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1.
Pol J Vet Sci ; 23(1): 127-132, 2020 Mar.
Article in English | MEDLINE | ID: covidwho-1575092

ABSTRACT

INTRODUCTION: Effective and safe anesthesia for rodents has long been a leading concern among biomedical researchers. Intraperitoneal injection constitutes an alternative to inhalant anesthesia. PURPOSE: The aim of this study was to identify a safe, reliable, and effective anesthesia and postoperative analgesia protocol for laboratory rats exposed to painful procedures. MATERIAL AND METHODS: Twenty-seven female Wistar rats in an ongoing study that required surgery were randomized into groups for three different intraperitoneal anesthesia protocols and three different analgesia regimens. The anesthesia groups were (1) medetomidine + ketamine (MK), (2) ketamine + xylacine (KX), and (3) fentanyl + medetomidine (FM). Three analgesia groups were equally distributed among the anesthesia groups: (1) local mepivacaine + oral ibuprofen (MI), (2) oral tramadol + oral ibuprofen (TI), and (3) local tramadol + oral tramadol + + oral ibuprofen (TTI). A core was assigned to measure anesthesia (0-3) and analgesia (0-2) effectiveness; the lower the score, the more effective the treatment. RESULTS: The mean MK score was 0.44 versus 2.00 for FM and 2.33 for KX. Mean score for analgesia on the first postoperative day was TTI (4.66) TI (9.13), and MI (10.14). Mean score 48 hours after surgery was TTI (3.4), TI (6.71), and MI (9.5). These differences were statistically significant. CONCLUSION: MK was shown to be a reliable, safe, and effective method of anesthesia. The TTI analgesia regimen is strongly recommended in light of these results.


Subject(s)
Fentanyl/pharmacology , Ketamine/pharmacology , Medetomidine/pharmacology , Xylazine/pharmacology , Adjuvants, Anesthesia/administration & dosage , Adjuvants, Anesthesia/pharmacology , Anesthetics, Dissociative/administration & dosage , Anesthetics, Dissociative/pharmacology , Animals , Drug Therapy, Combination , Female , Fentanyl/administration & dosage , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacology , Ketamine/administration & dosage , Medetomidine/administration & dosage , Random Allocation , Rats , Rats, Wistar , Xylazine/administration & dosage
2.
Emerg Microbes Infect ; 10(1): 2173-2182, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1493581

ABSTRACT

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, we compared African green monkeys infected intranasally with either the UK B.1.1.7 (Alpha) variant or its contemporary D614G progenitor. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases.


Subject(s)
COVID-19/virology , Chlorocebus aethiops/virology , Respiratory System/virology , Virus Replication , Virus Shedding , Administration, Intranasal , Animals , COVID-19/epidemiology , Gastrointestinal Tract/virology , Host Specificity , Polymorphism, Single Nucleotide , RNA, Viral/isolation & purification , Random Allocation , Rectum/virology , United Kingdom/epidemiology , Vero Cells , Viral Load
3.
PLoS One ; 16(10): e0258282, 2021.
Article in English | MEDLINE | ID: covidwho-1463314

ABSTRACT

In the absence of widespread vaccination for COVID-19, governments and public health officials have advocated for the public to wear masks during the pandemic. The decision to wear a mask in public is likely affected by both beliefs about its efficacy and the prevalence of the behavior. Greater mask use in the community may encourage others to follow this norm, but it also creates an incentive for individuals to free ride on the protection afforded to them by others. We report the results of two vignette-based experiments conducted in the United States (n = 3,100) and Italy (n = 2,659) to examine the causal relationship between beliefs, social norms, and reported intentions to engage in mask promoting behavior. In both countries, survey respondents were quota sampled to be representative of the country's population on key demographics. We find that providing information about how masks protect others increases the likelihood that someone would wear a mask or encourage others to do so in the United States, but not in Italy. There is no effect of providing information about how masks protect the wearer in either country. Additionally, greater mask use increases intentions to wear a mask and encourage someone else to wear theirs properly in both the United States and Italy. Thus, community mask use may be self-reinforcing.


Subject(s)
COVID-19/epidemiology , COVID-19/prevention & control , Masks , Pandemics/prevention & control , Risk Reduction Behavior , SARS-CoV-2 , Social Norms , Trust/psychology , Adult , COVID-19/psychology , COVID-19/virology , Female , Humans , Intention , Italy/epidemiology , Male , Middle Aged , Motivation , Public Health/methods , Random Allocation , Surveys and Questionnaires , United States/epidemiology
4.
Clin Infect Dis ; 73(3): e842, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1459353
5.
Sci Rep ; 11(1): 19458, 2021 09 30.
Article in English | MEDLINE | ID: covidwho-1447326

ABSTRACT

Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Ebolavirus/drug effects , Hemorrhagic Fever, Ebola/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacology , Administration, Intravenous , Aerosols , Alanine/administration & dosage , Alanine/pharmacology , Animals , Antiviral Agents/administration & dosage , Disease Models, Animal , Female , Hemorrhagic Fever, Ebola/blood , Kaplan-Meier Estimate , Liver/drug effects , Liver/virology , Lung/pathology , Lung/virology , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymph Nodes/virology , Macaca mulatta , Male , Random Allocation , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/virology , Viral Load/drug effects , Viremia/drug therapy
6.
PLoS One ; 16(9): e0257988, 2021.
Article in English | MEDLINE | ID: covidwho-1440994

ABSTRACT

To increase COVID-19 vaccine uptake in resistant populations, such as Republicans, focus groups suggest that it is best to de-politicize the issue by sharing five facts from a public health expert. Yet polls suggest that Trump voters trust former President Donald Trump for medical advice more than they trust experts. We conducted an online, randomized, national experiment among 387 non-vaccinated Trump voters, using two brief audiovisual artifacts from Spring 2021, either facts delivered by an expert versus political claims delivered by President Trump. Relative to the control group, Trump voters who viewed the video of Trump endorsing the vaccine were 85% more likely to answer "yes" as opposed to "no" in their intention to get fully vaccinated (RRR = 1.85, 95% CI 1.01 to 3.40; P = .048). There were no significant differences between those hearing the public health expert excerpt and the control group (for "yes" relative to "no" RRR = 1.14, 95% CI 0.61 to 2.12; P = .68). These findings suggest that a political speaker's endorsement of the COVID-19 vaccine may increase uptake among those who identify with that speaker. Contrary to highly-publicized focus group findings, our randomized experiment found that an expert's factually accurate message may not be effectual to increase vaccination intentions.


Subject(s)
COVID-19 Vaccines , Communications Media , Politics , Evidence-Based Practice , Humans , Intention , Public Health , Random Allocation , Surveys and Questionnaires , Trust
7.
Nat Microbiol ; 6(1): 11-18, 2021 01.
Article in English | MEDLINE | ID: covidwho-1387364

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/prevention & control , COVID-19/transmission , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/immunology , Chlorocebus aethiops , Cytidine/pharmacology , Cytokines/immunology , Disease Models, Animal , Disease Transmission, Infectious/prevention & control , Female , Ferrets , Random Allocation , Vero Cells
8.
Yonsei Med J ; 62(9): 806-813, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1370982

ABSTRACT

PURPOSE: We aimed to develop a novel mortality scoring system for inpatients with COVID-19 based on simple demographic factors and laboratory findings. MATERIALS AND METHODS: We reviewed and analyzed data from patients who were admitted and diagnosed with COVID-19 at 10 hospitals in Daegu, South Korea, between January and July 2020. We randomized and assigned patients to the development and validation groups at a 70% to 30% ratio. Each point scored for selected risk factors helped build a new mortality scoring system using Cox regression analysis. We evaluated the accuracy of the new scoring system in the development and validation groups using the area under the curve. RESULTS: The development group included 1232 patients, whereas the validation group included 528 patients. In the development group, predictors for the new scoring system as selected by Cox proportional hazards model were age ≥70 years, diabetes, chronic kidney disease, dementia, C-reactive protein levels >4 mg/dL, infiltration on chest X-rays at the initial diagnosis, and the need for oxygen support on admission. The areas under the curve for the development and validation groups were 0.914 [95% confidence interval (CI) 0.891-0.937] and 0.898 (95% CI 0.854-0.941), respectively. According to our scoring system, COVID-19 mortality was 0.4% for the low-risk group (score 0-3) and 53.7% for the very high-risk group (score ≥11). CONCLUSION: We developed a new scoring system for quickly and easily predicting COVID-19 mortality using simple predictors. This scoring system can help physicians provide the proper therapy and strategy for each patient.


Subject(s)
COVID-19 , Aged , COVID-19/mortality , Hospitalization , Humans , Proportional Hazards Models , Random Allocation , Risk Factors
9.
Clin Trials ; 18(5): 562-569, 2021 10.
Article in English | MEDLINE | ID: covidwho-1367665

ABSTRACT

BACKGROUND: Platform trials facilitate efficient use of resources by comparing multiple experimental agents to a common standard of care arm. They can accommodate a changing scientific paradigm within a single trial protocol by adding or dropping experimental arms-critical features for trials in rapidly developing disease areas such as COVID-19 or cancer therapeutics. However, in these trials, efficacy and safety issues may render certain participant subgroups ineligible to some experimental arms, and methods for stratified randomization do not readily apply to this setting. METHODS: We propose extensions for conventional methods of stratified randomization for platform trials whose experimental arms may differ in eligibility criteria. These methods balance on a prespecified set of stratification variables observable prior to arm assignment that remains the same across experimental arms. To do so, we suggest modifying block randomization by including experimental arm eligibility as a stratifying variable, and we suggest modifying the imbalance score calculation in dynamic balancing by performing pairwise comparisons between each eligible experimental arm and standard of care arm participants eligible to that experimental arm. RESULTS: We provide worked examples to illustrate the proposed extensions. In addition, we also provide a formula to quantify the relative efficiency loss of platform trials with varying eligibility compared with trials with non-varying eligibility as measured by the size of the common standard of care arm. CONCLUSIONS: This article presents important extensions to conventional methods for stratified randomization in order to facilitate the implementation of platform trials with differing experimental arm eligibility.


Subject(s)
Clinical Trials as Topic , Patient Selection , Random Allocation , Research Design , Humans , Treatment Outcome
10.
Dtsch Med Wochenschr ; 146(15): 988-993, 2021 Aug.
Article in German | MEDLINE | ID: covidwho-1338567

ABSTRACT

One in five hospitalized patients suffers acute kidney injury (AKI). Depending on its severity, AKI is associated with an up to 15-fold increased risk of mortality and constitutes a major risk factor for subsequent cardiovascular events and for the development of chronic kidney disease. This concise review summarizes recently published studies, focusing on 1.) automated AKI detection using electronic health records-based AKI alert systems, 2.) renal replacement therapy and its optimal timing and anticoagulation regimen, and 3.) coronavirus disease-2019 (COVID-19) associated AKI.


Subject(s)
Acute Kidney Injury/diagnosis , Acute Kidney Injury/therapy , COVID-19/complications , Diagnosis, Computer-Assisted/trends , Renal Replacement Therapy/trends , Acute Kidney Injury/complications , Acute Kidney Injury/etiology , Anticoagulants/therapeutic use , Humans , Random Allocation , Risk Factors
11.
PLoS One ; 16(7): e0255301, 2021.
Article in English | MEDLINE | ID: covidwho-1334776

ABSTRACT

In the context of the current global pandemic and the limitations of the RT-PCR test, we propose a novel deep learning architecture, DFCN (Denoising Fully Connected Network). Since medical facilities around the world differ enormously in what laboratory tests or chest imaging may be available, DFCN is designed to be robust to missing input data. An ablation study extensively evaluates the performance benefits of the DFCN as well as its robustness to missing inputs. Data from 1088 patients with confirmed RT-PCR results are obtained from two independent medical facilities. The data includes results from 27 laboratory tests and a chest x-ray scored by a deep learning model. Training and test datasets are taken from different medical facilities. Data is made publicly available. The performance of DFCN in predicting the RT-PCR result is compared with 3 related architectures as well as a Random Forest baseline. All models are trained with varying levels of masked input data to encourage robustness to missing inputs. Missing data is simulated at test time by masking inputs randomly. DFCN outperforms all other models with statistical significance using random subsets of input data with 2-27 available inputs. When all 28 inputs are available DFCN obtains an AUC of 0.924, higher than any other model. Furthermore, with clinically meaningful subsets of parameters consisting of just 6 and 7 inputs respectively, DFCN achieves higher AUCs than any other model, with values of 0.909 and 0.919.


Subject(s)
COVID-19 Nucleic Acid Testing , COVID-19/diagnosis , Databases, Factual , Deep Learning , Models, Theoretical , SARS-CoV-2 , Humans , Random Allocation
12.
Respir Res ; 21(1): 154, 2020 Jun 18.
Article in English | MEDLINE | ID: covidwho-1331943

ABSTRACT

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.


Subject(s)
Coronavirus Infections/epidemiology , Electronic Nicotine Delivery Systems , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia/metabolism , Vaping/adverse effects , alpha7 Nicotinic Acetylcholine Receptor/genetics , Angiotensin-Converting Enzyme 2 , Animals , Blood Gas Analysis , Blotting, Western , Bronchoalveolar Lavage Fluid , COVID-19 , Cytokines/analysis , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pandemics , Pneumonia/physiopathology , Random Allocation , Reference Values , Role , Severe Acute Respiratory Syndrome/epidemiology , Signal Transduction/genetics
13.
Sports Health ; 13(5): 463-470, 2021.
Article in English | MEDLINE | ID: covidwho-1292155

ABSTRACT

BACKGROUND: While increased face mask use has helped reduce COVID-19 transmission, there have been concerns about its influence on thermoregulation during exercise in the heat, but consistent, evidence-based recommendations are lacking. HYPOTHESIS: No physiological differences would exist during low-to-moderate exercise intensity in the heat between trials with and without face masks, but perceptual sensations could vary. STUDY DESIGN: Crossover study. LEVEL OF EVIDENCE: Level 2. METHODS: Twelve physically active participants (8 male, 4 female; age = 24 ± 3 years) completed 4 face mask trials and 1 control trial (no mask) in the heat (32.3°C ± 0.04°C; 54.4% ± 0.7% relative humidity [RH]). The protocol was 60 minutes of walking and jogging between 35% and 60% of relative VO2max. Rectal temperature (Trec), heart rate (HR), temperature and humidity inside and outside of the face mask (Tmicro_in, Tmicro_out, RHmicro_in, RHmicro_out) and perceptual variables (rating of perceived exertion (RPE), thermal sensation, thirst sensation, fatigue level, and overall breathing discomfort) were monitored throughout all trials. RESULTS: Mean Trec and HR increased at 30- and 60-minute time points compared with 0-minute time points, but no difference existed between face mask trials and control trials (P > 0.05). Mean Tmicro_in, RHmicro_in, and humidity difference inside and outside of the face mask (ΔRHmicro) were significantly different between face mask trials (P < 0.05). There was no significant difference in perceptual variables between face mask trials and control trials (P > 0.05), except overall breathing discomfort (P < 0.01). Higher RHmicro_in, RPE, and thermal sensation significantly predicted higher overall breathing discomfort (r2 = 0.418; P < 0.01). CONCLUSION: Face mask use during 60 minutes of low-to-moderate exercise intensity in the heat did not significantly affect Trec or HR. Although face mask use may affect overall breathing discomfort due to the changes in the face mask microenvironment, face mask use itself did not cause an increase in whole body thermal stress. CLINICAL RELEVANCE: Face mask use is feasible and safe during exercise in the heat, at low-to-moderate exercise intensities, for physically active, healthy individuals.


Subject(s)
Body Temperature Regulation , COVID-19/prevention & control , Hot Temperature , Jogging/physiology , Masks , Walking/physiology , Adult , Cross-Over Studies , Female , Heart Rate , Humans , Humidity , Male , Perception , Physical Exertion/physiology , Random Allocation , SARS-CoV-2 , Thermosensing , Work of Breathing , Young Adult
14.
BMC Med Res Methodol ; 20(1): 222, 2020 09 03.
Article in English | MEDLINE | ID: covidwho-1282238

ABSTRACT

BACKGROUND: Parallel intervention studies involving volunteers usually require a procedure to allocate the subjects to study-arms. Statistical models to evaluate the different outcomes of the study-arms will include study-arm as a factor along with any covariate that might affect the results. To ensure that the effects of the covariates are confounded to the least possible extent with the effects of the arms, stratified randomization can be applied. However, there is at present no clear-cut procedure when there are multiple covariates. METHODS: For parallel study designs with simultaneous enrollment of all subjects prior to intervention, we propose a D-optimal blocking procedure to allocate subjects with known values of the covariates to the study arms. We prove that the procedure minimizes the variances of the baseline differences between the arms corrected for the covariates. The procedure uses standard statistical software. RESULTS: We demonstrate the potential of the method by an application to a human parallel nutritional intervention trial with three arms and 162 healthy volunteers. The covariates were gender, age, body mass index, an initial composite health score, and a categorical indicator called first-visit group, defining groups of volunteers who visit the clinical centre on the same day (17 groups). Volunteers were allocated equally to the study-arms by the D-optimal blocking procedure. The D-efficiency of the model connecting an outcome with the study-arms and correcting for the covariates equals 99.2%. We simulated 10,000 random allocations of subjects to arms either unstratified or stratified by first-visit group. Intervals covering the middle 95% of the D-efficiencies for these allocations were [82.0, 92.0] and [93.2, 98.4], respectively. CONCLUSIONS: Allocation of volunteers to study-arms with a D-optimal blocking procedure with the values of the covariates as inputs substantially improves the efficiency of the statistical model that connects the response with the study arms and corrects for the covariates. TRIAL REGISTRATION: Dutch Trial Register NL7054 ( NTR7259 ). Registered May 15, 2018.


Subject(s)
COVID-19 , Humans , Models, Statistical , Random Allocation , Research Design , SARS-CoV-2
16.
Stud Health Technol Inform ; 281: 1124-1125, 2021 May 27.
Article in English | MEDLINE | ID: covidwho-1247831

ABSTRACT

Randomization is an inherent part of Randomized Clinical Trials (RCTs), typically requiring the split of participants in intervention and control groups. We present a web service supporting randomized patient distribution, developed in the context of the MyPal project RCT. The randomization process is based on a block permutation approach to mitigate the risk of various kind of biases. The presented service can be used via its web user interface to produce randomized lists of patients distributed in the various study groups, with a variant block size. Alternatively, the presented service can be integrated as part of wider IT systems supporting clinical trials via a REST interface following a micro-service architectural pattern.


Subject(s)
COVID-19 , Randomized Controlled Trials as Topic , Humans , Internet , Random Allocation , SARS-CoV-2
17.
Trials ; 22(1): 363, 2021 May 25.
Article in English | MEDLINE | ID: covidwho-1243818

ABSTRACT

OBJECTIVES: The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs. TRIAL DESIGN: Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization PARTICIPANTS: We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls. INTERVENTION AND COMPARATOR: The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab). MAIN OUTCOMES: The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable - e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome. RANDOMISATION: We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation. BLINDING (MASKING): This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain. TRIAL STATUS: Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04790786 . Registered March 10, 2021 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.


Subject(s)
COVID-19 , Aged , Antibodies, Monoclonal/adverse effects , Bayes Theorem , Humans , Random Allocation , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
18.
PLoS One ; 16(5): e0251661, 2021.
Article in English | MEDLINE | ID: covidwho-1238764

ABSTRACT

BACKGROUND: Understanding the false negative rates of SARS-CoV-2 RT-PCR testing is pivotal for the management of the COVID-19 pandemic and it has implications for patient management. Our aim was to determine the real-life clinical sensitivity of SARS-CoV-2 RT-PCR. METHODS: This population-based retrospective study was conducted in March-April 2020 in the Helsinki Capital Region, Finland. Adults who were clinically suspected of SARS-CoV-2 infection and underwent SARS-CoV-2 RT-PCR testing, with sufficient data in their medical records for grading of clinical suspicion were eligible. In addition to examining the first RT-PCR test of repeat-tested individuals, we also used high clinical suspicion for COVID-19 as the reference standard for calculating the sensitivity of SARS-CoV-2 RT-PCR. RESULTS: All 1,194 inpatients (mean [SD] age, 63.2 [18.3] years; 45.2% women) admitted to COVID-19 cohort wards during the study period were included. The outpatient cohort of 1,814 individuals (mean [SD] age, 45.4 [17.2] years; 69.1% women) was sampled from epidemiological line lists by systematic quasi-random sampling. The sensitivity (95% CI) for laboratory confirmed cases (repeat-tested patients) was 85.7% (81.5-89.1%) inpatients; 95.5% (92.2-97.5%) outpatients, 89.9% (88.2-92.1%) all. When also patients that were graded as high suspicion but never tested positive were included in the denominator, the sensitivity (95% CI) was: 67.5% (62.9-71.9%) inpatients; 34.9% (31.4-38.5%) outpatients; 47.3% (44.4-50.3%) all. CONCLUSIONS: The clinical sensitivity of SARS-CoV-2 RT-PCR testing was only moderate at best. The relatively high false negative rates of SARS-CoV-2 RT-PCR testing need to be accounted for in clinical decision making, epidemiological interpretations, and when using RT-PCR as a reference for other tests.


Subject(s)
COVID-19 Nucleic Acid Testing/standards , Adult , Aged , COVID-19 Nucleic Acid Testing/methods , False Negative Reactions , Female , Humans , Male , Middle Aged , Random Allocation , Reagent Kits, Diagnostic/standards
19.
Vopr Virusol ; 66(1): 47-54, 2021 03 07.
Article in Russian | MEDLINE | ID: covidwho-1121351

ABSTRACT

INTRODUCTION: Interferons are produced in response to the presence of pathogens in cells and are responsible for the proper formation of immune reaction. Preliminary data obtained in studies of properties of recombinant interferon gamma (IFN-γ) that involved patients with community-acquired pneumonia (including bacterial), acute respiratory viral infection (ARVI), influenza and new coronavirus infection have shown promising results.The purpose of the study was to assess the effect of subcutaneous administration of IFN-γ in patients with viral pneumonia on the changes of vital signs and the duration of hospital stay. MATERIAL AND METHODS: An open-label, randomized, low-interventional study included patients with moderate new coronavirus infection COVID-19 over 18 years of age of both sexes. IFN-γ 500,000 IU was administered s/c, daily, once a day, during 5 days. RESULTS: IFN-y in addition to complex therapy of the disease resulted in more favorable changes in the stabilization of vital signs, as well as in reduced length of fever and hospital stay by 2 days what allows suggesting a positive effect of this substance on the recovery processes in patients with moderate COVID-19. Special emphasis should be made to the fact that patients who received recombinant IFN- γ experienced no progression of respiratory failure and required no transfer to intensive care unit. DISCUSSION: This study confirms earlier obtained data on the positive effect of IFN-y on the rate of clinical stabilization and recovery of patients with community-acquired pneumonia and viral infections. Presented results are limited to a small number of patients; further study of drug properties in post-marketing studies is required. CONCLUSION: Progress in the treatment of patients with moderate COVID-19 by adding recombinant IFN-γ to the complex therapy may reasonably expand the range of existing treatment options for this infection.


Subject(s)
Anti-Infective Agents/therapeutic use , Anticoagulants/therapeutic use , COVID-19/drug therapy , Immunologic Factors/therapeutic use , Interferon-gamma/therapeutic use , Aged , Ampicillin/therapeutic use , Azithromycin/therapeutic use , Blood Pressure/drug effects , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Enoxaparin/therapeutic use , Female , Humans , Hydroxychloroquine/therapeutic use , Male , Middle Aged , Random Allocation , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Severity of Illness Index , Treatment Outcome , Vancomycin/therapeutic use
20.
Virol J ; 18(1): 46, 2021 02 27.
Article in English | MEDLINE | ID: covidwho-1105717

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and broke out as a global pandemic in late 2019. The acidic pH environment of endosomes is believed to be essential for SARS-CoV-2 to be able to enter cells and begin replication. However, the clinical use of endosomal acidification inhibitors, typically chloroquine, has been controversial with this respect. METHODS: In this study, RT-qPCR method was used to detect the SARS-CoV-2N gene to evaluate viral replication. The CCK-8 assay was also used to evaluate the cytotoxic effect of SARS-CoV-2. In situ hybridization was used to examine the distribution of the SARS-CoV-2 gene in lung tissues. Hematoxylin and eosin staining was also used to evaluate virus-associated pathological changes in lung tissues. RESULTS: In this study, analysis showed that endosomal acidification inhibitors, including chloroquine, bafilomycin A1 and NH4CL, significantly reduced the viral yields of SARS-CoV-2 in Vero E6, Huh-7 and 293T-ACE2 cells. Chloroquine and bafilomycin A1 also improved the viability and proliferation of Vero E6 cells after SARS-CoV-2 infection. Moreover, in the hACE2 transgenic mice model of SARS-CoV-2 infection, chloroquine and bafilomycin A1 reduced viral replication in lung tissues and alleviated viral pneumonia with reduced inflammatory exudation and infiltration in peribronchiolar and perivascular tissues, as well as improved structures of alveolar septum and pulmonary alveoli. CONCLUSIONS: Our research investigated the antiviral effects of endosomal acidification inhibitors against SARS-CoV-2 in several infection models and provides an experimental basis for further mechanistic studies and drug development.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Endosomes/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Replication/drug effects , Ammonium Chloride/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Cell Survival/drug effects , Chlorocebus aethiops , Chloroquine/pharmacology , Endosomes/metabolism , Female , HEK293 Cells , Humans , Hydrogen-Ion Concentration , Lung/pathology , Macrolides/pharmacology , Mice , Mice, Transgenic , Random Allocation , SARS-CoV-2/genetics , Vero Cells
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