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1.
Med J Aust ; 217 Suppl 9: S7-S13, 2022 Nov 06.
Article in English | MEDLINE | ID: covidwho-2090766

ABSTRACT

Early treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can prevent hospitalisation and death in patients with coronavirus disease 2019 (COVID-19) who have one or more risk factors for serious COVID-19 progression. While early treatment presents a range of logistical challenges, clinicians are nevertheless aided by a growing number of approved medications for early treatment of COVID-19. Medications include drugs that inhibit SARS-CoV-2 viral replication, anti-SARS-CoV-2 monoclonal antibody formulations that provide passive immunisation, and immunomodulatory drugs that suppress the body's inflammatory response. Several drugs with different modes of action are approved in Australia for early treatment of COVID-19, including nirmatrelvir plus ritonavir, molnupiravir, and monoclonal antibody formulations. Although these drugs are recommended, clinicians are encouraged to remain up to date on current indications, contraindications and the clinical efficacy of these drugs against SARS-CoV-2 variants currently circulating in communities. Other treatments, including hydroxychloroquine, ivermectin and dietary supplements, have been popularised but are not recommended for early treatment of COVID-19. As new drugs and new data on use of existing approved drugs become available, clinicians face a growing challenge in determining the optimal treatments from the array of options. As it stands, early treatment of COVID-19 needs to be individualised depending on age, pregnancy status, existing medications, and renal and liver disease status. Future treatments in development might have roles in patients with lower risk profiles and in reducing transmission as we learn to live with SARS-CoV-2.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Humans , Pregnancy , Female , SARS-CoV-2 , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Antibodies, Viral , Antibodies, Monoclonal , Antiviral Agents/therapeutic use
2.
Preprint in English | medRxiv | ID: ppmedrxiv-22282297

ABSTRACT

The continuing emergence of SARS-CoV-2 variants of concern (VOCs) presents a serious public health threat, exacerbating the effects of the COVID19 pandemic. Although millions of genomes have been deposited in public archives since the start of the pandemic, predicting SARS-CoV-2 clinical characteristics from the genome sequence remains challenging. In this study, we used a collection of over 29,000 high quality SARS-CoV-2 genomes to build machine learning models for predicting clinical detection cycle threshold (Ct) values, which correspond with viral load. After evaluating several machine learning methods and parameters, our best model was a random forest regressor that used 10-mer oligonucleotides as features and achieved an R2 score of 0.521 {+/-} 0.010 (95% confidence interval over 5 folds) and an RMSE of 5.7 {+/-} 0.034, demonstrating the ability of the models to detect the presence of a signal in the genomic data. In an attempt to predict Ct values for newly emerging variants, we predicted Ct values for Omicron variants using models trained on previous variants. We found that approximately 5% of the data in the model needed to be from the new variant in order to learn its Ct values. Finally, to understand how the model is working, we evaluated the top features and found that the model is using a multitude of k-mers from across the genome to make the predictions. However, when we looked at the top k-mers that occurred most frequently across the set of genomes, we observed a clustering of k-mers that span spike protein regions corresponding with key variations that are hallmarks of the VOCs including G339, K417, L452, N501, and P681, indicating that these sites are informative in the model and may impact the Ct values that are observed in clinical samples.

3.
J Infect ; 2022 Oct 20.
Article in English | MEDLINE | ID: covidwho-2082953

ABSTRACT

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of ß-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI.

4.
JMIR Form Res ; 6(11): e39861, 2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2079991

ABSTRACT

BACKGROUND: The COVID-19 pandemic was accompanied by the accelerated uptake of virtual care, leading to a proliferation of virtual ward models as alternatives to facility-based care. Early in the pandemic, our program implemented a virtual mental health crisis ward (vWard) to provide options for individuals requiring intense psychiatric and/or crisis support but who preferred to remain in the community and were deemed safe to do so. OBJECTIVE: The aim of this study was to identify early learnings from the vWard, which was implemented rapidly in a resource-constrained environment, to inform the future state should it be sustained beyond the pandemic. METHODS: Mixed methods of data collection were used to evaluate provider perspectives on the vWard, develop archetypes for individuals who are a good fit for the vWard model, and create a driver diagram. Data sources included an anonymous survey of clinical and managerial staff involved in the vWard, a service planning workshop, and program discharge forms for all individuals admitted between March 2020 and April 2021. Survey responses were coded for themes under categories of "benefits" and "challenges." Discharge forms where the team indicated that the vWard was a good fit for an individual were examined for characteristics common to these admissions. These findings were reviewed in the service planning workshop and refined with input from the participants into patient archetypes. A driver diagram was created for the future state. RESULTS: Survey respondents (N=60) represented diverse roles in crisis services and the vWard team. Ten providers took part in the service planning workshop. A total of 467 discharge forms were reviewed. The vWard was felt to be a model that worked by 39 survey respondents, one respondent felt it did not work, and the remaining participants had no response. Several benefits for the individual and the system were identified alongside challenges, including certain processes and materials related to the nature of rapid implementation during the pandemic, and others due to lack of fit for certain individuals. The model was felt to be a good fit for 67.5% of admissions. Four patient archetypes representing a good fit with the model were developed. The driver diagram connected the program aim with primary drivers of (1) reduce barriers to care; (2) improve outcomes; and (3) provide collaborative, patient- and family-centered care to secondary drivers and interventions that leveraged virtual technology among other crisis care interventions. CONCLUSIONS: Despite some challenges, the vWard demonstrated high levels of provider acceptance and a range of mechanisms by which the model works for a variety of patient archetypes. These early learnings provide a foundation for growth, sustainability, and spread of this model going forward beyond the pandemic.

5.
Nuclear medicine and biology ; 2022.
Article in English | EuropePMC | ID: covidwho-2074013

ABSTRACT

Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system. Methods HA of 10 kDa molecular weight (HA10) was radiolabeled with 125I and 99mTc respectively to produce [125I]I-HA10 and [99mTc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [99mTc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS. Results [99mTc]Tc-HA10 and [125I]I-HA10 had similar biodistribution and localization at inflammatory sites. [99mTc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [99mTc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [99mTc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining. Conclusions [99mTc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [99mTc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS. Graphical Unlabelled Image

7.
Am J Public Health ; 112(11): 1620-1629, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2065248

ABSTRACT

Objectives. To characterize COVID-19 vaccine uptake and hesitancy among US nurses. Methods. We surveyed nurses in 3 national cohorts during spring 2021. Participants who indicated that they did not plan to receive or were unsure whether they planned to receive the vaccine were considered vaccine hesitant. Results. Among 32 426 female current and former nurses, 93% had been or planned to be vaccinated. After adjustment for age, race/ethnicity, and occupational variables, vaccine hesitancy was associated with lower education, living in the South, and working in a group care or home health setting. Those who experienced COVID-19 deaths and those reporting personal or household vulnerability to COVID-19 were less likely to be hesitant. Having contracted COVID-19 doubled the risk of vaccine hesitancy (95% confidence interval [CI] = 1.85, 2.53). Reasons for hesitancy that were common among nurses who did not plan to receive the vaccine were religion/ethics, belief that the vaccine was ineffective, and lack of concern about COVID-19; those who were unsure often cited concerns regarding side effects or medical reasons or reported that they had had COVID-19. Conclusions. Vaccine hesitancy was unusual and stemmed from specific concerns. Public Health Implications. Targeted messaging and outreach might reduce vaccine hesitancy. (Am J Public Health. 2022;112(11):1620-1629. https://doi.org/10.2105/AJPH.2022.307050).


Subject(s)
COVID-19 , Vaccines , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Female , Humans , Patient Acceptance of Health Care , Vaccination
8.
J Neuroeng Rehabil ; 19(1): 108, 2022 10 08.
Article in English | MEDLINE | ID: covidwho-2064818

ABSTRACT

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.


Subject(s)
Brachial Plexus , COVID-19 , Peripheral Nerve Injuries , Wearable Electronic Devices , Brachial Plexus/injuries , COVID-19/diagnosis , Feasibility Studies , Humans
9.
J Acquir Immune Defic Syndr ; 2022 Oct 10.
Article in English | MEDLINE | ID: covidwho-2063114

ABSTRACT

BACKGROUND: New York State (NYS) was at the intersection of the HIV epidemic and COVID-19 pandemic leading to a disruption in HIV-preventive services. This study sought to determine the impact of the COVID-19 pandemic and mitigation efforts on HIV-testing trends in NYS among AIDS Institute-funded providers. METHODS: We analyzed weekly testing data from the AIDS Institute Reporting System (AIRS) from 1/1/2017-to-6/27/ 2021, to fit an interrupted time-series model that predicted the expected number of HIV tests among AI-funded providers in NYS had the COVID-19 pandemic not occurred. The actual observed numbers of HIV testing that occurred from weeks beginning 3/15/2020-to- 6/30/2021, were compared with the number of HIV tests predicted by the model. RESULTS: In the absence of the COVID-19 pandemic, our model predicted that there would have been 45,605 HIV tests among AI-funded providers between the weeks beginning 3/15/2020 -to-6/27/2021. We observed 20,742-HIV tests, representing a 54.5% reduction. We observed percent decreases of greater than 50% for HIV testing among AI-funded providers for New York City (52.9%) and Rest of State (59.8%) regions, male (50.6%) and female (66.8%) genders, as well as black (59.2%), Hispanic (52.8%), mixed-race (57.5%), other (50.3%), and white (50.1%) race and ethnicities. CONCLUSION: HIV testing among AI-funded providers in NYS has declined substantially following the COVID-19 pandemic, reflecting decreased access to, and/or demand for, testing among persons at elevated risk for HIV. Initiatives to increase HIV testing and maintain access to HIV prevention services need to be explored following COVID-19.

10.
BMJ Open ; 12(9), 2022.
Article in English | Scopus | ID: covidwho-2053212

ABSTRACT

Objectives Examine if pre-COVID-19 pandemic (prior March 2020) health-related behaviours during primary school are associated with (1) being tested for SARS-CoV-2 and (2) testing positive between 1 March 2020 and 31 August 2021. Design Retrospective cohort study using an online cohort survey (January 2018 to February 2020) linked with routine PCR SARS-CoV-2 test results. Setting Children attending primary schools in Wales (2018-2020), UK, who were part of the Health and Attainment of Pupils in a Primary Education Network (HAPPEN)_school network. Participants Complete linked records of eligible participants were obtained for n=7062 individuals. 39.1% (n=2764) were tested (age 10.6±0.9;48.9% girls) and 8.1% (n=569) tested positive for SARS-CoV-2 (age 10.6±1.0;54.5% girls). Main outcome measures Logistic regression of health-related behaviours and demographics were used to determine the ORs of factors associated with (1) being tested for SARS-CoV-2 and (2) testing positive for SARS-CoV-2. Results Consuming sugary snacks (1-2 days/week OR=1.24, 95% CI 1.04 to 1.49;5-6 days/week OR=1.31, 95% CI 1.07 to 1.61;reference 0 days), can swim 25 m (OR=1.21, 95% CI 1.06 to 1.39) and age (OR=1.25, 95% CI 1.16 to 1.35) were associated with an increased likelihood of being tested for SARS-CoV-2. Eating breakfast (OR=1.52, 95% CI 1.01 to 2.27), weekly physical activity ≥60 min (1-2 days OR=1.69, 95% CI 1.04 to 2.74;3-4 days OR=1.76, 95% CI 1.10 to 2.82;reference 0 days), out-of-school club participation (OR=1.06, 95% CI 1.02 to 1.10), can ride a bike (OR=1.39, 95% CI 1.00 to 1.93), age (OR=1.16, 95% CI 1.05 to 1.28) and girls (OR=1.21, 95% CI 1.00 to 1.46) were associated with an increased likelihood of testing positive for SARS-CoV-2. Living in least deprived areas (quintile 4 OR=0.64, 95% CI 0.46 to 0.90;quintile 5 OR=0.64, 95% CI 0.46 to 0.89) compared with the most deprived (quintile 1) was associated with a decreased likelihood. Conclusions Associations may be related to parental health literacy and monitoring behaviours. Physically active behaviours may include coparticipation with others and exposure to SARS-CoV-2. A risk-versus-benefit approach must be considered in relation to promoting these health behaviours, given the importance of health-related behaviours such as childhood physical activity for development. © 2022 BMJ Publishing Group. All rights reserved.

11.
PLoS One ; 17(9): e0274571, 2022.
Article in English | MEDLINE | ID: covidwho-2054344

ABSTRACT

MAIN OBJECTIVE: There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. STUDY DESIGN AND METHODS: University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. RESULTS AND SIGNIFICANCE: The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. CONCLUSIONS: Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).


Subject(s)
COVID-19 , Intensive Care Units , Adult , Aged , COVID-19/mortality , COVID-19/therapy , Female , Hospital Mortality , Hospitalization , Humans , Intubation, Intratracheal , Male , Medicare , Middle Aged , Pandemics , United States/epidemiology
12.
PLoS Comput Biol ; 18(10): e1010602, 2022 10.
Article in English | MEDLINE | ID: covidwho-2054252

ABSTRACT

We analyze an ensemble of n-sub-epidemic modeling for forecasting the trajectory of epidemics and pandemics. These ensemble modeling approaches, and models that integrate sub-epidemics to capture complex temporal dynamics, have demonstrated powerful forecasting capability. This modeling framework can characterize complex epidemic patterns, including plateaus, epidemic resurgences, and epidemic waves characterized by multiple peaks of different sizes. We systematically assess their calibration and short-term forecasting performance in short-term forecasts for the COVID-19 pandemic in the USA from late April 2020 to late February 2022. We compare their performance with two commonly used statistical ARIMA models. The best fit sub-epidemic model and three ensemble models constructed using the top-ranking sub-epidemic models consistently outperformed the ARIMA models in terms of the weighted interval score (WIS) and the coverage of the 95% prediction interval across the 10-, 20-, and 30-day short-term forecasts. In our 30-day forecasts, the average WIS ranged from 377.6 to 421.3 for the sub-epidemic models, whereas it ranged from 439.29 to 767.05 for the ARIMA models. Across 98 short-term forecasts, the ensemble model incorporating the top four ranking sub-epidemic models (Ensemble(4)) outperformed the (log) ARIMA model 66.3% of the time, and the ARIMA model, 69.4% of the time in 30-day ahead forecasts in terms of the WIS. Ensemble(4) consistently yielded the best performance in terms of the metrics that account for the uncertainty of the predictions. This framework can be readily applied to investigate the spread of epidemics and pandemics beyond COVID-19, as well as other dynamic growth processes found in nature and society that would benefit from short-term predictions.


Subject(s)
COVID-19 , Humans , United States/epidemiology , COVID-19/epidemiology , Pandemics , Forecasting , Models, Statistical , Time
14.
Cell Host Microbe ; 30(9): 1242-1254.e6, 2022 09 14.
Article in English | MEDLINE | ID: covidwho-2035852

ABSTRACT

The worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the repeated emergence of variants of concern. For the Omicron variant, sub-lineages BA.1 and BA.2, respectively, contain 33 and 29 nonsynonymous and indel spike protein mutations. These amino acid substitutions and indels are implicated in increased transmissibility and enhanced immune evasion. By reverting individual spike mutations of BA.1 or BA.2, we characterize the molecular effects of the Omicron spike mutations on expression, ACE2 receptor affinity, and neutralizing antibody recognition. We identified key mutations enabling escape from neutralizing antibodies at a variety of epitopes. Stabilizing mutations in the N-terminal and S2 domains of the spike protein can compensate for destabilizing mutations in the receptor binding domain, enabling the record number of mutations in Omicron. Our results provide a comprehensive account of the mutational effects in the Omicron spike protein and illustrate previously uncharacterized mechanisms of host evasion.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/genetics , Antibodies, Neutralizing/genetics , Antibodies, Viral , Epitopes , Humans , Membrane Glycoproteins , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins
15.
Frontiers in public health ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-2033894

ABSTRACT

Background Implementation mapping (IM) is a promising five-step method for guiding planning, execution, and maintenance of an innovation. Case examples are valuable for implementation practitioners to understand considerations for applying IM. This pilot study aimed to determine the feasibility of using IM within a federally qualified health center (FQHC) with limited funds and a 1-year timeline. Methods An urban FQHC partnered with an academic team to employ IM for implementing a computerized strategy of tobacco cessation: the 5A's (Ask, Advise, Assess, Assist, Arrange). Each step of IM was supplemented with theory-driven methods and frameworks. Data collection included surveys and interviews with clinic staff, analyzed via rapid data analysis. Results Medical assistants and clinicians were identified as primary implementers of the 5A's intervention. Salient determinants of change included the perceived compatibility and relative priority of 5A's. Performance objectives and change objectives were derived to address these determinants, along with a suite of implementation strategies. Despite indicators of adoptability and acceptability of the 5A's, reductions in willingness to adopt the implementation package occurred over time and the intervention was not adopted by the FQHC within the study timeframe. This is likely due to the strain of the COVID-19 pandemic altering health clinic priorities. Conclusions Administratively, the five IM steps are feasible to conduct with FQHC staff within 1 year. However, this study did not obtain its intended outcomes. Lessons learned include the importance of re-assessing barriers over time and ensuring a longer timeframe to observe implementation outcomes.

16.
Preprint in English | medRxiv | ID: ppmedrxiv-22280118

ABSTRACT

BackgroundPatients with severe SARS-CoV-2 pneumonia experience longer durations of critical illness yet similar mortality rates compared to patients with severe pneumonia secondary to other etiologies. As secondary bacterial infection is common in SARS-CoV-2 pneumonia, we hypothesized that unresolving ventilator-associated pneumonia (VAP) drives the apparent disconnect between length-of-stay and mortality rate among these patients. MethodsWe analyzed VAP in a prospective single-center observational study of 585 mechanically ventilated patients with suspected pneumonia, including 190 patients with severe SARS-CoV-2 pneumonia. We developed CarpeDiem, a novel machine learning approach based on the practice of daily ICU team rounds to identify clinical states for each of the 12,495 ICU patient-days in the cohort. We used the CarpeDiem approach to evaluate the effect of VAP and its resolution on clinical trajectories. FindingsPatients underwent a median [IQR] of 4 [2,7] transitions between 14 clinical states during their ICU stays. Clinical states were associated with differential hospital mortality. The long length-of-stay among patients with severe SARS-CoV-2 pneumonia was associated with prolonged stays in clinical states defined by severe respiratory failure and with a lower frequency of transitions between clinical states. In all patients, including those with COVID-19, unresolving VAP episodes were associated with transitions to unfavorable states and hospital mortality. InterpretationCarpeDiem offers a machine learning approach to examine the effect of VAP on clinical outcomes. Our findings suggest an underappreciated contribution of unresolving secondary bacterial pneumonia to outcomes in mechanically ventilated patients with pneumonia, including due to SARS-CoV-2. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/22280118v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@1d27ccorg.highwire.dtl.DTLVardef@1ff77aorg.highwire.dtl.DTLVardef@b094b5org.highwire.dtl.DTLVardef@f3100c_HPS_FORMAT_FIGEXP M_FIG Graphical abstract Disentangling the contributions of ICU complications and interventions to ICU outcomes. (A) Traditional approaches evaluate the ICU stay as a black box with severity of illness measured on presentation and dichotomized survival at an arbitrary time point (e.g., day 28) or on ICU or hospital discharge. Hence, the effect of intercurrent complications and interventions cannot be easily measured, a problem that is compounded when ICU stays are long or significantly differ between groups. (B) Defining the ICU course by clinical features during each day in the ICU permits the association of a complication or intervention with transitions toward clinical states associated with favorable or unfavorable outcomes. C_FIG

17.
Am J Prev Med ; 2022 Sep 12.
Article in English | MEDLINE | ID: covidwho-2027840

ABSTRACT

INTRODUCTION: Events during 2019 and 2020, such as the outbreak of e-cigarette, or vaping, product use‒associated lung injury; manufacturer product withdrawals; federal regulations; and coronavirus disease 2019, potentially affected the retail availability of ENDS in the U.S. Measuring changes in ENDS availability informs the understanding of the ENDS marketplace and contextualizes sales trends. METHODS: Joinpoint regression was used to estimate slope changes in the number of available ENDS in 2019 and 2020 and considered correspondence with tobacco marketplace events. Availability, the weekly number of unique universal product codes with nonzero sales, was derived from NielsenIQ scanner data. U.S. ENDS availability was modeled overall and by subproduct and flavor category within subproduct: mint, menthol, tobacco flavored, and undetermined. RESULTS: ENDS availability increased by 66% from January 2019 to December 2020. Availability decreased by 43% among prefilled cartridges and increased by 511% among disposables, both led by flavored varieties. During January 2020-February 2020, prefilled cartridge availability decreased by 23.71 universal product codes per week. During July 2020-August 2020, disposable availability increased by 27.90 universal product codes per week, led by flavored products. CONCLUSIONS: ENDS availability increased during 2019 through 2020, led by a rise in flavored disposables. Multiple slope changes in ENDS availability occurred, many coinciding with tobacco marketplace events. The slope of ENDS explicitly prioritized for federal enforcement (i.e., flavored prefilled cartridges) notably decreased in early 2020 and, soon thereafter, the slope of ENDS not explicitly prioritized for enforcement (e.g., flavored disposables) notably increased, suggesting an association with U.S. Food and Drug Administration's prioritized enforcement guidance.

18.
PLoS Pathog ; 18(9): e1010807, 2022 09.
Article in English | MEDLINE | ID: covidwho-2021985

ABSTRACT

Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.


Subject(s)
COVID-19 , Prolyl-Hydroxylase Inhibitors , Animals , Antiviral Agents , Cricetinae , Hypoxia , Lung/pathology , Mesocricetus , Oxygen , RNA, Viral , SARS-CoV-2
19.
PLoS One ; 17(8): e0271359, 2022.
Article in English | MEDLINE | ID: covidwho-2021873

ABSTRACT

The viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly its cell-binding spike protein gene, has undergone rapid evolution during the coronavirus disease 2019 (COVID-19) pandemic. Variants including Omicron BA.1 and Omicron BA.2 now seriously threaten the efficacy of therapeutic monoclonal antibodies and vaccines that target the spike protein. Viral evolution over a much longer timescale has generated a wide range of genetically distinct sarbecoviruses in animal populations, including the pandemic viruses SARS-CoV-2 and SARS-CoV-1. The genetic diversity and widespread zoonotic potential of this group complicates current attempts to develop drugs in preparation for the next sarbecovirus pandemic. Receptor-based decoy inhibitors can target a wide range of viral strains with a common receptor and may have intrinsic resistance to escape mutant generation and antigenic drift. We previously generated an affinity-matured decoy inhibitor based on the receptor target of the SARS-CoV-2 spike protein, angiotensin-converting enzyme 2 (ACE2), and deployed it in a recombinant adeno-associated virus vector (rAAV) for intranasal delivery and passive prophylaxis against COVID-19. Here, we demonstrate the exceptional binding and neutralizing potency of this ACE2 decoy against SARS-CoV-2 variants including Omicron BA.1 and Omicron BA.2. Tight decoy binding tracks with human ACE2 binding of viral spike receptor-binding domains across diverse clades of coronaviruses. Furthermore, in a coronavirus that cannot bind human ACE2, a variant that acquired human ACE2 binding was bound by the decoy with nanomolar affinity. Considering these results, we discuss a strategy of decoy-based treatment and passive protection to mitigate the ongoing COVID-19 pandemic and future airway virus threats.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Animals , COVID-19/drug therapy , Humans , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Receptors, Virus/metabolism , SARS-CoV-2/genetics
20.
J Urol ; 208(4): 788-790, 2022 10.
Article in English | MEDLINE | ID: covidwho-2018301
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