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1.
ACS Omega ; 7(36): 31935-31944, 2022 Sep 13.
Article in English | MEDLINE | ID: covidwho-2185524

ABSTRACT

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib is a kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), as well as the RET-tyrosine kinase. In the current study, it was tested in different cell lines and showed promising results on inhibition versus the toxic effect on A549-hACE2 cells (IC50 0.79 µM) while also showing a reduction of >3 log TCID50/mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, and TNF-α and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib also decreased CCL2, CCL3, and CCL4 compared to the infected animals. Vandetanib additionally rescued the decreased IFN-1ß caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved anticancer drug vandetanib is worthy of further assessment as a potential therapeutic candidate to block the COVID-19 cytokine storm.

2.
Biosensors ; 13(2):165, 2023.
Article in English | MDPI | ID: covidwho-2199770

ABSTRACT

Throughout the SARS-CoV-2 pandemic, diagnostic technology played a crucial role in managing outbreaks on a national and global level. One diagnostic modality that has shown promise is breath analysis, due to its non-invasive nature and ability to give a rapid result. In this study, a portable FTIR (Fourier Transform Infra-Red) spectrometer was used to detect chemical components in the breath from Covid positive symptomatic and asymptomatic patients versus a control cohort of Covid negative patients. Eighty-five patients who had a nasopharyngeal polymerase chain reaction (PCR) test for the detection of SARS-CoV-2 within the last 5 days were recruited to the study (36 symptomatic PCR positive, 23 asymptomatic PCR positive and 26 asymptomatic PCR negative). Data analysis indicated significant difference between the groups, with SARS-CoV-2 present on PCR versus the negative PCR control group producing an area under the curve (AUC) of 0.87. Similar results were obtained comparing symptomatic versus control and asymptomatic versus control. The asymptomatic results were higher than the symptomatic (0.88 vs. 0.80 AUC). When analysing individual chemicals, we found ethanol, methanol and acetaldehyde were the most important, with higher concentrations in the COVID-19 group, with symptomatic patients being higher than asymptomatic patients. This study has shown that breath analysis can provide significant results that distinguish patients with or without COVID-19 disease/carriage.

4.
Journal of the Royal Statistical Society: Series A (Statistics in Society) ; 185(S1), 2022.
Article in English | Web of Science | ID: covidwho-2193233

ABSTRACT

We propose a new framework to model the COVID-19 epidemic of the United Kingdom at the local authority level. The model fits within a general framework for semi-mechanistic Bayesian models of the epidemic based on renewal equations, with some important innovations, including a random walk modelling the reproduction number, incorporating information from different sources, including surveys to estimate the time-varying proportion of infections that lead to reported cases or deaths, and modelling the underlying infections as latent random variables. The model is designed to be updated daily using publicly available data. We envisage the model to be useful for now-casting and short-term projections of the epidemic as well as estimating historical trends. The model fits are available on a public website: . The model is currently being used by the Scottish government to inform their interventions.

5.
Nurs Crit Care ; 2022.
Article in English | Web of Science | ID: covidwho-2193055

ABSTRACT

BACKGROUND: Critical illness is a traumatic experience, often resulting in post-intensive care syndrome, affecting people's physical, psychological, emotional, and social well-being. The early recovery period is associated with increased risk, negatively impacting longer-term outcomes. AIMS: The aims of this study were to understand the recovery and rehabilitation needs of people who survive a COVID-19 critical illness. DESIGN AND METHODS: An exploratory descriptive qualitative interview study with 20 survivors of COVID-19 critical illness from two community-based healthcare settings in London, England. Data collection took place September 2020-April 2021, at least 1 month after hospital discharge by telephone or virtual platform. Data were subjected to inductive thematic analysis and mapped deductively to the three core concepts of self-determination theory: autonomy, competence and relatedness. FINDINGS: Three key themes emerged: traumatic experience, human connection and navigating a complex system. Participants described how societal restrictions, fear and communication problems caused by the pandemic added to their trauma and the challenge of recovery. The importance of positive human connections, timely information and support to navigate the system was emphasized. CONCLUSIONS: Whilst findings to some extent mirror those of other qualitative pre-pandemic studies, our findings highlight how the uncertainty and instability caused by the pandemic add to the challenge of recovery affecting all core concepts of self-determination (autonomy, competence, relatedness). RELEVANCE TO CLINICAL PRACTICE: Understanding survivors' perspectives of rehabilitation needs following COVID-19 critical illness is vital to delivery of safe, high-quality care. To optimize chances of effective recovery, survivors desire a specialist, co-ordinated and personalized recovery pathway, which reflects humanized care. This should be considered when planning future service provisions.

6.
Respir Res ; 22(1): 255, 2021 Sep 27.
Article in English | MEDLINE | ID: covidwho-2196282

ABSTRACT

INTRODUCTION: There is relatively little published on the effects of COVID-19 on respiratory physiology, particularly breathing patterns. We sought to determine if there were lasting detrimental effect following hospital discharge and if these related to the severity of COVID-19. METHODS: We reviewed lung function and breathing patterns in COVID-19 survivors > 3 months after discharge, comparing patients who had been admitted to the intensive therapy unit (ITU) (n = 47) to those who just received ward treatments (n = 45). Lung function included spirometry and gas transfer and breathing patterns were measured with structured light plethysmography. Continuous data were compared with an independent t-test or Mann Whitney-U test (depending on distribution) and nominal data were compared using a Fisher's exact test (for 2 categories in 2 groups) or a chi-squared test (for > 2 categories in 2 groups). A p-value of < 0.05 was taken to be statistically significant. RESULTS: We found evidence of pulmonary restriction (reduced vital capacity and/or alveolar volume) in 65.4% of all patients. 36.1% of all patients has a reduced transfer factor (TLCO) but the majority of these (78.1%) had a preserved/increased transfer coefficient (KCO), suggesting an extrapulmonary cause. There were no major differences between ITU and ward lung function, although KCO alone was higher in the ITU patients (p = 0.03). This could be explained partly by obesity, respiratory muscle fatigue, localised microvascular changes, or haemosiderosis from lung damage. Abnormal breathing patterns were observed in 18.8% of subjects, although no consistent pattern of breathing pattern abnormalities was evident. CONCLUSIONS: An "extrapulmonary restrictive" like pattern appears to be a common phenomenon in previously admitted COVID-19 survivors. Whilst the cause of this is not clear, the effects seem to be similar on patients whether or not they received mechanical ventilation or had ward based respiratory support/supplemental oxygen.


Subject(s)
COVID-19/physiopathology , Hospitalization/trends , Lung/physiology , Respiratory Mechanics/physiology , Spirometry/trends , Survivors , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/therapy , Female , Humans , Lung Diseases/diagnosis , Lung Diseases/physiopathology , Lung Diseases/therapy , Male , Middle Aged , Patient Discharge/trends , Respiratory Function Tests/methods , Respiratory Function Tests/trends , Spirometry/methods , Young Adult
7.
biorxiv; 2023.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2023.01.28.525917

ABSTRACT

Main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that mutations in Mpro may alter structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOC) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and rate of cleavage of a viral peptide. Crystal structures of 11 Mpro mutants provided structural insight into their altered functionality. Additionally, we show Mpro mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and subsequent significant decrease in cytokine secretion, providing evidence for alterations in escape of host-antiviral mechanisms. Accordingly, mutations associated with the highly virulent Delta VOC resulted in significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting Mpro will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.

8.
Preventive Medicine ; : 107415, 2022.
Article in English | ScienceDirect | ID: covidwho-2165969

ABSTRACT

By the end of 2021, approximately 15% of U.S. adults remained unvaccinated against COVID-19, and vaccination initiation rates had stagnated. We used unsupervised machine learning (K-means clustering) to identify clusters of unvaccinated respondents based on Behavioral and Social Drivers (BeSD) of COVID-19 vaccination and compared these clusters to vaccinated participants to better understand social/behavioral factors of non-vaccination. The National Immunization Survey Adult COVID Module collects data on U.S. adults from September 26–December 31,2021 (n = 187,756). Among all participants, 51.6% were male, with a mean age of 61 years, and the majority were non-Hispanic White (62.2%), followed by Hispanic (17.2%), Black (11.9%), and others (8.7%). K-means clustering procedure was used to classify unvaccinated participants into three clusters based on 9 survey BeSD items, including items assessing COVID-19 risk perception, social norms, vaccine confidence, and practical issues. Among unvaccinated adults (N = 23,397), 3 clusters were identified: the "Reachable” (23%), "Less reachable” (27%), and the "Least reachable” (50%). The least reachable cluster reported the lowest concern about COVID-19, mask-wearing behavior, perceived vaccine confidence, and were more likely to be male, non-Hispanic White, with no health conditions, from rural counties, have previously had COVID-19, and have not received a COVID-19 vaccine recommendation from a healthcare provider. This study identified, described, and compared the characteristics of the three unvaccinated subgroups. Public health practitioners, healthcare providers and community leaders can use these characteristics to better tailor messaging for each sub-population. Our findings may also help inform decisionmakers exploring possible policy interventions.

9.
American Journal of Preventive Medicine ; 2022.
Article in English | ScienceDirect | ID: covidwho-2165043

ABSTRACT

Introduction : Focusing on subpopulations who express intention to receive a COVID-19 vaccination but are unvaccinated may improve the yield of COVID-19 vaccination efforts. Methods : A nationally representative sample of 789,658 U.S. adults ages ≥18 years participated in the National Immunization Survey Adult COVID Module (NIS-ACM) from May 2021 to April 2022. The survey assessed respondents' COVID-19 vaccination status and intent by demographic characteristics (age, urbanicity, educational attainment, region, insurance, income, and race/ethnicity). This study compared composition and within-group estimates of those who responded they "definitely” or "probably” will get vaccinated or are "unsure” ("moveable middle”) from the first and last month of data collection. Results : As vaccination uptake increased over the study period, the moveable middle declined among persons ≥18 years. Adults aged 18‒39 years and suburban residents comprised most of the moveable middle in April 2022. Groups with the largest moveable middles in April 2022 included persons with no insurance (10%), aged 18‒29 years (8%), and incomes below poverty (8%);followed by non-Hispanic Native Hawaiian or other Pacific Islander (7%), non-Hispanic multiple or "other” race (6%), non-Hispanic American Indian or Alaska Native persons (6%), non-Hispanic Black or African American persons (6%), below high school education (6%), high school education (5%), and aged 30‒39 years (5%). Conclusions : A sizeable percentage of adults open to receiving COVID-19 vaccination remain in several demographic groups. Emphasizing engagement of persons who are unvaccinated in some racial/ethnic groups, aged 18‒39 years, without health insurance, or with lower income may reach more persons open to vaccination.

10.
arxiv; 2023.
Preprint in English | PREPRINT-ARXIV | ID: ppzbmed-2301.03716v1

ABSTRACT

Prior research suggests that taste preferences relate to personality traits, values, shifts in mood, and immigration destination, but understanding everyday patterns of listening and the function music plays in life have remained elusive, despite speculations that musical nostalgia may compensate for local disruption. Using more than a hundred million streams of 4 million songs by tens of thousands of international listeners from a global music service catering to local tastes, here we show that breaches in personal routine are systematically associated with personal musical exploration. As people visited new cities and countries, their preferences diversified, converging towards their destinations. As people experienced COVID-19 lock-downs, and then again when they experienced reopenings, their preferences diversified further.


Subject(s)
59585
11.
medrxiv; 2023.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2023.01.04.22283691

ABSTRACT

Not all COVID-19 deaths are officially reported and, particularly in low-income and humanitarian settings the magnitude of such reporting gaps remain sparsely characterised. Alternative data sources, including burial site worker reports, satellite imagery of cemeteries and social-media-conducted surveys of infection, may offer solutions. By merging these data with independently conducted, representative serological studies within a mathematical modelling framework, we aim to better understand the range of under-reporting using the example of three major cities: Addis Ababa (Ethiopia), Aden (Yemen) and Khartoum (Sudan) during 2020. We estimate 69% - 100%, 0.8% - 8.0% and 3.0% - 6.0% of COVID-19 deaths were reported in these three settings, respectively. In future epidemics, and in settings where vital registrations systems are absent or limited, using multiple alternative data sources could provide critically-needed, improved estimates of epidemic impact. However, ultimately, functioning vital registration systems are needed to ensure that, in contrast to COVID-19, the impact of future pandemics or other drivers of mortality are reported and understood worldwide.


Subject(s)
59585 , 3660
12.
preprints.org; 2022.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202209.0430.v2

ABSTRACT

Objectives Assess rates of adverse events (AE) after COVID-19 vaccines experienced by women of reproductive age, focusing on pregnancy and menstruation, using data collected by the US Centers for Disease Control and Prevention (CDC) Vaccine Adverse Events Reporting System (VAERS) database. Design Population-based retrospective cohort study. Setting US and global entries in US Centers for Disease Control and Prevention (CDC) Vaccine Adverse Events Reporting System (VAERS). Participants CDC VAERS entries from January 1, 1998 to June 30, 2022. Interventions None. Main Outcome Measures A proportional reporting ratio analysis is performed using data in the VAERS system comparing adverse events (AE) reported post-COVID-19 vaccines with that of post-Influenza vaccines. Results COVID-19 vaccines, when compared to the Influenza vaccines, are associated with a significant increase in AE with all proportional reporting ratios of > 2.0: menstrual abnormalities, miscarriage, fetal chromosomal abnormalities, fetal malformation, fetal cystic hygroma, fetal cardiac disorders, fetal arrhythmias, fetal cardiac arrest, fetal vascular malperfusion, fetal growth abnormalities, fetal abnormal surveillance, fetal placental thrombosis, low amniotic fluid, preeclampsia, premature delivery, preterm premature rupture of membrane, fetal death/stillbirth, and premature baby death (all p values were much smaller than 0.05). When normalized by time-available, doses-given, or persons-received, all COVID-19 vaccine AE far exceed the safety signal on all recognized thresholds. Conclusions Pregnancy complications and menstrual abnormalities are significantly more frequent following COVID-19 vaccinations than Influenza vaccinations. A worldwide moratorium on the use of COVID-19 vaccines in pregnancy is advised until randomized prospective trials document safety in pregnancy and long-term follow-up in offspring.


Subject(s)
6475 , 6484 , 59585 , 51252 , 3660 , 14312 , 5428 , 5426 , 1150 , 8768
13.
European Psychiatry ; 65(Supplement 1):S133, 2022.
Article in English | EMBASE | ID: covidwho-2153821

ABSTRACT

Introduction: Cognitive functioning and psychological well-being are considered negatively affected by COVID-19. An estimated 15%-40% of COVID-19 patients report disrupted cognitive performance. Higher rates of anxiety, depression and sleep disturbances are also reported post infection. Objective(s): We examined the profile of cognitive changes in a group of adults with a confirmed COVID-19 diagnosis, compared to those without a COVID-19 diagnosis (cross-sectional betweensubjects investigation);and for a subgroup, compared to their pre-COVID-19 cognitive function (longitudinal within-subjects investigation). Method(s): One hundred and twenty-one adults (57 with no known history of COVID-19;64 with confirmed COVID-19;17/64 with long COVID symptoms) were assessed online for psychological well-being and cognitive function (attention, processing speed, working memory, episodic memory and executive function). Pre-COVID-19 cognitive data were available for 56 of 121 adults (24 adults with a confirmed diagnosis of COVID-19;22 with no known history of COVID-19) through the MyCognition database. Result(s): The COVID-19 group showed reduced processing speed in both cross-sectional and longitudinal investigations, and also showed significant attentional impairment when examined crosssectionally. Five long COVID symptoms (abdominal pain, chest pain, sore eyes/conjunctivitis, sore throat and vomiting/nausea) were associated with reduced performance in multiple cognitive domains. Higher levels of depression and anxiety were also present in the COVID-19 group but these symptoms were mostly unrelated to cognitive performance. Conclusion(s): COVID-19 survivors, especially those with long COVID symptoms, are very likely to experience cognitive disruption. Measures need to be implemented to support their cognitive recovery in addition to the physical recovery.

14.
Drug Ther Bull ; 60(1): 2, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-2157411
16.
Mucosal Immunol ; 15(6): 1405-1415, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-2133297

ABSTRACT

Multiple SARS-CoV-2 vaccine candidates have been approved for use and have had a major impact on the COVID-19 pandemic. There remains, however, a significant need for vaccines that are safe, easily transportable and protective against infection, as well as disease. Mucosal vaccination is favored for its ability to induce immune memory at the site of infection, making it appealing for SARS-CoV-2 vaccine strategies. In this study we performed in-depth analysis of the immune responses in mice to a subunit recombinant spike protein vaccine formulated with the delta-inulin adjuvant Advax when administered intratracheally (IT), versus intramuscular delivery (IM). Both routes produced robust neutralizing antibody titers (NAb) and generated sterilizing immunity against SARS-CoV-2. IT delivery, however, produced significantly higher systemic and lung-local NAb that resisted waning up to six months post vaccination, and only IT delivery generated inducible bronchus-associated lymphoid tissue (iBALT), a site of lymphocyte antigen presentation and proliferation. This was coupled with robust and long-lasting lung tissue-resident memory CD4+ and CD8+ T cells that were not observed in IM-vaccinated mice. This study provides a detailed view of the lung-resident cellular response to IT vaccination against SARS-CoV-2 and demonstrates the importance of delivery site selection in the development of vaccine candidates.


Subject(s)
COVID-19 , SARS-CoV-2 , Mice , Animals , Humans , Inulin , COVID-19 Vaccines , CD8-Positive T-Lymphocytes , Immunologic Memory , Pandemics , COVID-19/prevention & control , Immunization , Vaccines, Synthetic , Vaccination , Adjuvants, Immunologic , Gastric Mucosa , Lung
17.
Missouri Medicine ; 117(2):83, 2020.
Article in English | ProQuest Central | ID: covidwho-2124907
18.
Missouri Medicine ; 117(2):82, 2020.
Article in English | ProQuest Central | ID: covidwho-2124906
19.
Elife ; 112022 Nov 16.
Article in English | MEDLINE | ID: covidwho-2119277

ABSTRACT

Background: The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear. Methods: We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic viral RNA kinetics models were used to quantify the effect of age, variant, symptom status, infection history, vaccination status and antibody titer to the founder SARS-CoV-2 strain on the duration of potential infectiousness and overall viral kinetics. The frequency of viral rebounds was quantified under multiple cycle threshold (Ct) value-based definitions. Results: Among individuals detected partway through their infection, 51.0% (95% credible interval [CrI]: 48.3-53.6%) remained potentially infectious (Ct <30) 5 days post detection, with small differences across variants and vaccination status. Only seven viral rebounds (0.7%; N=999) were observed, with rebound defined as 3+days with Ct <30 following an initial clearance of 3+days with Ct ≥30. High antibody titers against the founder SARS-CoV-2 strain predicted lower peak viral loads and shorter durations of infection. Among Omicron BA.1 infections, boosted individuals had lower pre-booster antibody titers and longer clearance times than non-boosted individuals. Conclusions: SARS-CoV-2 viral kinetics are partly determined by immunity and variant but dominated by individual-level variation. Since booster vaccination protects against infection, longer clearance times for BA.1-infected, boosted individuals may reflect a less effective immune response, more common in older individuals, that increases infection risk and reduces viral RNA clearance rate. The shifting landscape of viral kinetics underscores the need for continued monitoring to optimize isolation policies and to contextualize the health impacts of therapeutics and vaccines. Funding: Supported in part by CDC contract #200-2016-91779, a sponsored research agreement to Yale University from the National Basketball Association contract #21-003529, and the National Basketball Players Association.

20.
Nat Commun ; 13(1): 6972, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2119165

ABSTRACT

Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. Here, we report testing of a subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant (Pam2Cys), delivered to mice parenterally or mucosally. Both routes of vaccination induce substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generates anti-Spike IgA, increases nAb in the serum and airways, and increases lung CD4+ T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determine that TLR2 expression in either compartment facilitates early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells is essential for optimal lung-localised, antigen-specific responses. In K18-hACE2 mice, vaccination provides complete protection against disease and sterilising lung immunity against SARS-CoV-2, with a short-term non-specific protective effect from mucosal Pam2Cys alone. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.


Subject(s)
COVID-19 , Viral Vaccines , Mice , Humans , Animals , SARS-CoV-2 , Toll-Like Receptor 2 , COVID-19 Vaccines , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus , Vaccination , Lung , Antibodies, Viral , Immunity, Mucosal , Antibodies, Neutralizing
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