Shortening Door-to-Needle Time by Multidisciplinary Collaboration and Workflow Optimization During the COVID-19 Pandemic.

OBJECTIVES: This study aims to evaluate shortening door-to-needle time of intravenous recombinant tissue plasminogen activator of acute ischemic stroke patients by multidisciplinary collaboration and workflow optimization based on our hospital resources. MATERIALS AND METHODS: We included patients undergoing thrombolysis with intravenous recombinant tissue plasminogen activator from January 1, 2018, to September 30, 2020. Patients were divided into pre- (January 1, 2018, to December 31, 2019) and post-intervention groups (January 1, 2020, to September 31, 2020). We conducted multi-department collaboration and process optimization by implementing 16 different measures in prehospital, in-hospital, and post-acute feedback stages for acute ischemic stroke patients treated with intravenous thrombolysis. A comparison of outcomes between both groups was analyzed. RESULTS: Two hundred and sixty-three patients received intravenous recombinant tissue plasminogen activator in our hospital during the study period, with 128 and 135 patients receiving treatment in the pre-intervention and post-intervention groups, respectively. The median (interquartile range) door-to-needle time decreased significantly from 57.0 (45.3-77.8) min to 37.0 (29.0-49.0) min. Door-to-needle time was shortened to 32 min in the post-intervention period in the 3rd quarter of 2020. The door-to-needle times at the metrics of ≤ 30 min, ≤ 45 min, ≤ 60 min improved considerably, and the DNT> 60 min metric exhibited a significant reduction. CONCLUSIONS: A multidisciplinary collaboration and continuous process optimization can result in overall shortened door-to-needle despite the challenges incurred by the COVID-19 pandemic.

Modeling non-pharmaceutical interventions in the COVID-19 pandemic with survey-based simulations.

Governments around the globe use non-pharmaceutical interventions (NPIs) to curb the spread of coronavirus disease 2019 (COVID-19) cases. Making decisions under uncertainty, they all face the same temporal paradox: estimating the impact of NPIs before they have been implemented. Due to the limited variance of empirical cases, researchers could so far not disentangle effects of individual NPIs or their impact on different demographic groups. In this paper, we utilize large-scale agent-based simulations in combination with Susceptible-Exposed-Infectious-Recovered (SEIR) models to investigate the spread of COVID-19 for some of the most affected federal states in Germany. In contrast to other studies, we sample agents from a representative survey. Including more realistic demographic attributes that influence agents' behavior yields accurate predictions of COVID-19 transmissions and allows us to investigate counterfactual what-if scenarios. Results show that quarantining infected people and exploiting industry-specific home office capacities are the most effective NPIs. Disentangling education-related NPIs reveals that each considered institution (kindergarten, school, university) has rather small effects on its own, yet, that combined openings would result in large increases in COVID-19 cases. Representative survey-characteristics of agents also allow us to estimate NPIs' effects on different age groups. For instance, re-opening schools would cause comparatively few infections among the risk-group of people older than 60 years.

Early combination therapy with hydroxychloroquine and azithromycin reduces mortality in 10,429 COVID-19 outpatients.

We evaluated the age-specific mortality of unselected adult outpatients infected with SARS-CoV-2 treated early in a dedicated COVID-19 day hospital and we assessed whether the use of hydroxychloroquine (HCQ) + azithromycin (AZ) was associated with improved survival in this cohort. A retrospective monocentric cohort study was conducted in the day hospital of our center from March to December 2020 in adults with PCR-proven infection who were treated as outpatients with a standardized protocol. The primary endpoint was 6-week mortality, and secondary endpoints were transfer to the intensive care unit and hospitalization rate. Among 10,429 patients (median age, 45 [IQR 32-57] years; 5597 [53.7%] women), 16 died (0.15%). The infection fatality rate was 0.06% among the 8315 patients treated with HCQ+AZ. No deaths occurred among the 8414 patients younger than 60 years. Older age and male sex were associated with a higher risk of death, ICU transfer, and hospitalization. Treatment with HCQ+AZ (0.17 [0.06-0.48]) was associated with a lower risk of death, independently of age, sex and epidemic period. Meta-analysis evidenced consistency with 4 previous outpatient studies (32,124 patients-Odds ratio 0.31 [0.20-0.47], I2 = 0%). Early ambulatory treatment of COVID-19 with HCQ+AZ as a standard of care is associated with very low mortality, and HCQ+AZ improve COVID-19 survival compared to other regimens.

Impact of early corticosteroids on 60-day mortality in critically ill patients with COVID-19: A multicenter cohort study of the OUTCOMEREA network.

OBJECTIVES: In severe COVID-19 pneumonia, the appropriate timing and dosing of corticosteroids (CS) is not known. Patient subgroups for which CS could be more beneficial also need appraisal. The aim of this study was to assess the effect of early CS in COVID-19 pneumonia patients admitted to the ICU on the occurrence of 60-day mortality, ICU-acquired-bloodstream infections(ICU-BSI), and hospital-acquired pneumonia and ventilator-associated pneumonia(HAP-VAP). METHODS: We included patients with COVID-19 pneumonia admitted to 11 ICUs belonging to the French OutcomeReaTM network from January to May 2020. We used survival models with ponderation with inverse probability of treatment weighting (IPTW). RESULTS: The study population comprised 303 patients having a median age of 61.6 (53-70) years of whom 78.8% were male and 58.6% had at least one comorbidity. The median SAPS II was 33 (25-44). Invasive mechanical ventilation was required in 34.8% of the patients. Sixty-six (21.8%) patients were in the Early-C subgroup. Overall, 60-day mortality was 29.4%. The risks of 60-day mortality (IPTWHR = 0.86;95% CI 0.54 to 1.35, p = 0.51), ICU-BSI and HAP-VAP were similar in the two groups. Importantly, early CS treatment was associated with a lower mortality rate in patients aged 60 years or more (IPTWHR, 0.53;95% CI, 0.3-0.93; p = 0.03). In contrast, CS was associated with an increased risk of death in patients younger than 60 years without inflammation on admission (IPTWHR = 5.01;95% CI, 1.05, 23.88; p = 0.04). CONCLUSION: For patients with COVID-19 pneumonia, early CS treatment was not associated with patient survival. Interestingly, inflammation and age can significantly influence the effect of CS.

Children and Adolescent Mental Health in a Time of COVID-19: A Forgotten Priority.

Globally, 10-20% of children and adolescents experience mental health conditions, but most of them do not receive the appropriate care when it is needed. The COVID-19 deaths and prevention measures, such as the lockdowns, economic downturns, and school closures, have affected many communities physically, mentally, and economically and significantly impacted the already-neglected children and adolescents' mental health. As a result, evidence has shown that many children and adolescents are experiencing psychological effects such as depression and anxiety without adequate support. The consequences of not addressing the mental health conditions in children and adolescents extend through adulthood and restrict them from reaching their full potential. The effects of COVID-19 on children and adolescents' mental health highlight the urgent need for multisectoral home-grown solutions to provide early diagnosis and treatment and educate caregivers on home-based interventions and community outreach initiatives to address children and adolescents' mental health challenges during this pandemic and beyond.

Outcome of noncritical COVID-19 patients with early hospitalization and early antiviral treatment outside the ICU

Background/aim: Despite the fact that the COVID-19 pandemic has been going on for over 5 months, there is yet to be a standard management policy for all patients including those with mild-to-moderate cases. We evaluated the role of early hospitalization in combination with early antiviral therapy with COVID-19 patients in a tertiary care university hospital. Materials and methods: This was a prospective, observational, single-center study on probable/confirmed COVID-19 patients hospitalized in a tertiary care hospital on COVID-19 wards between March 20 and April 30, 2020. The demographic, laboratory, and clinical data were collected. Results: We included 174 consecutive probable/confirmed COVID-19 adult patients hospitalized in the Internal Medicine wards of the University Adult Hospital between March 20 and April 30, 2020. The median age was 45.5 (19­92) years and 91 patients (52.3%) were male. One hundred and twenty (69%) were confirmed microbiologically, 41 (23.5%) were radiologically diagnosed, and 13 (7.5%) were clinically suspected (negative microbiological and radiological findings compatible with COVID-19); 35 (20.1%) had mild, 107 (61.5%) moderate disease, and 32 (18.4%) had severe pneumonia. Out of 171 cases, 130 (74.3%) showed pneumonia; 80 were typical, and 50 showed indeterminate infiltration for COVID-19. Patients were admitted within a median of 3 days (0-14 days) after symptoms appear. The median duration of hospitalization was 4 days (0-28 days). In this case series, 13.2% patients were treated with hydroxychloroquine alone, 64.9% with hydroxychloroquine plus azithromycin, and 18.4% with regimens including favipiravir. A total of 15 patients (8.5%) were transferred to the ICU. Four patients died (2.2%). Conclusion: In our series, 174 patients were admitted to the hospital wards for COVID-19, 69% were confirmed with PCR and/or antibody test. At the time of admission, nearly one fifth of the patients had severe diseases. Of the patients, 95.4% received hydroxychloroquine alone or in combination. The overall case fatality rate was 2.2%.

Role of the early short-course corticosteroids treatment in ARDS caused by COVID-19: A single-center, retrospective analysis.

PURPOSE: Severe coronavirus disease 2019 (COVID-19) is strongly related to interstitial pneumonia with frequent development of acute respiratory distress syndrome (ARDS). The role of corticosteroids (CS) treatment in these patients is still controversial. Some studies evidenced a possible role of an early short-term course of CS treatment in the treatment of severe pneumonia. PATIENTS AND METHODS: This is a single-center, retrospective study considering the patients with confirmed COVID-19 pneumonia admitted to our hospital between 9th March and 15th June 2020. Two groups were considered: early high-dose of methyl-prednisolone (eHDM; n â€‹= â€‹31) and the control group (n â€‹= â€‹52). Patients in the eHDM group received the dose of 5-8 â€‹mg/kg/day of methyl-prednisolone for 2 consecutive days. Primary outcome was the mortality evaluation; secondary outcomes were clinical improvement, side-effects and laboratory/radiographic changes. RESULTS: Significant differences between the two groups were: length of hospitalization (21.5 vs 28.4 days, p â€‹= â€‹0.026), length of non-invasive ventilation (NIV) or mechanical ventilation (11.5 vs 14.5 days, p â€‹= â€‹0.031), death (5 vs 12, p â€‹= â€‹0.006) and clinical improvement (16 vs 11, p=0.018). The following factors were related to in-hospital mortality in the multivariate analysis: comorbidities (OR â€‹= â€‹2.919; 95%CI â€‹= â€‹1.515-16.705; p<0.001), days from the onset of symptoms and the hospital admission (OR â€‹= â€‹1.404; 95%CI â€‹= â€‹1.069-12.492; p â€‹= â€‹0.011), PaO2/FiO2 (P/F) ratio (OR â€‹= â€‹3.111; 95%CI â€‹= â€‹2.334-16.991; p â€‹= â€‹0.009) and eHDM treatment (OR â€‹= â€‹0.741; 95%CI â€‹= â€‹0.129-0.917; p â€‹= â€‹0.007). CONCLUSION: The eHDM is an interesting and promising approach in the ARDS related to COVID-19 pneumonia, which reduces mortality, length of hospitalization and the need for mechanical ventilation.

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.

Importance: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. Objective: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. Design, Setting, and Participants: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. Interventions: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. Main Outcomes and Measures: The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. Results: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.

Anticoagulation Before Hospitalization Is a Potential Protective Factor for COVID-19: Insight From a French Multicenter Cohort Study.

Background Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with thrombotic outcomes with coagulation and endothelial disorders. Based on that, several anticoagulation guidelines have been proposed. We aimed to determine whether anticoagulation therapy modifies the risk of developing severe COVID-19. Methods and Results Patients with COVID-19 initially admitted in medical wards of 24 French hospitals were included prospectively from February 26 to April 20, 2020. We used a Poisson regression model, Cox proportional hazard model, and matched propensity score to assess the effect of anticoagulation on outcomes (intensive care unit admission or in-hospital mortality). The study enrolled 2878 patients with COVID-19, among whom 382 (13.2%) were treated with oral anticoagulation therapy before hospitalization. After adjustment, anticoagulation therapy before hospitalization was associated with a better prognosis with an adjusted hazard ratio of 0.70 (95% CI, 0.55-0.88). Analyses performed using propensity score matching confirmed that anticoagulation therapy before hospitalization was associated with a better prognosis, with an adjusted hazard ratio of 0.43 (95% CI, 0.29-0.63) for intensive care unit admission and adjusted hazard ratio of 0.76 (95% CI, 0.61-0.98) for composite criteria intensive care unit admission or death. In contrast, therapeutic or prophylactic low- or high-dose anticoagulation started during hospitalization were not associated with any of the outcomes. Conclusions Anticoagulation therapy used before hospitalization in medical wards was associated with a better prognosis in contrast with anticoagulation initiated during hospitalization. Anticoagulation therapy introduced in early disease could better prevent COVID-19-associated coagulopathy and endotheliopathy, and lead to a better prognosis.

Early combination treatment with existing HIV antivirals: an effective treatment for COVID-19?

OBJECTIVE: Since no effective therapy exists, we aimed to test existing HIV antivirals for combination treatment of Coronavirus disease 19 (COVID-19). MATERIALS AND METHODS: The crystal structures of SARS-CoV-2 main protein (Mpro) (PDB ID: 6Y2F) and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) (PDB ID: 7BV2) both available from Protein Data Bank were used in the study. Automated Docking by using blind and standard method both on Mpro and RdRp bound to the modified template-primer RNA was performed with AutoDock 4.2.6 program suite. Lamarckian genetic algorithm (LGA) was used for structures docking. All inhibitors were docked with all bonds completely free to rotate. RESULTS: Our molecular docking findings suggest that lopinavir, ritonavir, darunavir, and atazanavir activated interactions with the key binding sites of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) protease with a better inhibition constant (Ki) for lopinavir, ritonavir, and darunavir. Furthermore, we evidenced the ability of remdesivir, tenofovir, emtricitabine, and lamivudine to be incorporated in SARS-CoV-2 RdRp in the same protein pocket where poses the corresponding natural nucleoside substrates with comparable Ki and activating similar interactions. In principle, the four antiviral nucleotides might be used effectively against SARS-CoV-2. CONCLUSIONS: The combination of a protease inhibitor and two nucleoside analogues, drugs widely used to treat HIV infection, could be evaluated in clinical trials for the treatment of COVID-19.

Early antiviral treatment in outpatients with COVID-19 (FLARE): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The objective of this trial is to assess whether early antiviral therapy in outpatients with COVID-19 with either favipiravir plus lopinavir/ritonavir, lopinavir/ritonavir alone, or favipiravir alone, is associated with a decrease in viral load of SARS-CoV-2 compared with placebo. TRIAL DESIGN: FLARE is a phase IIA randomised, double-blind, 2x2 factorial placebo-controlled, interventional trial. PARTICIPANTS: This trial is being conducted in the United Kingdom, with Royal Free Hospital, London as the lead site. Participants are non-hospitalised adults with highly suspected COVID-19 within the first 5 days of symptom onset, or who have tested positive with SARS-CoV-2 causing COVID-19 within the first 7 days of symptom onset, or who are asymptomatic but tested positive for SARS-CoV-2 for the first time within the last 48 hours. Inclusion criteria are as follows: 1. Any adult with the following: Symptoms compatible with COVID-19 disease (Fever >37.8°C on at least one occasion AND either cough and/ or anosmia) within the first 5 days of symptom onset (date/time of enrolment must be within the first 5 days of symptom onset) OR ANY symptoms compatible with COVID-19 disease (may include, but are not limited to fever, cough, shortness of breath, malaise, myalgia, headache, coryza) and tested positive for SARS-CoV-2 within the first 7 days of symptom onset) (date/time of enrolment must be within the first 7 days of symptom onset) OR no symptoms but tested positive for SARS-CoV-2 within the last 48 hours (date/time of test must be within 48 hours of enrolment) 2. Male or female aged 18 years to 70 years old inclusive at screening 3. Willing and able to take daily saliva samples 4. Able to provide full informed consent and willing to comply with trial-related procedures Exclusion criteria are as follows: 1. Known hypersensitivity to any of the active ingredients or excipients in favipiravir and matched placebo, and in lopinavir/ritonavir and matched placebo (See Appendix 2) 2. Chronic liver disease at screening (known cirrhosis of any aetiology, chronic hepatitis (e.g. autoimmune, viral, steatohepatitis), cholangitis or any known elevation of liver aminotransferases with AST or ALT > 3 X ULN)* 3. Chronic kidney disease (stage 3 or beyond) at screening: eGFR < 60 ml/min/1.73m2 * 4. HIV infection, if untreated, detectable viral load or on protease inhibitor therapy 5. Any clinical condition which the investigator considers would make the participant unsuitable for the trial 6. Concomitant medications known to interact with favipiravir and matched placebo, and with lopinavir/ritonavir and matched placebo, and carry risk of toxicity for the participant 7. Current severe illness requiring hospitalisation 8. Pregnancy and/ or breastfeeding 9. Eligible female participants of childbearing potential and male participants with a partner of childbearing potential not willing to use highly effective contraceptive measures during the trial and within the time point specified following last trial treatment dose. 10. Participants enrolled in any other interventional drug or vaccine trial (co-enrolment in observational studies is acceptable) 11. Participants who have received the COVID-19 vaccine *Considering the importance of early treatment of COVID-19 to impact viral load, the absence of known chronic liver/ kidney disease will be confirmed verbally by the participant during pre-screening and Screening/Baseline visit. Safety blood samples will be collected at Screening/Baseline visit (Day 1) and test results will be examined as soon as they become available and within 24 hours. INTERVENTION AND COMPARATOR: Participants will be randomised 1:1:1:1 using a concealed online minimisation process into one of the following four arms: Arm 1: Favipiravir + Lopinavir/ritonavir Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 2: Favipiravir + Lopinavir/ritonavir placebo Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 3: Favipiravir placebo + Lopinavir/ritonavir Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 4: Favipiravir placebo + Lopinavir/ritonavir placebo Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. MAIN OUTCOMES: The primary outcome is upper respiratory tract viral load at Day 5. SECONDARY OUTCOMES: Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy Proportion of participants with undetectable stool viral load after 7 days of therapy Rate of decrease in upper respiratory tract viral load during 7 days of therapy Duration of fever following commencement of trial medications Proportion of participants with hepatotoxicity after 7 days of therapy Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation Proportion of participants admitted to hospital with COVID-19 related illness Proportion of participants admitted to ICU with COVID-19 related illness Proportion of participants who have died with COVID-19 related illness Pharmacokinetic and pharmacodynamic analysis of favipiravir Exploratory: Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 RANDOMISATION: Participants will be randomised 1:1:1:1 using a concealed online minimisation process, with the following factors: trial site, age (≤ 55 vs > 55 years old), gender, obesity (BMI <30 vs ≥30), symptomatic or asymptomatic, current smoking status (Yes = current smoker, No = ex-smoker, never smoker), ethnicity (Caucasian, other) and presence or absence of comorbidity (defined as diabetes, hypertension, ischaemic heart disease (including previous myocardial infarction), other heart disease (arrhythmia and valvular heart disease), asthma, COPD, other chronic respiratory disease). BLINDING (MASKING): Participants and investigators will both be blinded to treatment allocation (double-blind). NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 240 participants, 60 in each arm. TRIAL STATUS: Protocol version 4.0 dated 7th January 2021. Date of first enrolment: October 2020. Recruitment is ongoing, with anticipated finish date of 31st March 2021. TRIAL REGISTRATION: The FLARE trial is registered with Clinicaltrials.gov, trial identifying number NCT04499677 , date of registration 4th August 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial.

BACKGROUND: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression. METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion. CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration. TRIAL REGISTRATION: NCT04375098.

Effect of early treatment with polyvalent immunoglobulin on acute respiratory distress syndrome associated with SARS-CoV-2 infections (ICAR trial): study protocol for a randomized controlled trial.

BACKGROUND: As of mid-June 2020, 7,500,000 people were infected with SARS-CoV-2 worldwide and 420,000 people died, mainly from coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). COVID-19-related ARDS is subject to a mortality rate of 50% and prolonged period of mechanical ventilation, with no specific pharmacological treatment currently available (Infection au nouveau Coronavirus (SARS-CoV-2), COVID-19, France et Monde. https://www.santepubliquefrance.fr/dossiers/coronavirus-covid-19 ). Because of its immunomodulatory action, we propose to evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) administration in patients developing COVID-19-related ARDS. METHODS: The trial is a phase III double-blind, randomized, multicenter, parallel group, concurrent, controlled study in hospitalized participants with COVID-19 requiring mechanical ventilation using a sequential design. Participants in the treatment group will receive infusions of polyvalent immunoglobulin for 4 consecutive days, and the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration. The primary outcome is the number of ventilator-free days up to the 28th day. Secondary objectives are to evaluate the effect of IVIG on (1) organ failure according to the Sequential Organ Failure Assessment (SOFA) score at 14 and 28 days, (2) lung injury score at 14 and 28 days, (3) the occurrence of grade 3 or 4 adverse events of IVIG, (4) length of intensive care unit (ICU) stay, (5) length of hospital stay, (6) functional outcomes at day 90 defined by the activities of daily living and instrumental activities of the daily living scales, and (7) 90-day survival. One hundred thirty-eight subjects will be randomized in a 1:1 ratio to IVIG or placebo groups (69 in each group), considering 90% power, alpha level 0.05 (two sides), and 0.67 effect size level. DISCUSSION: The ICAR trial investigates the effect of IVIG in COVID-19-related ARDS. We expect an increase in the survival rate and a reduction in the duration of mechanical ventilation, which is associated with significant morbidity. TRIAL REGISTRATION: EudraCT 2020-001570-30. ClinicalTrials.gov NCT04350580 . Registered on 17 April 2020.

Bilateral liquefactive corneal necrosis: a rare and devastating complication of vitamin A deficiency in the adult.

A 34year-old man presented with diminution of vision, pain and whitish opacity in both eyes (right eye followed by left eye) since 1 week. He is a known case of chronic alcoholic abuse. He had multiple episodes of haemoptysis in the past. On general physical examination, he was severely malnourished with multiple oral ulcers. Visual acuity at presentation was light perception in both eyes with projection of rays accurate in all quadrants. Slit-lamp biomicroscopy revealed bilateral total corneal melt with diffuse conjunctival congestion. Corneal scrapings and blood investigations were done and he was started on empirical topical and systemic therapy followed by surgical intervention, with large corneal grafts in both the eyes (right eye followed by left eye) with 1 day interval. The visual gain in both the eyes were 20/400 at first postoperative day. The right eye developed severe fibrinous reaction on the second postoperative day which resolved with topical antibiotics, topical steroids and systemic steroids. The patient was followed up via telemedicine (due to COVID-19 outbreak) and he is able to carry out his daily routine work independently.

Effects of non-drug interventions on depression, anxiety and sleep in COVID-19 patients: a systematic review and meta-analysis.

OBJECTIVE: Patients with Coronavirus Disease 2019 (COVID-19) suffer from anxiety, depression and sleep disorders due to isolation treatment, among other reasons. Whether non-drug interventions can be alternative therapies for COVID-19 patients with anxiety, depression and sleep disorders is controversial. Therefore, we conducted a meta-analysis and systematic review to evaluate the effects of non-drug interventions on anxiety, depression and sleep in patients with COVID-19 to provide guidance for clinical application. MATERIALS AND METHODS: We searched the following databases for randomized controlled trials (RCTs) from December 2019 to July 2020: China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chongqing VIP Chinese Science and Technology Periodical Database (VIP), Wanfang, Cochrane Library, Web of Science, PubMed, MEDLINE and Embase. Two investigators independently screened the literature according to the inclusion and exclusion criteria, extracted data and evaluated the risk of bias in the included studies. Meta-analysis was performed using RevMan5.3 software. RESULTS: A total of 5 articles with 768 subjects were included. Meta-analysis results indicated that non-drug interventions can reduce anxiety [SMD=-1.40, 95% CI (-1.62, -1.17), p<0.00001] and depression [SMD=-1.22, 95% CI (-2.01, -0.43), p=0.002] scores in patients with COVID-19. Descriptive analysis indicated that non-drug interventions can improve the sleep status of COVID-19 patients. Sensitivity analysis indicated that the meta-analysis results were stable. Egger's test and Begg's test showed no publication bias. CONCLUSIONS: This meta-analysis found that non-drug interventions can reduce the anxiety and depression scores of patients with COVID-19. Due to the limitations of this study, more high-quality studies are needed to verify the findings, especially the effect of non-drug interventions on improving the sleep status of COVID-19 patients.

At-admission hyperglycemia is consistently associated with poor prognosis and early intervention can improve outcomes in patients with COVID-19.

BACKGROUND & AIMS: At-admission hyperglycemia have been associated with poorer outcome during critical illnesses. At-admission hyperglycemia in previously unknown diabetes is not uncommonly encountered entity in patients with COVID-19. We sought to find out the outcomes of at-admission hyperglycemia and effect of early intervention to achieve optimal glycemic control in relation to COVID-19 patients. METHODS: We searched the PubMed and Google Scholar database up till August 20, 2020 using specific keywords related to our aims and objectives. RESULTS: All currently available evidences clearly hint that at-admission hyperglycemia in patients with COVID-19 is associated with a poorer outcome, compared with normoglycemic individuals. Fortunately, early intervention by achieving an optimal glycemic control has also been associated with a significant improvement in the outcomes in patients with COVID-19. CONCLUSION: At-admission hyperglycemia should be taken seriously by all clinicians treating patients with COVID-19. All efforts should be made towards an optimal glycemic control in patients with COVID-19, even in absence of pre-existing diabetes.

Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit Patients with COVID-19 Pneumonia: A Multicenter, Single-Blind, Randomized Control Trial.

BACKGROUND: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. OBJECTIVE: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. METHODS: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. RESULTS: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6-16 days), which was significantly longer than that in the control group (8 days [2-12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). CONCLUSIONS: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04273321.