\ 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
TitleVenueYearImpactSource
601Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection  

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4(+) T cells and CD8(+) T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4(+) T cell, and CD8(+) T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

Science2021       LitCov and CORD-19
602Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials  

N/A

JAMA2020       LitCov and CORD-19
603Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia  

N/A

N Engl J Med2012       CORD-19
604Occupational burnout and job satisfaction among physicians in times of COVID-19 crisis: a convergent parallel mixed-method study  

BACKGROUND: Healthcare professionals including physicians were subjected to an increased workload during the COVID-19 crisis, leaving them exposed to significant physical and psychological distress. Therefore, our present study aimed to (i) assess the prevalence of burnout and levels of job satisfaction among physicians in Jordan, and (ii) explore physicians’ opinions, experiences, and perceptions during the pandemic crisis. METHODS: This was a mixed-method study that utilized a structured web-based questionnaire and semi-structured individual interviews. The 10-Item Burnout Measure-Short version (BMS), and the 5-Item Short Index of Job Satisfaction (SIJS) were adopted to assess occupational burnout and job satisfaction, respectively. Semi-structured interviews were conducted, based on a conceptual framework that was developed from Herzberg’s Two-Factor Theory of Motivation and Job Demands-Resources Model. Descriptive statistics and regression models, as well as inductive thematic analysis, were used to analyze quantitative and qualitative data, respectively. RESULTS: A total of 973 survey responses and 11 interviews were included in our analysis. The prevalence of burnout among physicians was (57.7%). Several significant factors were positively associated with burnout, including female gender, working at highly loaded hospitals, working for long hours, doing night shifts, lack of sufficient access to personal protective equipment, and being positively tested for SARS-CoV-2. Regarding job satisfaction, regression analysis revealed that age was positively associated with higher levels of job satisfaction. On contrary, being a general practitioner or specialist, working at highly loaded hospitals, low salaries, and suffering from burnout have predicted lower levels of job satisfaction. Besides, four themes have emerged from the thematic analysis: (i) Work-induced psychological distress during the pandemic, (ii) Decision-driven satisfactory and dissatisfactory experiences, (iii) Impact of the pandemic on doctor-patient communication and professional skills, and (iv) Economic impacts of the pandemic crisis and lockdown. CONCLUSION: A significant physical and psychological burden was associated with the COVID-19 pandemic. Reliable efforts should be implemented aiming at protecting physicians’ physical and mental wellbeing, enhancing their working conditions, and raising awareness about burnout. Evidence-based decisions and proper utilization of financial and human resources at institutional and national levels are believed to be crucial for the sustainability of the health workforce, especially in crises. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-021-10897-4.

BMC Public Health2021       LitCov and CORD-19
605Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial  

BACKGROUND: Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine. METHODS: In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248. FINDINGS: Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebos −1·29%, 95% CI −14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, −6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (–12·9%, −34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, −13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, −5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, −11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected. INTERPRETATION: Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need. FUNDING: National Institute for Health Research Policy Research Programme

Lancet2021       LitCov and CORD-19
606Detection of SARS-CoV-2 in Different Types of Clinical Specimens  

N/A

JAMA2020       LitCov and CORD-19
607Impact of COVID-19 and lockdown on mental health of children and adolescents: A narrative review with recommendations  

BACKGROUND: COVID-19 pandemic and lockdown has brought about a sense of fear and anxiety around the globe. This phenomenon has led to short term as well as long term psychosocial and mental health implications for children and adolescents. The quality and magnitude of impact on minors is determined by many vulnerability factors like developmental age, educational status, pre-existing mental health condition, being economically underprivileged or being quarantined due to infection or fear of infection. AIMS: This paper is aimed at narratively reviewing various articles related to mental-health aspects of children and adolescents impacted by COVID-19 pandemic and enforcement of nationwide or regional lockdowns to prevent further spread of infection. METHODOLOGY: We conducted a review and collected articles and advisories on mental health aspects of children and adolescents during the COVID-19 pandemic. We selected articles and thematically organized them. We put up their major findings under the thematic areas of impact on young children, school and college going students, children and adolescents with mental health challenges, economically underprivileged children, impact due to quarantine and separation from parents and the advisories of international organizations. We have also provided recommendations to the above. CONCLUSION: There is a pressing need for planning longitudinal and developmental studies, and implementing evidence based elaborative plan of action to cater to the psycho social and mental health needs of the vulnerable children and adolescents during pandemic as well as post pandemic. There is a need to ameliorate children and adolescents’ access to mental health support services geared towards providing measures for developing healthy coping mechanisms during the current crisis. For this innovative child and adolescent mental health policies policies with direct and digital collaborative networks of psychiatrists, psychologists, paediatricians, and community volunteers are deemed necessary.

Psychiatry Res2020       LitCov and CORD-19
608Lifestyle behaviors trend and their relationship with fear level of COVID-19: Cross-sectional study in Saudi Arabia  

INTRODUCTION: COVID-19 pandemic cautionary measures have affected the daily life of people around the globe. Further, understanding the complete lifestyle behaviors profile can help healthcare providers in designing effective interventions and assessing overall health impact on risk of disease development. Thus, this study aims to assess the complete spectrum of lifestyle behaviors (physical activity, sedentary behavior, sleep, distress, social support, dietary habits, and smoking) prevalence and its association with fear of COVID-19 in people living in Saudi Arabia. METHODS: Self-administered survey consisted of seven sections was used to collect data on fear of COVID-19 using Fear of COVID-19 Scale (FCV-19S), physical activity and sedentary behavior using the Global Physical Activity Questionnaire (GPAQ), sleep quality using the Pittsburgh Sleep Quality Index (PSQI), psychosocial distress using Kessler Psychological Distress Scale (K-10), social support using the MOS social support survey, and dietary habits using a short version of food frequency questionnaire (FFQ). The online survey was distributed via social media platforms during lockdown period of COVID-19 pandemic (May–June 2020). Each section consisted of validated questionnaire examining one of aforementioned lifestyle behaviors. Associations were analyzed using multiple linear regression. RESULTS: A total of 669 individuals attempted to complete the online survey, 554 participants completed at least 2 sections of the survey (82.8%), and 41.3% (n = 276) completed the whole online survey. The majority of the sample were female (83%), not smokers (86.5%), had sufficient sleep duration (7.5 hrs ± 2.1), and only indicated mild level of distress (21.4 ± 8.9); they also reported high level of sedentary behavior (7.7 hrs ± 4.5), poor sleep quality (5.4 ± 2.4), were not engaged in healthy eating habits, and moderate level of perceived social support (62.0% ± 27). Only physical activity results indicated that about half of the sample were engaged in moderate to vigorous level of physical activity (54.3%). Further, being female (β = 0.12; 95% CI: 0.45, 2.94) and married (β = 0.13; 95% CI: 0.3, 2.63) were associated with fear of COVID-19 level (β = 0.21; 95% IC: 0.05, 0.19) with a confidence interval level of 95%. In addition, distress was associated with fear. CONCLUSION: The trend of lifestyle behaviors measured during lockdown period changed from previously published rates. Future research needs to establish the short-term and long-term effect of lifestyle behaviors complete profile on physical and mental health.

PLoS One2021       LitCov and CORD-19
609A qualitative insight into the perceptions and COVID-19 vaccine hesitancy among Pakistani pharmacists  

A qualitative exploration of pharmacists’ perceptions regarding COVID-19 conspiracies and their willingness to get vaccinated. A semi-structured questionnaire guide was developed using ground theory to conduct in-depth interviews. A total of 36 participants gave consent for an audio-recorded interview. Results have shown that most of the respondents believed that SARS-CoV-2 is a natural virus, not man-made, that causes a disease just like other viruses and it is absurd to believe that the vaccine is being used by foreign powers for the implantation of microchips just to control humans. A general opinion thatwhich reflected from the in-depth interview is that the pharmaceutical companies may be hiding some important information on COVID-19 to promote the sale of their product. Some doubts on the reliability and trustworthiness on the COVID-19 vaccine safety and efficacy data were noticed among the respondents. Factors leading to COVID-19 vaccine hesitancy were adverse reaction, cost of COVID-19 vaccine, and limited data on safety and efficacy profile of COVID-19 vaccine. COVID-19 vaccine hesitancy among health professionals is a major hindrance to our current fight against COVID-19 pandemic. Findings of this study are alarming, and the stakeholders must consider this ongoing vaccination campaign as an opportunity to formulate a mechanism to ensure high vaccination rate among general public and healthcare providers in Pakistan. KEY POINTS What was already known? According to World Health Organization (WHO), vaccine hesitancy is one of the ten major threats to global healthcare system and it is a major barrier to achieve herd immunity around the globe. Pakistan has begun vaccinating its people in a systematic phase-wise manner under which the healthcare workers and elderly people are prioritized for vaccination. Previous experience tells us that vaccine hesitancy is a major problem in Pakistan and it is better to understand perceptions of pharmacists about COVID-19 vaccine who are the primary source of information for most of general population. What this study adds: This study is first of its kind to explore vaccine hesitancy among Pakistani pharmacists and the results of this study show that majority of the participants were willing to get COVID-19 vaccine and few of them have even got themselves vaccinated at the start of vaccination campaign. Many among the willing participants considered cost of vaccine, adverse reactions, limited data, safety, and efficacy as major hindrance to their decision to get vaccine. Few participants were found highly vaccine-hesitant because of their staunch belief in the prevalent myths and rumors about COVID-19 vaccine.

Hum Vaccin Immunother2022       LitCov and CORD-19
610Social, Cognitive and eHealth Mechanisms of COVID-19-Related Lockdown and Mandatory Quarantine That Potentially Affect the Mental Health of Pregnant Women in China: Cross-Sectional Survey Study  

BACKGROUND: Although lockdown and mandatory quarantine measures have played crucial roles in the sharp decrease of the number of newly confirmed/suspected COVID-19 cases, concerns have been raised over the threat that these measures pose to mental health, especially the mental health of vulnerable groups, including pregnant women. Few empirical studies have assessed whether and how these control measures may affect mental health, and no study has investigated the prevalence and impacts of the use of eHealth resources among pregnant women during the COVID-19 outbreak. OBJECTIVE: This study investigated (1) the effects of lockdown and mandatory quarantine on mental health problems (ie, anxiety and depressive symptoms), (2) the potential mediation effects of perceived social support and maladaptive cognition, and (3) the moderation effects of eHealth-related factors (ie, using social media to obtain health information and using prenatal care services during the COVID-19 pandemic) on pregnant women in China. METHODS: An online cross-sectional survey was conducted among 19,515 pregnant women from all 34 Chinese provincial-level administrative regions from February 25 to March 10, 2020. RESULTS: Of the 19,515 participants, 12,209 (62.6%) were subjected to lockdown in their areas of residence, 737 (3.8%) were subjected to mandatory quarantine, 8712 (44.6%) had probable mild to severe depression, 5696 (29.2%) had probable mild to severe anxiety, and 1442 (7.4%) had suicidal ideations. Only 640 (3.3%) participants reported that they used online prenatal care services during the outbreak. Significant sociodemographic/maternal factors of anxiety/depressive symptoms included age, education, occupation, the area of residence, gestational duration, the number of children born, complication during pregnancy, the means of using prenatal care services, and social media use for obtaining health information. Multiple indicators multiple causes modeling (χ(2)(14)=495.21; P<.05; comparative fit index=.99; nonnormed fit index=.98; root mean square error of approximation=.04, 90% CI 0.038-0.045) showed that quarantine was directly and indirectly strongly associated with poor mental health through decreased perceived social support and increased maladaptive cognition (B=.04; β=.02, 95% CI 0.01-0.02; P=.001), while lockdown was indirectly associated with mental health through increased social support and maladaptive cognition among pregnant women (B=.03; β=.03, 95% CI 0.02-0.03; P=.001). Multigroup analyses revealed that the use of social media for obtaining health information and the means of using prenatal care services were significant moderators of the model paths. CONCLUSIONS: Our findings provide epidemiological evidence for the importance of integrating mental health care and eHealth into the planning and implementation of control measure policies. The observed social and cognitive mechanisms and moderators in this study are modifiable, and they can inform the design of evidence-based mental health promotion among pregnant women.

J Med Internet Res2021       LitCov and CORD-19
611Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors  

N/A

Nature2020       LitCov and CORD-19
612Predictors of Mortality in Adults Admitted with COVID-19: Retrospective Cohort Study from New York City  

INTRODUCTION: Rapid spread of coronavirus disease 2019 (COVID-19) in the United States, especially in New York City (NYC), led to a tremendous increase in hospitalizations and mortality. There is very limited data available that associates outcomes during hospitalization in patients with COVID-19. METHODS: In this retrospective cohort study, we reviewed the health records of patients with COVID-19 who were admitted from March 9–April 9, 2020, to a community hospital in NYC. Subjects with confirmed reverse transcriptase-polymerase chain reaction (RT-PCR) of the nasopharyngeal swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were included. We collected data related to demographics, laboratory results, and outcome of hospitalization. Outcome was measured based on whether the patient was discharged home or died during hospitalization. RESULTS: There were 888 consecutive admissions with COVID-19 during the study period, of which 513 were excluded with pending outcome or incomplete information. We included a total of 375 patients in the study, of whom 215 (57%) survived and 160 (43%) died during hospitalization. The majority of patients were male (63%) and of Hispanic origin (66%) followed by Blacks (25%), and others (9%). Hypertension (60%) stands out to be the most common comorbidity followed by diabetes mellitus (47%), cardiovascular disease (17%), chronic kidney disease (17%), and human immunodeficiency virus/acquired immunodeficiency syndrome (9%). On multiple regression analysis, increasing odds of mortality during hospitalization was associated with older age (odds ratio [OR] 1.04; 95% confidence interval [CI], 1.01–1.06 per year increase; p < 0.0001), admission D-dimer more than 1000 nanograms per milliliter (ng/mL) (OR 3.16; 95% CI, 1.75–5.73; p<0.0001), admission C-reactive protein (CRP) levels of more than 200 milligrams per liter (mg/L) (OR 2.43; 95% CI, 1.36–4.34; p = 0.0028), and admission lymphopenia (OR 2.63; CI, 1.47–4.69; p 0.0010). CONCLUSION: In this retrospective cohort study originating in NYC, older age, admission levels of D-dimer of more than 1000 ng/mL, CRP of more than 200 mg/L and lymphopenia were associated with mortality in individuals hospitalized for COVID-19. We recommend using these risk factors on admission to triage patients to critical care units or surge units to maximize the use of surge capacity beds.

West J Emerg Med2020       LitCov and CORD-19
613Deep vein thrombosis and pulmonary embolism among hospitalized COVID-19-positive patients predicted for higher mortality and prolonged intensive care unit and hospital stays in a multisite healthcare system  

OBJECTIVE: We assessed the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients with coronavirus disease 2019 (COVID-19) compared with that in a matched cohort with similar cardiovascular risk factors and the effects of DVT and PE on the hospital course. METHODS: We performed a retrospective review of prospectively collected data from COVID-19 patients who had been hospitalized from March 11, 2020 to September 4, 2020. The patients were randomly matched in a 1:1 ratio by age, sex, hospital of admission, smoking history, diabetes mellitus, and coronary artery disease with a cohort of patients without COVID-19. The primary endpoint was the incidence of DVT/PE and the odds of developing DVT/PE using a conditional logistic regression model. The secondary endpoint was the hospitalization outcomes for COVID-19 patients with and without DVT/PE, including mortality, intensive care unit (ICU) admission, ICU stay, and length of hospitalization (LOH). Multivariable regression analysis was performed to identify the variables associated with mortality, ICU admission, discharge disposition, ICU duration, and LOH. RESULTS: A total of 13,310 patients had tested positive for COVID-19, 915 of whom (6.9%) had been hospitalized across our multisite health care system. The mean age of the hospitalized patients was 60.8 ± 17.0 years, and 396 (43.3%) were women. Of the 915 patients, 82 (9.0%) had had a diagnosis of DVT/PE confirmed by ultrasound examination of the extremities and/or computed tomography angiography of the chest. The odds of presenting with DVT/PE in the setting of COVID-19 infection was greater than that without COVID-19 infection (0.6% [5 of 915] vs 9.0% [82 of 915]; odds ratio [OR], 18; 95% confidence interval [CI], 8.0-51.2; P < .001). The vascular risk factors were not different between the COVID-19 patients with and without DVT/PE. Mortality (P = .02), the need for ICU stay (P < .001), duration of ICU stay (P < .001), and LOH (P < .001) were greater in the DVT/PE cohort than in the cohort without DVT/PE. On multivariable logistic regression analysis, the hemoglobin (OR, 0.71; 95% CI, 0.46-0.95; P = .04) and D-dimer (OR, 1.0; 95% CI, 0.33-1.56; P = .03) levels were associated with higher mortality. Higher activated partial thromboplastin times (OR, 1.1; 95% CI, 1.00-1.12; P = .03) and higher interleukin-6 (IL-6) levels (OR, 1.0; 95% CI, 1.01-1.07; P = .05) were associated with a greater risk of ICU admission. IL-6 (OR, 1.0; 95% CI, 1.00-1.02; P = .05) was associated with a greater risk of rehabilitation placement after discharge. On multivariable gamma regression analysis, hemoglobin (coefficient, −3.0; 95% CI, 0.03-0.08; P = .005) was associated with a prolonged ICU stay, and the activated partial thromboplastin time (coefficient, 2.0; 95% CI, 0.003-0.006; P = .05), international normalized ratio (coefficient, −3.2; 95% CI, 0.06-0.19; P = .002) and IL-6 (coefficient, 2.4; 95% CI, 0.0011-0.0027; P = .02) were associated with a prolonged LOH. CONCLUSIONS: A significantly greater incidence of DVT/PE occurred in hospitalized COVID-19–positive patients compared with a non–COVID-19 cohort matched for cardiovascular risk factors. Patients affected by DVT/PE were more likely to experience greater mortality, to require ICU admission, and experience prolonged ICU stays and LOH compared with COVID-19–positive patients without DVT/PE. Advancements in DVT/PE prevention are needed for patients hospitalized for COVID-19 infection.

J Vasc Surg Venous Lymphat Dis2021       LitCov and CORD-19
614The Fear of COVID-19 Scale: Development and Initial Validation  

BACKGROUND: The emergence of the COVID-19 and its consequences has led to fears, worries, and anxiety among individuals worldwide. The present study developed the Fear of COVID-19 Scale (FCV-19S) to complement the clinical efforts in preventing the spread and treating of COVID-19 cases. METHODS: The sample comprised 717 Iranian participants. The items of the FCV-19S were constructed based on extensive review of existing scales on fears, expert evaluations, and participant interviews. Several psychometric tests were conducted to ascertain its reliability and validity properties. RESULTS: After panel review and corrected item-total correlation testing, seven items with acceptable corrected item-total correlation (0.47 to 0.56) were retained and further confirmed by significant and strong factor loadings (0.66 to 0.74). Also, other properties evaluated using both classical test theory and Rasch model were satisfactory on the seven-item scale. More specifically, reliability values such as internal consistency (α = .82) and test–retest reliability (ICC = .72) were acceptable. Concurrent validity was supported by the Hospital Anxiety and Depression Scale (with depression, r = 0.425 and anxiety, r = 0.511) and the Perceived Vulnerability to Disease Scale (with perceived infectability, r = 0.483 and germ aversion, r = 0.459). CONCLUSION: The Fear of COVID-19 Scale, a seven-item scale, has robust psychometric properties. It is reliable and valid in assessing fear of COVID-19 among the general population and will also be useful in allaying COVID-19 fears among individuals.

Int J Ment Health Addict2020       LitCov and CORD-19
615Attitudes Towards a Potential SARS-CoV-2 Vaccine: A Survey of US Adults  

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly instigated a global pandemic. Vaccine development is proceeding at an unprecedented pace. Once available, it will be important to maximize vaccine uptake and coverage. OBJECTIVE: To assess intent to be vaccinated against COVID-19 among a representative sample of adults in the United States and identify predictors of and reasons for vaccine hesitancy. DESIGN: Cross-sectional survey, fielded from 16 through 20 April 2020. SETTING: Representative sample of adults residing in the United States. PARTICIPANTS: Approximately 1000 adults drawn from the AmeriSpeak probability-based research panel, covering approximately 97% of the U.S. household population. MEASUREMENTS: Intent to be vaccinated against COVID-19 was measured with the question, “When a vaccine for the coronavirus becomes available, will you get vaccinated?” Response options were “yes,” “no,” and “not sure.” Participants who responded “no” or “not sure” were asked to provide a reason. RESULTS: A total of 991 AmeriSpeak panel members responded. Overall, 57.6% of participants (n = 571) intended to be vaccinated, 31.6% (n = 313) were not sure, and 10.8% (n = 107) did not intend to be vaccinated. Factors independently associated with vaccine hesitancy (a response of “no” or “not sure”) included younger age, Black race, lower educational attainment, and not having received the influenza vaccine in the prior year. Reasons for vaccine hesitancy included vaccine-specific concerns, a need for more information, antivaccine attitudes or beliefs, and a lack of trust. LIMITATIONS: Participants' intent to be vaccinated was explored before a vaccine was available and when the pandemic was affecting a narrower swath of the United States. Questions about specific information or factors that might increase vaccination acceptance were not included. The survey response rate was 16.1%. CONCLUSION: This national survey, conducted during the coronavirus pandemic, revealed that approximately 3 in 10 adults were not sure they would accept vaccination and 1 in 10 did not intend to be vaccinated against COVID-19. Targeted and multipronged efforts will be needed to increase acceptance of a COVID-19 vaccine when one becomes available. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Ann Intern Med2020       LitCov and CORD-19
616eLearning in Physical Therapy: Lessons Learned From Transitioning a Professional Education Program to Full eLearning During the COVID-19 Pandemic  

OBJECTIVE: The objectives of this cross-sectional qualitative study were to explore the perspectives of students enrolled in one physical therapist undergraduate education program in Australia about their experience with transitioning to full eLearning and student recommendations to improve the learning experience during the COVID-19 pandemic. METHODS: Seven focus groups with 28 undergraduate physical therapist students were conducted following the transitioning to full eLearning as a result of strict physical distancing measures. Focus group questions explored the students’ experiences of the transition from face-to-face to full eLearning approach and the students’ recommendations for improving future eLearning experiences. Data were analyzed using inductive thematic analysis. RESULTS: The 3 themes identified were: (1) students presenting heightened negative feelings such as anxiety, stress, and reduced motivation to study; (2) students continuing to value the face-to-face learning, as it provided social support and facilitated feedback from peers and tutors; (3) student recommendations for eLearning included having online lectures and supplementary videos but face-to-face practical classes and developing healthy learning habits such as scheduled times for studying, exercise, and other activities that regulate stress. CONCLUSIONS: The transition to a full eLearning approach in an undergraduate physical therapist education program during the COVID-19 pandemic revealed that students had heightened negative emotions due to the pandemic. Students valued face-to-face practical classes to learn and receive social support from peers and tutors. Student recommendations to future eLearning suggested changes to curriculum development geared toward a greater blended approach to learning. Blended learning may include using online lectures instead of face-to-face lectures and online resources to supplement student learning of practical skills. IMPACT: As higher education moves toward a more blended approach, lessons learned from this study can help educators design future physical therapist education programs. The findings can also assist programs in delivering a full eLearning approach as the COVID-19 pandemic continues.

Phys Ther2021       LitCov and CORD-19
617Clinical manifestations, risk factors and maternal and perinatal outcomes of COVID-19 in pregnancy: living systematic review and meta-analysis  

OBJECTIVE: To determine the clinical manifestations, risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane database, WHO COVID-19 database, China National Knowledge Infrastructure (CNKI), and Wanfang databases from 1 December 2019 to 26 June 2020, along with preprint servers, social media, and reference lists. STUDY SELECTION: Cohort studies reporting the rates, clinical manifestations (symptoms, laboratory and radiological findings), risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed covid-19. DATA EXTRACTION: At least two researchers independently extracted the data and assessed study quality. Random effects meta-analysis was performed, with estimates pooled as odds ratios and proportions with 95% confidence intervals. All analyses will be updated regularly. RESULTS: 77 studies were included. Overall, 10% (95% confidence interval 7% to14%; 28 studies, 11 432 women) of pregnant and recently pregnant women attending or admitted to hospital for any reason were diagnosed as having suspected or confirmed covid-19. The most common clinical manifestations of covid-19 in pregnancy were fever (40%) and cough (39%). Compared with non-pregnant women of reproductive age, pregnant and recently pregnant women with covid-19 were less likely to report symptoms of fever (odds ratio 0.43, 95% confidence interval 0.22 to 0.85; I(2)=74%; 5 studies; 80 521 women) and myalgia (0.48, 0.45 to 0.51; I(2)=0%; 3 studies; 80 409 women) and were more likely to need admission to an intensive care unit (1.62, 1.33 to 1.96; I(2)=0%) and invasive ventilation (1.88, 1.36 to 2.60; I(2)=0%; 4 studies, 91 606 women). 73 pregnant women (0.1%, 26 studies, 11 580 women) with confirmed covid-19 died from any cause. Increased maternal age (1.78, 1.25 to 2.55; I(2)=9%; 4 studies; 1058 women), high body mass index (2.38, 1.67 to 3.39; I(2)=0%; 3 studies; 877 women), chronic hypertension (2.0, 1.14 to 3.48; I(2)=0%; 2 studies; 858 women), and pre-existing diabetes (2.51, 1.31 to 4.80; I(2)=12%; 2 studies; 858 women) were associated with severe covid-19 in pregnancy. Pre-existing maternal comorbidity was a risk factor for admission to an intensive care unit (4.21, 1.06 to 16.72; I(2)=0%; 2 studies; 320 women) and invasive ventilation (4.48, 1.40 to 14.37; I(2)=0%; 2 studies; 313 women). Spontaneous preterm birth rate was 6% (95% confidence interval 3% to 9%; I(2)=55%; 10 studies; 870 women) in women with covid-19. The odds of any preterm birth (3.01, 95% confidence interval 1.16 to 7.85; I(2)=1%; 2 studies; 339 women) was high in pregnant women with covid-19 compared with those without the disease. A quarter of all neonates born to mothers with covid-19 were admitted to the neonatal unit (25%) and were at increased risk of admission (odds ratio 3.13, 95% confidence interval 2.05 to 4.78, I(2)=not estimable; 1 study, 1121 neonates) than those born to mothers without covid-19. CONCLUSION: Pregnant and recently pregnant women are less likely to manifest covid-19 related symptoms of fever and myalgia than non-pregnant women of reproductive age and are potentially more likely to need intensive care treatment for covid-19. Pre-existing comorbidities, high maternal age, and high body mass index seem to be risk factors for severe covid-19. Preterm birth rates are high in pregnant women with covid-19 than in pregnant women without the disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178076. READERS’ NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

BMJ2020       LitCov and CORD-19
618Racial and Ethnic Disparities in Rates of COVID-19 Associated Hospitalization, Intensive Care Unit Admission and In-Hospital Death in the United States From March 2020 to February 2021  

IMPORTANCE: Racial and ethnic minority groups are disproportionately affected by COVID-19. OBJECTIVES: To evaluate whether rates of severe COVID-19, defined as hospitalization, intensive care unit (ICU) admission, or in-hospital death, are higher among racial and ethnic minority groups compared with non-Hispanic White persons. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included 99 counties within 14 US states participating in the COVID-19–Associated Hospitalization Surveillance Network. Participants were persons of all ages hospitalized with COVID-19 from March 1, 2020, to February 28, 2021. EXPOSURES: Laboratory-confirmed COVID-19–associated hospitalization, defined as a positive SARS-CoV-2 test within 14 days prior to or during hospitalization. MAIN OUTCOMES AND MEASURES: Cumulative age-adjusted rates (per 100 000 population) of hospitalization, ICU admission, and death by race and ethnicity. Rate ratios (RR) were calculated for each racial and ethnic group compared with White persons. RESULTS: Among 153 692 patients with COVID-19–associated hospitalizations, 143 342 (93.3%) with information on race and ethnicity were included in the analysis. Of these, 105 421 (73.5%) were 50 years or older, 72 159 (50.3%) were male, 28 762 (20.1%) were Hispanic or Latino, 2056 (1.4%) were non-Hispanic American Indian or Alaska Native, 7737 (5.4%) were non-Hispanic Asian or Pacific Islander, 40 806 (28.5%) were non-Hispanic Black, and 63 981 (44.6%) were White. Compared with White persons, American Indian or Alaska Native, Latino, Black, and Asian or Pacific Islander persons were more likely to have higher cumulative age-adjusted rates of hospitalization, ICU admission, and death as follows: American Indian or Alaska Native (hospitalization: RR, 3.70; 95% CI, 3.54-3.87; ICU admission: RR, 6.49; 95% CI, 6.01-7.01; death: RR, 7.19; 95% CI, 6.47-7.99); Latino (hospitalization: RR, 3.06; 95% CI, 3.01-3.10; ICU admission: RR, 4.20; 95% CI, 4.08-4.33; death: RR, 3.85; 95% CI, 3.68-4.01); Black (hospitalization: RR, 2.85; 95% CI, 2.81-2.89; ICU admission: RR, 3.17; 95% CI, 3.09-3.26; death: RR, 2.58; 95% CI, 2.48-2.69); and Asian or Pacific Islander (hospitalization: RR, 1.03; 95% CI, 1.01-1.06; ICU admission: RR, 1.91; 95% CI, 1.83-1.98; death: RR, 1.64; 95% CI, 1.55-1.74). CONCLUSIONS AND RELEVANCE: In this cross-sectional analysis, American Indian or Alaska Native, Latino, Black, and Asian or Pacific Islander persons were more likely than White persons to have a COVID-19–associated hospitalization, ICU admission, or in-hospital death during the first year of the US COVID-19 pandemic. Equitable access to COVID-19 preventive measures, including vaccination, is needed to minimize the gap in racial and ethnic disparities of severe COVID-19.

JAMA Netw Open2021       LitCov and CORD-19
619What Media Helps, What Media Hurts: A Mixed Methods Survey Study of Coping with COVID-19 Using the Media Repertoire Framework and the Appraisal Theory of Stress  

BACKGROUND: Social and physical distancing in response to the coronavirus disease (COVID-19) pandemic has made screen-mediated information and communication technologies (media) indispensable. Whether an increase in screen use is a source of or a relief for stress remains to be seen. OBJECTIVE: In the immediate aftermath of the COVID-19 lockdowns, we investigated the relation between subjective stress and changes in the pattern of media use. Based on Lazarus’s transactional model of appraisal and coping, and building on an earlier similar survey, we hypothesize that individual differences in the appraisal of media predict variations in approach or avoidance of media for coping with COVID-19 stress. METHODS: Between March 20 and April 20, 2020, a brief snowball survey entitled: “What media helps, what media hurts: coping with COVID19 through screens” was distributed via Concordia University’s mailing lists and social media (PERFORM Centre, EngAGE Centre, and Media Health Lab). Using a media repertoire method, we asked questions about preferences, changes in use, and personal appraisal of media experiences (approach, avoid, and ignore) as a result of the COVID-19 pandemic and investigated interindividual differences in media use by factors such as subjective stress, age, gender, and self-reported mental health. RESULTS: More than 90% of the survey respondents were in Canada and the east coast of the United States. From 685 completed responses, 169 respondents were “very stressed” and 452 were “slightly worried” about the pandemic. COVID-19 stress led to increased use of Facebook (χ(2)(3)=11.76, P=.008), television (χ(2)(3)=12.40, P=.006), YouTube (χ(2)(3)=8.577, P=.04), and streaming services such as Netflix (χ(2)(3)=10.71, P=.01). Respondents who considered their mental health “not good” were twice as likely to prefer streaming services as a coping tool for self-isolation. Women and nonbinary respondents were twice as likely than men to pick social media for coping. Individuals younger than 35 years were 3 times more likely to pick computer games, and individuals older than 55 years were more likely to pick network television or print media. Gender affected the appraisal of media (less in men than others) in terms of avoid (F(1,637)=5.84, P=.02) and approach scores (F(1,637)=14.31, P<.001). Subjective mental health affected the ignore score (less in those who said “good” than others; F(1,637)=13.88, P<.001). The appraisal score and use increase explained variations in worrying about physical and mental health stress due to increased screen time. A qualitative analysis of open-ended questions revealed that media (especially social networks) were important for coping if they provided support and connection through the dissemination of factual and positive information while avoiding the overflow of sensational and false news. CONCLUSIONS: The relationship between appraisal of media’s positive and negative facets vary with demographic differences in mental health resiliency. The media repertoire approach is an important tool in studies that focus on assessing the benefits and harms of screen overuse in different populations, especially in the context of the COVID-19 pandemic.

J Med Internet Res2020       LitCov and CORD-19
620Pregnancy and neonatal outcomes of COVID-19: coreporting of common outcomes from PAN-COVID and AAP-SONPM registries  

OBJECTIVE: Few large cohort studies have reported data on maternal, fetal, perinatal and neonatal outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in pregnancy. We report the outcome of infected pregnancies from a collaboration formed early during the pandemic between the investigators of two registries, the UK and Global Pregnancy and Neonatal outcomes in COVID‐19 (PAN‐COVID) study and the American Academy of Pediatrics (AAP) Section on Neonatal–Perinatal Medicine (SONPM) National Perinatal COVID‐19 Registry. METHODS: This was an analysis of data from the PAN‐COVID registry (1 January to 25 July 2020), which includes pregnancies with suspected or confirmed maternal SARS‐CoV‐2 infection at any stage in pregnancy, and the AAP‐SONPM National Perinatal COVID‐19 registry (4 April to 8 August 2020), which includes pregnancies with positive maternal testing for SARS‐CoV‐2 from 14 days before delivery to 3 days after delivery. The registries collected data on maternal, fetal, perinatal and neonatal outcomes. The PAN‐COVID results are presented overall for pregnancies with suspected or confirmed SARS‐CoV‐2 infection and separately in those with confirmed infection. RESULTS: We report on 4005 pregnant women with suspected or confirmed SARS‐CoV‐2 infection (1606 from PAN‐COVID and 2399 from AAP‐SONPM). For obstetric outcomes, in PAN‐COVID overall and in those with confirmed infection in PAN‐COVID and AAP‐SONPM, respectively, maternal death occurred in 0.5%, 0.5% and 0.2% of cases, early neonatal death in 0.2%, 0.3% and 0.3% of cases and stillbirth in 0.5%, 0.6% and 0.4% of cases. Delivery was preterm (< 37 weeks' gestation) in 12.0% of all women in PAN‐COVID, in 16.1% of those women with confirmed infection in PAN‐COVID and in 15.7% of women in AAP‐SONPM. Extreme preterm delivery (< 27 weeks' gestation) occurred in 0.5% of cases in PAN‐COVID and 0.3% in AAP‐SONPM. Neonatal SARS‐CoV‐2 infection was reported in 0.9% of all deliveries in PAN‐COVID overall, in 2.0% in those with confirmed infection in PAN‐COVID and in 1.8% in AAP‐SONPM; the proportions of neonates tested were 9.5%, 20.7% and 87.2%, respectively. The rates of a small‐for‐gestational‐age (SGA) neonate were 8.2% in PAN‐COVID overall, 9.7% in those with confirmed infection and 9.6% in AAP‐SONPM. Mean gestational‐age‐adjusted birth‐weight Z‐scores were −0.03 in PAN‐COVID and −0.18 in AAP‐SONPM. CONCLUSIONS: The findings from the UK and USA registries of pregnancies with SARS‐CoV‐2 infection were remarkably concordant. Preterm delivery affected a higher proportion of women than expected based on historical and contemporaneous national data. The proportions of pregnancies affected by stillbirth, a SGA infant or early neonatal death were comparable to those in historical and contemporaneous UK and USA data. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN‐COVID study, although not in the AAP‐SONPM study. The data presented support strong guidance for enhanced precautions to prevent SARS‐CoV‐2 infection in pregnancy, particularly in the context of increased risks of preterm delivery and maternal mortality, and for priority vaccination of pregnant women and women planning pregnancy. Copyright © 2021 ISUOG. Published by John Wiley & Sons Ltd.

Ultrasound Obstet Gynecol2021       LitCov and CORD-19
621Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site  

Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 M(pro)), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 M(pro) active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 M(pro) crystal structures. Several key preferences for strong binding to the four subsites (S1, S1′, S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 −log(10)(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 M(pro) inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 −log(10)(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 M(pro) [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals.

Viruses2020       LitCov and CORD-19
622SARS-CoV-2 infection in immunocompromised patients: humoral vs cell-mediated immunity  

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic placed unprecedented pressure on various healthcare systems, including departments that use immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy and immunosuppression therapy in organ transplantation units. The true impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on immunocompromised CAR T-cell therapy recipients and kidney transplant recipients (KTRs) has not yet been established. CASE PRESENTATION: In this report, we compare two patients with severe COVID-19 pneumonia in either the humoral or cell-mediated immunodeficient states. The first patient was a man in his early 30s who was diagnosed with refractory multiple myeloma. He received fully humanized, anti-B-cell maturation antigen, CAR T-cell therapy before 4 months and achieved strict complete remission. He was infected with SARS-CoV-2 starting on January 26, 2019 and gradually progressed to severe pneumonia. Throughout the clinical progression of the disease, SARS-CoV-2 could not be cleared due to his humoral immunodeficient state. During this period of his severe COVID-19 pneumonia, elevated cytotoxic T-cells were observed in this patient’s peripheral blood while elevated plasma levels of interleukin (IL)-2R, IL-6, tumor necrosis factor α, and ferritin were observed in his cytokine profiles. This patient eventually progressed into acute respiratory distress syndrome and recieved non-invasive ventilatory support. He failed to generate specific SARS-CoV-2 antibodies and died of respiratory failure on day 33 (d33). The second patient was a 52-year-old kidney transplant recipient (KTR) who took ciclosporin after renal transplantation for more than 7 years. He confirmed SARS-CoV-2 infection on January 20, 2019 and gradually progressed into severe pneumonia on d16 with a slightly elevated B-cell percentage and normal T-lymphocyte subsets. Viral clearance occurred together with the generation of specific anti-immunoglobulin G-SARS-CoV-2 antibodies after 2 weeks of treatment. He was symptom-free and discharged from the hospital on d42. CONCLUSION: We report a CAR T-cell therapy recipient diagnosed with COVID-19 for the first time. His virus clearance failure and life-threating cytokine storm during SARS-CoV-2 infection suggested that any decision to proceed CAR T-cell therapy during COVID-19 pandemics will require extensive discussion of potential risks and benefits. Immunosuppressant treatment based on ciclosporin could be relatively safe for KTRs diagnosed with COVID-19. TRIAL REGISTRATION NUMBER: ChiCTR-OPN-1800018137.

J Immunother Cancer2020       LitCov and CORD-19
623A nationwide survey of psychological distress among Chinese people in the COVID-19 epidemic: implications and policy recommendations  

The Coronavirus Disease 2019 (COVID-19) epidemic emerged in Wuhan, China, spread nationwide and then onto half a dozen other countries between December 2019 and early 2020. The implementation of unprecedented strict quarantine measures in China has kept a large number of people in isolation and affected many aspects of people’s lives. It has also triggered a wide variety of psychological problems, such as panic disorder, anxiety and depression. This study is the first nationwide large-scale survey of psychological distress in the general population of China during the COVID-19 epidemic.

Gen Psychiatr2020       LitCov and CORD-19
624Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19  

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

Front Immunol2021       LitCov and CORD-19
625Using social and behavioural science to support COVID-19 pandemic response  

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Nat Hum Behav2020       LitCov and CORD-19
626Evidence of Coronavirus (CoV) Pathogenesis and Emerging Pathogen SARS-CoV-2 in the Nervous System: A Review on Neurological Impairments and Manifestations  

The coronavirus disease 2019 (COVID-19) pandemic is an issue of global significance that has taken the lives of many across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for its pathogenesis. The pulmonary manifestations of COVID-19 have been well described in the literature. Initially, it was thought to be limited to the respiratory system; however, we now recognize that COVID-19 also affects several other organs, including the nervous system. Two similar human coronaviruses (CoV) that cause severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) are also known to cause disease in the nervous system. The neurological manifestations of SARS-CoV-2 infection are growing rapidly, as evidenced by several reports. There are several mechanisms responsible for such manifestations in the nervous system. For instance, post-infectious immune-mediated processes, direct virus infection of the central nervous system (CNS), and virus-induced hyperinflammatory and hypercoagulable states are commonly involved. Guillain-Barré syndrome (GBS) and its variants, dysfunction of taste and smell, and muscle injury are numerous examples of COVID-19 PNS (peripheral nervous system) disease. Likewise, hemorrhagic and ischemic stroke, encephalitis, meningitis, encephalopathy acute disseminated encephalomyelitis, endothelialitis, and venous sinus thrombosis are some instances of COVID-19 CNS disease. Due to multifactorial and complicated pathogenic mechanisms, COVID-19 poses a large-scale threat to the whole nervous system. A complete understanding of SARS-CoV-2 neurological impairments is still lacking, but our knowledge base is rapidly expanding. Therefore, we anticipate that this comprehensive review will provide valuable insights and facilitate the work of neuroscientists in unfolding different neurological dimensions of COVID-19 and other CoV associated abnormalities.

J Mol Neurosci2021       LitCov and CORD-19
627Myocarditis After BNT162b2 and mRNA-1273 Vaccination  

Supplemental Digital Content is available in the text.

Circulation2021       LitCov and CORD-19
628Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease  

BACKGROUND: Some people with SARS‐CoV‐2 infection remain asymptomatic, whilst in others the infection can cause mild to moderate COVID‐19 disease and COVID‐19 pneumonia, leading some patients to require intensive care support and, in some cases, to death, especially in older adults. Symptoms such as fever or cough, and signs such as oxygen saturation or lung auscultation findings, are the first and most readily available diagnostic information. Such information could be used to either rule out COVID‐19 disease, or select patients for further diagnostic testing. OBJECTIVES: To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in primary care or to hospital outpatient settings, such as the emergency department or dedicated COVID‐19 clinics, has COVID‐19 disease or COVID‐19 pneumonia. SEARCH METHODS: On 27 April 2020, we undertook electronic searches in the Cochrane COVID‐19 Study Register and the University of Bern living search database, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID‐19 publications. We did not apply any language restrictions. SELECTION CRITERIA: Studies were eligible if they included patients with suspected COVID‐19 disease, or if they recruited known cases with COVID‐19 disease and controls without COVID‐19. Studies were eligible when they recruited patients presenting to primary care or hospital outpatient settings. Studies including patients who contracted SARS‐CoV‐2 infection while admitted to hospital were not eligible. The minimum eligible sample size of studies was 10 participants. All signs and symptoms were eligible for this review, including individual signs and symptoms or combinations. We accepted a range of reference standards including reverse transcription polymerase chain reaction (RT‐PCR), clinical expertise, imaging, serology tests and World Health Organization (WHO) or other definitions of COVID‐19. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected all studies, at both title and abstract stage and full‐text stage. They resolved any disagreements by discussion with a third review author. Two review authors independently extracted data and resolved disagreements by discussion with a third review author. Two review authors independently assessed risk of bias using the QUADAS‐2 checklist. Analyses were descriptive, presenting sensitivity and specificity in paired forest plots, in ROC (receiver operating characteristic) space and in dumbbell plots. We did not attempt meta‐analysis due to the small number of studies, heterogeneity across studies and the high risk of bias. MAIN RESULTS: We identified 16 studies including 7706 participants in total. Prevalence of COVID‐19 disease varied from 5% to 38% with a median of 17%. There were no studies from primary care settings, although we did find seven studies in outpatient clinics (2172 participants), and four studies in the emergency department (1401 participants). We found data on 27 signs and symptoms, which fall into four different categories: systemic, respiratory, gastrointestinal and cardiovascular. No studies assessed combinations of different signs and symptoms and results were highly variable across studies. Most had very low sensitivity and high specificity; only six symptoms had a sensitivity of at least 50% in at least one study: cough, sore throat, fever, myalgia or arthralgia, fatigue, and headache. Of these, fever, myalgia or arthralgia, fatigue, and headache could be considered red flags (defined as having a positive likelihood ratio of at least 5) for COVID‐19 as their specificity was above 90%, meaning that they substantially increase the likelihood of COVID‐19 disease when present. Seven studies carried a high risk of bias for selection of participants because inclusion in the studies depended on the applicable testing and referral protocols, which included many of the signs and symptoms under study in this review. Five studies only included participants with pneumonia on imaging, suggesting that this is a highly selected population. In an additional four studies, we were unable to assess the risk for selection bias. These factors make it very difficult to determine the diagnostic properties of these signs and symptoms from the included studies. We also had concerns about the applicability of these results, since most studies included participants who were already admitted to hospital or presenting to hospital settings. This makes these findings less applicable to people presenting to primary care, who may have less severe illness and a lower prevalence of COVID‐19 disease. None of the studies included any data on children, and only one focused specifically on older adults. We hope that future updates of this review will be able to provide more information about the diagnostic properties of signs and symptoms in different settings and age groups. AUTHORS' CONCLUSIONS: The individual signs and symptoms included in this review appear to have very poor diagnostic properties, although this should be interpreted in the context of selection bias and heterogeneity between studies. Based on currently available data, neither absence nor presence of signs or symptoms are accurate enough to rule in or rule out disease. Prospective studies in an unselected population presenting to primary care or hospital outpatient settings, examining combinations of signs and symptoms to evaluate the syndromic presentation of COVID‐19 disease, are urgently needed. Results from such studies could inform subsequent management decisions such as self‐isolation or selecting patients for further diagnostic testing. We also need data on potentially more specific symptoms such as loss of sense of smell. Studies in older adults are especially important.

Cochrane Database Syst Rev2020       LitCov and CORD-19
629Kinetics of the B- and T-Cell Immune Responses After 6 Months From SARS-CoV-2 mRNA Vaccination in Patients With Rheumatoid Arthritis  

OBJECTIVE: To assess the kinetics of the humoral and cell-mediated responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in rheumatoid arthritis (RA) patients treated with different immunosuppressive therapies. METHODS: Following vaccine completed schedule, health care workers (HCWs, n = 49) and RA patients (n = 35) were enrolled at 5 weeks (T1) and 6 months (T6) after the first dose of BNT162b2-mRNA vaccination. Serological response was assessed by quantifying anti-receptor-binding domain (RBD)-specific immunoglobulin G (IgG) and SARS-CoV-2 neutralizing antibodies, while cell-mediated response was assessed by a whole-blood test quantifying the interferon (IFN)-γ response to spike peptides. B-cell phenotype and IFN-γ-specific T-cell responses were evaluated by flow cytometry. RESULTS: After 6 months, anti-RBD antibodies were still detectable in 91.4% of RA patients, although we observed a significant reduction of the titer in patients under Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)-Ig [median: 16.4 binding antibody units (BAU)/ml, interquartile range (IQR): 11.3–44.3, p < 0.0001] or tumor necrosis factor (TNF)-α inhibitors (median: 26.5 BAU/ml, IQR: 14.9–108.8, p = 0.0034) compared to controls (median: 152.7 BAU/ml, IQR: 89.3–260.3). All peripheral memory B-cell (MBC) subpopulations, in particular, the switched IgG(+) MBCs (CD19(+)CD27(+)IgD(-)IgM(-)IgG(+)), were significantly reduced in RA subjects under CTLA-4-Ig compared to those in HCWs (p = 0.0012). In RA patients, a significantly reduced anti-RBD IgG titer was observed at T6 vs. T1, mainly in those treated with CTLA-4-Ig (p = 0.002), interleukin (IL)-6 inhibitors (p = 0.015), and disease-modifying antirheumatic drugs (DMARDs) ± corticosteroids (CCSs) (p = 0.015). In contrast, a weak nonsignificant reduction of the T-cell response was reported at T6 vs. T1. T-cell response was found in 65.7% of the RA patients at T6, with lower significant magnitude in patients under CTLA-4-Ig compared to HCWs (p < 0.0001). The SARS-CoV-2 IFN-γ-S-specific T-cell response was mainly detected in the CD4(+) T-cell compartment. CONCLUSIONS: In this study, in RA patients after 6 months from COVID-19 vaccination, we show the kinetics, waning, and impairment of the humoral and, to a less extent, of the T-cell response. Similarly, a reduction of the specific response was also observed in the controls. Therefore, based on these results, a booster dose of the vaccine is crucial to increase the specific immune response regardless of the immunosuppressive therapy.

Front Immunol2022       LitCov and CORD-19
630Maternal and perinatal outcomes of SARS-CoV-2 infection in unvaccinated pregnancies during Delta and Omicron waves  

OBJECTIVES: Currently, there is little evidence related to the effects of the Omicron variant on pregnancy outcomes, particularly in unvaccinated women. This study aims to compare pregnancy outcomes of SARS‐CoV‐2 infected, unvaccinated women during the pre‐Delta, Delta, and Omicron waves. METHODS: This was a retrospective cohort study at two tertiary care facilities: Sancaktepe Training and Research Hospital, Istanbul, Turkey, and St. George's University Hospitals NHS Foundation Trust, London, UK. Included were people testing RT‐PCR positive for SARS‐CoV‐2 during pregnancy, between April 01, 2020 and February 14, 2022, and divided into three epochs: (i) pre‐Delta, 1 Apr 2020 to 8 Jun 2021 in Turkey, and 1 Apr 2020 to 31 Jul 2021 in the UK; (ii) Delta, 9 Jun 2021 to 27 Dec 2021 in Turkey, and 1 Aug 2021 to 27 Dec 2021 in the UK; and (iii) Omicron, after 27 Dec 2021 in each of Turkey and the UK, according to the date of their positive RT‐PCR test. Baseline data collected included maternal age, parity, body mass index (BMI), smoking status, gestational age at diagnosis, and comorbidities. The primary outcome was the need for oxygen supplementation, classified as oxygen support via nasal cannula or breather mask, non‐invasive mechanical ventilation with continuous positive airway pressure (CPAP) or high‐flow oxygen, mechanical ventilation with intubation, or extracorporeal membrane oxygenation (ECMO). Inferences were made after balancing of confounders, using an evolutionary search algorithm. RESULTS: 1285 RT‐PCR‐proven SARS‐CoV‐2 infections of unvaccinated pregnant women were identified during the pre‐Delta (N=870), Delta (N=339), and Omicron (N=77) epochs. In the confounder‐balanced cohort, infection during the Delta wave was associated with increased need for nasal oxygen support (RR 2.53, 95% confidence interval [CI] 1.75‐3.65, P<.001), CPAP or high‐flow oxygen (RR 2.50, 95% CI 1.37‐4.56, P=.002), mechanical ventilation (RR 4.20, 95% CI 1.60‐11.0, P=.003), and ECMO (RR 11.0, 95% CI 1.43‐84.7, P=.021). The maternal mortality rate was also 3‐4 fold higher during the Delta wave compared to pre‐Delta (5.3% vs 1.5%, P=0.010). An infection during the Omicron wave was not associated with an increased need for nasal oxygen support (RR 0.62, 95% CI 0.25‐1.55, P=0.251), CPAP or high‐flow oxygen (RR 1.07, 95% CI 0.36‐3.12, P=0.906), or mechanical ventilation (RR 0.44, 95% CI 0.06‐3.45, P=0.438). The maternal mortality rate was similar during the Omicron wave and the pre‐Delta period (1.3% vs 1.3%, P=0.999). Nasal oxygen support during the Omicron wave was significantly lower compared to Delta‐wave infection (RR 0.26, 95% CI 0.11‐0.64, P=0.003). Perinatal outcomes were available for a subset of the confounder‐balanced cohort. Preterm birth below 34 weeks’ gestation was significantly increased (P<0.001) during the Delta wave compared with pre‐Delta. CONCLUSIONS: Among unvaccinated pregnant women, SARS‐CoV‐2 infection during (vs. before) the Delta wave was associated with increased requirement for oxygen support (including ECMO) and higher maternal mortality. Disease severity and pregnancy complications were similar during the Omicron wave (vs. pre‐Delta). SARS‐CoV‐2 infection in unvaccinated pregnant women carries considerable risks of morbidity and mortality, and COVID‐19 vaccination remains key. Miscommunication of risks of Omicron infection may adversely impact the vaccination rate among pregnant women, who are already at increased risk of complications related to COVID‐19. This article is protected by copyright. All rights reserved.

Ultrasound Obstet Gynecol2022       LitCov and CORD-19
631COVID-19 vaccine hesitancy in Zambia: a glimpse at the possible challenges ahead for COVID-19 vaccination rollout in sub-Saharan Africa  

With unprecedented speed, multiple vaccines against SARS-CoV-2 are available 1 year after the COVID-19 pandemic was first identified. As we push to achieve global control through these new vaccines, old challenges present themselves, including cold-chain storage, the logistics of mass vaccination, and vaccine hesitancy. Understanding how much hesitancy toward COVID-19 vaccines might occur and what factors may be driving these concerns can improve the ability of public health workers and communicators to maximize vaccine uptake. We nested a survey within a measles-rubella mass vaccination campaign in Zambia in November 2020 and asked about sentiments and beliefs toward COVID-19 and COVID-19 vaccines. Among parents bringing their children to receive a measles-rubella vaccine, we found high acceptability of COVID-19 vaccination of their children, but substantial uncertainty and hesitancy about receiving the vaccine themselves. COVID-19 vaccination hesitancy was correlated with beliefs around COVID-19 severity and risk, as well as vaccine safety and effectiveness.

Hum Vaccin Immunother2021       LitCov and CORD-19
632Symptom prevalence, duration and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study  

BACKGROUND: The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population. METHODS: In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16–99 years, based in the UK, with a body-mass index between 15 and 55 kg/m(2), had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence. FINDINGS: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16–0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43–1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57–0·98, p=0·03). INTERPRETATION: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work–health policies and public health advice. FUNDING: Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, and Medical Research Council

Lancet2022       LitCov and CORD-19
633BNT162b2 Protection against the Omicron Variant in Children and Adolescents  

BACKGROUND: Spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, which led to increased U.S. hospitalizations for coronavirus disease 2019 (Covid-19), generated concern about immune evasion and the duration of protection from vaccines in children and adolescents. METHODS: Using a case–control, test-negative design, we assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2 messenger RNA vaccine) at least 14 days before illness among case patients and controls, according to time since vaccination for patients 12 to 18 years of age and in periods coinciding with circulation of B.1.617.2 (delta) (July 1, 2021, to December 18, 2021) and omicron (December 19, 2021, to February 17, 2022) among patients 5 to 11 and 12 to 18 years of age. RESULTS: We enrolled 1185 case patients (1043 [88%] of whom were unvaccinated, 291 [25%] of whom received life support, and 14 of whom died) and 1627 controls. During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval [CI], 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, −25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days). CONCLUSIONS: BNT162b2 vaccination reduced the risk of omicron-associated hospitalization by two thirds among children 5 to 11 years of age. Although two doses provided lower protection against omicron-associated hospitalization than against delta-associated hospitalization among adolescents 12 to 18 years of age, vaccination prevented critical illness caused by either variant. (Funded by the Centers for Disease Control and Prevention.)

N Engl J Med2022       LitCov and CORD-19
634Safety and humoral response rate of inactivated and mRNA vaccines against SARS-CoV-2 in patients with Multiple Sclerosis  

BACKGROUND: Safety and effectiveness outcomes in Multiple Sclerosis (MS) patients receiving different disease-modifying therapies (DMT) and different types of vaccines against SARS-CoV-2 are limited. Growing evidence coming mainly from Israel, Europe and North America using mRNA and adenoviral vector vaccines has been published. OBJECTIVES: To assess the safety and humoral response of inactivated virus and mRNA vaccines against SARS-CoV-2 in patients with MS. METHODS: Ongoing, multicentric, prospective, observational study performed between February and September 2021. Humoral response (antibodies against spike-1 protein) was determined at least 4 weeks after the complete schedule of anti-SARS-CoV-2 vaccines. Categorical outcome (positive/negative) and total antibody titres were recorded. Adverse events supposedly attributable to vaccination (AESAV) were collected. RESULTS: 178 patients, 68% women, mean age 39.7 ± 11.2 years, 123 received inactivated (Coronavac-Sinovac), 51 mRNA (Pfizer-BioNtech), and 4 adenoviral vector vaccines (CanSino n = 2, Jonhson&Johnson-Jannsen n = 1, Oxford-AstraZeneca n = 1). Six patients had a history of COVID-19 before vaccination. Overall humoral response was observed in 66.9% (62.6% inactivated vs. 78.4% mRNA, p = 0.04). Positive anti-S1-antibodies were observed in 100% of patients with no DMT (n = 3), 100% with interferon/glatiramer-acetate (n = 11), 100% with teriflunomide/dimethyl-fumarate (n = 16), 100% with natalizumab (n = 10), 100% with alemtuzumab (n = 8), 90% with cladribine (n = 10), and 88% with fingolimod (n = 17), while 43% of patients receiving antiCD20 (n = 99) were positive (38% inactivated vaccine vs. 59% mRNA vaccine, p = 0.05). In the multivariate analysis including antiCD20 patients, the predictors for a positive humoral response were receiving the mRNA vaccine (OR 8.11 (1.79–36.8), p = 0.007) and a lower number of total infusions (OR 0.44 (0.27–0.74) p = 0.002. The most frequent AESAV was local pain (14%), with 4 (2.2%) patients experiencing mild-moderate relapses within 8 weeks of first vaccination compared to 11 relapses (6.2%) within the 8 weeks before vaccination (Chi-squared 3.41, p = 0.06). DISCUSSION: A higher humoral response rate was observed using the mRNA compared to the inactivated vaccine, while patients using antiCD20 had a significantly lower response rate, and patients using antiCD20 and fingolimod had lower antibody titres. In this MS patient cohort, inactivated and mRNA vaccines against SARS-CoV-2 appear to be safe, with no increase in relapse rate. This information may help guidelines including booster shots and types of vaccines in selected populations.

Mult Scler Relat Disord2022       LitCov and CORD-19
635Safety, tolerability and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial  

BACKGROUND: A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. METHODS: We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 10(10), 1 × 10(11), and 1·5 × 10(11) viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127. FINDINGS: Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination. INTERPRETATION: The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation. FUNDING: National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.

Lancet2020       LitCov and CORD-19
636Children's rates of COVID-19 vaccination as reported by parents, vaccine hesitancy and determinants of COVID-19 vaccine uptake among children: a multi-country study from the Eastern Mediterranean Region  

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BMC Public Health2022       LitCov
637Students' Views towards Sars-Cov-2 Mass Asymptomatic Testing, Social Distancing and Self-Isolation in a University Setting during the COVID-19 Pandemic: A Qualitative Study  

We aimed to explore university students’ perceptions and experiences of SARS-CoV-2 mass asymptomatic testing, social distancing and self-isolation, during the COVID-19 pandemic. This qualitative study comprised of four rapid online focus groups conducted at a higher education institution in England, during high alert (tier 2) national COVID-19 restrictions. Participants were purposively sampled university students (n = 25) representing a range of gender, age, living circumstances (on/off campus), and SARS-CoV-2 testing/self-isolation experiences. Data were analysed using an inductive thematic approach. Six themes with 16 sub-themes emerged from the analysis of the qualitative data: ‘Term-time Experiences’, ‘Risk Perception and Worry’, ‘Engagement in Protective Behaviours’, ‘Openness to Testing’, ‘Barriers to Testing’ and ‘General Wellbeing’. Students described feeling safe on campus, believed most of their peers are adherent to protective behaviours and were positive towards asymptomatic testing in university settings. University communications about COVID-19 testing and social behaviours need to be timely and presented in a more inclusive way to reach groups of students who currently feel marginalised. Barriers to engagement with SARS-CoV-2 testing, social distancing and self-isolation were primarily associated with fear of the mental health impacts of self-isolation, including worry about how they will cope, high anxiety, low mood, guilt relating to impact on others and loneliness. Loneliness in students could be mitigated through increased intra-university communications and a focus on establishment of low COVID-risk social activities to help students build and enhance their social support networks. These findings are particularly pertinent in the context of mass asymptomatic testing programmes being implemented in educational settings and high numbers of students being required to self-isolate. Universities need to determine the support needs of students during self-isolation and prepare for the long-term impacts of the pandemic on student mental health and welfare support services.

Int J Environ Res Public Healt2021       LitCov and CORD-19
638Sequential Analysis of Binding and Neutralizing Antibody in COVID-19 Convalescent Patients at 14 Months After SARS-CoV-2 Infection  

Durability of SARS-CoV-2 Spike antibody responses after infection provides information relevant to understanding protection against COVID-19 in humans. We report the results of a sequential evaluation of anti-SARS-CoV-2 antibodies in convalescent patients with a median follow-up of 14 months (range 12.4-15.4) post first symptom onset. We report persistence of antibodies for all four specificities tested [Spike, Spike Receptor Binding Domain (Spike-RBD), Nucleocapsid, Nucleocapsid RNA Binding Domain (N-RBD)]. Anti-Spike antibodies persist better than anti-Nucleocapsid antibodies. The durability analysis supports a bi-phasic antibody decay with longer half-lives of antibodies after 6 months and antibody persistence for up to 14 months. Patients infected with the Wuhan (WA1) strain maintained strong cross-reactive recognition of Alpha and Delta Spike-RBD but significantly reduced binding to Beta and Mu Spike-RBD. Sixty percent of convalescent patients with detectable WA1-specific NAb also showed strong neutralization of the Delta variant, the prevalent strain of the present pandemic. These data show that convalescent patients maintain functional antibody responses for more than one year after infection, suggesting a strong long-lasting response after symptomatic disease that may offer a prolonged protection against re-infection. One patient from this cohort showed strong increase of both Spike and Nucleocapsid antibodies at 14 months post-infection indicating SARS-CoV-2 re-exposure. These antibodies showed stronger cross-reactivity to a panel of Spike-RBD including Beta, Delta and Mu and neutralization of a panel of Spike variants including Beta and Gamma. This patient provides an example of strong anti-Spike recall immunity able to control infection at an asymptomatic level. Together, the antibodies from SARS-CoV-2 convalescent patients persist over 14 months and continue to maintain cross-reactivity to the current variants of concern and show strong functional properties.

Front Immunol2021       LitCov and CORD-19
639Cardiovascular Implications of Fatal Outcomes of Patients With COVID-19  

IMPORTANCE: Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents. Information regarding the impact of cardiovascular complication on fatal outcome is scarce. OBJECTIVE: To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020. Analysis began February 25, 2020. MAIN OUTCOMES AND MEASURES: Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels. RESULT: Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died. The mean (SD) age was 58.50 (14.66) years. Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels. The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs. Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]). Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro–brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001). Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16). During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (41 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels. The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 25.6% (43 of 168). CONCLUSIONS AND RELEVANCE: Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable. Myocardial injury is associated with cardiac dysfunction and arrhythmias. Inflammation may be a potential mechanism for myocardial injury. Aggressive treatment may be considered for patients at high risk of myocardial injury.

JAMA Cardiol2020       LitCov and CORD-19
640Trajectories of anxiety and depressive symptoms during enforced isolation due to COVID-19 in England: a longitudinal observational study  

BACKGROUND: There is major concern about the impact of the global COVID-19 outbreak on mental health. Several studies suggest that mental health deteriorated in many countries before and during enforced isolation (ie, lockdown), but it remains unknown how mental health has changed week by week over the course of the COVID-19 pandemic. This study aimed to explore the trajectories of anxiety and depression over the 20 weeks after lockdown was announced in England, and compare the growth trajectories by individual characteristics. METHODS: In this prospective longitudinal observational study, we analysed data from the UCL COVID-19 Social Study, a panel study weighted to population proportions, which collects information on anxiety (using the Generalised Anxiety Disorder assessment) and depressive symptoms (using the Patient Health Questionnaire) weekly in the UK since March 21, 2020. We included data from adults living in England who had at least three repeated measures between March 23 and Aug 9, 2020. Analyses were done using latent growth models, which were fitted to account for sociodemographic and health covariates. FINDINGS: Between March 23, and Aug 9, data from over 70 000 adults were collected in the UCL COVID-19 Social Study. When including participants living in England with three follow-up measures and no missing values, our analytic sample consisted of 36 520 participants. The average depression score was 6·6 (SD=6·0, range 0–27) and the average anxiety score 5·7 (SD=5·6, range 0–21) in week 1. Anxiety and depression levels both declined across the first 20 weeks following the introduction of lockdown in England (b=–1·93, SE=0·26, p<0·0001 for anxiety; b=–2·52, SE=0·28, p<0·0001 for depressive symptoms). The fastest decreases were seen across the strict lockdown period (between weeks 2 and 5), with symptoms plateauing as further lockdown easing measures were introduced (between weeks 16 and 20). Being a woman or younger, having lower educational attainment, lower income, or pre-existing mental health conditions, and living alone or with children were all risk factors for higher levels of anxiety and depression at the start of lockdown. Many of these inequalities in experiences were reduced as lockdown continued, but differences were still evident 20 weeks after the start of lockdown. INTERPRETATION: These data suggest that the highest levels of depression and anxiety occurred in the early stages of lockdown but declined fairly rapidly, possibly because individuals adapted to circumstances. Our findings emphasise the importance of supporting individuals in the lead-up to future lockdowns to try to reduce distress, and highlight that groups already at risk for poor mental health before the pandemic have remained at risk throughout lockdown and its aftermath. FUNDING: Nuffield Foundation, UK Research and Innovation, Wellcome Trust.

Lancet Psychiatry2020       LitCov and CORD-19
641Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets  

Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.

mBio2020       LitCov and CORD-19
642Evaluating risk factors associated with COVID-19 infections among vaccinated people early in the US vaccination campaign: an observational study of five states, January-March 2021  

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BMC Infect Dis2022       LitCov
643Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19  

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J Biol Regul Homeost Agents2020       LitCov and CORD-19
644Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD  

OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine. DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3–10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine. RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn’s disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine. CONCLUSION: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Gut2021       LitCov and CORD-19
645A global survey of potential acceptance of a COVID-19 vaccine  

Several coronavirus disease 2019 (COVID-19) vaccines are currently in human trials. In June 2020, we surveyed 13,426 people in 19 countries to determine potential acceptance rates and factors influencing acceptance of a COVID-19 vaccine. Of these, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine, and 61.4% reported that they would accept their employer’s recommendation to do so. Differences in acceptance rates ranged from almost 90% (in China) to less than 55% (in Russia). Respondents reporting higher levels of trust in information from government sources were more likely to accept a vaccine and take their employer’s advice to do so.

Nat Med2020       LitCov and CORD-19
646Burnout and Associated Factors Among Healthcare Workers in Singapore During the COVID-19 Pandemic  

Objectives The strain on healthcare systems due to the COVID-19 pandemic has led to increased psychological distress among healthcare workers (HCWs). As this global crisis continues with little signs of abatement, we examine burnout and associated factors among HCWs. Design Cross-sectional survey study. Setting and Participants Doctors, nurses, allied health professionals, administrative and support staff in four public hospitals and one primary care service in Singapore 3 months after COVID-19 was declared a global pandemic. Methods Study questionnaire captured demographic and workplace environment information and comprised three validated instruments, namely the Oldenberg Burnout Inventory (OLBI), Safety Attitudes Questionnaire (SAQ), and Hospital Anxiety and Depression Scale (HADS). Multivariate mixed model regression analyses were employed to evaluate independent associations of mean OLBI-Disengagement and -Exhaustion scores. Further subgroup analysis was performed among redeployed HCWs. Results Among 11,286 invited HCWs, 3,075 valid responses were received, giving an overall response rate of 27.2%. Mean OLBI scores were 2.38 and 2.50 for Disengagement and Exhaustion respectively. Burnout thresholds in Disengagement and Exhaustion were met by 79.7% and 75.3% of respondents respectively. On multivariate regression analysis, Chinese or Malay ethnicity, HADS anxiety or depression scores ≥8, shifts lasting ≥8 hours and being redeployed were significantly associated with higher OLBI mean scores, while high SAQ scores were significantly associated with lower scores. Among redeployed HCWs, those redeployed to high-risk areas in a different facility (offsite) had lower burnout scores than those redeployed within their own work facility (onsite). A higher proportion of HCWs redeployed offsite assessed their training to be good or better compared to those redeployed onsite. Conclusions and Implications Every level of the healthcare workforce is susceptible to high levels of burnout during this pandemic. Modifiable workplace factors include adequate training, avoiding prolonged shifts ≥8 hours and promoting safe working environments. Mitigating strategies should target every level of the healthcare workforce including frontline and non-frontline staff. Addressing and ameliorating burnout among HCWs should be a key priority for the sustainment of efforts to care for patients in the face of a prolonged pandemic.

J Am Med Dir Assoc2020       LitCov and CORD-19
647COVID-19 Pandemic and Mental Health Status of Saudi Citizens Living Abroad  

Background: The COVID-19 pandemic is a global health crisis associated with unprecedented levels of morbidity and mortality worldwide. The COVID-19 pandemic has been suggested to contribute to a great burden on global mental health. We assumed that individuals in quarantine outside their home country would be more vulnerable to developing mental health disorders during the current pandemic and might face difficulties in accessing mental health services. Aim: To explore the degree of association between the COVID-19 pandemic and mental health status of Saudi citizens living abroad. Objectives: (1) To measure the prevalence and risk factors of mental health problems among Saudi citizens studying and living abroad during the COVID-19 pandemic; (2) to assess the correlation between the COVID-19 pandemic and mental health status of Saudi citizens living abroad; and (3) to explore the level of anxiety/depression during the COVID-19 pandemic. Methods: A cross-sectional survey was conducted from August 2020 to September 2020 using a self-administrated questionnaire composed of sociodemographic, (GAD-7) and (PHQ-9) scales. Results: A total of 64% of participants experienced psychiatric symptoms during the pandemic, and 34% and 30% met the diagnostic criteria for symptoms of depression and anxiety, respectively. The risk of psychological symptoms was more likely experienced by females, young, single, or divorced, or those who were living alone. In addition, those who lived in the UK and Ireland were more likely to develop depressive and anxiety symptoms. More than 80% appreciated the response of the Saudi government and embassy to meet the MH needs of students undergoing quarantine abroad and in Saudi Arabia. Conclusions: The COVID-19 pandemic represents an unprecedented threat to global mental health. Two-thirds of study participants who were in foreign countries during the COVID-19 pandemic reported anxiety or depressive symptoms. Living away from family and friends was significantly associated with increased loneliness and psychological distress. These and other findings highlight the need to remove barriers preventing easily accessible online mental health services, social and family support, and timely provision of resources.

Int J Environ Res Public Healt2021       LitCov and CORD-19
648Safety Monitoring after the BNT162b2 COVID-19 Vaccine among Adults Aged 75 Years or Older  

BACKGROUND: Older adults are given high priority for coronavirus disease 2019 (COVID-19) vaccination; however, little is known about the safety of vaccines. This study was conducted to examine the safety of the COVID-19 vaccine for people who were ≥ 75 years of age, specifically those who first took two doses of the vaccine at the COVID-19 central vaccination center in South Korea. METHODS: Safety monitoring after the BNT162b2 vaccine was conducted in three ways for older adults who received the first dose of the vaccine at our center between April 5 and April 23, 2021. For immediate adverse reactions, every person who was vaccinated was observed for 15–30 minutes after injection at the center. For active surveillance, a telephone interview was conducted for stratified randomly sampled people after 7 days of each vaccination to enquire regarding types of adverse reactions they experienced, and its severity and duration. For passive surveillance, reported adverse event data were collected from the COVID-19 vaccine adverse event following immunization (AEFI) surveillance system—run by the Korea Disease Control and Prevention Agency (KDCA). The data were then reviewed. RESULTS: In total, 2,123 older adults received at least one vaccine dose during the study period. The frequency of acute adverse reactions that developed during the observed 15–30 minutes after injection was 8.5 cases per 1,000 doses. None of the reactions was assessed as acute allergic reactions to the vaccine and no cases required special treatment or drug administration. Overall, 638 people were followed up at least once by telephone interview 7 days post vaccination. The overall response rate was 82.3%. The rates of local reactions were 50.3% after the first dose and 45.2% after the second dose, and the rates of systemic reactions were 15.2% and 26.0%, respectively. During the study period, 23 medically attended adverse events (5.4 cases per 1,000 administered doses) were reported to the KDCA AEFI surveillance system. The most common symptoms of medically attended cases were nonspecific general weakness (26%) and dizziness (26%), followed by muscle pain (22%), headache (13%), fever (13%), and skin rash or urticaria (13%). Among them, there were five serious adverse events reported, which required hospitalization, including one death. However, most of them were not related to the vaccines. CONCLUSION: BNT162b2 vaccination was tolerable among adults who were ≥ 75 years of age.

J Korean Med Sci2021       LitCov and CORD-19
649Video calls for reducing social isolation and loneliness in older people: a rapid review  

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Cochrane Database Syst Rev2020       LitCov and CORD-19
650A Generic, Scalable and Rapid Time-Resolved Förster Resonance Energy Transfer-Based Assay for Antigen Detection-SARS-CoV-2 as a Proof of Concept  

The ongoing coronavirus disease 2019 (COVID-19) pandemic has seen an unprecedented increase in the demand for rapid and reliable diagnostic tools, leaving many laboratories scrambling for resources. We present a fast and simple assay principle for antigen detection and demonstrate its functionality by detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in nasopharyngeal swabs. The method is based on the detection of SARS-CoV-2 nucleoprotein (NP) and S protein (SP) via time-resolved Förster resonance energy transfer (TR-FRET) with donor- and acceptor-labeled polyclonal anti-NP and -SP antibodies. Using recombinant proteins and cell culture-grown SARS-CoV-2, the limits of detection were established as 25 pg of NP or 20 infectious units (IU) and 875 pg of SP or 625 IU. Testing reverse transcription-PCR (RT-PCR)-positive (n = 48, with cycle threshold [C(T)] values from 11 to 30) or -negative (n = 96) nasopharyngeal swabs demonstrated that the assay yielded positive results for all samples with C(T) values of <25 and for a single RT-PCR-negative sample. Virus isolation from the RT-PCR-positive nasopharyngeal swabs showed a strong association between the presence of infectious virus and a positive antigen test result. The NP-based assay showed 97.4% (37/38) sensitivity and 100% (10/10) specificity in comparison with virus isolation and 77.1% (37/48) sensitivity and 99.0% (95/96) specificity in comparison with SARS-CoV-2 RT-PCR. The assay is performed in a buffer that neutralizes SARS-CoV-2 infectivity, and the assay is relatively simple to set up as an “in-house” test. Here, SARS-CoV-2 served as the model pathogen, but the assay principle is applicable to other viral infections, and the test format could easily be adapted to high-throughput testing.

mBio2021       LitCov and CORD-19

(1) COVID-19 Open Research Dataset (CORD-19). 2020. Version 2022-06-02. Retrieved from https://ai2-semanticscholar-cord-19.s3-us-west-2.amazonaws.com/historical_releases.html. Accessed 2022-06-05. doi:10.5281/zenodo.3715506
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(3) Currently tweets of June 23rd to June 29th 2022 have been considered.

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