\ BIP! Finder for COVID-19 - Impact-based ranking

BIP! Finder for COVID-19

This version of BIP! Finder aims to ease the exploration of COVID-19-related literature by enabling ranking articles based on various impact metrics.

Last Update: 18 - 01 - 2023 (628506 entries)

Provided impact measures:
Popularity: Citation-based measure reflecting the current impact.
Influence: Citation-based measure reflecting the total impact.
Reader Attention: The current number of Mendeley readers.
Social Media Attention: The number of recent tweets related to this article.
*More details on these impact measures can be found here.
Score interpretations:
Exceptional score (in top 0.01%).
Substantial score (in top 1%).
Average score (in bottom 99%).
Score not available.
Main data sources:
CORD-19 dataset(1) (list of papers)
LitCovid hub(2) (list of papers)
PMC & PubMed (citations)
Mendeley (number of readers)
COVID-19-TweetIDs(3) (tweets)

Use:  Impact  Relevance & Impact
301Effects of the COVID-19 Emergency and National Lockdown on Italian Citizens' Economic Concerns, Government Trust and Health Engagement: Evidence From a Two-Wave Panel Study  

POLICY POINTS: Preventive measures such as the national lockdown in Italy have been effective in slowing the spread of COVID‐19. However, they also had psychological and economic impacts on people’s lives, which should not be neglected as they may reduce citizens’ trust and compliance with future health mandates. Engaging citizens in their own health management and in the collaboration with health care professionals and authorities via the adoption of a collaborative approach to health policy development is fundamental to fostering such measures’ effectiveness. Psychosocial analysis of citizens’ concerns and emotional reactions to preventive policies is important in order to plan personalized health communication campaigns. CONTEXT: Because of the COVID‐19 pandemic, between February 23 and March 8, 2020, some areas of Italy were declared “red zones,” with citizens asked to stay home and avoid unnecessary interpersonal contacts. Such measures were then extended, between March 10 and May 4, 2020, to the whole country. However, compliance with such behaviors had an important impact on citizens’ personal, psychological, and economic well‐being. This could result in reduced trust in authorities and lowered compliance. Keeping citizens engaged in their own health and in preventive behaviors is thus a key strategy for the success of such measures. This paper presents the results from a study conducted in Italy to monitor levels of people’s health engagement, sentiment, trust in authorities, and perception of risk at two different time points. METHODS: Two independent samples (n = 968 and n = 1,004), weighted to be representative of the adult Italian population, were recruited in two waves corresponding to crucial moments of the Italian COVID‐19 epidemic: between February 28 and March 4 (beginning of “phase 1,” after the first regional lockdowns), and between May 12 and May 18 (beginning of “phase 2,” after the national lockdown was partially dismissed). Respondents were asked to complete an online survey with a series of both validated measures and ad hoc items. A series of t‐tests, general linear models, and contingency tables were carried out to assess if and how our measures changed over time in different social groups. FINDINGS: Although sense of self and social responsibility increased between the two waves, and trust toward authorities remained substantially the same, trust in science, consumer sentiment, and health engagement decreased. Our results showed that while both the level of general concern for the emergency and the perceived risk of infection increased between the two waves, in the second wave our participants reported being more concerned for the economic consequences of the pandemic than the health risk. CONCLUSIONS: The potentially disruptive psychological impact of lockdown may hamper citizens’ compliance with, and hence the effectiveness of, behavioral preventive measures. This suggests that preventive measures should be accompanied by collaborative educational plans aimed at promoting people’s health engagement by making citizens feel they are partners in the health preventive endeavor and involved in the development of health policies.

Milbank Q2021       LitCov and CORD-19
302Safety, immunogenicity and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial  

BACKGROUND: Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19. METHODS: The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing. FINDINGS: Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group). INTERPRETATION: Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose. FUNDING: UK Vaccine Task Force and National Institute for Health Research.

Lancet Infect Dis2022       LitCov and CORD-19
303Psychological Adjustment of Healthcare Workers in Italy during the COVID-19 Pandemic: Differences in Stress, Anxiety, Depression, Burnout, Secondary Trauma and Compassion Satisfaction between Frontline and Non-Frontline Professionals  

Emergency situations have been associated with negative psychological adjustment outcomes in healthcare professionals, although studies on the impact of the Coronavirus Disease 2019 (COVID-19) pandemic amongst Italian health workers are limited. The main aim of this study was to investigate the psychological adjustment of healthcare professionals during the peak of the COVID-19 pandemic, evaluating differences according to working or not with patients affected by COVID-19 and in areas with a more severe spread of this pandemic. Healthcare professionals’ attitudes toward psychological support were analyzed. The levels of anxiety, depression, psychological stress, and professional quality of life (compassion satisfaction, burnout, and compassion fatigue) and attitudes toward psychological support were measured among 627 Italian healthcare workers (mean age = 40.55 years; SD = 11.49; range: 27–72). Significantly higher levels of stress, burnout, secondary trauma, anxiety, and depression were observed among professionals working with COVID-19 patients. Higher levels of stress and burnout and lower levels of compassion satisfaction were detected in professionals working in areas with higher rates of contagion. No interaction effects were found between working (or not) with patients affected by COVID-19 and working (or not) in areas with a more severe diffusion of this pandemic. Finally, in the group of professionals who worked with COVID-19 patients, the percentage of professionals who thought to ask for psychological support was twice that of the group that did not work with COVID-19 patients. The overall findings indicate that the mental health of frontline healthcare workers requires further consideration and that targeted prevention and intervention programs are necessary.

Int J Environ Res Public Healt2020       LitCov and CORD-19
304Effect of COVID-19 pandemic on mental health among Bangladeshi healthcare professionals: A cross-sectional study  


Sci Prog2021       LitCov and CORD-19
305Online learning during COVID-19 produced equivalent or better student course performance as compared with pre-pandemic: empirical evidence from a school-wide comparative study  

BACKGROUND: The COVID-19 pandemic forced dental schools to close their campuses and move didactic instruction online. The abrupt transition to online learning, however, has raised several issues that have not been resolved. While several studies have investigated dental students’ attitude towards online learning during the pandemic, mixed results have been reported. Additionally, little research has been conducted to identify and understand factors, especially pedagogical factors, that impacted students’ acceptance of online learning during campus closure. Furthermore, how online learning during the pandemic impacted students’ learning performance has not been empirically investigated. In March 2020, the dental school studied here moved didactic instruction online in response to government issued stay-at-home orders. This first-of-its-kind comparative study examined students’ perceived effectiveness of online courses during summer quarter 2020, explored pedagogical factors impacting their acceptance of online courses, and empirically evaluated the impact of online learning on students’ course performance, during the pandemic. METHOD: The study employed a quasi-experimental design. Participants were 482 pre-doctoral students in a U.S dental school. Students’ perceived effectiveness of online courses during the pandemic was assessed with a survey. Students’ course grades for online courses during summer quarter 2020 were compared with that of a control group who received face-to-face instruction for the same courses before the pandemic in summer quarter 2019. RESULTS: Survey results revealed that most online courses were well accepted by the students, and 80 % of them wanted to continue with some online instruction post pandemic. Regression analyses revealed that students’ perceived engagement with faculty and classmates predicted their perceived effectiveness of the online course. More notably, Chi Square tests demonstrated that in 16 out of the 17 courses compared, the online cohort during summer quarter 2020 was equally or more likely to get an A course grade than the analogous face-to-face cohort during summer quarter 2019. CONCLUSIONS: This is the first empirical study in dental education to demonstrate that online courses during the pandemic could achieve equivalent or better student course performance than the same pre-pandemic in-person courses. The findings fill in gaps in literature and may inform online learning design moving forward. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12909-021-02909-z.

BMC Med Educ2021       LitCov and CORD-19
306Determinants of COVID-19 disease severity in patients with underlying rheumatic disease  

BACKGROUND: Over the month of April, Spain has become the European country with more confirmed cases of COVID-19 infection, after surpassing Italy on April 2nd. The community of Castile and León in Spain is one of the most affected by COVID-19 infection and the province of León has a total of 3711 cases and 425 deaths so far. Rheumatic patients should be given special attention regarding COVID-19 infection due to their immunocompromised state resulting from their underlying immune conditions and use of targeted immune-modulating therapies. Studying epidemiological and clinical characteristics of patients with rheumatic diseases infected with SARS-CoV2 is pivotal to clarify determinants of COVID-19 disease severity in patients with underlying rheumatic disease. OBJECTIVES: To describe epidemiological characteristics of patients with rheumatic diseases hospitalized with COVID-19 and determine risk factors associated with mortality in a third level Hospital setting in León, Spain. METHODS: We performed a prospective observational study, from 1st March 2020 until the 1st of June including adults with rheumatic diseases hospitalized with COVID-19 and performed a univariate and multivariate logistic regression model to estimate ORs and 95% CIs of mortality. Age, sex, comorbidities, rheumatic disease diagnosis and treatment, disease activity prior to infection, radiographic and laboratorial results at arrival were analysed. RESULTS: During the study period, 3711 patients with COVID-19 were admitted to our hospital, of whom 38 (10%) had a rheumatic or musculoskeletal disease. Fifty-three percent were women, with a mean age at hospital admission of 75.3 (IQR 68–83) years. The median length of stay was 11 days. A total of 10 patients died (26%) during their hospital admission. Patients who died from COVID-19 were older (median age 78.4 IQR 74.5–83.5) than those who survived COVID-19 (median age 75.1 IQR 69.3–75.8) and more likely to have arterial hypertension (9 [90%] vs 14 [50%] patients; OR 9 (95% CI 1.0–80.8), p 0.049), dyslipidaemia (9 (90%) vs 12 (43%); OR 12 (95% CI 1.33–108), p 0.03), diabetes ((9 (90%) vs 6 (28%) patients; OR 33, p 0.002), interstitial lung disease (6 (60%) vs 6 (21%); OR 5.5 (95% CI 1.16–26), p 0.03), cardiovascular disease (8 (80%) vs 11 (39%); OR 6.18 (95% IC 1.10–34.7, p 0.04) and a moderate/high index of rheumatic disease activity (7 (25%) vs 6(60%); OR 41.4 (4.23–405.23), p 0.04). In univariate analyses, we also found that patients who died from COVID-19 had higher hyperinflammation markers than patients who survived: C-reactive protein (181 (IQR 120–220) vs 107.4 (IQR 30–150; p 0.05); lactate dehydrogenase (641.8 (IQR 465.75–853.5) vs 361 (IQR 250–450), p 0.03); serum ferritin (1026 (IQR 228.3–1536.3) vs 861.3 (IQR 389–1490.5), p 0.04); D-dimer (12,019.8 (IQR 843.5–25,790.5) vs 1544.3 (IQR 619–1622), p 0.04). No differences in sex, radiological abnormalities, rheumatological disease, background therapy or symptoms before admission between deceased patients and survivors were found. In the multivariate analysis, the following risk factors were associated with mortality: rheumatic disease activity (p = 0.003), dyslipidaemia (p = 0.01), cardiovascular disease (p = 0.02) and interstitial lung disease (p = 0.02). Age, hypertension and diabetes were significant predictors in univariate but not in multivariate analysis. Rheumatic disease activity was significantly associated with fever (p = 0.05), interstitial lung disease (p = 0.03), cardiovascular disease (p = 0.03) and dyslipidaemia (p = 0.01). CONCLUSIONS: Our results suggest that comorbidities, rheumatic disease activity and laboratorial abnormalities such as C-reactive protein (CRP), D-Dimer, lactate dehydrogenase (LDH), serum ferritin elevation significantly associated with mortality whereas previous use of rheumatic medication did not. Inflammation is closely related to severity of COVID-19.

Clin Rheumatol2020       LitCov and CORD-19
307Determinants of early antibody responses to COVID-19 mRNA vaccines in a cohort of exposed and naïve healthcare workers  

BACKGROUND: Two doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naïve adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness. METHODS: We measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events. FINDINGS: Vaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects (p<0·05). A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with 43% (95% CI, 19-59) and 45% (95% CI, 63-18) lower neutralization, respectively, and 35% (95% CI, 3-57%) and 55% (95% CI, 33-70%) lower antibody levels, respectively. Among fully vaccinated, 6·3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection. INTERPRETATION: Our data support administering a single-dose in pre-exposed healthy individuals as primary vaccination. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination and in face of variants that escape immunity such as Omicron. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year. FUNDING: This work was supported by Institut de Salut Global de Barcelona (ISGlobal) internal funds, in-kind contributions from Hospital Clínic de Barcelona, the Fundació Privada Daniel Bravo Andreu, and European Institute of Innovation and Technology (EIT) Health (grant number 20877), supported by the European Institute of Innovation and Technology, a body of the European Union receiving support from the H2020 Research and Innovation Programme. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. L. I. work was supported by PID2019-110810RB-I00 grant from the Spanish Ministry of Science & Innovation. Development of SARS-CoV-2 reagents was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (contract number HHSN272201400008C). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.

EBioMedicine2022       LitCov and CORD-19
308Omicron variant showed lower neutralizing sensitivity than other SARS-CoV-2 variants to immune sera elicited by vaccines after boost  

The emerging new VOC B.1.1.529 (Omicron) variant has raised serious concerns due to multiple mutations, reported significant immune escape, and unprecedented rapid spreading speed. Currently, studies describing the neutralization ability of different homologous and heterologous booster vaccination against Omicron are still lacking. In this study, we explored the immunogenicity of COVID-19 breakthrough patients, BBIBP-CorV homologous booster group and BBIBP-CorV/ZF2001 heterologous booster group against SARS-CoV-2 pseudotypes corresponding to the prototype, Beta, Delta, and the emergent Omicron variant. Notably, at 14 days post two-dose inactivated vaccines, pVNT titre increased to 67.4 GMTs against prototype, 8.85 against Beta and 35.07 against Delta, while neutralization activity against Omicron was below the lower limit of quantitation in 80% of the samples. At day 14 post BBIBP-CorV homologous booster vaccination, GMTs of pVNT significantly increased to 285.6, 215.7, 250.8, 48.73 against prototype, Beta, Delta, and Omicron, while at day 14 post ZF2001 heterologous booster vaccination, GMTs of pVNT significantly increased to 1436.00, 789.6, 1501.00, 95.86, respectively. Post booster vaccination, 100% samples showed positive neutralization activity against Omicron, albeit illustrated a significant reduction (5.86- to 14.98-fold) of pVNT against Omicron compared to prototype at 14 days after the homologous or heterologous vaccine boosters. Overall, our study demonstrates that vaccine-induced immune protection might more likely be escaped by Omicron compared to prototypes and other VOCs. After two doses of inactivated whole-virion vaccines as the “priming” shot, a third heterologous protein subunit vaccine and a homologous inactivated vaccine booster could improve neutralization against Omicron.

Emerg Microbes Infect2022       LitCov and CORD-19
309Tolerability of COVID-19 Infection and Messenger RNA Vaccination Among Patients With a History of Kawasaki Disease  


JAMA Netw Open2022       LitCov
310Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China  


JAMA Cardiol2020       LitCov and CORD-19
311Assessing the Impact of the COVID-19 Pandemic in Spain: Large-Scale, Online, Self-Reported Population Survey  

BACKGROUND: Spain has been one of the countries most impacted by the COVID-19 pandemic. Since the first confirmed case was reported on January 31, 2020, there have been over 405,000 cases and 28,000 deaths in Spain. The economic and social impact is without precedent. Thus, it is important to quickly assess the situation and perception of the population. Large-scale online surveys have been shown to be an effective tool for this purpose. OBJECTIVE: We aim to assess the situation and perception of the Spanish population in four key areas related to the COVID-19 pandemic: social contact behavior during confinement, personal economic impact, labor situation, and health status. METHODS: We obtained a large sample using an online survey with 24 questions related to COVID-19 in the week of March 28-April 2, 2020, during the peak of the first wave of COVID-19 in Spain. The self-selection online survey method of nonprobability sampling was used to recruit 156,614 participants via social media posts that targeted the general adult population (age >18 years). Given such a large sample, the 95% CI was ±0.843 for all reported proportions. RESULTS: Regarding social behavior during confinement, participants mainly left their homes to satisfy basic needs. We found several statistically significant differences in social behavior across genders and age groups. The population’s willingness to comply with the confinement measures is evident. From the survey answers, we identified a significant adverse economic impact of the pandemic on those working in small businesses and a negative correlation between economic damage and willingness to stay in confinement. The survey revealed that close contacts play an important role in the transmission of the disease, and 28% of the participants lacked the necessary resources to properly isolate themselves. We also identified a significant lack of testing, with only 1% of the population tested and 6% of respondents unable to be tested despite their doctor’s recommendation. We developed a generalized linear model to identify the variables that were correlated with a positive SARS-CoV-2 test result. Using this model, we estimated an average of 5% for SARS-CoV-2 prevalence in the Spanish population during the time of the study. A seroprevalence study carried out later by the Spanish Ministry of Health reported a similar level of disease prevalence (5%). CONCLUSIONS: Large-scale online population surveys, distributed via social media and online messaging platforms, can be an effective, cheap, and fast tool to assess the impact and prevalence of an infectious disease in the context of a pandemic, particularly when there is a scarcity of official data and limited testing capacity.

J Med Internet Res2020       LitCov and CORD-19
312Seroprevalence of Unidentified SARS-CoV-2 Infection in Hong Kong During 3 Pandemic Waves  

IMPORTANCE: Seroprevalence studies inform the extent of infection and assist evaluation of mitigation strategies for the COVID-19 pandemic. OBJECTIVE: To estimate the prevalence of unidentified SARS-CoV-2 infection in the general population of Hong Kong. DESIGN, SETTING, AND PARTICIPANTS: A prospective cross-sectional study was conducted in Hong Kong after each major wave of the COVID-19 pandemic (April 21 to July 7, 2020; September 29 to November 23, 2020; and January 15 to April 18, 2021). Adults (age ≥18 years) who had not been diagnosed with COVID-19 were recruited during each period, and their sociodemographic information, symptoms, travel, contact, quarantine, and COVID-19 testing history were collected. MAIN OUTCOMES AND MEASURES: The main outcome was prevalence of SARS-CoV-2 infection. SARS-CoV-2 IgG antibodies were detected by an enzyme-linked immunosorbent assay based on spike (S1/S2) protein, followed by confirmation with a commercial electrochemiluminescence immunoassay based on the receptor binding domain of spike protein. RESULTS: The study enrolled 4198 participants (2539 [60%] female; median age, 50 years [IQR, 25 years]), including 903 (22%), 1046 (25%), and 2249 (53%) during April 21 to July 7, 2020; during September 29 to November 23, 2020; and during January 15 to April 18, 2021, respectively. The numbers of participants aged 18 to 39 years, 40 to 59 years, and 60 years or older were 1328 (32%), 1645 (39%), and 1225 (29%), respectively. Among the participants, 2444 (58%) stayed in Hong Kong since November 2019 and 2094 (50%) had negative SARS-CoV-2 RNA test results. Only 170 (4%) reported ever having contact with individuals with confirmed cases, and 5% had been isolated or quarantined. Most (2803 [67%]) did not recall any illnesses, whereas 737 (18%), 212 (5%), and 385 (9%) had experienced respiratory symptoms, gastrointestinal symptoms, or both, respectively, before testing. Six participants were confirmed to be positive for anti-SARS-CoV-2 IgG; the adjusted prevalence of unidentified infection was 0.15% (95% CI, 0.06%-0.32%). Extrapolating these findings to the whole population, there were fewer than 1.9 unidentified infections for every recorded confirmed case. The overall prevalence of SARS-CoV-2 infection in Hong Kong before the roll out of vaccination was less than 0.45%. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of participants from the general public in Hong Kong, the prevalence of unidentified SARS-CoV-2 infection was low after 3 major waves of the pandemic, suggesting the success of the pandemic mitigation by stringent isolation and quarantine policies even without complete city lockdown. More than 99.5% of the general population of Hong Kong remain naive to SARS-CoV-2, highlighting the urgent need to achieve high vaccine coverage.

JAMA Netw Open2021       LitCov and CORD-19
313The Influence of Coronavirus Diseases 2019 Pandemic and the Quarantine Practices on University Students' Beliefs About the Online Learning Experience in Jordan  

Coronavirus Disease 2019 (COVID-19) is a contagious disease that affects the respiratory system. In addition to the severe effects of the disease on health, the pandemic caused a negative impact on basic needs and services, employment, education, and economy worldwide. In Jordan, the whole country locked down, and quarantine was enforced by the military forces, which successfully controlled the spread of the disease. This research aims to study the influence of the COVID-19 pandemic and its associated quarantine on university students' beliefs about online learning practice in Jordan. An online descriptive survey involved questions that covered students' demographic information, student's basic and advanced knowledge about COVID-19, students' online learning experience during the quarantine, and finally students' views on the enforced quarantine practice in Jordan. Results showed that students have a good knowledge (>50%) about the COVID-19 basic information and a moderate knowledge (<50%) regarding COVID-19 advanced information. In general, students were pessimistic about the future of COVID-19 both locally and worldwide. Although some students acknowledged that they learned new skills in the fields of electronics, informatics, and computer software during the pandemic, most of them were unsatisfied about the quality and quantity of the given material, online exams, and the evaluation processes. Unfortunately, most of the students faced internet technical problems or challenges to electronic accessibility. The majority of the participants (>90%) supported the military-enforced quarantine implemented in the country despite the hard time the students had during the quarantine. We conclude that university students were able to protect themselves from COVID-19 through their good knowledge about the infectious disease and their commitment to follow the rules imposed by the Government of Jordan. Nevertheless, the challenges caused by the pandemic and its associated quarantine, combined with the sudden unprecedented online experience, negatively impacted students' thoughts and beliefs about the online learning experience during the quarantine. Further studies need to be performed in this context. We hope our results will help decision-makers better understand the students' attitudes and motivation toward online learning and how this will affect their future plans and decisions.

Front Public Health2020       LitCov and CORD-19
314Safety and efficacy of antiviral combination therapy in symptomatic patients of Covid-19 infection-a randomised controlled trial (SEV-COVID Trial): A structured summary of a study protocol for a randomized controlled trial  

OBJECTIVES: 1. To compare the safety and efficacy of Hydroxychloroquine with Ribavirin and standard treatment in patients with non-severe COVID-19 infection 2. To compare the safety and efficacy of standard treatment, Lopinavir-ritonavir with Ribavarin, and Hydroxychloroquine with Ribavirin in patients with severe COVID-19 infection TRIAL DESIGN: The study is an Open label, Parallel arm design, stratified randomised controlled trial. Patients will be categorised as non-severe or severe based on predefined criteria. Those who satisfy all inclusion criteria and no exclusion criteria in the respective categories, will be randomly assigned to one of the three treatment groups in a ratio of 1:1 in the non-severe category and 1:1:1 in the severe category. PARTICIPANTS: The trial will be undertaken in a tertiary care center of the country where both Covid and non-Covid patients are getting treated. All patients who are confirmed positive and admitted will be screened for the eligibility criteria and will be enrolled in the study after a written informed consent. Patients will be categorised as non-severe or severe based on predefined criteria. INCLUSION CRITERIA (ALL REQUIRED): 1. Age ≥18 years at time of participation in the study 2. Laboratory (RT-PCR) confirmed infection with SARS-CoV-2 3. Symptomatic (severe or non-severe) Covid-19 disease 4. Willingness of study participant to accept randomization to any assigned treatment arm EXCLUSION CRITERIA: 1. Use of medications that are contraindicated with Lopinavir/Ritonavir, Hydroxychloroquine/Chloroquine, or Ribavirin and that cannot be replaced or stopped 2. Patient already on antiretroviral therapy with Lopinavir-Ritonavir based regimen or on Hydroxychloroquine/Chloroquine or on Ribavirin 3. Any known contraindication to test drugs such as retinopathy and QT prolongation 4. Known allergic reaction or inability to take orally of Lopinavir-ritonavir, Hydroxychloroquine/ Chloroquine, Ribavarin 5. Pregnant or breastfeeding females 6. Receipt of any experimental treatment for 2019-nCoV (off-label, compassionate use, or trial related) within 30 days prior to participation in the present study or want to participate after enrolment INTERVENTION AND COMPARATOR: Two therapeutic interventions for non-severe category and three for severe category as described below NON-SEVERE TREATMENT ARMS (NS-GROUP): Standard Treatment for non-severe cases (STNS): Strict Isolation, Standard Precautions (Hand hygiene, Cough Etiquette, Wear surgical mask), Hydration, Proper Nutrition, Supportive Pharmacotherapy (Antipyretic, Antiallergic, Cough Suppressant), Treatment of Comorbid Diseases, Oseltamivir (75 mg BD) for patients who are tested positive for H1N1. SEVERE GROUP TREATMENT ARMS (S-GROUP): Standard Treatment for severe patients (STs): Strict Isolation, Standard Precautions (Hand hygiene, Cough Etiquette, Wear surgical mask), Fluid Therapy, Supportive Pharmacotherapy (Antipyretic, Antiallergic, Cough Suppressant), Oxygen supplementation (As required), Invasive ventilation (As required), Antibiotic agents for other associated infections (according to 2019 ATS/IDSA guidelines for non-ICU and ICU patients), Vasopressor support, Renal-replacement therapy, Treatment of Comorbid Diseases, Oseltamivir (75 mg BD) for patients who are tested positive for H1N1. MAIN OUTCOMES: Primary endpoints: (1) Time to Clinical recovery (TTCR) defined as the time (in hours) from initiation of study treatment (active or placebo) until normalisation of fever, respiratory rate, oxygen saturation, and alleviation of cough, sustained for at least 72 hours. (2) Time to SARS-CoV-2 RT-PCR negative in upper respiratory tract specimen, time to laboratory recovery of each organ involvement. Secondary Endpoints: All causes mortality, Frequency of respiratory progression (defined as SPO2≤ 94% on room air or PaO2/FiO2 <300mmHg and requirement for supplemental oxygen or more advanced ventilator support), time to defervescence (in those with fever at enrolment), frequency of requirement for supplemental oxygen or non-invasive ventilation, frequency of requirement for mechanical ventilation, frequency of serious adverse events as per DAIDS table grade of severity. Outcomes are monitored for 28 days from the time of enrolment into the study OR until the patient is discharged or death whichever is longer. RANDOMIZATION: The randomization will be done using a secured central computer-based randomization using a secure website using a central, computer-based randomisation program in a ratio of 1:1 in the non-severe category and 1:1:1 in the severe category. BLINDING (MASKING): This is an open labelled study i.e. Study assigned treatment will be known to the research team, the investigators and participants. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Since it is an exploratory trial as COVID-19 being a new disease, all patients who came under the purview of the inclusion criteria within the study period (5 months duration of the recruitment period of the total 6 months duration of the study i.e. from the month of June, 2020 to October 2020) and who have consented for the study will be included. TRIAL STATUS: Protocol version:1.0 Recruitment start: June 3(rd), 2020 (Ongoing) Recruitment finish (expected): October 31(st), 2020 TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI): CTRI/2020/06/025575. Registration on 03 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Trials2020       LitCov and CORD-19
315Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicenter study in pediatric intensive care units in Spain  

BACKGROUND: Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. METHODS: A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. RESULTS: Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5–11.8) vs 3.4 years (IQR 0.4–9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5–8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. CONCLUSIONS: MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients.

Crit Care2020       LitCov and CORD-19
316Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus  

Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells(1,2). Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2)(3,4), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.

Nature2003       CORD-19
317Surviving SARS and living through COVID-19: Healthcare worker mental health outcomes and insights for coping  

OBJECTIVE: Explore how previous work during the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak affects the psychological response of clinical and non-clinical healthcare workers (HCWs) to the current COVID-19 pandemic. METHODS: A cross-sectional, multi-centered hospital online survey of HCWs in the Greater Toronto Area, Canada. Mental health outcomes of HCWs who worked during the COVID-19 pandemic and the SARS outbreak were assessed using Impact of Events—Revised scale (IES-R), Generalized Anxiety Disorder scale (GAD-7), and Patient Health Questionnaire (PHQ-9). RESULTS: Among 3852 participants, moderate/severe scores for symptoms of post- traumatic stress disorder (PTSD) (50.2%), anxiety (24.6%), and depression (31.5%) were observed among HCWs. Work during the 2003 SARS outbreak was reported by 1116 respondents (29.1%), who had lower scores for symptoms of PTSD (P = .002), anxiety (P < .001), and depression (P < .001) compared to those who had not worked during the SARS outbreak. Multivariable logistic regression analysis showed non-clinical HCWs during this pandemic were at higher risk of anxiety (OR, 1.68; 95% CI, 1.19–2.15, P = .01) and depressive symptoms (OR, 2.03; 95% CI, 1.34–3.07, P < .001). HCWs using sedatives (OR, 2.55; 95% CI, 1.61–4.03, P < .001), those who cared for only 2–5 patients with COVID-19 (OR, 1.59; 95% CI, 1.06–2.38, P = .01), and those who had been in isolation for COVID-19 (OR, 1.36; 95% CI, 0.96–1.93, P = .05), were at higher risk of moderate/severe symptoms of PTSD. In addition, deterioration in sleep was associated with symptoms of PTSD (OR, 4.68, 95% CI, 3.74–6.30, P < .001), anxiety (OR, 3.09, 95% CI, 2.11–4.53, P < .001), and depression (OR 5.07, 95% CI, 3.48–7.39, P < .001). CONCLUSION: Psychological distress was observed in both clinical and non-clinical HCWs, with no impact from previous SARS work experience. As the pandemic continues, increasing psychological and team support may decrease the mental health impacts.

PLoS One2021       LitCov and CORD-19
318A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial  

OBJECTIVES: Primary objective: to evaluate the efficacy of melatonin as a prophylactic treatment on prevention of symptomatic SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. To evaluate the efficacy of melatonin as a prophylactic treatment on prevention of asymptomatic SARS-CoV-2 infection. To evaluate the efficacy of melatonin to prevent the development of severe COVID-19 in the participants enrolled in this study who develop SARS-CoV-2 infection along the trial. To evaluate the duration of COVID-19 symptoms in participants receiving melatonin before the infection. To evaluate seroconversion timing post-symptom onset. Exploratory objectives: To compare severity of COVID-19 between men and women. To evaluate the influence of sleep and diet on prevention from SARS-CoV-2 infection. To evaluate the effect of melatonin on the incidence and characteristics of lymphopenia and increase of inflammatory cytokines related to COVID-19. TRIAL DESIGN: This is a two-arm parallel randomised double-blind controlled trial to evaluate the efficacy of melatonin versus placebo in the prophylaxis of coronavirus disease 2019 among healthcare workers. PARTICIPANTS: Male or female participants ≥ 18 and ≤ 80 years of age. Healthcare workers from the public and private Spanish hospital network at risk of SARS-CoV 2 infection. Not having a previous COVID19 diagnosis. Understanding the purpose of the trial and not having taken any pre-exposure prophylaxis (PrEP) including HIV PrEP from March 1(st) 2020 until study enrolment. Having a negative SARS-CoV 2 reverse-transcription PCR (RT-PCR) result or a negative serologic rapid test (IgM/IgG) result before randomization. Premenopausal women must have a negative urinary pregnancy test in the 7 days before starting the trial treatment. Premenopausal women and males with premenopausal couples must commit to using a high efficiency anticonceptive method. HIV infection. Active hepatitis B infection. Renal failure (CrCl < 60 mL/min/1.73 m2) or need for hemodialysis. Osteoporosis. Myasthenia gravis. Pre-existent maculopathy. Retinitis pigmentosa. Bradycardia (less than 50 bpm). Weight less than 40 Kg. Participant with any immunosuppressive condition or hematological disease. Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days including: azithromycin, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone. Hereditary intolerance to galactose, Lapp lactase deficiency or glucose or galactose malabsorption. Treatment with fluvoxamine. Treatment with benzodiazepines or benzodiazepine analogues such as zolpidem, zopiclone or zaleplon. Pregnancy. Breastfeeding. History of potentially immune derived diseases such as: lupus, Crohn's disease, ulcerative colitis, vasculitis or rheumatoid arthritis. Insulin-dependent diabetes mellitus. Known history of hypersensitivity to the study drug or any of its components. Patients that should not be included in the study at the judgment of the research team. Participants will be recruited from the following eight hospitals in Madrid, Spain: Hospital Universitario La Paz, Hospital Ramón y Cajal, Hospital Infanta Sofía, Hospital 12 de Octubre, Hospital Clínico San Carlos, Hospital Central de la defensa Gómez Ulla,Hospital de La Princesa and Hospital Infanta Leonor. INTERVENTION AND COMPARATOR: Experimental: Melatonin (Circadin®, Exeltis Healthcare, Spain): 2 mg of melatonin orally before bedtime for 12 weeks. Comparator: Identical looking placebo (Laboratorios Liconsa, Spain) orally before bedtime for 12 weeks. MAIN OUTCOMES: Number of SARS-CoV-2 (COVID-19) symptomatic infections confirmed by polymerase chain reaction (PCR) test or serologic test or according to each centre diagnosis protocol. Primary outcome will be measured until the end of treatment for each participant (until the date of the last dose taken by each patient). RANDOMISATION: Patients who meet all inclusion and no exclusion criteria will be randomised, stratified by centres, sex and age (<50 and ≥ 50 years old). The randomisation sequence was created using SAS version 9.4 statistical software (procedure ‘PROC PLAN’) with a 1:1 allocation. No randomisation seed was specified. The randomisation seed was generated taking the hour of the computer where the program was executed. Randomization will be done centrally through the electronic system RedCAP® in order to conceal the sequence until interventions are assigned BLINDING (MASKING): Participants, caregivers, and those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 450 participants are planned to be enrolled in this clinical trial, 225 in the experimental arm and 225 in the placebo arm. TRIAL STATUS: Protocol version 3.0, 17th of April 2020. Recruitment ongoing. First participant was recruited on the 21st of April 2020. The final participant is anticipated to be recruited on the 31st of May 2020. As of May 18th, 2020, a total of 312 participants have been enrolled (154 at Hospital La Paz, 85 at Hospital Infanta Sofía and 73 at Hospital 12 de Octubre). TRIAL REGISTRATION: EU Clinical Trials Register: 2020-001530-35; Date of trial registration: 13th of April 2020; https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001530-35/ES 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.

Trials2020       LitCov and CORD-19
319Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review  


Cochrane Database Syst Rev2020       LitCov and CORD-19
320Vaccination coverage among COVID-19 prevention and control management teams at primary healthcare facilities in China and their attitudes towards COVID-19 vaccine: a cross-sectional online survey  

OBJECTIVE: To investigate the COVID-19 vaccination coverage rate and differences among various COVID-19 prevention primary healthcare (PHC) facilities in China and understand their attitudes towards COVID-19 vaccine. These findings are helpful to provide important suggestions to further improve national COVID-19 vaccination rate. DESIGN: A nationwide cross-sectional online survey was designed and conducted among COVID-19 prevention and control management teams at PHC facilities in mainland China. In the self-designed questionnaires, each subject was asked to evaluate on a 1–10 scale (10=extremely important/acceptable/influential) the COVID-19 vaccination importance, acceptance and factors related to vaccine hesitancy. SETTING: Subjects from 31 provinces and autonomous regions including minorities across mainland China were invited to complete the questionnaire between 22 February 2021 and 2 March 2021. PARTICIPANTS: Were selected by multistage stratified sampling, 998 valid questionnaires (valid rate 99.11%) were collected. The respondents were divided into group A (≤5 respondents within each PHC facility, n(1)=718) and group B (>5 respondents within each PHC facility, n(2)=280). OUTCOME MEASURES: Survey on vaccination rate and attitude towards COVID-19 vaccine included the following: (1) if the subjects think the vaccination is important in containment of COVID-19 pandemic (1–10 scale, 10=extremely important), (2) if they would accept COVID-19 vaccine (1–10 scale, 10=extremely acceptable) and (3) their opinions on 7 factors possibly related to vaccine hesitancy (1–10 scale, 10=extremely influential). All the items were designed based on the previous expert interviews. RESULTS: Our results showed vaccination rate was greater in group A (85.93%) than in group B (66.43%) (p<0.001). Detailed analyses revealed that in group A, male members were twice as likely to get vaccinated as compared with female members (adjusted OR (aOR): 2.07; 95% CI: 1.26 to 3.43, p=0.004). In group B, those who were at or under the median age had twice the odds of vaccination coverage compared with those who were over the median age (aOR: 2.29; 95% CI: 1.22 to 4.33, p=0.010). In addition, those who were specialised in traditional Chinese medicine were less likely to get vaccinated against COVID-19 compared with those who were specialised in general medicine, with the aOR: 0.10 (95% CI: 0.01 to 0.83, p=0.033). By analysing the factors that influenced the vaccination attitudes among the 998 respondents, we found no significant difference between the vaccinated and unvaccinated participants. However, further detailed analyses found that team members with undergraduate college education were less likely to score higher in COVID-19 vaccination importance than those with technical secondary school education (aOR: 0.35; 95% CI: 0.13 to 0.93, p=0.035); Furthermore, those with non-medical job titles had nearly twice the odds of giving a higher score for the uncertainty of vaccine efficacy compared with those with junior medical titles (aOR: 1.70; 95% CI: 1.02 to 2.85, p=0.016). Team members with a non-medical title were more likely to give a higher score for advice on social sources compared with those with a junior medical title (aOR: 1.70; 95% CI: 1.02 to 2.85, p=0.042). CONCLUSION: In PHC facilities, although there was a higher COVID-19 vaccination rate among COVID-19 prevention and control teams, some subgroups with different descriptive characters showed negative attitudes towards COVID-19 vaccination. Because primary care workers in China are highly expected to receive the vaccination, and support and educate the public for COVID-19 vaccination. Thus, it is important and necessary to continue to educate them about their vaccination concerns and change their attitudes towards vaccination. Our findings are highly beneficial for designing public vaccination education strategies.

BMJ Open2022       LitCov and CORD-19
321High prevalence of SARS-CoV-2 infection among symptomatic healthcare workers in a large university tertiary hospital in São Paulo, Brazil  

BACKGROUND: Brazil became the epicenter of the COVID-19 pandemic in Latin America since May 2020, reporting the highest number of cases and deaths in the region. Healthcare workers (HCWs) are at increased risk of SARS-CoV-2 infection, experiencing a significant burden from COVID-19. Identifying and understanding the clinical characteristics and risk factors associated with infection are of paramount importance to inform screening strategies and infection control practices in this scenario. The aims of this study were to investigate the prevalence and clinical characteristics of HCWs with COVID-19 symptoms. METHODS: Between March 21st and May 22nd, 2020 a cross-sectional study was performed in a tertiary university hospital in São Paulo. Prevalence of SARS-CoV-2 infection among HCWs with COVID-19 symptoms was determined by RT-PCR testing on nasopharyngeal and oropharyngeal samples. Participants were asked to complete an electronic structured questionnaire including clinical and demographic data. RESULTS: Overall, 125 (42.37%) of 295 symptomatic HCWs tested positive for SARS-CoV-2. Over the 10-week study period, positivity rates varied from 22.2% (95% CI 15.9–60.3%) in the second week to 55.9% (95% CI 43.2–68.6%) in the sixth week, reaching a plateau (38–46%) thereafter. Median (SD) age was 34.2 (9.9) years and 205 (69.5%) were female. We did not find significant differences in the prevalence of the most commonly reported underlying medical condition among healthcare workers that tested positive or negative for SARS-CoV-2 infection. After multivariable analysis, using logistic regression, anosmia (adjusted OR 4.4 95% CI 2.21–8.74) and ocular pain (adjusted OR 1.95 95% CI 1.14–3.33) were the only symptoms independently associated with positivity for SARS-CoV-2 infection. Follow-up information on clinical outcomes showed that 9 (7.2%) HCWs were hospitalized (seven were male) and 2 (1.6%) died. CONCLUSIONS: The findings of this study confirmed the high burden of SARS-CoV-2 infection among healthcare workers in the hardest hit city by the pandemic in Latin America. Anosmia and ocular pain were symptoms independently associated with COVID-19 diagnosis. In low and middle-income countries, where limited availability of tests is frequent, these findings may contribute to optimize a targeted symptom-oriented screening strategy.

BMC Infect Dis2020       LitCov and CORD-19
322Prospective Assessment of SARS-CoV-2 Seroconversion (PASS) study: an observational cohort study of SARS-CoV-2 infection and vaccination in healthcare workers  

BACKGROUND: SARS-CoV-2 is a recently emerged pandemic coronavirus (CoV) capable of causing severe respiratory illness. However, a significant number of infected people present as asymptomatic or pauci-symptomatic. In this prospective assessment of at-risk healthcare workers (HCWs) we seek to determine whether pre-existing antibody or T cell responses to previous seasonal human coronavirus (HCoV) infections affect immunological or clinical responses to SARS-CoV-2 infection or vaccination. METHODS: A cohort of 300 healthcare workers, confirmed negative for SARS-CoV-2 exposure upon study entry, will be followed for up to 1 year with monthly serology analysis of IgM and IgG antibodies against the spike proteins of SARS-CoV-2 and the four major seasonal human coronavirus - HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63. Participants will complete monthly questionnaires that ask about Coronavirus Disease 2019 (COVID-19) exposure risks, and a standardized, validated symptom questionnaire (scoring viral respiratory disease symptoms, intensity and severity) at least twice monthly and any day when any symptoms manifest. SARS-CoV-2 PCR testing will be performed any time participants develop symptoms consistent with COVID-19. For those individuals that seroconvert and/or test positive by SARS-CoV-2 PCR, or receive the SARS-CoV-2 vaccine, additional studies of T cell activation and cytokine production in response to SARS-CoV-2 peptide pools and analysis of Natural Killer cell numbers and function will be conducted on that participant’s cryopreserved baseline peripheral blood mononuclear cells (PBMCs). Following the first year of this study we will further analyze those participants having tested positive for COVID-19, and/or having received an authorized/licensed SARS-CoV-2 vaccine, quarterly (year 2) and semi-annually (years 3 and 4) to investigate immune response longevity. DISCUSSION: This study will determine the frequency of asymptomatic and pauci-symptomatic SARS-CoV-2 infection in a cohort of at-risk healthcare workers. Baseline and longitudinal assays will determine the frequency and magnitude of anti-spike glycoprotein antibodies to the seasonal HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63, and may inform whether pre-existing antibodies to these human coronaviruses are associated with altered COVID-19 disease course. Finally, this study will evaluate whether pre-existing immune responses to seasonal HCoVs affect the magnitude and duration of antibody and T cell responses to SARS-CoV-2 vaccination, adjusting for demographic covariates. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-021-06233-1.

BMC Infect Dis2021       LitCov and CORD-19
323What Have We Learnt About the Sourcing of Personal Protective Equipment During Pandemics? Leadership and Management in Healthcare Supply Chain Management: A Scoping Review  

Introduction: During the ongoing COVID-19 pandemic there have been much publicised shortages in Personal Protective Equipment for frontline health care workers, from masks to gowns. Recent previous airborne pandemics provide an opportunity to learn how to effectively lead and manage supply chains during crisis situations. Identifying and plotting this learning against time will reveal what has been learnt, when and, significantly, what can be learnt for the future. Aims: (i) To identify the temporal trajectory of leadership and management learning in health supply chain management through pandemics and (ii) to identify leadership and management lessons to enable the resilient supply of key items such as PPE in future pandemics. Methods: We undertook a scoping review in line with PRISMA (scoping review extension) searching Business Source Premier, Health Business Elite, Medline, ProQuest Business Collection and PubMed. Search terms were focused on recent airborne pandemics (SARS; Ebola; Zika virus; H1N1 swine flu, COVID-19), supply chain management, PPE, leadership, learning, inhibitors and facilitators and resilience e.g., SARS AND supply chain(*) AND (“personal protective equipment” OR PPE) (leaders(*) OR manage(*)) Titles and abstracts were downloaded to Endnote and duplicates removed. Two authors independently screened all of the titles and abstracts. Inclusion criteria focused on leadership and management in health supply chains during pandemics, peer reviewed or grey literature (either from business journals or reports): exclusion criteria included not in English and not focused on a named pandemic. Once interrater reliability was assured, authors completed a title and abstract screening independently. Ten percent of the resultant full text articles were screened by both authors, once agreement was reached the full text articles were screened independently noting reasons for exclusion. A data extraction tool was designed to capture findings from the final articles included in the review. Results/Discussion: We found 92 articles and, after screening, included 30 full text articles. The majority were focused on COVID-19 (N = 27) and most were from the USA (N = 13). We identified four themes related to leadership and management of pandemic PPE supply chains, (i) Leadership and management learning for pandemic PPE supply chain management, (ii) Inhibitors of PPE supply chain resilience during a pandemic, (iii) Facilitators employed to manage the immediate impacts of PPE supply chain demands during a pandemic,and (iv) Facilitators proposed to ensure longer term resilience of PPE supply chains during pandemics Our study suggests there has been limited leadership and management learning for PPE supply chains from previous pandemics, however there has been extensive learning through the COVID-19 pandemic. Lessons included the importance of planning, the significance of collaboration and relationship building. Resilience of PPE supply chains was reported to be dependent on multiple levels from individuals to organisation level and also interdependent on (i) sustainability, (ii) the practise of PPE and (iii) long term environmental impact of PPE suggesting the need, long term, to move to a circular economy approach.

Front Public Health2021       LitCov and CORD-19
324How has COVID-19 affected mental health nurses and the delivery of mental health nursing care in the UK? Results of a mixed-methods study  

WHAT IS KNOWN ON THE SUBJECT? During the COVID‐19 pandemic, there has been research considering the impact on medical healthcare professionals and the mental health needs of the general population. However, limited focus has been placed on mental health services or mental health staff providing care in the community and in hospitals. While nurses make up the largest section of the mental health workforce in the UK, the impact that this pandemic has had on their work has been largely ignored. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE? This paper provides a unique insight into the experiences and impact that the COVID‐19 pandemic has had on mental health nurses across a range of community and inpatient settings to understand what has changed in their work and the care they can and do provide during this crisis. This includes exploring how services have changed, the move to remote working, the impact of the protective equipment crisis on nurses and the difficult working conditions facing those in inpatient settings where there is minimal guidance provided. WHAT ARE THE IMPLICATIONS FOR PRACTICE? By understanding the impact the pandemic has had on mental health nursing care, we can understand the gaps in guidance that exist, the challenges being faced and the impact the crisis has had on care for mental health service users. By doing so, we can plan for the ongoing nature of this pandemic and the aftermath that the crisis may leave for our service users and workforce alike. ABSTRACT: INTRODUCTION: While evidence has emerged concerning the impact of COVID‐19 on the general population and the challenges facing health services, much less is known regarding how the pandemic has directly affected the delivery of mental health nursing care. AIM: This paper aimed to explore how COVID‐19 has affected the ability of mental health nurses to deliver care in community and inpatient mental health services in the UK. METHOD: We investigated staff reports regarding the impact of the COVID‐19 pandemic on mental healthcare and mental health service users in the UK, using a mixed‐methods online survey. A total of 897 nurses across a range of inpatient and community settings participated. DISCUSSION: Key themes within the data explore the following: new ways of working; remote working; risks of infection/infection control challenges; and the impact on service users. Targeted guidelines are required to support mental health nurses providing care and support during a pandemic to people in severe mental distress, often in unsuitable environments. IMPLICATIONS FOR PRACTICE: Service developments need to occur alongside tailored guidance and support for staff welfare supported by clear leadership. These findings identify areas requiring attention and investment to prepare for future crises and the consequences of the pandemic.

J Psychiatr Ment Health Nurs2021       LitCov and CORD-19
325SARS-CoV-2 infection in the first trimester and the risk of early miscarriage: a UK population-based prospective cohort study of 3041 pregnancies conceived during the pandemic  

STUDY QUESTION: Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week’s gestation? SUMMARY ANSWER: Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage. WHAT IS KNOWN ALREADY: Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection. STUDY DESIGN, SIZE, DURATION: This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week’s gestation at the time of recruitment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: ‘presumed infected’, i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; ‘uncertain’, i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and ‘presumed uninfected’, i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7–9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8–11). Seventy-seven women were in the ‘presumed infected’ group (77/3041, 2.5% [95% CI 2–3]), 295/3041 were in the uncertain group (9.7% [95% CI 9–11]) and the rest in the ‘presumed uninfected’ (87.8%, 2669/3041 [95% CI 87–89]). The rate of early miscarriage was 14% in the ‘presumed infected’ group, 5% in the ‘uncertain’ and 8% in the ‘presumed uninfected’ (11/77 [95% CI 6–22] versus 15/295 [95% CI 3–8] versus 212/2669 [95% CI 7–9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the ‘presumed infected’ group (relative rate 1.7, 95% CI 1.0–3.0, P = 0.06). LIMITATIONS, REASONS FOR CAUTION: We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the ‘presumed uninfected’ and ‘uncertain’ groups may have had asymptomatic infections. The number of ‘presumed infected’ in our study was low and therefore the study was relatively underpowered. WIDER IMPLICATIONS OF THE FINDINGS: This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Hum Reprod2022       LitCov and CORD-19
326The SARS-CoV-2 Ivermectin Navarra-ISGlobal Trial (SAINT) to Evaluate the Potential of Ivermectin to Reduce COVID-19 Transmission in low risk, nonsevere COVID-19 patients in the first 48 hours after symptoms onset: A structured summary of a study protocol for a randomized control pilot trial  

OBJECTIVES: The primary objective is to determine the efficacy of a single dose of ivermectin, administered to low risk, non-severe COVID-19 patients in the first 48 hours after symptom onset to reduce the proportion of patients with detectable SARS-CoV-2 RNA by Polymerase Chain Reaction (PCR) test from nasopharyngeal swab at day 7 post-treatment. 1. To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the nasopharyngeal swab at day 7 post treatment. 2. To assess the efficacy of ivermectin to improve symptom progression in treated patients. 3. To assess the proportion of seroconversions in treated patients at day 21. 4. To assess the safety of ivermectin at the proposed dose. 5. To determine the magnitude of immune response against SARS-CoV-2. 6. To assess the early kinetics of immunity against SARS-CoV-2. TRIAL DESIGN: SAINT is a single centre, double-blind, randomized, placebo-controlled, superiority trial with two parallel arms. Participants will be randomized to receive a single dose of 400 μg/kg ivermectin or placebo, and the number of patients in the treatment and placebo groups will be the same (1:1 ratio). PARTICIPANTS: The population for the study will be patients with a positive nasopharyngeal swab PCR test for SARS-CoV-2, with non-severe COVID-19 disease, and no risk factors for progression to severity. Vulnerable populations such as pregnant women, minors (i.e.; under 18 years old), and seniors (i.e.; over 60 years old) will be excluded. Inclusion criteria: 1. Patients diagnosed with COVID-19 in the emergency room of the Clínica Universidad de Navarra (CUN) with a positive SARS-CoV-2 PCR. 2. Residents of the Pamplona basin (“Cuenca de Pamplona”). 3. The patient must be between the ages of 18 and 60 years of age. 4. Negative pregnancy test for women of child bearing age*. 5. The patient or his/her representative, has given informed consent to participate in the study. 6. The patient should, in the PI's opinion, be able to comply with all the requirements of the clinical trial (including home follow up during isolation). Exclusion criteria: 1. Known history of ivermectin allergy. 2. Hypersensitivity to any component of ivermectin. 3. Diagnosed by the attending physician. Identified in a chest X-ray. 4. Fever or cough present for more than 48 hours. 5. Positive IgG against SARS-CoV-2 by rapid diagnostic test. 6. Age under 18 or over 60 years. 7. Immunosuppression. Chronic Obstructive Pulmonary Disease. Diabetes. Hypertension. Obesity. Acute or chronic renal failure. History of coronary disease. History of cerebrovascular disease. Current neoplasm. 8. Recent travel history to countries that are endemic for Loa loa (Angola, Cameroon, Central African Republic, Chad, Democratic Republic of Congo, Ethiopia, Equatorial, Guinea, Gabon, Republic of Congo, Nigeria and Sudan). 9. Current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, indinavir, ritonavir or cobicistat. Use of critical CYP3A4 substrate drugs such as warfarin. *Women of child bearing age may participate if they use a safe contraceptive method for the entire period of the study and at least one month afterwards. A woman is considered to not have childbearing capacity if she is post-menopausal (minimum of 2 years without menstruation) or has undergone surgical sterilization (at least one month before the study). The trial is currently planned at a single center, Clínica Universidad de Navarra, in Navarra (Spain), and the immunology samples will be analyzed at the Barcelona Institute for Global Health (ISGlobal), in Barcelona (Spain). Participants will be recruited by the investigators at the emergency room and/or COVID-19 area of the CUN. They will remain in the trial for a period of 28 days at their homes since they will be patients with mild disease. In the interest of public health and to contain transmission of infection, follow-up visits will be conducted in the participant's home by a clinical trial team comprising nursing and medical members. Home visits will assess clinical and laboratory parameters of the patients. INTERVENTION AND COMPARATOR: Ivermectin will be administered to the treatment group at a 400μg/Kg dose (included in the EU approved label of Stromectol and Scabioral). The control group will receive placebo. There is no current data on the efficacy of ivermectin against the virus in vivo, therefore the use of placebo in the control group is ethically justified. MAIN OUTCOMES: Primary Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 post-treatment. : 1. Mean viral load as determined by PCR cycle threshold (Ct) at baseline and on days 4, 7, 14, and 21. 2. Proportion of patients with fever and cough at days 4, 7, 14, and 21 as well as proportion of patients progressing to severe disease or death during the trial. 3. Proportion of patients with seroconversion at day 21. 4. Proportion of drug-related adverse events during the trial. 5. Median levels of IgG, IgM, IgA measured by Luminex, frequencies of innate and SARS-CoV-2-specific T cells assessed by flow cytometry, median levels of inflammatory and activation markers measured by Luminex and transcriptomics. 6. Median kinetics of IgG, IgM, IgA levels during the trial, until day 28. RANDOMISATION: Eligible patients will be allocated in a 1:1 ratio using a randomization list generated by the trial statistician using blocks of four to ensure balance between the groups. A study identification code with the format “SAINT-##” (##: from 01 to 24) will be generated using a sequence of random numbers so that the randomization number does not match the subject identifier. The sequence and code used will be kept in an encrypted file accessible only to the trial statistician. A physical copy will be kept in a locked cabinet at the CUN, accessible only to the person administering the drug who will not enrol or attend to patient care. A separate set of 24 envelopes for emergency unblinding will be kept in the study file. BLINDING (MASKING): The clinical trial team and the patients will be blinded. The placebo will not be visibly identical, but it will be administered by staff not involved in the clinical care or participant follow up. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is 24 patients: 12 participants will be randomised to the treatment group and 12 participants to the control group. TRIAL STATUS: Current protocol version: 1.0 dated 16 of April 2020. Recruitment is envisioned to begin by May 14th and end by June 14th. TRIAL REGISTRATION: EudraCT number: 2020-001474-29, registered April 1(st). Clinicaltrials.gov: submitted, pending number 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.

Trials2020       LitCov and CORD-19
327Associations of Mental Health and Personal Preventive Measure Compliance With Exposure to COVID-19 Information During Work Resumption Following the COVID-19 Outbreak in China: Cross-Sectional Survey Study  

BACKGROUND: Risk and crisis communication plays an essential role in public health emergency responses. The COVID-19 pandemic has triggered spontaneous and intensive media attention, which has affected people’s adoption of personal preventive measures and their mental health. OBJECTIVE: The aim of this study was to investigate the associations between exposure to COVID-19–specific information and mental health (depression and sleep quality) and self-reported compliance with personal preventive measures (face mask wearing and hand sanitizing). We also tested whether these associations were moderated by thoughtful consideration of the veracity of the information to which people were exposed. METHODS: A cross-sectional, closed web-based survey was conducted among a sample of 3035 factory workers at the beginning of work resumption following the COVID-19 outbreak in Shenzhen, China. A stratified two-stage cluster sampling design was used for recruitment. Multivariate linear and logistic regression models were used for the analyses. RESULTS: The prevalence of probable moderate-to-severe depression was 170/3035 (5.6%), while that of good or excellent sleep quality was 2110/3035 (69.5%). The prevalence of self-reported consistent face mask wearing in public places was 2903/3035 (95.7%), while that of sanitizing hands every time after returning from public spaces or touching public installations was 2151/3035 (70.9%). Of the 3035 respondents, 1013 to 1638 (33.3% to 54.0%) reported >1 hour of daily exposure to COVID-19–specific information through web-based media and television. After controlling for significant background variables, higher information exposure via television and via newspapers and magazines was associated with better sleep quality and higher compliance with hand sanitizing. Higher exposure via unofficial web-based media was associated with higher compliance with hand sanitizing but was also associated with higher depressive symptoms. In contrast, higher exposure through face-to-face communication was associated with higher depressive symptoms, worse sleep quality, and lower compliance with hand sanitizing. Exposure to information about positive outcomes for patients with COVID-19, development of vaccines and effective treatments, and heroic stories about frontline health care workers were associated with both better mental health and higher compliance with preventive measures. Higher overall information exposure was associated with higher depressive symptoms among participants who were less likely to carefully consider the veracity of the information to which they were exposed; it was also associated with better sleep quality among people who reported more thoughtful consideration of information veracity. CONCLUSIONS: This study provides empirical evidence of how the amount, sources, and contents of information to which people were exposed influenced their mental health and compliance with personal preventive measures at the initial phase of work resumption in China. Thoughtful consideration of information quality was found to play an important moderating role. Our findings may inform strategic risk communication by government and public health authorities during the COVID-19 pandemic.

J Med Internet Res2020       LitCov and CORD-19
328Top Concerns of Tweeters During the COVID-19 Pandemic: Infoveillance Study  

BACKGROUND: The recent coronavirus disease (COVID-19) pandemic is taking a toll on the world’s health care infrastructure as well as the social, economic, and psychological well-being of humanity. Individuals, organizations, and governments are using social media to communicate with each other on a number of issues relating to the COVID-19 pandemic. Not much is known about the topics being shared on social media platforms relating to COVID-19. Analyzing such information can help policy makers and health care organizations assess the needs of their stakeholders and address them appropriately. OBJECTIVE: This study aims to identify the main topics posted by Twitter users related to the COVID-19 pandemic. METHODS: Leveraging a set of tools (Twitter’s search application programming interface (API), Tweepy Python library, and PostgreSQL database) and using a set of predefined search terms (“corona,” “2019-nCov,” and “COVID-19”), we extracted the text and metadata (number of likes and retweets, and user profile information including the number of followers) of public English language tweets from February 2, 2020, to March 15, 2020. We analyzed the collected tweets using word frequencies of single (unigrams) and double words (bigrams). We leveraged latent Dirichlet allocation for topic modeling to identify topics discussed in the tweets. We also performed sentiment analysis and extracted the mean number of retweets, likes, and followers for each topic and calculated the interaction rate per topic. RESULTS: Out of approximately 2.8 million tweets included, 167,073 unique tweets from 160,829 unique users met the inclusion criteria. Our analysis identified 12 topics, which were grouped into four main themes: origin of the virus; its sources; its impact on people, countries, and the economy; and ways of mitigating the risk of infection. The mean sentiment was positive for 10 topics and negative for 2 topics (deaths caused by COVID-19 and increased racism). The mean for tweet topics of account followers ranged from 2722 (increased racism) to 13,413 (economic losses). The highest mean of likes for the tweets was 15.4 (economic loss), while the lowest was 3.94 (travel bans and warnings). CONCLUSIONS: Public health crisis response activities on the ground and online are becoming increasingly simultaneous and intertwined. Social media provides an opportunity to directly communicate health information to the public. Health systems should work on building national and international disease detection and surveillance systems through monitoring social media. There is also a need for a more proactive and agile public health presence on social media to combat the spread of fake news.

J Med Internet Res2020       LitCov and CORD-19
329The impacts of coping style and perceived social support on the mental health of undergraduate students during the early phases of the COVID-19 pandemic in China: a multicenter survey  

BACKGROUND: An increasing number of undergraduate students in China have been reported to have psychological problems. In response to the COVID-19 pandemic, a series of preventive and control measures were implemented, which undoubtedly worsened their psychological health. Coping style and social support were probably important factors that affected the psychological well-being of undergraduate students during the pandemic. This study aimed to explore the effects of coping style and perceived social support on the psychological well-being of college students and relevant risk factors. METHODS: This cross-sectional study was performed in February and March of 2020 by distributing an online questionnaire among undergraduate students from seven geographical regions across China. The questionnaire included sociodemographic information; the 21-item Depression, Anxiety and Stress Scale (DASS-21); the Perceived Social Support Scale (PSSS); and the Simplified Coping Style Questionnaire (SCSQ). For the analyses, t-tests, one-way analysis of variance (ANOVA), the Kruskal–Wallis test and multiple linear regression were utilized. The level of significance was set at P < 0.05. RESULTS: Among 3113 college students, the rates of anxiety, depression and stress symptoms were 13.3, 15.4 and 6.8%, respectively. Increased rates of current smoking and drinking (5.5 and 25.2%, respectively) among undergraduates were identified. The results indicated that the PSSS subscales and SCSQ subscales were significantly associated with DASS-21 scores (P < 0.001). Multiple linear regression analysis showed that active coping style and family support were protective factors while passive coping style could aggravate psychological problems among participants (P < 0.001). CONCLUSIONS: A remarkable number of college students adopted passive coping strategies to cope with negative feelings, such as smoking and drinking, which were detrimental to their mental health. In contrast, active coping strategies helped improve their psychological well-being. Moreover, family support was particularly important for maintaining their mental health and ameliorating mental health challenges in this major health crisis. Consequently, suitable psychointervention, routine screening for risk behaviors, and provision of further social support are needed for undergraduate students in the COVID-19 pandemic or other emergency public health events.

BMC Psychiatry2021       LitCov and CORD-19
330Real-world serological responses to extended-interval and heterologous COVID-19 mRNA vaccination in frail, older people (UNCoVER): an interim report from a prospective observational cohort study  

BACKGROUND: The use of COVID-19 vaccines has been prioritised to protect the most vulnerable—notably, older people. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been used. However, the effectiveness of these strategies in frail, older people are unknown. We aimed to assess the antigenicity of mRNA-based COVID-19 vaccines in frail, older people in a real-world setting, with a rationed interval dosing of 16 weeks between the prime and boost doses. METHODS: This prospective observational cohort study was done across 12 long-term care facilities of the Montréal Centre-Sud – Integrated University Health and Social Services Centre in Montréal, Québec, Canada. Under a rationing strategy mandated by the provincial government, adults aged 65 years and older residing in long-term care facilities in Québec, Canada, with or without previously documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. All older residents in participating long-term care facilities who received two vaccine doses were eligible for inclusion in this study. Participants were enrolled from Dec 31, 2020, to Feb 16, 2021, and data were collected up to June 9, 2021. Clinical data and blood samples were serially collected from participants at the following timepoints: at baseline, before the first dose; 4 weeks after the first dose; 6–10 weeks after the first dose; 16 weeks after the first dose, up to 2 days before administration of the second dose; and 4 weeks after the second dose. Sera were tested for SARS-CoV-2-specific IgG antibodies (to the trimeric spike protein, the receptor-binding domain [RBD] of the spike protein, and the nucleocapsid protein) by automated chemiluminescent ELISA. Two cohorts were used in this study: a discovery cohort, for which blood samples were collected before administration of the first vaccine dose and longitudinally thereafter; and a confirmatory cohort, for which blood samples were only collected from 4 weeks after the prime dose. Analyses were done in the discovery cohort, with validation in the confirmatory cohort, when applicable. FINDINGS: The total study sample consisted of 185 participants. 65 participants received two doses of mRNA-1273 (Spikevax; Moderna), 36 received two doses of BNT162b2 (Comirnaty; Pfizer–BioNTech), and 84 received mRNA-1273 followed by BNT162b2. In the discovery cohort, after a significant increase in anti-RBD and anti-spike IgG concentrations 4 weeks after the prime dose (from 4·86 log binding antibody units [BAU]/mL to 8·53 log BAU/mL for anti-RBD IgG and from 5·21 log BAU/mL to 8·05 log BAU/mL for anti-spike IgG), there was a significant decline in anti-RBD and anti-spike IgG concentrations until the boost dose (7·10 log BAU/mL for anti-RBD IgG and 7·60 log BAU/mL for anti-spike IgG), followed by an increase 4 weeks later for both vaccines (9·58 log BAU/mL for anti-RBD IgG and 9·23 log BAU/mL for anti-spike IgG). SARS-CoV-2-naive individuals showed lower antibody responses than previously infected individuals at all timepoints tested up to 16 weeks after the prime dose, but achieved similar antibody responses to previously infected participants by 4 weeks after the second dose. Individuals primed with the BNT162b2 vaccine showed a larger decrease in mean anti-RBD and anti-spike IgG concentrations with a 16-week interval between doses (from 8·12 log BAU/mL to 4·25 log BAU/mL for anti-RBD IgG responses and from 8·18 log BAU/mL to 6·66 log BAU/mL for anti-spike IgG responses) than did those who received the mRNA-1273 vaccine (two doses of mRNA-1273: from 8·06 log BAU/mL to 7·49 log BAU/mL for anti-RBD IgG responses and from 6·82 log BAU/mL to 7·56 log BAU/mL for anti-spike IgG responses; mRNA-1273 followed by BNT162b2: from 8·83 log BAU/mL to 7·95 log BAU/mL for anti-RBD IgG responses and from 8·50 log BAU/mL to 7·97 log BAU/mL for anti-spike IgG responses). No differences in antibody responses 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations. INTERPRETATION: Interim results of this ongoing longitudinal study show that among frail, older people, previous SARS-CoV-2 infection and the type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. In these cohorts of frail, older individuals with a similar age and comorbidity distribution, we found that serological responses were similar and clinically equivalent between the discovery and confirmatory cohorts. Homologous and heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following the second dose, supporting their interchangeability. FUNDING: Public Health Agency of Canada, Vaccine Surveillance Reference Group; and the COVID-19 Immunity Task Force. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Lancet Healthy Longev2022       LitCov and CORD-19
331Diagnostic Delays for Non-melanoma Skin Cancers in Renal Transplant Recipients during the COVID-19 Pandemic: What is Hiding Behind the Mask?  


Acta Dermatovenerol Croat2021       LitCov and CORD-19
332Spring in London with Covid-19: a personal view  


Med Leg J2020       LitCov and CORD-19
333Psychological distress surveillance and related impact analysis of hospital staff during the COVID-19 epidemic in Chongqing, China  

Background: Hospital staff are vulnerable and at high risk of novel coronavirus disease (COVID-19) infection. The aim of this study was to monitor the psychological distress in hospital staff and examine the relationship between the psychological distress and possible causes during the COVID-19 epidemic. Methods: An online survey was conducted from February 1 to February 14, 2020. Hospital staff from five national COVID-19 designated hospitals in Chongqing participated. Data collected included demographics and stress responses to COVID-19: 1) the impact of event scale to measure psychological stress reactions; 2) generalized anxiety disorder 7 to measure anxiety symptoms; 3) Patient Health Questionnaire 9 to measure depression symptoms; 4) Yale-Brown Obsessive-Compulsive Scale to measure obsessive-compulsive symptoms (OCS); and 5) Patient Health Questionnaire 15 to measure somatization symptoms. Multiple logistic regression analysis was used to identify factors that were correlated with psychological distress. Results: Hospital staff that participated in this study were identified as either doctors or nurses. A total of 456 respondents completed the questionnaires with a response rate of 91.2%. The mean age was 30.67 ± 7.48 years (range, 17 to 64 years). Of all respondents, 29.4% were men. Of the staff surveyed, 43.2% had stress reaction syndrome. The highest prevalence of psychological distress was OCS (37.5%), followed by somatization symptoms (33.3%), anxiety symptoms (31.6%), and depression symptoms (29.6%). Univariate analyses indicated that female subjects, middle aged subjects, subjects in the low income group, and subjects working in isolation wards were prone to experience psychological distress. Multiple logistic regression analysis showed “Reluctant to work or considered resignation” (odds ratio [OR], 5.192; 95%CI, 2.396–11.250; P < .001), “Afraid to go home because of fear of infecting family” (OR, 2.099; 95%CI, 1.299–3.391; P = .002) “Uncertainty about frequent modification of infection and control procedures” (OR, 1.583; 95%CI, 1.061–2.363; P = .025), and“Social support” (OR, 1.754; 95%CI, 1.041–2.956; P = .035) were correlated with psychological reactions. “Reluctant to work or considered resignation” and “Afraid to go home because of fear of infecting family” were associated with a higher risk of symptoms of Anxiety (OR, 3.622; 95% CI, 1.882–6.973; P < .001; OR, 1.803; 95% CI, 1.069–3.039; P = .027), OCS (OR, 5.241; 95% CI, 2.545–10.793; P < .001; OR, 1.999; 95% CI, 1.217–3.282; P = .006) and somatization (OR, 5.177; 95% CI, 2.595–10.329; P < .001; OR, 1.749; 95% CI, 1.051–2.91; P = .031). “Stigmatization and rejection in neighborhood because of hospital work”, “Reluctant to work or considered resignation” and “Uncertainty about frequent modification of infection and control procedures” were associated with a higher risk of symptoms of Depression(OR, 2.297; 95% CI, 1.138–4.637; P = .020; OR, 3.134; 95% CI, 1.635–6.006; P = .001; OR, 1.645; 95% CI, 1.075–2.517; P = .022). Conclusions: Hospital staff showed different prevalence of psychological distress during the COVID-19 epidemic. Our study confirmed the severity of negative psychological distress on hospital staff and identified factors associated with negative psychological distress that can be used to provide valuable information for psychological interventions to improve the mental health of vulnerable groups during the COVID-19 epidemic.

Compr Psychiatry2020       LitCov and CORD-19
334Characteristics and outcomes of patients with COVID-19 admitted to hospital and intensive care in the first phase of the pandemic in Canada: a national cohort study  

BACKGROUND: Clinical data on patients admitted to hospital with coronavirus disease 2019 (COVID-19) provide clinicians and public health officials with information to guide practice and policy. The aims of this study were to describe patients with COVID-19 admitted to hospital and intensive care, and to investigate predictors of outcome to characterize severe acute respiratory infection. METHODS: This observational cohort study used Canadian data from 32 selected hospitals included in a global multisite cohort between Jan. 24 and July 7, 2020. Adult and pediatric patients with a confirmed diagnosis of COVID-19 who received care in an intensive care unit (ICU) and a sampling of up to the first 60 patients receiving care on hospital wards were included. We performed descriptive analyses of characteristics, interventions and outcomes. The primary analyses examined in-hospital mortality, with secondary analyses of the length of hospital and ICU stay. RESULTS: Between January and July 2020, among 811 patients admitted to hospital with a diagnosis of COVID-19, the median age was 64 (interquartile range [IQR] 53–75) years, 495 (61.0%) were men, 46 (5.7%) were health care workers, 9 (1.1%) were pregnant, 26 (3.2%) were younger than 18 years and 9 (1.1%) were younger than 5 years. The median time from symptom onset to hospital admission was 7 (IQR 3–10) days. The most common symptoms on admission were fever, shortness of breath, cough and malaise. Diabetes, hypertension and cardiac, kidney and respiratory disease were the most common comorbidities. Among all patients, 328 received care in an ICU, admitted a median of 0 (IQR 0–1) days after hospital admission. Critically ill patients received treatment with invasive mechanical ventilation (88.8%), renal replacement therapy (14.9%) and extracorporeal membrane oxygenation (4.0%); 26.2% died. Among those receiving mechanical ventilation, 31.2% died. Age was an influential predictor of mortality (odds ratio per additional year of life 1.06, 95% confidence interval 1.03–1.09). INTERPRETATION: Patients admitted to hospital with COVID-19 commonly had fever, respiratory symptoms and comorbid conditions. Increasing age was associated with the development of critical illness and death; however, most critically ill patients in Canada, including those requiring mechanical ventilation, survived and were discharged from hospital.

CMAJ Open2021       LitCov and CORD-19
335Mathematical assessment of the impact of non-pharmaceutical interventions on curtailing the 2019 novel Coronavirus  

A pandemic of a novel Coronavirus emerged in December of 2019 (COVID-19), causing devastating public health impact across the world. In the absence of a safe and effective vaccine or antivirals, strategies for controlling and mitigating the burden of the pandemic are focused on non-pharmaceutical interventions, such as social-distancing, contact-tracing, quarantine, isolation, and the use of face-masks in public. We develop a new mathematical model for assessing the population-level impact of the aforementioned control and mitigation strategies. Rigorous analysis of the model shows that the disease-free equilibrium is locally-asymptotically stable if a certain epidemiological threshold, known as the reproduction number (denoted by [Formula: see text]), is less than unity. Simulations of the model, using data relevant to COVID-19 transmission dynamics in the US state of New York and the entire US, show that the pandemic burden will peak in mid and late April, respectively. The worst-case scenario projections for cumulative mortality (based on the baseline levels of anti-COVID non-pharmaceutical interventions considered in the study) decrease dramatically by 80% and 64%, respectively, if the strict social-distancing measures implemented are maintained until the end of May or June, 2020. The duration and timing of the relaxation or termination of the strict social-distancing measures are crucially-important in determining the future trajectory of the COVID-19 pandemic. This study shows that early termination of the strict social-distancing measures could trigger a devastating second wave with burden similar to those projected before the onset of the strict social-distancing measures were implemented. The use of efficacious face-masks (such as surgical masks, with estimated efficacy [Formula: see text] 70%) in public could lead to the elimination of the pandemic if at least 70% of the residents of New York state use such masks in public consistently (nationwide, a compliance of at least 80% will be required using such masks). The use of low efficacy masks, such as cloth masks (of estimated efficacy less than 30%), could also lead to significant reduction of COVID-19 burden (albeit, they are not able to lead to elimination). Combining low efficacy masks with improved levels of the other anti-COVID-19 intervention strategies can lead to the elimination of the pandemic. This study emphasizes the important role social-distancing plays in curtailing the burden of COVID-19. Increases in the adherence level of social-distancing protocols result in dramatic reduction of the burden of the pandemic, and the timely implementation of social-distancing measures in numerous states of the US may have averted a catastrophic outcome with respect to the burden of COVID-19. Using face-masks in public (including the low efficacy cloth masks) is very useful in minimizing community transmission and burden of COVID-19, provided their coverage level is high. The masks coverage needed to eliminate COVID-19 decreases if the masks-based intervention is combined with the strict social-distancing strategy.

Math Biosci2020       LitCov and CORD-19
336Different Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2 Infections  


Front Immunol2022       LitCov
337Effects of different types of written vaccination information on COVID-19 vaccine hesitancy in the UK (OCEANS-III): a single-blind, parallel-group, randomised controlled trial  

BACKGROUND: The effectiveness of the COVID-19 vaccination programme depends on mass participation: the greater the number of people vaccinated, the less risk to the population. Concise, persuasive messaging is crucial, particularly given substantial levels of vaccine hesitancy in the UK. Our aim was to test which types of written information about COVID-19 vaccination, in addition to a statement of efficacy and safety, might increase vaccine acceptance. METHODS: For this single-blind, parallel-group, randomised controlled trial, we aimed to recruit 15 000 adults in the UK, who were quota sampled to be representative. Participants were randomly assigned equally across ten information conditions stratified by level of vaccine acceptance (willing, doubtful, or strongly hesitant). The control information condition comprised the safety and effectiveness statement taken from the UK National Health Service website; the remaining conditions addressed collective benefit, personal benefit, seriousness of the pandemic, and safety concerns. After online provision of vaccination information, participants completed the Oxford COVID-19 Vaccine Hesitancy Scale (outcome measure; score range 7–35) and the Oxford Vaccine Confidence and Complacency Scale (mediation measure). The primary outcome was willingness to be vaccinated. Participants were analysed in the groups they were allocated. p values were adjusted for multiple comparisons. The study was registered with ISRCTN, ISRCTN37254291. FINDINGS: From Jan 19 to Feb 5, 2021, 15 014 adults were recruited. Vaccine hesitancy had reduced from 26·9% the previous year to 16·9%, so recruitment was extended to Feb 18 to recruit 3841 additional vaccine-hesitant adults. 12 463 (66·1%) participants were classified as willing, 2932 (15·6%) as doubtful, and 3460 (18·4%) as strongly hesitant (ie, report that they will avoid being vaccinated for as long as possible or will never get vaccinated). Information conditions did not alter COVID-19 vaccine hesitancy in those willing or doubtful (adjusted p values >0·70). In those strongly hesitant, COVID-19 vaccine hesitancy was reduced, in comparison to the control condition, by personal benefit information (mean difference –1·49, 95% CI –2·16 to –0·82; adjusted p=0·0015), directly addressing safety concerns about speed of development (−0·91, –1·58 to –0·23; adjusted p=0·0261), and a combination of all information (−0·86, –1·53 to –0·18; adjusted p=0·0313). In those strongly hesitant, provision of personal benefit information reduced hesitancy to a greater extent than provision of information on the collective benefit of not personally getting ill (−0·97, 95% CI –1·64 to –0·30; adjusted p=0·0165) or the collective benefit of not transmitting the virus (−1·01, –1·68 to –0·35; adjusted p=0·0150). Ethnicity and gender were found to moderate information condition outcomes. INTERPRETATION: In the approximately 10% of the population who are strongly hesitant about COVID-19 vaccines, provision of information on personal benefit reduces hesitancy to a greater extent than information on collective benefits. Where perception of risk from vaccines is most salient, decision making becomes centred on the personal. As such, messaging that stresses the counterbalancing personal benefits is likely to prove most effective. The messaging from this study could be used in public health communications. Going forwards, the study highlights the need for future health campaigns to engage with the public on the terrain that is most salient to them. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and NIHR Oxford Health Biomedical Research Centre.

Lancet Public Health2021       LitCov and CORD-19
338Effect of COVID-19 on maternal, perinatal and neonatal outcome: systematic review  

OBJECTIVE: To evaluate the effects of coronavirus disease 2019 (COVID‐19) on maternal, perinatal and neonatal outcomes by performing a systematic review of available published literature on pregnancies affected by COVID‐19. METHODS: We performed a systematic review to evaluate the effects of COVID‐19 on pregnancy, perinatal and neonatal outcomes. We conducted a comprehensive literature search using PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure Database and Wan Fang Data until 20 April 2020 (studies were identified through PubMed alert after that date). For the research strategy, combinations of the following keywords and MeSH terms were used: SARS‐CoV‐2, COVID‐19, coronavirus disease 2019, pregnancy, gestation, maternal, mothers, vertical transmission, maternal‐fetal transmission, intrauterine transmission, neonates, infant, delivery. Eligibility criteria included laboratory‐confirmed and/or clinically diagnosed COVID‐19, patient being pregnant on admission and availability of clinical characteristics, including at least one maternal, perinatal or neonatal outcome. Exclusion criteria were non‐peer‐reviewed or unpublished reports, unspecified date and location of the study, suspicion of duplicate reporting, and unreported maternal or perinatal outcomes. No language restrictions were applied. RESULTS: We identified a high number of relevant case reports and case series, but only 24 studies, including a total of 324 pregnant women with COVID‐19, met the eligibility criteria and were included in the systematic review. These comprised nine case series (eight consecutive) and 15 case reports. A total of 20 pregnant patients with laboratory‐confirmed COVID‐19 were included in the case reports. In the combined data from the eight consecutive case series, including 211 (71.5%) cases of laboratory‐confirmed and 84 (28.5%) of clinically diagnosed COVID‐19, the maternal age ranged from 20 to 44 years and the gestational age on admission ranged from 5 to 41 weeks. The most common symptoms at presentation were fever, cough, dyspnea/shortness of breath, fatigue and myalgia. The rate of severe pneumonia reported amongst the case series ranged from 0 to 14%, with the majority of the cases requiring admission to the intensive care unit. Almost all cases from the case series had positive computer tomography chest findings. All six and 22 cases that had nucleic‐acid testing in vaginal mucus and breast milk samples, respectively, were negative for SARS‐CoV‐2. Only four cases of spontaneous miscarriage or abortion were reported. In the consecutive case series, 219/295 women had delivered at the time of reporting, and the majority of these had Cesarean section. The gestational age at delivery ranged from 28 to 41 weeks. Apgar scores at 1 and 5 min ranged from 7 to 10 and 7 to 10, respectively. Only eight neonates had birth weight <2500 g and nearly one‐third of cases were transferred to the neonatal intensive care unit. There was one case each of neonatal asphyxia and neonatal death. In 155 neonates that had nucleic‐acid testing in throat swab, all, except three cases, were negative for SARS‐CoV‐2. There were seven maternal deaths, four intrauterine fetal deaths (one with twin pregnancy) and two neonatal deaths (twin pregnancy) reported in a non‐consecutive case series of nine cases with severe COVID‐19. From the case reports, two maternal deaths, one neonatal death and two cases of neonatal SARS‐CoV‐2 infection were reported. CONCLUSIONS: Despite the increasing number of published studies on COVID‐19 in pregnancy, there are insufficient good‐quality data to draw unbiased conclusions with regard to the severity of the disease or specific complications of COVID‐19 in pregnant women, as well as vertical transmission, perinatal and neonatal complications. In order to answer specific questions in relation to the impact of COVID‐19 on pregnant women and their fetuses through meaningful good‐quality research, we urge researchers and investigators to present complete outcome data and reference previously published cases in their publications, and to record such reporting when the data of a case are entered into a registry or several registries. This article is protected by copyright. All rights reserved.

Ultrasound Obstet Gynecol2020       LitCov and CORD-19
339Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of COVID-19  

Angiotensin‐converting enzyme‐2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID‐19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter‐regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin‐angiotensin‐aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID‐19 severity and progression, including age, sex, ethnicity, medication and several co‐morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2‐expressing organs do not equally participate in COVID‐19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID‐19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS‐CoV‐2 infection is crucially important as it has major implications for understanding COVID‐19 pathophysiology and the development of evidence‐based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers and RAAS inhibitors. Ultimately, prevention is key to combat COVID‐19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID‐19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID‐19 severity. In addition, we discuss the relevant pathological changes resulting from SARS‐CoV‐2 infection. Finally, we highlight a selection of potential treatment modalities for COVID‐19. This article is protected by copyright. All rights reserved.

J Pathol2020       LitCov and CORD-19
340Anti-SARS-CoV-2 IgA and IgG in human milk after vaccination is dependent on vaccine type and previous SARS-CoV-2 exposure: a longitudinal study  

BACKGROUND: Breast milk is a vehicle to transfer protective antibodies from the lactating mother to the neonate. After SARS-CoV-2 infection, virus-specific IgA and IgG have been identified in breast milk, however, there are limited data on the impact of different COVID-19 vaccine types in lactating women. This study is aimed to evaluate the time course of induction of SARS-CoV-2-specific IgA and IgG in breast milk after vaccination. METHODS: In this prospective observational study in Spain, 86 lactating women from priority groups receiving the vaccination against SARS-CoV-2 were included. Breast milk samples were collected longitudinally at seven or eight-time points (depending on vaccine type). A group with confirmed SARS-CoV-2 infection (n=19) and a group of women from pre-pandemic time (n=20) were included for comparison. RESULTS: Eighty-six vaccinated lactating women [mean age, 34.6 ± 3.7 years] of whom 96% were Caucasian and 92% were healthcare workers. A total number of 582 milk samples were included, and vaccine distribution was BioNTech/Pfizer (BNT162b2, n=34), Moderna (mRNA-1273, n=20), and AstraZeneca (ChAdOx1 nCoV-19, n=32). For each vaccine, 7 and 8 longitudinal time points were collected from baseline up to 30 days after the second dose for mRNA vaccines and adenovirus-vectored vaccines, respectively. A strong reactivity was observed for IgG and IgA after vaccination mainly after the 2(nd) dose. The presence and persistence of specific SARS-CoV-2 antibodies in breast milk were dependent on the vaccine type, with higher IgG and IgA levels in mRNA-based vaccines when compared to AstraZeneca, and on previous virus exposure. High intra- and inter-variability were observed, being relevant for IgA antibodies. In milk from vaccinated women, anti-SARS-CoV-2 IgG was significantly higher while IgA levels were lower than in milk from COVID-19-infected women. Women with previous COVID-19 increased their IgG antibodies levels after the first dose to a similar level observed in vaccinated women after the second dose. CONCLUSIONS: COVID-19 vaccination induced anti-SARS-CoV-2 IgA and IgG in breast milk with higher levels after the 2(nd) dose. Levels of anti-SARS-CoV-2 IgA and IgG are dependent on the vaccine type. Further studies are warranted to demonstrate the protective antibody effect against COVID-19 in infants from vaccinated and infected mothers. TRIAL REGISTRATION: NCT04751734 (date of registration is on February 12, 2021) SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-022-01043-9.

Genome Med2022       LitCov and CORD-19
341Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study  

BACKGROUND: The SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community. METHODS: Between Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status. FINDINGS: The SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for uninfected individuals (64 days [32–97], p=0·001). SAR among household contacts exposed to fully vaccinated index cases was similar to household contacts exposed to unvaccinated index cases (25% [95% CI 15–35] for vaccinated vs 23% [15–31] for unvaccinated). 12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked index cases, further confirmed by genomic and virological analysis in three index case–contact pairs. Although peak viral load did not differ by vaccination status or variant type, it increased modestly with age (difference of 0·39 [95% credible interval –0·03 to 0·79] in peak log(10) viral load per mL between those aged 10 years and 50 years). Fully vaccinated individuals with delta variant infection had a faster (posterior probability >0·84) mean rate of viral load decline (0·95 log(10) copies per mL per day) than did unvaccinated individuals with pre-alpha (0·69), alpha (0·82), or delta (0·79) variant infections. Within individuals, faster viral load growth was correlated with higher peak viral load (correlation 0·42 [95% credible interval 0·13 to 0·65]) and slower decline (–0·44 [–0·67 to –0·18]). INTERPRETATION: Vaccination reduces the risk of delta variant infection and accelerates viral clearance. Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the entire viral trajectory. FUNDING: National Institute for Health Research.

Lancet Infect Dis2022       LitCov and CORD-19
342Secondary traumatic stress and vicarious posttraumatic growth in healthcare workers during the first COVID-19 lockdown in Greece: The role of resilience and coping strategies  


Psychiatriki2021       LitCov and CORD-19
343Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization  


Nature2021       LitCov and CORD-19
344Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration in COVID-19 (REALIST-COVID-19): A structured summary of a study protocol for a randomised, controlled trial  

OBJECTIVES: The primary objective of the study is to assess the safety of a single intravenous infusion of Mesenchymal Stromal Cells (MSCs) in patients with Acute Respiratory Distress Syndrome (ARDS) due to COVID-19. Secondary objectives are to determine the effects of MSCs on important clinical outcomes, as described below. TRIAL DESIGN: REALIST COVID 19 is a randomised, placebo-controlled, triple blinded trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across the United Kingdom. Patients with moderate to severe ARDS as defined by the Berlin definition, receiving invasive mechanical ventilation and with a diagnosis of COVID-19 based on clinical diagnosis or PCR test will be eligible. Patients will be excluded for the following reasons: more than 72 hours from the onset of ARDS; age < 16 years; patient known to be pregnant; major trauma in previous 5 days; presence of any active malignancy (other than non-melanoma skin cancer); WHO Class III or IV pulmonary hypertension; venous thromboembolism currently receiving anti-coagulation or within the past 3 months; patient receiving extracorporeal life support; severe chronic liver disease (Child-Pugh > 12); Do Not Attempt Resuscitation order in place; treatment withdrawal imminent within 24 hours; prisoners; declined consent; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; previously enrolled in the REALIST trial. INTERVENTION AND COMPARATOR: Intervention: Allogeneic donor CD362 enriched human umbilical cord derived mesenchymal stromal cells (REALIST ORBCEL-C) supplied as sterile, single-use cryopreserved cell suspension of a fixed dose of 400 x10(6) cells in 40ml volume, to be diluted in Plasma-Lyte 148 to a total volume of 200mls for administration. Comparator (placebo): Plasma-Lyte 148 Solution for Infusion (200mls). The cellular product (REALIST ORBCEL-C) was developed and patented by Orbsen Therapeutics. MAIN OUTCOMES: The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is Oxygenation Index (OI) at day 7. Secondary outcomes include: OI at days 4 and 14; respiratory compliance, driving pressure and PaO(2)/FiO(2) ratio (PF ratio) at days 4, 7 and 14; Sequential Organ Failure Assessment (SOFA) score at days 4, 7 and 14; extubation and reintubation; ventilation free days at day 28; duration of mechanical ventilation; length of ICU and hospital stay; 28-day and 90-day mortality. RANDOMISATION: After obtaining informed consent, patients will be randomised via a centralised automated 24-hour telephone or web-based randomisation system (CHaRT, Centre for Healthcare Randomised Trials, University of Aberdeen). Randomisation will be stratified by recruitment centre and by vasopressor use and patients will be allocated to REALIST ORBCEL-C or placebo control in a 1:1 ratio. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and participants will be blinded. The cell therapy facility and clinical trials pharmacist will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A sample size of 60 patients with 30 patients randomised to the intervention and 30 to the control group. If possible, recruitment will continue beyond 60 patients to provide more accurate and definitive trial results. The total number of patients recruited will depend on the pandemic and be guided by the data monitoring and ethics committee (DMEC). TRIAL STATUS: REALIST Phase 1 completed in January 2020 prior to the COVID-19 pandemic. This was an open label dose escalation study of REALIST ORBCEL-C in patients with ARDS. The COVID-19 pandemic emerged as REALIST Phase 2 was planned to commence and the investigator team decided to repurpose the Phase 2 trial as a COVID-19 specific trial. This decision was discussed and approved by the Trial Steering Committee (TSC) and DMEC. Submissions were made to the Research Ethics Committee (REC) and MHRA to amend the protocol to a COVID-19 specific patient population and the protocol amendment was accepted by the REC on 27(th) March 2020 and MHRA on 30(th) March 2020 respectively. Other protocol changes in this amendment included an increase in the time of onset of ARDS from 48 to 72 hours, inclusion of clinical outcomes as secondary outcomes, the provision of an option for telephone consent, an indicative sample size and provision to continue recruitment beyond this indicative sample size. The current protocol in use is version 4.0 23.03.2020 (Additional file 1). Urgent Public Health status was awarded by the NIHR on 2 April 2020 and the trial opened to recruitment and recruited the first participant the same day. At the time of publication the trial was open to recruitment at 5 sites across the UK (Belfast Health and Social Care Trust, King’s College London, Guys and St Thomas’ Hospital London, Birmingham Heartlands Hospital and the Queen Elizabeth Hospital Birmingham) and 12 patients have been recruited across these sites. Additional sites are planned to open and appropriate approvals for these are being obtained. It is estimated recruitment will continue for 6 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT 03042143 (Registered 3 Feb 2017). EudraCT 2017-000585-33 (Registered 28 Nov 2017). FULL PROTOCOL: The full protocol (version 4.0 23.03.2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of 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. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Trials2020       LitCov and CORD-19
345COVID-19 CG enables SARS-CoV-2 mutation and lineage tracking by locations and dates of interest  

COVID-19 CG (covidcg.org) is an open resource for tracking SARS-CoV-2 single-nucleotide variations (SNVs), lineages, and clades using the virus genomes on the GISAID database while filtering by location, date, gene, and mutation of interest. COVID-19 CG provides significant time, labor, and cost-saving utility to projects on SARS-CoV-2 transmission, evolution, diagnostics, therapeutics, vaccines, and intervention tracking. Here, we describe case studies in which users can interrogate (1) SNVs in the SARS-CoV-2 spike receptor binding domain (RBD) across different geographical regions to inform the design and testing of therapeutics, (2) SNVs that may impact the sensitivity of commonly used diagnostic primers, and (3) the emergence of a dominant lineage harboring an S477N RBD mutation in Australia in 2020. To accelerate COVID-19 efforts, COVID-19 CG will be upgraded with new features for users to rapidly pinpoint mutations as the virus evolves throughout the pandemic and in response to therapeutic and public health interventions.

Elife2021       LitCov and CORD-19
346Physical distancing, face masks and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis  

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and is spread person-to-person through close contact. We aimed to investigate the effects of physical distance, face masks, and eye protection on virus transmission in health-care and non-health-care (eg, community) settings. METHODS: We did a systematic review and meta-analysis to investigate the optimum distance for avoiding person-to-person virus transmission and to assess the use of face masks and eye protection to prevent transmission of viruses. We obtained data for SARS-CoV-2 and the betacoronaviruses that cause severe acute respiratory syndrome, and Middle East respiratory syndrome from 21 standard WHO-specific and COVID-19-specific sources. We searched these data sources from database inception to May 3, 2020, with no restriction by language, for comparative studies and for contextual factors of acceptability, feasibility, resource use, and equity. We screened records, extracted data, and assessed risk of bias in duplicate. We did frequentist and Bayesian meta-analyses and random-effects meta-regressions. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. This study is registered with PROSPERO, CRD42020177047. FINDINGS: Our search identified 172 observational studies across 16 countries and six continents, with no randomised controlled trials and 44 relevant comparative studies in health-care and non-health-care settings (n=25 697 patients). Transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 m (n=10 736, pooled adjusted odds ratio [aOR] 0·18, 95% CI 0·09 to 0·38; risk difference [RD] −10·2%, 95% CI −11·5 to −7·5; moderate certainty); protection was increased as distance was lengthened (change in relative risk [RR] 2·02 per m; p(interaction)=0·041; moderate certainty). Face mask use could result in a large reduction in risk of infection (n=2647; aOR 0·15, 95% CI 0·07 to 0·34, RD −14·3%, −15·9 to −10·7; low certainty), with stronger associations with N95 or similar respirators compared with disposable surgical masks or similar (eg, reusable 12–16-layer cotton masks; p(interaction)=0·090; posterior probability >95%, low certainty). Eye protection also was associated with less infection (n=3713; aOR 0·22, 95% CI 0·12 to 0·39, RD −10·6%, 95% CI −12·5 to −7·7; low certainty). Unadjusted studies and subgroup and sensitivity analyses showed similar findings. INTERPRETATION: The findings of this systematic review and meta-analysis support physical distancing of 1 m or more and provide quantitative estimates for models and contact tracing to inform policy. Optimum use of face masks, respirators, and eye protection in public and health-care settings should be informed by these findings and contextual factors. Robust randomised trials are needed to better inform the evidence for these interventions, but this systematic appraisal of currently best available evidence might inform interim guidance. FUNDING: World Health Organization.

Lancet2020       LitCov and CORD-19
347Antibody Avidity and Neutralizing Response against SARS-CoV-2 Omicron Variant after Infection or Vaccination  


J Immunol Res2022       LitCov
348Decreased and Heterogeneous Neutralizing Antibody Responses Against RBD of SARS-CoV-2 Variants After mRNA Vaccination  

The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerging variants raises concerns about their capacity to evade immune protection provided by natural infection or vaccination. The receptor-binding domain (RBD) of the viral spike protein is the major target of neutralizing antibodies, and viral variants accumulate mutations in this region. In this study, we determined the antibody neutralization capacity against the RBD of SARS-CoV-2 variants Alpha (B.1.1.7), Gamma (P.1), Epsilon (B.1.427), Kappa (B.1.617.1), and Delta (B.1.617.2) in a cohort of healthcare workers naturally infected or receiving COVID-19 mRNA vaccines from Moderna or Pfizer-BioNTech. We show that the five RBD variants displayed an augmented binding to ACE2 compared to the original Wuhan strain. The most significant increase was observed in variants Epsilon and Delta, containing mutation L452R. Using a flow cytometry cell-based assay, we found that SARS-CoV-2-infected subjects presented low levels of RBD-specific neutralizing antibodies against all variants analyzed, except Alpha. However, the neutralizing activity incremented considerably after a subsequent mRNA-vaccine dose, to levels significantly higher than those in naïve individuals receiving two vaccine doses. Importantly, we observed partially impaired neutralizing responses against most variants in fully vaccinated individuals. Variants Gamma and Kappa encompassing RBD E484K/Q mutations presented the highest neutralizing resistance. Furthermore, a wide heterogeneity in the magnitude of RBD-specific neutralizing responses against all tested SARS-CoV-2 variants following both mRNA vaccines was detected. Altogether, our findings provide important knowledge regarding SARS-CoV-2 vaccine-induced immunity, and should be very useful to guide future vaccination regimens and personalized vaccine approaches.

Front Immunol2022       LitCov and CORD-19
349Association of Gestational Age at COVID-19 Vaccination, History of SARS-CoV-2 Infection and a Vaccine Booster Dose With Maternal and Umbilical Cord Antibody Levels at Delivery  


Obstet Gynecol2022       LitCov and CORD-19
350SARS-CoV-2 variants, spike mutations and immune escape  

Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of ‘variants of concern’, that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.

Nat Rev Microbiol2021       LitCov and CORD-19

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(3) Currently tweets of June 23rd to June 29th 2022 have been considered.

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