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2.
Nat Med ; 28(9): 1944-1955, 2022 09.
Article in English | MEDLINE | ID: covidwho-1991643

ABSTRACT

Influenza A virus's (IAV's) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV's genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem-loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA_WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term 'programmable antivirals', with implications for antiviral prophylaxis and post-exposure therapy.


Subject(s)
COVID-19 , Influenza A virus , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , Influenza A virus/genetics , Mice , Neuraminidase , RNA, Viral/genetics , SARS-CoV-2
3.
Cell Rep Med ; 3(8): 100721, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1984240

ABSTRACT

Understanding who is at risk of progression to severe coronavirus disease 2019 (COVID-19) is key to clinical decision making and effective treatment. We study correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (ClinicalTrials.gov04545060). Laboratory parameters identify study participants at greater risk of severe disease, including a high neutrophil-to-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test, and whole-blood transcriptome profiles. Sotrovimab treatment is associated with normalization of NLR and the transcriptomic profile and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provides the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identify a 10-gene signature with similar predictive accuracy. We identify markers of risk for disease progression and demonstrate that normalization of these parameters occurs with antibody treatment of established infection.


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , COVID-19/drug therapy , Humans , RNA, Viral , SARS-CoV-2
4.
J Infect Dis ; 2022 May 05.
Article in English | MEDLINE | ID: covidwho-1886451

ABSTRACT

In this retrospective cohort study of 94,595 SARS-CoV-2 positive cases, we developed and validated an algorithm to assess the association between COVID-19 severity and long-term complications (stroke, myocardial infarction, pulmonary embolism/deep vein thrombosis, heart failure, and mortality). COVID-19 severity was associated with a greater risk of experiencing a long-term complication days 31-120 post-infection. Most incident events occurred days 31-60 post-infection and diminished after day 91, except heart failure for severe patients and death for moderate patients, which peaked days 91-120. Understanding the differential impact of COVID-19 severity on long-term events provide insight into possible intervention modalities and critical prevention strategies.

5.
Marit Stud ; 21(2): 235-254, 2022.
Article in English | MEDLINE | ID: covidwho-1750886

ABSTRACT

Coastal communities are being impacted by climate change, affecting the livelihoods, food security, and wellbeing of residents. Human wellbeing is influenced by the heath of the environment through numerous pathways and is increasingly being included as a desired outcome in environmental management. However, the contributors to wellbeing can be subjective and the values and perspectives of decision-makers can affect the aspects of wellbeing that are included in planning. We used Q methodology to examine how a group of individuals in fisheries management prioritize components of wellbeing that may be important to coastal communities in the California Current social-ecological system (SES). The California Current SES is an integrated system of ecological and human communities with complex linkages and connections where commercial fishing is part of the culture and an important livelihood. We asked individuals that sit on advisory bodies to the Pacific Fisheries Management Council to rank 36 statements about coastal community wellbeing, ultimately revealing three discourses about how we can best support or improve wellbeing in those communities. We examine how the priorities differ between the discourses, identify areas of consensus, and discuss how these perspectives may influence decision-making when it comes to tradeoffs inherent in climate adaptation in fisheries. Lastly, we consider if and how thoughts about priorities have been affected by the COVID-19 pandemic.

6.
Preprint in English | medRxiv | ID: ppmedrxiv-21268197

ABSTRACT

Understanding who is at risk of progression to severe COVID-19 is key to effective treatment. We studied correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of SARS-CoV-2 infection. Several laboratory parameters identified study participants at greater risk of severe disease, including a high neutrophil-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test and whole blood transcriptome profiles. Sotrovimab treatment in these groups was associated with normalization of NLR and the transcriptomic profile, and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provided the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identified a 10-gene signature with similar predictive accuracy. In summary, we identified markers of risk for disease progression and demonstrated that normalization of these parameters occurs with antibody treatment of established infection.

7.
N Engl J Med ; 385(21): 1941-1950, 2021 11 18.
Article in English | MEDLINE | ID: covidwho-1493318

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease. METHODS: In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization. RESULTS: In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P = 0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively). CONCLUSIONS: Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060.).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/drug therapy , Disease Progression , SARS-CoV-2/immunology , Adult , Aged , Ambulatory Care , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Neutralizing/adverse effects , Double-Blind Method , Female , Hospitalization/statistics & numerical data , Humans , Incidence , Infusions, Intravenous , Intention to Treat Analysis , Length of Stay , Male , Middle Aged
8.
Nature ; 596(7873): 495-504, 2021 08.
Article in English | MEDLINE | ID: covidwho-1301175

ABSTRACT

There is a realistic expectation that the global effort in vaccination will bring the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) under control. Nonetheless, uncertainties remain about the type of long-term association that the virus will establish with the human population and, in particular, whether coronavirus disease 2019 (COVID-19) will become an endemic disease. Although the trajectory is difficult to predict, the conditions, concepts and variables that influence this transition can be anticipated. Persistence of SARS-CoV-2 as an endemic virus, perhaps with seasonal epidemic peaks, may be fuelled by pockets of susceptible individuals and waning immunity after infection or vaccination, changes in the virus through antigenic drift that diminish protection and re-entries from zoonotic reservoirs. Here we review relevant observations from previous epidemics and discuss the potential evolution of SARS-CoV-2 as it adapts during persistent transmission in the presence of a level of population immunity. Lack of effective surveillance or adequate response could enable the emergence of new epidemic or pandemic patterns from an endemic infection of SARS-CoV-2. There are key pieces of data that are urgently needed in order to make good decisions; we outline these and propose a way forward.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , Pandemics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Animals , COVID-19/immunology , COVID-19/transmission , COVID-19 Vaccines/immunology , COVID-19 Vaccines/supply & distribution , Evolution, Molecular , Humans , Immune Evasion , Immunization Programs , Influenza, Human/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , SARS-CoV-2/immunology , Time Factors
9.
Preprint in English | medRxiv | ID: ppmedrxiv-21257096

ABSTRACT

BackgroundCoronavirus disease 2019 (Covid-19) disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody designed to treat such high-risk patients early in the course of disease, thereby preventing Covid-19 progression. MethodsIn this ongoing, multicenter, double-blind, phase 3 trial, nonhospitalized patients with symptomatic Covid-19 and at least one risk factor for disease progression were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with Covid-19 progression, defined as hospitalization longer than 24 hours or death, through day 29. ResultsIn this preplanned interim analysis, which included an intent-to-treat population of 583 patients (sotrovimab, 291; placebo, 292), the primary efficacy endpoint was met. The risk of Covid-19 progression was significantly reduced by 85% (97.24% confidence interval, 44% to 96%; P = 0.002) with a total of three (1%) patients progressing to the primary endpoint in the sotrovimab group versus 21 (7%) patients in the placebo group. All five patients admitted to intensive care, including one who died by day 29, received placebo. Safety was assessed in 868 patients (sotrovimab, 430; placebo, 438). Adverse events were reported by 17% and 19% of patients receiving sotrovimab and placebo, respectively; serious adverse events were less common with sotrovimab (2%) versus placebo (6%). ConclusionSotrovimab reduced progression of Covid-19 in patients with mild/moderate disease, was well tolerated, and no safety signals were identified. Funded by Vir Biotechnology, Inc. and GlaxoSmithKline; ClinicalTrials.gov NCT04545060

11.
Am J Otolaryngol ; 41(5): 102574, 2020.
Article in English | MEDLINE | ID: covidwho-457287

ABSTRACT

OBJECTIVE: To determine if rapid implementation of simulation training for anticipated COVID-19 tracheostomy procedures can increase physician confidence regarding procedure competency and use of enhanced personal protective equipment (PPE). METHODS: A brief simulation training exercise was designed in conjunction with the development of a COVID-19 Tracheostomy Protocol. The simulation training focused primarily on provider safety, pre and post-surgical steps and the proper use of enhanced PPE. Simulation training was performed in the simulation lab at the institution over 2 days. Pre and post self-evaluations were measured using standardized clinical competency questionnaires on a 5-point Likert Scale ranging from "No knowledge, unable to perform" up to "Highly knowledgeable and confident, independent." RESULTS: Physicians self-reported a significant increase in knowledge and competency immediately after completing the training exercise. Resident physicians increased from a mean score of 3.00 to 4.67, p-value 0.0041, mean increase 1.67 (CI 95% 0.81 to 2.52). Attending physicians increased from a mean score of 2.89 to 4.67, p-value 0.0002, mean increase 1.78 (CI 95% 1.14 to 2.42). Overall, all participants increased from a mean score of 3.06 to 4.71, p-value 0.0001, mean increase 1.65 (CI 95% 1.24 to 2.05). DISCUSSION: Implementation of this simulation training at our institution resulted in a significant increase in physician confidence regarding the safe performance of tracheostomy surgery in COVID-19 patients. IMPLICATIONS FOR PRACTICE: Adoption of standardized COVID-19 tracheostomy simulation training at centers treating COVID-19 patients may result in improved physician safety and enhanced confidence in anticipation of performing these procedures in real-life scenarios.


Subject(s)
Betacoronavirus , Clinical Competence , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Simulation Training , Tracheostomy/education , COVID-19 , Clinical Protocols , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Humans , Pandemics , Patient Selection , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , SARS-CoV-2
13.
Otolaryngol Head Neck Surg ; 163(1): 162-169, 2020 07.
Article in English | MEDLINE | ID: covidwho-306312

ABSTRACT

OBJECTIVE: The objective of this study was to assess the strategic changes implemented in the departmental mission to continue safe delivery of otolaryngology care and to support the broader institutional mission during the COVID-19 pandemic response. STUDY DESIGN: Retrospective assessment was performed to the response and management strategy developed to transform the clinical and academic enterprise. SETTING: Large urban tertiary care referral center. RESULTS: The departmental structure was reorganized along new clinical teams to effectively meet the system directives for provision of otolaryngology care and support for inpatient cases of COVID-19. A surge deployment schedule was developed to assist frontline colleagues with clinical support as needed. Outpatient otolaryngology was consolidated across the system with conversion of the majority of visits to telehealth. Operative procedures were prioritized to ensure throughput for emergent and time-critical urgent procedures. A tracheostomy protocol was developed to guide management of emergent and elective airways. Educational and research efforts were redirected to focus on otolaryngology care in the clinical context of the COVID-19 crisis. CONCLUSION: Emergence of the COVID-19 global health crisis has challenged delivery of otolaryngology care in an unparalleled manner. The concerns for preserving health of the workforce while ethically addressing patient career needs in a timely manner has created significant dilemmas. A proactive, thoughtful approach that reorganizes the overall departmental effort through provider and staff engagement can facilitate the ability to meet the needs of otolaryngology patients and to support the greater institutional mission to combat the pandemic.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Disease Management , Otolaryngology/methods , Otorhinolaryngologic Diseases/therapy , Pneumonia, Viral/epidemiology , Telemedicine/methods , Urban Health Services/organization & administration , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/transmission , Disease Transmission, Infectious/prevention & control , Emergencies , Humans , Otorhinolaryngologic Diseases/complications , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/transmission , Retrospective Studies , SARS-CoV-2
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