% of residents with anticoagulants, 51%with antibiotics, 21% with oxygen therapy, and 3% with corticosteroids. The COVID-19 incidence was 51% based on presence of COVID-19 symptoms, 35% based on positive RT-PCR (amongst residents tested for RT-PCR) and 41% based on positive serology (amongst residents tested for serology), and the COVID-19 mortality rate was 8%. The Zemgor coefficient was 0.049±0.053 for patients with hypoxemia compared to 0.011±0.041 for patients without hypoxemia (P=0.001). CONCLUSIONS: The protocol for the prevention and treatment of COVID-19 implemented at this nursing facility resulted in a COVID-19 incidence and mortality at the lower end of that reported by other nursing facilities.