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: 16 - 06 - 2022 (568924 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
251Prevalence and determinants of SARS-CoV-2 vaccine hesitancy in Hong Kong: A population-based survey  

BACKGROUND: Although vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most desired solution to end the coronavirus disease (COVID-19) pandemic, there are growing concerns that vaccine hesitancy would undermine its potential. We examined the intention to receive vaccination against SARS-CoV-2 and the associated factors in a representative sample of Chinese adults in Hong Kong. METHODS: We did a dual-frame (landline and mobile) cross-sectional survey of a random sample of 1501 Hong Kong residents aged 18 years or older (53.6% females) in April 2020. We collected data on the intention to receive SARS-CoV-2 vaccine when it becomes available (yes/ no/ undecided), knowledge and perceptions of COVID-19, smoking, alcohol drinking, and sociodemographic factors. Prevalence estimates were weighted by the sex, age, and education of the general population of Hong Kong. RESULTS: Overall, 45.3% (95% CI: 42.3–48.4%) of the participants had intentions to vaccinate against SARS-CoV-2 when it becomes available, 29.2% (26.5–32.1%) were undecided, and 25.5% (22.9–28.2%) had no intention. The most common reason for vaccine hesitancy (undecided or no intention) was safety concerns (56.5%). Multivariable partial proportional odds model showed higher vaccine hesitancy in males, younger adults, those with no chronic disease, current smokers, and non-alcohol drinkers. After adjusting for sociodemographic and other factors, inadequate knowledge of SARS-CoV-2 transmission (adjusted ORs ranged from 1.27 to 2.63; P < 0.05) and lower perceived danger of COVID-19 (adjusted ORs ranged from 1.62 to 2.47; P < 0.001) were significantly associated with vaccine hesitancy. CONCLUSIONS: In a representative sample of Chinese adults in Hong Kong, only 45.3% of the participants intended to vaccinate against SARS-CoV-2 when available. Vaccine hesitancy was associated with inadequate knowledge about SARS-CoV-2 transmission and lower perceived danger of COVID-19, which needed to be addressed to improve vaccination uptake.

Vaccine2021       LitCov and CORD-19
252COVID-19 vaccine acceptance, hesitancy and determinants among physicians in a university-based teaching hospital in Thailand  

BACKGROUND: The COVID-19 vaccines provide renewed hope in the fight against the recent pandemic. To ensure widespread vaccination, it is crucial to analyze vaccine willingness and its determinants among physicians, key health care influencers. This study aimed to assess acceptance rate and identify factors associated with vaccine hesitancy among Thai physicians. METHODS: A cross-sectional online-based questionnaire was distributed to all physicians at King Chulalongkorn Memorial Hospital during March 31, 2021 to April 30, 2021 in order to assess their attitudes toward receiving the COVID-19 vaccine. Reasons for vaccine acceptance and refusal as well as predictors of vaccine hesitancy were analyzed by bivariate and multivariable analysis. RESULTS: A total of 705 complete responses were received with 95.6% (n = 675) of physicians expressing willingness to receive a COVID-19 vaccine. Only one of the 31 physicians (4.4%) who expressed a hesitancy or unwillingness to be vaccinated was a faculty member; the others were physicians-in-training. Approximately one-fifths of physicians surveyed were also not willing to recommend the vaccine to their family members (21.4%, n = 151) or patients (18.7%, n = 132). Using multivariable logistic regression, vaccine hesitancy was independently associated with preference for particular vaccines over the government allocated option, especially for mRNA vaccine (aOR 8.86; 95% CI 1.1–71.54; p = 0.041). Vaccine literacy showed an inverse relationship (aOR 0.34; 95% CI 0.13–0.9; p = 0.029) with vaccine hesitancy. Uncertainty of the vaccine efficacy (83.9%) and fear of adverse events (48.4%) were major concerns contributing to vaccine hesitancy. CONCLUSION: This study revealed a high rate of physician willingness to take the COVID-19 vaccine especially among staffs; however, a significant proportion would not currently suggest vaccination to their families or patients. Restrictions on vaccine choice and vaccine illiteracy, together with concerns over adverse effects and uncertainty of efficacy, were associated with negative attitudes toward vaccination. To raise acceptance of the vaccination program, efforts should be made to balance individual preference for vaccine type in addition to increasing the availability of accurate data on safety and efficacy for each vaccine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-021-06863-5.

BMC Infect Dis2021       LitCov and CORD-19
253The significant immune escape of pseudotyped SARS-CoV-2 variant Omicron  

The emergence of Omicron/BA.1 has brought new challenges to fight against SARS-CoV-2. A large number of mutations in the Spike protein suggest that its susceptibility to immune protection elicited by the existing COVID-19 infection and vaccines may be altered. In this study, we constructed the pseudotyped SARS-CoV-2 variant Omicron. The sensitivity of 28 serum samples from COVID-19 convalescent patients infected with SARS-CoV-2 original strain was tested against pseudotyped Omicron as well as the other variants of concern (VOCs, Alpha, Beta, Gamma, Delta) and variants of interest (VOIs, Lambda, Mu). Our results indicated that the mean neutralization ED50 of these sera against Omicron decreased to 66, which is about 8.4-folds compared to the D614G reference strain (ED50 = 556), whereas the neutralization activity of other VOC and VOI pseudotyped viruses decreased only about 1.2–4.5-folds. The finding from our in vitro assay suggest that Omicron variant may lead to more significant escape from immune protection elicited by previous SARS-CoV-2 infection and perhaps even by existing COVID-19 vaccines.

Emerg Microbes Infect2021       LitCov and CORD-19
254Exposure to COVID-19-Related Information and its Association With Mental Health Problems in Thailand: Nationwide, Cross-sectional Survey Study  

BACKGROUND: The COVID-19 pandemic has had a negative impact on both the physical and mental health of individuals worldwide. Evidence regarding the association between mental health problems and information exposure among Thai citizens during the COVID-19 outbreak is limited. OBJECTIVE: This study aimed to explore the relationship between information exposure and mental health problems during the COVID-19 pandemic in Thailand. METHODS: Between April 21 and May 4, 2020, we conducted a cross-sectional, nationwide online survey of the general population in Thailand. We categorized the duration of exposure to COVID-19-related information as follows: <1 h/day (reference group), 1-2 h/day, and ≥3 h/day. Mental health outcomes were assessed using the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 scale, the Perceived Stress Scale-10, and the Insomnia Severity Index for symptoms of depression, anxiety, perceived stress, and insomnia, respectively. Multivariable logistic regression models were used to evaluate the relationship between information exposure and the risk of developing the aforementioned symptoms. An ancillary analysis using multivariable multinomial logistic regression models was also conducted to assess the possible dose-response relationship across the severity strata of mental health problems. RESULTS: Of the 4322 eligible participants, 4004 (92.6%) completed the online survey. Of them, 1481 (37.0%), 1644 (41.1%), and 879 (22.0%) participants were exposed to COVID-19-related information for less than 1 hour per day, 1 to 2 hours per day, or 3 or more hours per day, respectively. The major source of information related to the COVID-19 pandemic was social media (95.3%), followed by traditional media (68.7%) and family members (34.9%). Those exposed to information for 3 or more hours per day had a higher risk of developing symptoms of depression (adjusted odds ratio [OR] 1.35, 95% CI 1.03-1.76; P=.03), anxiety (adjusted OR 1.88, 95% CI 1.43-2.46; P<.001), and insomnia (adjusted OR 1.52, 95% CI 1.17-1.97; P=.001) than people exposed to information for less than 1 hour per day. Meanwhile, people exposed to information for 1 to 2 hours per day were only at risk of developing symptoms of anxiety (adjusted OR 1.35, 95% CI 1.08-1.69; P=.008). However, no association was found between information exposure and the risk of perceived stress. In the ancillary analysis, a dose-response relationship was observed between information exposure of 3 or more hours per day and the severity of mental health problems. CONCLUSIONS: These findings suggest that social media is the main source of COVID-19-related information. Moreover, people who are exposed to information for 3 or more hours per day are more likely to develop psychological problems, including depression, anxiety, and insomnia. Longitudinal studies investigating the long-term effects of COVID-19-related information exposure on mental health are warranted.

J Med Internet Res2021       LitCov and CORD-19
255Mental burden and its risk and protective factors during the early phase of the SARS-CoV-2 pandemic: systematic review and meta-analyses  

BACKGROUND: Mental burden due to the SARS-CoV-2 pandemic has been widely reported for the general public and specific risk groups like healthcare workers and different patient populations. We aimed to assess its impact on mental health during the early phase by comparing pandemic with prepandemic data and to identify potential risk and protective factors. METHODS: For this systematic review and meta-analyses, we systematically searched PubMed, PsycINFO, and Web of Science from January 1, 2019 to May 29, 2020, and screened reference lists of included studies. In addition, we searched PubMed and PsycINFO for prepandemic comparative data. Survey studies assessing mental burden by the SARS-CoV-2 pandemic in the general population, healthcare workers, or any patients (eg, COVID-19 patients), with a broad range of eligible mental health outcomes, and matching studies evaluating prepandemic comparative data in the same population (if available) were included. We used multilevel meta-analyses for main, subgroup, and sensitivity analyses, focusing on (perceived) stress, symptoms of anxiety and depression, and sleep-related symptoms as primary outcomes. RESULTS: Of 2429 records retrieved, 104 were included in the review (n = 208,261 participants), 43 in the meta-analysis (n = 71,613 participants). While symptoms of anxiety (standardized mean difference [SMD] 0.40; 95% CI 0.15–0.65) and depression (SMD 0.67; 95% CI 0.07–1.27) were increased in the general population during the early phase of the pandemic compared with prepandemic conditions, mental burden was not increased in patients as well as healthcare workers, irrespective of COVID-19 patient contact. Specific outcome measures (eg, Patient Health Questionnaire) and older comparative data (published ≥5 years ago) were associated with increased mental burden. Across the three population groups, existing mental disorders, female sex, and concerns about getting infected were repeatedly reported as risk factors, while older age, a good economic situation, and education were protective. CONCLUSIONS: This meta-analysis paints a more differentiated picture of the mental health consequences in pandemic situations than previous reviews. High-quality, representative surveys, high granular longitudinal studies, and more research on protective factors are required to better understand the psychological impacts of the SARS-CoV-2 pandemic and to help design effective preventive measures and interventions that are tailored to the needs of specific population groups. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12992-021-00670-y.

Global Health2021       LitCov and CORD-19
256Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II)  

OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: 1. Adults aged 18-65 years; 2. Voluntarily participate in this clinical trial and sign the “informed consent form” or have consent from a legal representative. 3. Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg). 4. COVID-19 featured lung lesions in chest X-ray image. 1. Patients have received other experimental treatment for COVID-19 within the last 30 days; 2. Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit); 3. Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m(2)) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis; 4. Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses; 5. Female patients who have no sexual protection in the last 30 days prior to the screening assessment; 6. Pregnant or lactating women or women using estrogen contraception; 7. Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period; 8. Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h ± 30min, 24h ± 30min after the injection) and follow-up period D90 ± 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h ± 30min, 24h ± 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 ± 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 ± 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 β, IL-2, TNF-a, ITN-γ), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood β-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 ± 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h ± 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient’s randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16(th) April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Trials2020       LitCov and CORD-19
257The Technological Impact of COVID-19 on the Future of Education and Healthcare Delivery  


Pain Physician2020       LitCov and CORD-19
258Efficacy of hydroxychloroquine for post-exposure prophylaxis to prevent SARS-CoV-2 infection among adults exposed to coronavirus disease: a structured summary of a study protocol for a randomised controlled trial  

OBJECTIVES: Primary Objective • To test the efficacy of Hydroxychloroquine (HCQ) (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection Secondary objectives • To determine the safety and tolerability of HCQ as SARS-CoV-2 Post-exposure Prophylaxis (PEP) in adults • To test the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection 2 weeks after completing therapy, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection • To test the efficacy of HCQ to shorten the duration of SARS-CoV-2 shedding among those with SARS-CoV-2 infection in the HCQ PEP group • To test the efficacy of HCQ to prevent incident COVID-19 TRIAL DESIGN: This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the virus. PARTICIPANTS: This study will enroll up to 2000 asymptomatic adults 18 to 80 years of age (inclusive) at baseline who are close contacts of persons with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. This multisite trial will be conducted at seven sites in Seattle (UW), Los Angeles (UCLA), New Orleans (Tulane), Baltimore (UMB), New York City (NYU), Syracuse (SUNY-Upstate), and Boston (BMC). Inclusion criteria 1. Men or women 18 to 80 years of age inclusive, at the time of signing the informed consent. 2. Willing and able to provide informed consent. 3. Had a close contact of a person (index) with known PCR-confirmed SARS-CoV-2 infection or index who is currently being assessed for COVID-19. a. Household contact (i.e., residing with the index case in the 14 days prior to index diagnosis or prolonged exposure within a residence/vehicle/enclosed space without maintaining social distance). b. Medical staff, first responders, or other care persons who cared for the index case without personal protection (mask and gloves): 4. Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 infection) to the index case; 5. Access to device and internet for Telehealth visits; 6. Not planning to take HCQ in addition to the study medication. Exclusion criteria 1. Known hypersensitivity to HCQ or other 4-aminoquinoline compounds. 2. Currently hospitalized. 3. Symptomatic with subjective fever, cough, or shortness of breath. 4. Current medications exclude concomitant use of HCQ. 5. Concomitant use of other anti-malarial treatment or chemoprophylaxis, including chloroquine, mefloquine, artemether, or lumefantrine. 6. History of retinopathy of any etiology. 7. Psoriasis. 8. Porphyria. 9. Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K). 10. Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen. 11. Known moderate or severe liver disease. 12. Known long QT syndrome. 13. Severe renal impairment. 14. Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of the study drugs or planned use during the study period. INTERVENTION AND COMPARATOR: Households will be randomized 1:1 (at the level of household), with close contact participants receiving one of the following therapies: •HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days •Placebo-like control (ascorbic acid) 500 mg orally daily for 3 days then 250 mg orally daily for 11 days MAIN OUTCOMES: The primary outcome of the study is the incidence of SARS-CoV-2 infection through day 14 among participants who are SARS-CoV-2 negative at baseline by randomization group. RANDOMISATION: Participants will be randomized in a 1:1 ratio to HCQ or ascorbic acid at the level of the household (all eligible participants in 1 household will receive the same intervention). The randomization code and resulting allocation list will be generated and maintained by the Study Statistician. The list will be blocked and stratified by site and contact type (household versus healthcare worker). BLINDING (MASKING): This is a blinded study. HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be bitter and ascorbic acid will be sour. The participants will be blinded to their randomization group once assigned. Study team members, apart from the Study Pharmacist and the unblinded statistical staff, will be blinded. Laboratory staff are blinded to the group allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size for the study is N=2 000 participants randomized 1:1 to either HCZ (n=1 000) and ascorbic acid (n=1 000). TRIAL STATUS: Protocol version: 1.2 05 April 2020 Recruitment is ongoing, started March 31 and anticipated end date is September 30, 2020. TRIAL REGISTRATION:, Protocol Registry Number: NCT04328961 Date of registration: April 1, 2020, retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Trials2020       LitCov and CORD-19
259Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study  

BACKGROUND: Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients. METHODS: In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death. FINDINGS: Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47–66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44–84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p<0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI −7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients. INTERPRETATION: Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic. FUNDING: European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

Lancet Gastroenterol Hepatol2020       LitCov and CORD-19
260COVID-19 pandemic and mental health consequences: Systematic review of the current evidence  

BACKGROUND: During the COVID-19 pandemic general medical complications have received the most attention, whereas only few studies address the potential direct effect on mental health of SARS-CoV-2 and the neurotropic potential. Furthermore, the indirect effects of the pandemic on general mental health are of increasing concern, particularly since the SARS-CoV-1 epidemic (2002-2003) was associated with psychiatric complications. METHODS: We systematically searched the database Pubmed including studies measuring psychiatric symptoms or morbidities associated with COVID-19 among infected patients and among none infected groups the latter divided in psychiatric patients, health care workers and non-health care workers. RESULTS: A total of 43 studies were included. Out of these, only two studies evaluated patients with confirmed COVID-19 infection, whereas 41 evaluated the indirect effect of the pandemic (2 on patients with preexisting psychiatric disorders, 20 on medical health care workers, and 19 on the general public). 18 of the studies were case-control studies/compared to norm, while 25 of the studies had no control groups. The two studies investigating COVID-19 patients found a high level of post-traumatic stress symptoms (PTSS) (96.2%) and significantly higher level of depressive symptoms (p=0.016). Patients with preexisting psychiatric disorders reported worsening of psychiatric symptoms. Studies investigating health care workers found increased depression/depressive symptoms, anxiety, psychological distress and poor sleep quality. Studies of the general public revealed lower psychological well-being and higher scores of anxiety and depression compared to before COVID-19, while no difference when comparing these symptoms in the initial phase of the outbreak to four weeks later. A variety of factors were associated with higher risk of psychiatric symptoms and/or low psychological well-being including female gender, poor-self-related health and relatives with COVID-19. CONCLUSION: Research evaluating the direct neuropsychiatric consequences and the indirect effects on mental health is highly needed to improve treatment, mental health care planning and for preventive measures during potential subsequent pandemics.

Brain Behav Immun2020       LitCov and CORD-19
261Multisite Clinical Validation of Isothermal Amplification-Based SARS-CoV-2 Detection Assays Using Different Sampling Strategies  

Isothermal amplification-based tests have been introduced as rapid, low-cost, and simple alternatives to real-time reverse transcriptase PCR (RT-PCR) tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection. The clinical performance of two isothermal amplification-based tests (Atila Biosystems iAMP coronavirus disease of 2019 [COVID-19] detection test and OptiGene COVID-19 direct plus RT-loop-mediated isothermal amplification [LAMP] test) was compared with that of clinical RT-PCR assays using different sampling strategies. A total of 1,378 participants were tested across 4 study sites. Compared with standard of care RT-PCR testing, the overall sensitivity and specificity of the Atila iAMP test for detection of SARS-CoV-2 were 76.2% and 94.9%, respectively, and increased to 88.8% and 89.5%, respectively, after exclusion of an outlier study site. Sensitivity varied based on the anatomic site from which the sample was collected. Sensitivity for nasopharyngeal sampling was 65.4% (range across study sites, 52.8% to 79.8%), for midturbinate was 88.2%, for saliva was 55.1% (range across study sites, 42.9% to 77.8%), and for anterior nares was 66.7% (range across study sites, 63.6% to 76.5%). The specificity for these anatomic collection sites ranged from 96.7% to 100%. Sensitivity improved in symptomatic patients (overall, 82.7%) and those with a higher viral load (overall, 92.4% for cycle threshold [C(T)] of ≤25). Sensitivity and specificity of the OptiGene direct plus RT-LAMP test, which was conducted at a single study site, were 25.5% and 100%, respectively. The Atila iAMP COVID test with midturbinate sampling is a rapid, low-cost assay for detecting SARS-CoV-2, especially in symptomatic patients and those with a high viral load, and could be used to reduce the risk of SARS-CoV-2 transmission in clinical settings. Variation of performance between study sites highlights the need for site-specific clinical validation of these assays before clinical adoption. IMPORTANCE Numerous SARS-CoV-2 detection assays have been developed and introduced into the market under emergency use authorizations (EUAs). EUAs are granted primarily based on small studies of analytic sensitivity and specificity with limited clinical validations. A thorough clinical performance evaluation of SARS-CoV-2 assays is important to understand the strengths, limitations, and specific applications of these assays. In this first large-scale multicentric study, we evaluated the clinical performance and operational characteristics of two isothermal amplification-based SARS-CoV-2 tests, namely, (i) iAMP COVID-19 detection test (Atila BioSystems, USA) and (ii) COVID-19 direct plus RT-LAMP test (OptiGene Ltd., UK), compared with those of clinical RT-PCR tests using different sampling strategies (i.e., nasopharyngeal, self-sampled anterior nares, self-sampled midturbinate, and saliva). An important specific use for these isothermal amplification-based, rapid, low-cost, and easy-to-perform SARS-CoV-2 assays is to allow for a safer return to preventive clinical encounters, such as cancer screening, particularly in low- and middle-income countries that have low SARS-CoV-2 vaccination rates.

Microbiol Spectr2021       LitCov and CORD-19
262Virological assessment of hospitalized patients with COVID-2019  


Nature2020       LitCov and CORD-19
263Prospective Assessment of SARS-CoV-2 Seroconversion (PASS) study: an observational cohort study of SARS-CoV-2 infection and vaccination in healthcare workers  

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

BMC Infect Dis2021       LitCov and CORD-19
264Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant  

BACKGROUND: The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear. METHODS: We used a test-negative case–control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (S) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients’ vaccination status. RESULTS: Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant. CONCLUSIONS: Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations. (Funded by Public Health England.)

N Engl J Med2021       LitCov and CORD-19
265Safety, 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, 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
266B and T-cell response to SARS-CoV-2 vaccination in Healthcare professionals with and without previous COVID-19  

BACKGROUND: In recent months numerous health care professional acquired COVID-19 at the workplace resulting in significant shortages in medical and nursing staff. We investigated how prior COVID-19 affects SARS-CoV-2 vaccination and how such knowledge could facilitate frugal vaccination strategies. METHODS: In a cohort of 41 healthcare professionals with (n=14) and without (n=27) previous SARS-CoV-2 infection, we assessed the immune status before, during and after vaccination with BNT162b2. The humoral immune response was assessed by receptor binding domain ELISA and different SARS-CoV-2 neutralisation assays using wildtype and pseudo-typed viruses. T cell immunity against SARS-CoV-2 surface and nucleocapsid peptides were studied using interferon-γ release assays and intracellular flow cytometry. Vaccine-related side effects were captured. FINDINGS: Prior COVID-19 resulted in improved vaccine responses both in the B and T cell compartment. In vaccine recipients with prior COVID-19, the first vaccine dose induced high antibody concentrations comparable to seronegative vaccine recipients after two injections. This translated into more efficient neutralisation of virus particles, even more pronounced than expected from the RBD ELISA results. Furthermore, T cell responses were stronger in convalescents and particularly strong against the SARS-CoV-2 nucleocapsid protein. INTERPRETATION: Herein, we corroborate recent findings suggesting that in convalescents a single vaccine dose is sufficient to boost adequate in vitro neutralisation of SARS-CoV-2 and therefore may be sufficient to induce adequate protection against severe COVID-19. New spike mutated virus variants render the highly conserved nucleocapsid protein – eliciting strong SARS-CoV-2 specific T cell immunity – an interesting additional vaccine target. FUNDING: Christian Doppler Research Association, Johannes Kepler University Linz

EBioMedicine2021       LitCov and CORD-19
267Signs 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
268A high rate of COVID-19 vaccine hesitancy in a large-scale survey on Arabs  

BACKGROUND: Vaccine hesitancy can limit the benefits of available vaccines in halting the spread of COVID-19 pandemic. Previously published studies paid little attention to Arab countries, which has a population of over 440 million. In this study, we present the results of the first large-scale multinational study that measures vaccine hesitancy among Arab-speaking subjects. METHODS: An online survey in Arabic was conducted from 14 January 2021 to 29 January 2021. It consisted of 17 questions capturing demographic data, acceptance of COVID-19 vaccine, attitudes toward the need for COVID-19 vaccination and associated health policies, and reasons for vaccination hesitancy. R software v.4.0.2 was used for data analysis and visualization. RESULTS: The survey recruited 36,220 eligible participants (61.1% males, 38.9% females, mean age 32.6 ± 10.8 years) from all the 23 Arab countries and territories (83.4%) and 122 other countries (16.6%). Our analysis shows a significant rate of vaccine hesitancy among Arabs in and outside the Arab region (83% and 81%, respectively). The most cited reasons for hesitancy are concerns about side effects and distrust in health care policies, vaccine expedited production, published studies and vaccine producing companies. We also found that female participants, those who are 30–59 years old, those with no chronic diseases, those with lower level of academic education, and those who do not know the type of vaccine authorized in their countries are more hesitant to receive COVID-19 vaccination. On the other hand, participants who regularly receive the influenza vaccine, health care workers, and those from countries with higher rates of COVID-19 infections showed more vaccination willingness. Interactive representation of our results is posted on our project website at CONCLUSIONS: Our results show higher vaccine hesitancy and refusal among Arab subjects, related mainly to distrust and concerns about side effects. Health authorities and Arab scientific community have to transparently address these concerns to improve vaccine acceptance. FUNDING: This study received no funding.

Elife2021       LitCov and CORD-19
269Antibody responses after a single dose of ChAdOx1 nCoV-19 vaccine in healthcare workers previously infected with SARS-CoV-2  

BACKGROUND: Recent reports demonstrate robust serological responses to a single dose of messenger RNA (mRNA) vaccines in individuals previously infected with SARS-CoV-2. Data on immune responses following a single-dose adenovirus-vectored vaccine expressing the SARS-CoV-2 spike protein (ChAdOx1 nCoV-19) in individuals with previous SARS-CoV-2 infection are however limited, and current guidelines recommend a two-dose regimen regardless of preexisting immunity. METHODS: We compared RBD-specific IgG and RBD-ACE2 blocking antibodies against SARS-CoV-2 wild type and variants of concern following two doses of the mRNA vaccine BNT162b2 in SARS-CoV-2 naïve healthcare workers (n=65) and a single dose of the adenovector vaccine ChAdOx1 nCoV-19 in 82 healthcare workers more than (n=45) and less than (n=37) 11 months post mild SARS-CoV-2 infection at time of vaccination. FINDINGS: The post-vaccine levels of RBD-specific IgG and neutralizing antibodies against the SARS-CoV-2 wild type and variants of concern including Delta lineage 1.617.2 were similar or higher in participants receiving a single dose of ChAdOx1 nCoV-19 vaccine post SARS-CoV-2 infection (both more than and less than 11 months post infection) compared to SARS-CoV-2 naïve participants who received two doses of BNT162b2 vaccine. INTERPRETATION: Our data support that a single dose ChAdOx1 nCoV-19 vaccine that is administered up to at least 11 months post SARS-CoV-2 infection serves as an effective immune booster. This provides a possible rationale for a single-dose vaccine regimen. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section

EBioMedicine2021       LitCov and CORD-19
270Norwegian COVID-19 (NO COVID-19) Pragmatic Open label Study to assess early use of hydroxychloroquine sulphate in moderately severe hospitalised patients with COVID-19: A structured summary of a study protocol for a randomised controlled trial  

OBJECTIVES: The hypothesis of the study is that treatment with hydroxychloroquine sulphate in hospitalised patients with coronavirus disease 2019 (Covid-19) is safe and will accelerate the virological clearance rate for patients with moderately severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when compared to standard care. Furthermore, we hypothesize that early treatment with hydroxychloroquine sulphate is associated with more rapid resolve of clinical symptoms as assessed by the National Early Warning Score 2 (NEWS2), decreased admission rate to intensive care units and mortality, and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide). TRIAL DESIGN: The study is a two-arm, open label, pragmatic randomised controlled group sequential adaptive trial designed to assess the effect on viral loads and clinical outcome of hydroxychloroquine sulphate therapy in addition to standard care compared to standard care alone in patients with established Covid-19. By utilizing resources already paid for by the hospitals (physicians and nurses in daily clinical practice), this pragmatic trial can include a larger number of patients over a short period of time and at a lower cost than studies utilizing traditional randomized controlled trial designs with an external study organization. The pragmatic approach will enable swift initiation of randomisation and allocation to treatment. PARTICIPANTS: Patients will be recruited from all inpatients at Akershus University Hospital, Lørenskog, Norway. Electronic real-time surveillance of laboratory reports from the Department of Microbiology will be examined regularly for SARS-CoV-2 positive subjects. All of the following conditions must apply to the prospective patient at screening prior to inclusion: (1) Hospitalisation; (2) Adults 18 years or older; (3) Moderately severe Covid-19 disease (NEWS2 of 6 or less); (4) SARS-CoV-2 positive nasopharyngeal swab; (5) Expected time of hospitalisation > 48 hours; and (6) Signed informed consent must be obtained and documented according to Good Clinical Practice guidelines of the International Conference on Harmonization, and national/local regulations. Patients will be excluded from participation in the study if they meet any of the following criteria: (1) Requiring intensive care unit admission at screening; (2) History of psoriasis; (3) Known adverse reaction to hydroxychloroquine sulphate; (4) Pregnancy; or (5) Prolonged corrected QT interval (>450 ms). Clinical data, including standard hospital biochemistry, medical therapy, vital signs, NEWS2, and microbiology results (including blood culture results and reverse transcriptase polymerase chain reaction [RT-PCR] for other upper airway viruses), will be automatically extracted from the hospital electronic records and merged with the study specific database. INTERVENTION AND COMPARATOR: Included patients will be randomised in a 1:1 ratio to (1) standard care with the addition of 400 mg hydroxychloroquine sulphate (Plaquenil(TM)) twice daily for seven days or (2) standard care alone. MAIN OUTCOMES: The primary endpoint of the study is the rate of decline in SARS-CoV-2 viral load in oropharyngeal samples as assessed by RT-PCR in samples collected at baseline, 48 and 96 hours after randomization and administration of drug for the intervention arm. Secondary endpoints include change in NEWS2 at 96 hours after randomisation, admission to intensive care unit, mortality (in-hospital, and at 30 and 90 days), duration of hospital admission, clinical status on a 7-point ordinal scale 14 days after randomization ([1] Death [2] Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation [3] Hospitalised, on non-invasive ventilation or high flow oxygen devices [4] Hospitalized, requiring supplemental oxygen [5] Hospitalised, not requiring supplemental oxygen [6] Not hospitalized, but unable to resume normal activities [7] Not hospitalised, with resumption of normal activities), and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide) at 96 hours after randomization. RANDOMISATION: Eligible patients will be allocated in a 1:1 ratio, using a computer randomisation procedure. The allocation sequence has been prepared by an independent statistician. BLINDING (MASKING): Open label randomised controlled pragmatic trial without blinding, no active or placebo control. The virologist assessing viral load in the oropharyngeal samples and the statistician responsible for analysis of the data will be blinded to the treatment allocation for the statistical analyses. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): This is a group sequential adaptive trial where analyses are planned after 51, 101, 151 and 202 completed patients, with a maximum sample size of 202 patients (101 patients allocated to intervention and standard care and 101 patients allocated to standard care alone). TRIAL STATUS: Protocol version 1.3 (March 26, 2020). Recruitment of first patient on March 26, 2020, and 51 patients were included as per April 28, 2020. Study recruitment is anticipated to be completed by July 2020. TRIAL REGISTRATION: number, NCT04316377. Trial registered March 20, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Trials2020       LitCov and CORD-19
271The perspective of Canadian Healthcare professionals on abortion service during the COVID-19 pandemic  

BACKGROUND: The COVID-19 pandemic and pandemic response created novel challenges for abortion services. Canada was uniquely positioned to transition to telemedicine because internationally common restrictions on abortion medication were removed before the pandemic. OBJECTIVE: We sought to characterize the experiences of abortion health care professionals in Canada during the COVID-19 pandemic and the impact of the pandemic response on abortion services. METHODS: We conducted a sequential mixed methods study between July 2020 and January 2021. We invited physicians, nurse practitioners and administrators to participate in a cross-sectional survey containing an open-ended question about the impact of the pandemic response on abortion care. We employed an inductive codebook thematic analysis, which informed the development of a second, primarily quantitative survey. RESULTS: Our initial survey had 307 respondents and our second had 78. Fifty-three percent were family physicians. Our first survey found respondents considered abortion access essential. We identified three key topicss: access to abortion care was often maintained despite pandemic-related challenges (e.g. difficulty obtaining tests, additional costs); change of practice to low-touch medication abortion care and provider perceptions of patient experience, including shifting demand, telemedicine acceptability and increased rural access. The second survey indicated uptake of telemedicine medication abortion among 89% of participants except in Quebec, where regulations meant procedures were nearly exclusively surgical. Restrictions did not delay care according to 76% of participants. CONCLUSIONS: Canadian health care professionals report their facilities deemed abortion an essential service. Provinces and territories, except Quebec, described a robust pandemic transition to telemedicine to ensure access to services. PODCAST: An accompanying podcast is available in the Supplementary Data, in which the authors Dr Madeleine Ennis and Kate Wahl discuss their research on how family planning care and access to abortion services have changed during the COVID-19 pandemic.

Fam Pract2021       LitCov and CORD-19
272Colchicine for the treatment of COVID-19  


Cochrane Database Syst Rev2021       LitCov and CORD-19
273Combination of a Sindbis-SARS-CoV-2 Spike Vaccine and alphaOX40 Antibody Elicits Protective Immunity Against SARS-CoV-2 Induced Disease and Potentiates Long-Term SARS-CoV-2-Specific Humoral and T-Cell Immunity  

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world’s population at record speeds. However, there is still a demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (αOX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T-cell response in mice. Protein binding, immunohistochemical, and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles, and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response, which can be used as a new candidate to combat SARS-CoV-2. Given the T-cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

Front Immunol2021       LitCov and CORD-19
274Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on haemodialysis  

BACKGROUND: Patients with chronic renal insufficiency on maintenance haemodialysis face an increased risk of COVID-19 induced mortality and impaired vaccine responses. To date, only a few studies have addressed SARS-CoV-2 vaccine elicited immunity in this immunocompromised population. METHODS: We assessed immunogenicity of the mRNA vaccine BNT162b2 in at-risk dialysis patients and characterised systemic cellular and humoral immune responses in serum and saliva using interferon γ release assay and multiplex-based cytokine and immunoglobulin measurements. We further compared binding capacity and neutralization efficacy of vaccination-induced immunoglobulins against emerging SARS-CoV-2 variants Alpha, Beta, Epsilon and Cluster 5 by ACE2-RBD competition assay. FINDINGS: Patients on maintenance haemodialysis exhibit detectable but variable cellular and humoral immune responses against SARS-CoV-2 and variants of concern after a two-dose regimen of BNT162b2. Although vaccination-induced immunoglobulins were detectable in saliva and plasma, both anti-SARS-CoV-2 IgG and neutralization efficacy was reduced compared to a vaccinated non-dialysed control population. Similarly, T-cell mediated interferon γ release after stimulation with SARS-CoV-2 spike peptides was significantly diminished. INTERPRETATION: Quantifiable humoral and cellular immune responses after BNT162b2 vaccination in individuals on maintenance haemodialysis are encouraging, but urge for longitudinal follow-up to assess longevity of immunity. Diminished virus neutralization and interferon γ responses in the face of emerging variants of concern may favour this at-risk population for re-vaccination using modified vaccines at the earliest opportunity. FUNDING: Initiative and Networking Fund of the Helmholtz Association of German Research Centres, EU Horizon 2020 research and innovation program, State Ministry of Baden-Württemberg for Economic Affairs, Labour and Tourism.

EBioMedicine2021       LitCov and CORD-19
275The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic  

The rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike-protein raised concerns that the virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by Sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent or BNT162b2-vaccinated individuals with 10- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1/BNT162b2-vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.

Cell2021       LitCov and CORD-19
276Racial and Ethnic Digital Divides in Posting COVID-19 Content on Social Media Among US Adults: Secondary Survey Analysis  

BACKGROUND: Public health surveillance experts are leveraging user-generated content on social media to track the spread and effects of COVID-19. However, racial and ethnic digital divides, which are disparities among people who have internet access and post on social media, can bias inferences. This bias is particularly problematic in the context of the COVID-19 pandemic because due to structural inequalities, members of racial and ethnic minority groups are disproportionately vulnerable to contracting the virus and to the deleterious economic and social effects from mitigation efforts. Further, important demographic intersections with race and ethnicity, such as gender and age, are rarely investigated in work characterizing social media users; however, they reflect additional axes of inequality shaping differential exposure to COVID-19 and its effects. OBJECTIVE: The aim of this study was to characterize how the race and ethnicity of US adults are associated with their odds of posting COVID-19 content on social media and how gender and age modify these odds. METHODS: We performed a secondary analysis of a survey conducted by the Pew Research Center from March 19 to 24, 2020, using a national probability sample (N=10,510). Respondents were recruited from an online panel, where panelists without an internet-enabled device were given one to keep at no cost. The binary dependent variable was responses to an item asking whether respondents “used social media to share or post information about the coronavirus.” We used survey-weighted logistic regressions to estimate the odds of responding in the affirmative based on the race and ethnicity of respondents (white, black, Latino, other race/ethnicity), adjusted for covariates measuring sociodemographic background and COVID-19 experiences. We examined how gender (female, male) and age (18 to 30 years, 31 to 50 years, 51 to 64 years, and 65 years and older) intersected with race and ethnicity by estimating interactions. RESULTS: Respondents who identified as black (odds ratio [OR] 1.29, 95% CI 1.02-1.64; P=.03), Latino (OR 1.66, 95% CI 1.36-2.04; P<.001), or other races/ethnicities (OR 1.33, 95% CI 1.02-1.72; P=.03) had higher odds than respondents who identified as white of reporting that they posted COVID-19 content on social media. Women had higher odds of posting than men regardless of race and ethnicity (OR 1.58, 95% CI 1.39-1.80; P<.001). Among men, respondents who identified as black, Latino, or members of other races/ethnicities were significantly more likely to post than respondents who identified as white. Older adults (65 years or older) had significantly lower odds (OR 0.73, 95% CI 0.57-0.94; P=.01) of posting compared to younger adults (18-29 years), particularly among those identifying as other races/ethnicities. Latino respondents were the most likely to report posting across all age groups. CONCLUSIONS: In the United States, members of racial and ethnic minority groups are most likely to contribute to COVID-19 content on social media, particularly among groups traditionally less likely to use social media (older adults and men). The next step is to ensure that data collection procedures capture this diversity by encompassing a breadth of search criteria and social media platforms.

J Med Internet Res2020       LitCov and CORD-19
277Remdesivir for the Treatment of Covid-19-Final Report  

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). CONCLUSIONS: Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 number, NCT04280705.)

N Engl J Med2020       LitCov and CORD-19
278COVID-19: a conundrum to decipher  


Eur Rev Med Pharmacol Sci2020       LitCov and CORD-19
279Cross-Neutralization of Emerging SARS-CoV-2 Variants of Concern by Antibodies Targeting Distinct Epitopes on Spike  

Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, we generated 43 monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484, and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and variants of concern (VOCs), including B.1.1.7 (alpha), P.1 (gamma), and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting that different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to the first pandemic wave of prototype SARS-CoV-2 possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern.

mBio2021       LitCov and CORD-19
280Clinical characteristics of 116 hospitalized patients with COVID-19 in Wuhan, China: a single-centered, retrospective, observational study  

BACKGROUND: A cluster of acute respiratory illness, now known as Corona Virus Disease 2019 (COVID-19) caused by 2019 novel coronavirus (SARS-CoV-2), has become a global pandemic. Aged population with cardiovascular diseases are more likely be to infected with SARS-CoV-2 and result in more severe outcomes and elevated case-fatality rate. Meanwhile, cardiovascular diseases have a high prevalence in the middle-aged and elderly population. However, despite of several researches in COVID-19, cardiovascular implications related to it still remains largely unclear. Therefore, a specific analysis in regard to cardiovascular implications of COVID-19 patients is in great need. METHODS: In this single-centered, retrospective, observational study, 116 patients with laboratory-confirmed COVID-19 were enrolled, who admitted to the General Hospital of Central Theater Command (Wuhan, China) from January 20 to March 8, 2020. The demographic data, underlying comorbidities, clinical symptoms and signs, laboratory findings, chest computed tomography, treatment measures, and outcome data were collected from electronic medical records. Data were compared between non-severe and severe cases. RESULTS: Of 116 hospitalized patients with COVID-19, the median age was 58.5 years (IQR, 47.0–69.0), and 36 (31.0%) were female. Hypertension (45 [38.8%]), diabetes (19 [16.4%]), and coronary heart disease (17 [14.7%]) were the most common coexisting conditions. Common symptoms included fever [99 (85.3%)], dry cough (61 [52.6%]), fatigue (60 [51.7%]), dyspnea (52 [44.8%]), anorexia (50 [43.1%]), and chest discomfort (50 [43.1%]). Local and/or bilateral patchy shadowing were the typical radiological findings on chest computed tomography. Lymphopenia (lymphocyte count, 1.0 × 10(9)/L [IQR, 0.7–1.3]) was observed in 66 patients (56.9%), and elevated lactate dehydrogenase (245.5 U/L [IQR, 194.3–319.8]) in 69 patients (59.5%). Hypokalemia occurred in 24 (20.7%) patients. Compared with non-severe cases, severe cases were older (64.0 years [IQR, 53.0–76.0] vs 56.0 years [IQR, 37.0–64.0]), more likely to have comorbidities (35 [63.6%] vs 24 [39.3%]), and more likely to develop acute cardiac injury (19 [34.5%] vs 4 [6.6%]), acute heart failure (18 [32.7%] vs 3 [4.9%]), and ARDS (20 [36.4%] vs 0 [0%]). During hospitalization, the prevalence of new onset hypertension was significantly higher in severe patients (55.2% vs 19.0%) than in non-severe ones. CONCLUSIONS: In this single-centered, retrospective, observational study, we found that the infection of SARS-CoV-2 was more likely to occur in middle and aged population with cardiovascular comorbidities. Cardiovascular complications, including new onset hypertension and heart injury were common in severe patients with COVID-19. More detailed researches in cardiovascular involvement in COVID-19 are urgently needed to further understand the disease.

BMC Infect Dis2020       LitCov and CORD-19
281Infliximab 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
282Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past  

After the 1918 flu pandemic, the world is again facing a similar situation. However, the advancement in medical science has made it possible to identify that the novel infectious agent is from the coronavirus family. Rapid genome sequencing by various groups helped in identifying the structure and function of the virus, its immunogenicity in diverse populations, and potential preventive measures. Coronavirus attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. Viral components like spike and nucleocapsid proteins trigger an immune response in the host to eliminate the virus. These viral antigens can be either recognized by the B cells or presented by MHC complexes to the T cells, resulting in antibody production, increased cytokine secretion, and cytolytic activity in the acute phase of infection. Genetic polymorphism in MHC enables it to present some of the T cell epitopes very well over the other MHC alleles. The association of MHC alleles and its downregulated expression has been correlated with disease severity against influenza and coronaviruses. Studies have reported that infected individuals can, after recovery, induce strong protective responses by generating a memory T-cell pool against SARS-CoV and MERS-CoV. These memory T cells were not persistent in the long term and, upon reactivation, caused local damage due to cross-reactivity. So far, the reports suggest that SARS-CoV-2, which is highly contagious, shows related symptoms in three different stages and develops an exhaustive T-cell pool at higher loads of viral infection. As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. A classical immunotherapy of convalescent plasma transfusion from recovered patients has also been initiated for the neutralization of viremia in terminally ill COVID-19 patients. Due to the limitations of plasma transfusion, researchers are now focusing on developing neutralizing antibodies against virus particles along with immuno-modulation of cytokines like IL-6, Type I interferons (IFNs), and TNF-α that could help in combating the infection. This review highlights the similarities of the coronaviruses that caused SARS and MERS to the novel SARS-CoV-2 in relation to their pathogenicity and immunogenicity and also focuses on various treatment strategies that could be employed for curing COVID-19.

Front Immunol2020       LitCov and CORD-19
283How do children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD) experience lockdown during the COVID-19 outbreak?  

OBJECTIVES: During the COVID-19 pandemic, the French government has decided a general lockdown. This unprecedented situation has raised concerns about children's and adolescent's mental health. Children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD) may find this context of restrained activity particularly tricky. The objectives of our study are to gather information about the well-being and global life conditions of children and adolescents with ADHD during the COVID-19 outbreak in France. METHODS: We designed a survey including both open-ended questions and questionnaire items for parents of children and adolescents with ADHD. Parents responded to the following open-ended questions: 1) “How is your child doing since the lockdown?” 2) “How is life at home since the lockdown?” 3) “If you had a remote service provision with a mental health professional (e.g. by telephone or video technology), please share your thoughts and any suggestions with us” 4) “Please share any other items that you think are important about ADHD symptoms of your child and the lockdown situation”. This survey was posted on social media on the 6th of April and disseminated by French ADHD-parent and patient organizations. The present article reports the descriptive, qualitative and textometrical analyses of the survey. RESULTS: Between day 20 and 30 of lockdown, 538 parents responded to the survey, and we included 533 responses in the final analysis. The vast majority of responders were women 95 % (95 % CI 93,50; 97,18) with children whose mean age was 10,5 (95 % CI 7.58; 13.44). Since the lockdown, 34.71 % (95 % CI 30.70; 38.94) of children experienced a worsening in well-being, 34.33 % (95 % CI 30.34; 38.56) showed no significant changes and 30.96 % (95 % CI 27.09; 35.10) were doing better according to their parents. The thematic analysis showed that an improvement of their children's anxiety was one of the main topics addressed by parents. This improvement related to less school-related strain and flexible schedules that respected their children's rhythm. Improved self-esteem was another topic that parents linked with a lesser exposure of their children to negative feed-back. Parents repeatedly reported both inattention and hyperactivity/impulsivity. However, optimal lockdown life conditions seemed to compensate for the impact of ADHD symptoms (e.g. sufficient space at home, presence of a garden). Some parents reported worsening of general well-being in their children, and this manifested as oppositional/defiant attitudes and emotional outbursts. Parents also cited sleep problems and anxiety in this context. As regards everyday life during lock-down, at-home schooling was another major topic–parents described that their children struggled to complete school-related tasks and that teachers seemed to have forgotten about academic accommodations. The lockdown situation seems to have raised parents’ awareness of the role of inattention and ADHD symptoms in their children's learning difficulties. Due to potential selection biases, the results of our survey may not be generalizable to all children and adolescents with ADHD. The main strengths of this rapid survey-based study lies in the reactivity of the participants and the quality and diversity of their responses to the open-ended questions. CONCLUSIONS: According to their parents, most children and adolescents with ADHD experience stability or improvement of their well-being. An improvement in school-related anxiety and the flexible adjustment to the children's’ rhythms as well as parents’ increased awareness of the difficulties their children experience are among the key topics in parents’ descriptions.

Encephale2020       LitCov and CORD-19
284Vaccine induced Antibody Responses against SARS-CoV-2 Variants-Of-Concern Six Months after the BNT162b2 COVID-19 mRNA Vaccination  

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has raised concern about increased transmissibility, infectivity, and immune evasion from a vaccine and infection-induced immune responses. Although COVID-19 mRNA vaccines have proven to be highly effective against severe COVID-19 disease, the decrease in vaccine efficacy against emerged Beta and Delta variants emphasizes the need for constant monitoring of new virus lineages and studies on the persistence of vaccine-induced neutralizing antibodies. To analyze the dynamics of COVID-19 mRNA vaccine-induced antibody responses, we followed 52 health care workers in Finland for 6 months after receiving two doses of BNT162b2 vaccine with a 3-week interval. We demonstrate that, although anti-S1 antibody levels decrease 2.3-fold compared to peak antibody levels, anti-SARS-CoV-2 antibodies persist for months after BNT162b2 vaccination. Variants D614G, Alpha, and Eta are neutralized by sera of 100% of vaccinees, whereas neutralization of Delta is 3.8-fold reduced and neutralization of Beta is 5.8-fold reduced compared to D614G. Despite this reduction, 85% of sera collected 6 months postvaccination neutralizes Delta variant. IMPORTANCE A decrease in vaccine efficacy against emerging SARS-CoV-2 variants has increased the importance of assessing the persistence of SARS-CoV-2 spike protein-specific antibodies and neutralizing antibodies. Our data show that after 6 months post two doses of BNT162b2 vaccine, antibody levels decrease yet remain detectable and capable of neutralizing emerging variants. By monitoring the vaccine-induced antibody responses, vaccination strategies and administration of booster doses can be optimized.

Microbiol Spectr2022       LitCov and CORD-19
285Determining the optimal strategy for reopening schools, the impact of test and trace interventions and the risk of occurrence of a second COVID-19 epidemic wave in the UK: a modelling study  

BACKGROUND: As lockdown measures to slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection begin to ease in the UK, it is important to assess the impact of any changes in policy, including school reopening and broader relaxation of physical distancing measures. We aimed to use an individual-based model to predict the impact of two possible strategies for reopening schools to all students in the UK from September, 2020, in combination with different assumptions about relaxation of physical distancing measures and the scale-up of testing. METHODS: In this modelling study, we used Covasim, a stochastic individual-based model for transmission of SARS-CoV-2, calibrated to the UK epidemic. The model describes individuals' contact networks stratified into household, school, workplace, and community layers, and uses demographic and epidemiological data from the UK. We simulated six different scenarios, representing the combination of two school reopening strategies (full time and a part-time rota system with 50% of students attending school on alternate weeks) and three testing scenarios (68% contact tracing with no scale-up in testing, 68% contact tracing with sufficient testing to avoid a second COVID-19 wave, and 40% contact tracing with sufficient testing to avoid a second COVID-19 wave). We estimated the number of new infections, cases, and deaths, as well as the effective reproduction number (R) under different strategies. In a sensitivity analysis to account for uncertainties within the stochastic simulation, we also simulated infectiousness of children and young adults aged younger than 20 years at 50% relative to older ages (20 years and older). FINDINGS: With increased levels of testing (between 59% and 87% of symptomatic people tested at some point during an active SARS-CoV-2 infection, depending on the scenario), and effective contact tracing and isolation, an epidemic rebound might be prevented. Assuming 68% of contacts could be traced, we estimate that 75% of individuals with symptomatic infection would need to be tested and positive cases isolated if schools return full-time in September, or 65% if a part-time rota system were used. If only 40% of contacts could be traced, these figures would increase to 87% and 75%, respectively. However, without these levels of testing and contact tracing, reopening of schools together with gradual relaxing of the lockdown measures are likely to induce a second wave that would peak in December, 2020, if schools open full-time in September, and in February, 2021, if a part-time rota system were adopted. In either case, the second wave would result in R rising above 1 and a resulting second wave of infections 2·0–2·3 times the size of the original COVID-19 wave. When infectiousness of children and young adults was varied from 100% to 50% of that of older ages, we still found that a comprehensive and effective test–trace–isolate strategy would be required to avoid a second COVID-19 wave. INTERPRETATION: To prevent a second COVID-19 wave, relaxation of physical distancing, including reopening of schools, in the UK must be accompanied by large-scale, population-wide testing of symptomatic individuals and effective tracing of their contacts, followed by isolation of diagnosed individuals. FUNDING: None.

Lancet Child Adolesc Health2020       LitCov and CORD-19
286Characteristics Associated With Racial/Ethnic Disparities in COVID-19 Outcomes in an Academic Healthcare System  

IMPORTANCE: Black patients are overrepresented in the number of COVID-19 infections, hospitalizations, and deaths in the US. Reasons for this disparity may be due to underlying comorbidities or sociodemographic factors that require further exploration. OBJECTIVE: To systematically determine patient characteristics associated with racial/ethnic disparities in COVID-19 outcomes. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used comparative groups of patients tested or treated for COVID-19 at the University of Michigan from March 10, 2020, to April 22, 2020, with an outcome update through July 28, 2020. A group of randomly selected untested individuals were included for comparison. Examined factors included race/ethnicity, age, smoking, alcohol consumption, comorbidities, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and residential-level socioeconomic characteristics. EXPOSURE: In-house polymerase chain reaction (PCR) tests, commercial antibody tests, nasopharynx or oropharynx PCR deployed by the Michigan Department of Health and Human Services and reverse transcription–PCR tests performed in external labs. MAIN OUTCOMES AND MEASURES: The main outcomes were being tested for COVID-19, having test results positive for COVID-19 or being diagnosed with COVID-19, being hospitalized for COVID-19, requiring intensive care unit (ICU) admission for COVID-19, and COVID-19–related mortality (including inpatient and outpatient). Medical comorbidities were defined from the International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, codes and were aggregated into a comorbidity score. Associations with COVID-19 outcomes were examined using odds ratios (ORs). RESULTS: Of 5698 patients tested for COVID-19 (mean [SD] age, 47.4 [20.9] years; 2167 [38.0%] men; mean [SD] BMI, 30.0 [8.0]), most were non-Hispanic White (3740 patients [65.6%]) or non-Hispanic Black (1058 patients [18.6%]). The comparison group included 7168 individuals who were not tested (mean [SD] age, 43.1 [24.1] years; 3257 [45.4%] men; mean [SD] BMI, 28.5 [7.1]). Among 1139 patients diagnosed with COVID-19, 492 (43.2%) were White and 442 (38.8%) were Black; 523 (45.9%) were hospitalized, 283 (24.7%) were admitted to the ICU, and 88 (7.7%) died. Adjusting for age, sex, socioeconomic status, and comorbidity score, Black patients were more likely to be hospitalized compared with White patients (OR, 1.72 [95% CI, 1.15-2.58]; P = .009). In addition to older age, male sex, and obesity, living in densely populated areas was associated with increased risk of hospitalization (OR, 1.10 [95% CI, 1.01-1.19]; P = .02). In the overall population, higher risk of hospitalization was also observed in patients with preexisting type 2 diabetes (OR, 1.82 [95% CI, 1.25-2.64]; P = .02) and kidney disease (OR, 2.87 [95% CI, 1.87-4.42]; P < .001). Compared with White patients, obesity was associated with higher risk of having test results positive for COVID-19 among Black patients (White: OR, 1.37 [95% CI, 1.01-1.84]; P = .04. Black: OR, 3.11 [95% CI, 1.64-5.90]; P < .001; P for interaction = .02). Having any cancer was associated with higher risk of positive COVID-19 test results for Black patients (OR, 1.82 [95% CI, 1.19-2.78]; P = .005) but not White patients (OR, 1.08 [95% CI, 0.84-1.40]; P = .53; P for interaction = .04). Overall comorbidity burden was associated with higher risk of hospitalization in White patients (OR, 1.30 [95% CI, 1.11-1.53]; P = .001) but not in Black patients (OR, 0.99 [95% CI, 0.83-1.17]; P = .88; P for interaction = .02), as was type 2 diabetes (White: OR, 2.59 [95% CI, 1.49-4.48]; P < .001; Black: OR, 1.17 [95% CI, 0.66-2.06]; P = .59; P for interaction = .046). No statistically significant racial differences were found in ICU admission and mortality based on adjusted analysis. CONCLUSIONS AND RELEVANCE: These findings suggest that preexisting type 2 diabetes or kidney diseases and living in high–population density areas were associated with higher risk for COVID-19 hospitalization. Associations of risk factors with COVID-19 outcomes differed by race.

JAMA Netw Open2020       LitCov and CORD-19
287Coagulopathy of hospitalised COVID-19: A Pragmatic Randomised Controlled Trial of Therapeutic Anticoagulation vs Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG-RAPID Trial): A structured summary of a study protocol for a randomised controlled trial  

OBJECTIVES: To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. TRIAL DESIGN: Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. 1. Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2. Admitted to hospital for COVID-19; 3. a. D-Dimer ≥2 times ULN OR. b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4. > 18 years of age; 5. Informed consent from the patient (or legally authorized substitute decision maker). 1. pregnancy; 2. hemoglobin <80 g/L in the last 72 hours; 3. platelet count <50 x 10(9)/L in the last 72 hours; 4. known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5. known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6. patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7. patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8. patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9. known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10. known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11. known history of heparin-induced thrombocytopenia; 12. known allergy to UFH or LMWH; 13. admitted to the intensive care unit at the time of screening; 14. treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15. Imminent death according to the judgement of the most responsible physician; 16. enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. INTERVENTION AND COMPARATOR: Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician’s discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. MAIN OUTCOMES: The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. 1. All-cause death. 2. Composite of ICU admission or all-cause death. 3. Composite of mechanical ventilation or all-cause death. 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. RANDOMISATION: Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. BLINDING (MASKING): No blinding involved. This is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. TRIAL STATUS: Protocol Version Number 1.4. Recruitment began on May 11(th), 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. TRIAL REGISTRATION: Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-021-05076-0.

Trials2021       LitCov and CORD-19
288SARS-CoV-2 and coronavirus disease-2019: The epidemic and the challenges  

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously provisionally named 2019 novel coronavirus or 2019-nCoV) disease (COVID-19) in China at the end of 2019 has caused a large global outbreak and is a major public health issue. As of 11 February 2020, data from the World Health Organization (WHO) have shown that more than 43 000 confirmed cases have been identified in 28 countries/regions, with >99% of cases being detected in China. On 30 January 2020, the WHO declared COVID-19 as the sixth public health emergency of international concern. SARS-CoV-2 is closely related to two bat-derived severe acute respiratory syndrome-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21. It is spread by human-to-human transmission via droplets or direct contact, and infection has been estimated to have mean incubation period of 6.4 days and a basic reproduction number of 2.24–3.58. Among patients with pneumonia caused by SARS-CoV-2 (novel coronavirus pneumonia or Wuhan pneumonia), fever was the most common symptom, followed by cough. Bilateral lung involvement with ground-glass opacity was the most common finding from computed tomography images of the chest. The one case of SARS-CoV-2 pneumonia in the USA is responding well to remdesivir, which is now undergoing a clinical trial in China. Currently, controlling infection to prevent the spread of SARS-CoV-2 is the primary intervention being used. However, public health authorities should keep monitoring the situation closely, as the more we can learn about this novel virus and its associated outbreak, the better we can respond.

Int J Antimicrob Agents2020       LitCov and CORD-19
289Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment  

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), harboring spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) mutations, exhibit reduced in vitro susceptibility to convalescent-phase serum, commercial antibody cocktails, and vaccine neutralization and have been associated with reinfections. The accumulation of these mutations could be the consequence of intrahost viral evolution due to prolonged infection in immunocompromised hosts. In this study, we document the microevolution of SARS-CoV-2 recovered from sequential tracheal aspirates from an immunosuppressed patient on steroids and convalescent plasma therapy and identify the emergence of multiple NTD and RBD mutations. SARS-CoV-2 genomes from the first swab (day 0) and from three tracheal aspirates (days 7, 21, and 27) were compared at the sequence level. We identified a mixed viral population with five different S protein mutations (141 to 144 deletion, 243 to 244 deletion, E484K, Q493K, and Q493R) at the NTD or RBD region from the second tracheal aspirate sample (day 21) and a predominance of the S protein 141 to 144 LGVY deletion and E484K mutant on day 27. The neutralizing antibodies against various S protein lentiviral pseudovirus mutants, as well as the anti-SARS-CoV-2 total Ig and IgG, showed “U” shape dynamics, in support of the endogenous development of neutralizing antibodies. The patient’s compromised immune status, the antirejection regiment, convalescent plasma treatment, and the development of neutralizing antibodies may have resulted in unique selective pressures on the intrahost genomic evolution, and this observation supports the hypotheses that VOCs can independently arise and that immunocompromised patients on convalescent plasma therapy are potential breeding grounds for immune escape mutants. IMPORTANCE Over a year of the COVID-19 pandemic, distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages have arisen in multiple geographic areas around the world. SARS-CoV-2 variants of concern (VOCs), i.e., B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta), harboring mutations and/or deletions in spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) regions showed evidence of increased transmissibility and disease severity and possible reduced vaccine efficacy. In this study, we report the emergence of five different NTD and RBD mutations in an uncommon SARS-CoV-2 B.1.369 lineage from an immunosuppressed patient undergoing steroid and convalescent plasma therapy. The observation highlighted that VOCs can independently arise in immunocompromised populations undergoing anti-SARS-CoV-2 therapy, and enhanced measures will be required to reduce the transmission.

mSphere2021       LitCov and CORD-19
290SARS-CoV-2 seroprevalence and transmission risk factors among high-risk close contacts: a retrospective cohort study  

BACKGROUND: The proportion of asymptomatic carriers and transmission risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among household and non-household contacts remains unclear. In Singapore, extensive contact tracing by the Ministry of Health for every diagnosed COVID-19 case, and legally enforced quarantine and intensive health surveillance of close contacts provided a rare opportunity to determine asymptomatic attack rates and SARS-CoV-2 transmission risk factors among community close contacts of patients with COVID-19. METHODS: This retrospective cohort study involved all close contacts of confirmed COVID-19 cases in Singapore, identified between Jan 23 and April 3, 2020. Household contacts were defined as individuals who shared a residence with the index COVID-19 case. Non-household close contacts were defined as those who had contact for at least 30 min within 2 m of the index case. All patients with COVID-19 in Singapore received inpatient treatment, with access restricted to health-care staff. All close contacts were quarantined for 14 days with thrice-daily symptom monitoring via telephone. Symptomatic contacts underwent PCR testing for SARS-CoV-2. Secondary clinical attack rates were derived from the prevalence of PCR-confirmed SARS-CoV-2 among close contacts. Consenting contacts underwent serology testing and detailed exposure risk assessment. Bayesian modelling was used to estimate the prevalence of missed diagnoses and asymptomatic SARS-CoV-2-positive cases. Univariable and multivariable logistic regression models were used to determine SARS-CoV-2 transmission risk factors. FINDINGS: Between Jan 23 and April 3, 2020, 7770 close contacts (1863 household contacts, 2319 work contacts, and 3588 social contacts) linked to 1114 PCR-confirmed index cases were identified. Symptom-based PCR testing detected 188 COVID-19 cases, and 7582 close contacts completed quarantine without a positive SARS-CoV-2 PCR test. Among 7518 (96·8%) of the 7770 close contacts with complete data, the secondary clinical attack rate was 5·9% (95% CI 4·9–7·1) for 1779 household contacts, 1·3% (0·9–1·9) for 2231 work contacts, and 1·3% (1·0–1·7) for 3508 social contacts. Bayesian analysis of serology and symptom data obtained from 1150 close contacts (524 household contacts, 207 work contacts, and 419 social contacts) estimated that a symptom-based PCR-testing strategy missed 62% (95% credible interval 55–69) of COVID-19 diagnoses, and 36% (27–45) of individuals with SARS-CoV-2 infection were asymptomatic. Sharing a bedroom (multivariable odds ratio [OR] 5·38 [95% CI 1·82–15·84]; p=0·0023) and being spoken to by an index case for 30 min or longer (7·86 [3·86–16·02]; p<0·0001) were associated with SARS-CoV-2 transmission among household contacts. Among non-household contacts, exposure to more than one case (multivariable OR 3·92 [95% CI 2·07–7·40], p<0·0001), being spoken to by an index case for 30 min or longer (2·67 [1·21–5·88]; p=0·015), and sharing a vehicle with an index case (3·07 [1·55–6·08]; p=0·0013) were associated with SARS-CoV-2 transmission. Among both household and non-household contacts, indirect contact, meal sharing, and lavatory co-usage were not independently associated with SARS-CoV-2 transmission. INTERPRETATION: Targeted community measures should include physical distancing and minimising verbal interactions. Testing of all household contacts, including asymptomatic individuals, is warranted. FUNDING: Ministry of Health of Singapore, National Research Foundation of Singapore, and National Natural Science Foundation of China.

Lancet Infect Dis2020       LitCov and CORD-19
291Double-blind, randomized, controlled, trial to assess the efficacy of allogenic mesenchymal stromal cells in patients with acute respiratory distress syndrome due to COVID-19 (COVID-AT): A structured summary of a study protocol for a randomised controlled trial  

OBJECTIVES: 1. To assess the efficacy of Mesenchymal Stromal Cells (MSC) versus a control arm as described in the primary endpoint. 2. To evaluate the effects of MSC on the secondary efficacy endpoints. 3. To evaluate the safety and tolerability profiles of MSC. 4. To study soluble and cellular biomarkers that might be involved in the course of the disease and the response to the investigational product. TRIAL DESIGN: A double-blind, randomized, controlled, trial to evaluate the efficacy and safety of MSC intravenous administration in patients with COVID-induced Acute Respiratory Distress Syndrome (ARDS) compared to a control arm. PARTICIPANTS: The trial is being conducted at a third level hospital, Hospital Universitario Puerta de Hierro, in Majadahonda, Madrid (Spain). Inclusion criteria 1. Informed consent prior to performing study procedures (witnessed oral consent with written consent by representatives will be accepted to avoid paper handling). Written consent by patient or representatives will be obtained whenever possible. 2. Adult patients ≥18 years of age at the time of enrolment. 3. Laboratory-confirmed SARS-CoV-2 infection as determined by Polymerase Chain Reaction (PCR), in oropharyngeal swabs or any other relevant specimen obtained during the course of the disease. Alternative tests (e.g., rapid antigen tests) are also acceptable as laboratory confirmation if their specificity has been accepted by the Sponsor. 4. Moderate to severe ARDS (PaO2/FiO2 ratio equal or less than 200 mmHg) for less than 96 hours at the time of randomization. 5. Patients requiring invasive ventilation are eligible within 72 hours from intubation. 6. Eligible for ICU admission, according to the clinical team. Exclusion criteria 1. Imminent and unavoidable progression to death within 24 hours, irrespective of the provision of treatments (in the opinion of the clinical team). 2. “Do Not Attempt Resuscitation” order in place. 3. Any end-stage organ disease or condition, which in the investigator’s opinion, makes the patient an unsuitable candidate for treatment. 4. History of a moderate/severe lung disorder requiring home-based oxygen therapy. 5. Patient requiring Extracorporeal Membrane Oxygenation (ECMO), haemodialysis or hemofiltration at the time of treatment administration. 6. Current diagnosis of pulmonary embolism. 7. Active neoplasm, except carcinoma in situ or basalioma. 8. Known allergy to the products involved in the allogeneic MSC production process. 9. Current pregnancy or lactation (women with childbearing potential should have a negative pregnancy test result at the time of study enrolment). 10. Current participation in a clinical trial with an experimental treatment for COVID-19 (the use of any off-label medicine according to local treatment protocols is not an exclusion criteria). 11. Any circumstances that in the investigator’s opinion compromises the patient’s ability to participate in the clinical trial. INTERVENTION AND COMPARATOR: - Experimental treatment arm: Allogeneic MSC (approximately 1 x 10(6) cells/kg). - Control arm: placebo solution (same composition as the experimental treatment, without the MSC). One single intravenous dose of the assigned treatment will be administered on Day 0 of the study. All trial participants will receive standard of care (SOC). In the context of the current worldwide pandemic, SOC can include medicines that are being used in clinical practice (e.g. lopinavir/ritonavir; hydroxy/chloroquine, tocilizumab, etc.), as well as those authorised for COVID (e.g., remdesivir). MAIN OUTCOMES: Primary endpoint: Change in the PaO2/FiO2 ratio from baseline to day 7 of treatment administration, or to the last available PaO2/FiO2 ratio if death occurs before day 7. Secondary endpoints: - All-cause mortality on days 7, 14, and 28 after treatment. - PaO2/FiO2 ratio at baseline and days 2, 4, 7, 14 and 28 after treatment. - Oxygen saturation (by standardized measurement) at baseline, daily until day 14, and on day 28 after treatment. - Time to PaO2/FiO2 ratio greater than 200 mmHg. - Subjects’ clinical status on the WHO 7-point ordinal scale at baseline, daily until day 14, and on day 28 after treatment. - Time to an improvement of one category from admission on the WHO 7-point ordinal scale. - Percentage of patients that worsen at least one category on the WHO 7-point ordinal scale. - Percentage of patients that improve at least one category (maintained 48h) on the WHO 7-point ordinal scale. - Sequential Organ Failure Assessment (SOFA) scale at baseline and days 2, 4, 7, 14 and 28 after treatment. - Duration of hospitalization (days). - Duration of ICU stay (days). - Oxygen therapy-free days in the first 28 days after treatment. - Duration of supplemental oxygen. - Incidence of and duration of non-invasive and invasive mechanical ventilation in the first 28 days after treatment. - Mechanical ventilation-free days in the first 28 days after treatment. - Ventilation parameters. - Incidence of new onset pulmonary fibrosis at 3 and 12 months after treatment, based on CT scan and pulmonary function tests. - Survival at 3 and 12 months. - Cumulative incidence of Serious Adverse events (SAEs) and Grade 3 and 4 Adverse Events (AEs). - Cumulative incidence of Adverse Drug Reactions (ADR) in the experimental treatment arm. - Cumulative incidence of AEs of special interest. - Levels of analytical markers (C-Reactive Protein, lymphocyte and neutrophil counts, lymphocyte subpopulations, LDH, ferritin, D-dimer, coagulation tests and cytokines...) at baseline and days 2, 4, 7, 14 and 28 after treatment. - Other soluble and cellular biomarkers that might be involved in the course of the disease and the response to MSC. RANDOMISATION: The assignment to treatment will be carried out randomly and blinded, with a 1:1 allocation. Randomization will be done through a centralized system embedded in the electronic Case Report Form (CRF). BLINDING (MASKING): To ensure blinding, treatments will be prepared for administration at the Cell Production Unit and the administration of the treatment will be masked, not allowing the identification of the Investigational Medicinal Product (IMP). NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 20 participants are planned to be randomized, 10 to each treatment group. TRIAL STATUS: Protocol version: 1.2, dated October 14th, 2020 Start of recruitment: 01/10/2020 End of recruitment (estimated): December 2020. TRIAL REGISTRATION: EudraCT Number: 2020-002193-27, registered on July 14(th), 2020. NCT number: NCT04615429, registered on November 4(th), 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-020-04964-1.

Trials2021       LitCov and CORD-19
292Behavioral Intention to Receive a COVID-19 Vaccination Among Chinese Factory Workers: Cross-sectional Online Survey  

BACKGROUND: COVID-19 vaccines will become available in China soon. Understanding communities’ responses to the forthcoming COVID-19 vaccines is important. We applied the theory of planned behavior as the theoretical framework. OBJECTIVE: This study investigates the prevalence of and factors associated with behavioral intention to receive self-financed or free COVID-19 vaccinations among Chinese factory workers who resumed work during the pandemic. We examined the effects of factors including sociodemographics, perceptions related to COVID-19 vaccination, exposure to information about COVID-19 vaccination through social media, and COVID-19 preventive measures implemented by individuals and factories. METHODS: Participants were full-time employees 18 years or older who worked in factories in Shenzhen. Factory workers in Shenzhen are required to receive a physical examination annually. Eligible workers attending six physical examination sites were invited to complete a survey on September 1-7, 2020. Out of 2653 eligible factory workers, 2053 (77.4%) completed the online survey. Multivariate two-level logistic regression models and ordinal logistic regression models were fitted. RESULTS: The prevalence of behavioral intention to receive a COVID-19 vaccination was 66.6% (n=1368, conditional on 80% vaccine efficacy and market rate) and 80.6% (n=1655, conditional on 80% vaccine efficacy and free vaccines). After adjusting for significant background characteristics, positive attitudes toward COVID-19 vaccination (adjusted odds ratio [AOR] 1.20, 95% CI 1.15-1.25 and AOR 1.24, 95% CI 1.19-1.30), perceived support from significant others for getting a COVID-19 vaccination (AOR 1.43, 95% CI 1.32-1.55 and AOR 1.37, 95% CI 1.25-1.50), and perceived behavioral control to get a COVID-19 vaccination (AOR 1.51, 95% CI 1.32-1.73 and AOR 1.28, 95% CI 1.09-1.51) were positively associated with both dependent variables (conditional on 80% vaccine efficacy and market rate or free vaccines, respectively). Regarding social media influence, higher frequency of exposure to positive information related to COVID-19 vaccination was associated with a higher intention to receive a COVID-19 vaccination at market rate (AOR 1.53, 95% CI 1.39-1.70) or a free vaccination (AOR 1.52, 95% CI 1.35-1.71). Higher self-reported compliance with wearing a face mask in the workplace (AOR 1.27, 95% CI 1.02-1.58 and AOR 1.67, 95% CI 1.24-2.27) and other public spaces (AOR 1.80, 95% CI 1.42-2.29 and AOR 1.34, 95% CI 1.01-1.77), hand hygiene (AOR 1.21, 95% CI 1.00-1.47 and AOR 1.52, 95% CI 1.19-1.93), and avoiding social gatherings (AOR 1.22, 95% CI 1.01-1.47 and AOR 1.55, 95% CI 1.23-1.95) and crowded places (AOR 1.24, 95% CI 1.02-1.51 and AOR 1.73, 95% CI 1.37-2.18) were also positively associated with both dependent variables. The number of COVID-19 preventive measures implemented by the factory was positively associated with the intention to receive a COVID-19 vaccination under both scenarios (AOR 1.08, 95% CI 1.04-1.12 and AOR 1.06, 95% CI 1.01-1.11). CONCLUSIONS: Factory workers in China reported a high behavioral intention to receive a COVID-19 vaccination. The theory of planned behavior is a useful framework to guide the development of future campaigns promoting COVID-19 vaccination.

J Med Internet Res2021       LitCov and CORD-19
293Non-pharmacological measures implemented in the setting of long-term care facilities to prevent SARS-CoV-2 infections and their consequences: a rapid review  


Cochrane Database Syst Rev2021       LitCov and CORD-19
294Clinical Characteristics and Outcome of Hospitalized COVID-19 Patients in a MERS-CoV Endemic Area  

Background: The Kingdom of Saudi Arabia (KSA) reported 170,639 cases and 1430 deaths from COVID-19 since the first case emerged in the country on March 2 through June 25, 2020. The objective of this report is to describe the characteristics and outcome observed among 99 hospitalized COVID-19 patients in the largest academic hospital in KSA, and assess co-infection with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Methods: This single-center case series data included select epidemiological, clinical, radiological features and laboratory findings of all confirmed hospitalized cases of COVID-19 in King Saud University Medical City (KSUMC), Riyadh, KSA, from March 22 until May 31, 2020, followed through June 6, 2020. We conducted retrospective analysis of listed data from 99 hospitalized patients and present characteristics and factors associated with severity in percentages and univariate odds ratios. Cases were confirmed using nasopharyngeal or throat swab by real-time Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and MERS-CoV by RT-PCR. Results: The 99 hospitalized COVID-19 patients included in this analysis constitute 16% of 632 positive SARS-CoV-2 among 6633 persons who were tested at the KSUMC (positivity rate, 9.4%). MERS-CoV PCR was negative in all 99 patients tested. The majority of these 99 hospitalized patients were males (66%), had a mean age of 44 years (range, 19–87), and a quarter (25.3%) were health care workers. Patients with comorbid conditions accounted for 52.5% of patients including the 8.1% who were asymptomatic; diabetes mellitus being the most frequent (31.3%), followed by hypertension (22.2%). The most common presenting symptoms were fever (67.7%), cough (60.6%), dyspnea (43.4%), upper respiratory symptoms (27.3%), fatigue (26.3%), diarrhea (19.2%) and loss of smell (9.1%). The clinical conditions among these 99 patients included upper respiratory tract infection (47.5%), abnormal chest X-ray, lymphopenia, high inflammatory markers a fifth (21%) of patients had moderate pneumonia, while 7% had severe pneumonia with 22.2% requiring admission to the intensive care unit and 12.1% died. Late presentation with severe disease, an abnormal chest X-ray, lymphopenia, high inflammatory markers (C-reactive protein, ferritin, and procalcitonin), and end organ damage (high creatinine or high aspartate aminotransferase) were predictors for admission to critical care unit or died. Conclusion: We observed no MERS-CoV co-infection in this early cohort of hospitalized COVID-19 patients who were relatively young, more than half had comorbid conditions, presented with fever and/or cough, an abnormal chest X-ray, lymphopenia, and high inflammatory markers. Given MERS-CoV endemicity in the country, co-monitoring of MERS-CoV and SARS-CoV-2 coinfection is critical.

J Epidemiol Glob Health2020       LitCov and CORD-19
295Did social isolation during the SARS-CoV-2 epidemic have an impact on the lifestyles of citizens?  


Epidemiol Prev2020       LitCov and CORD-19
296COVID-19 vaccination during pregnancy: coverage and safety  

Background Concerns have been raised regarding a potential surge of COVID-19 in pregnancy, secondary to rising numbers of COVID-19 in the community, easing of societal restrictions, and vaccine hesitancy. Even though COVID-19 vaccination is now offered to all pregnant women in the UK, there are limited data on its uptake and safety. Objectives and study design : This was a cohort study of pregnant women who gave birth at St George’s University Hospitals NHS Foundation Trust, London, UK, between March 1st and July 4th 2021. The primary outcome was uptake of COVID-19 vaccination and its determinants. The secondary outcomes were perinatal safety outcomes. Data were collected on COVID-19 vaccination uptake, vaccination type, gestational age at vaccination, as well as maternal characteristics including age, parity, ethnicity, index of multiple deprivation score and co-morbidities. Further data were collected on perinatal outcomes including stillbirth (fetal death ≥24 weeks’ gestation), preterm birth, fetal/congenital abnormalities and intrapartum complications. Pregnant women who received the vaccine were compared with a matched cohort of propensity balanced pregnant women to compare outcomes. Effect magnitudes of vaccination on perinatal outcomes were reported as mean differences or odds ratios with 95% confidence intervals. Factors associated with antenatal vaccination were assessed with logistic regression analysis. Results Data were available for 1328 pregnant women of whom 141 received at least one dose of vaccine before giving birth and 1187 women who did not; 85.8% of those vaccinated received their vaccine in the third trimester and 14.2% in the second trimester. Of those vaccinated, 128 (90.8%) received an mRNA vaccine and 13 (9.2%) a viral vector vaccine. There was evidence of reduced vaccine uptake in younger women (P=0.002), those with high levels of deprivation (i.e., fifth quintile of Index of Multiple Deprivation, P=0.008) and women of Afro-Caribbean or Asian ethnicity, compared to Caucasian ethnicity (P<0.001). Women with pre-pregnancy diabetes had increased vaccine uptake (P=0.008). In the multivariable model adjusting for variables that had a significant effect according to the univariable analysis, fifth deprivation quintile (most deprived) was significantly associated with lower antenatal vaccine uptake (adjusted OR 0.09, 95% CI 0.02–0.39, P=0.002), while pre-pregnancy diabetes was significantly associated with higher antenatal vaccine uptake (adjusted OR 11.1, 95% CI 2.01–81.6, P=0.008). In a propensity score matched cohort, compared with non-vaccinated pregnant women, 133 women who received at least one dose of the COVID-19 vaccine in pregnancy (vs. those unvaccinated) had similar rates of adverse pregnancy outcomes (P>0.05 for all): stillbirth (0.0% vs 0.3%), fetal abnormalities (2.2% vs 2.7%), intrapartum pyrexia (3.7% vs 1.5%), postpartum hemorrhage (9.8% vs 9.5%), cesarean section (30.8% vs. 30.6%), small for gestational age (12.0% vs 15.8%), maternal high dependency unit or intensive care admission (6.0% vs 3.5%) or neonatal intensive care unit admission (5.3% vs 5.4%). Mixed-effects Cox regression showed that vaccination was not significantly associated with birth <40 weeks’ gestation (hazard ratio 0.93, 95% CI 0.71–1.23, P=0.630). Conclusions Of pregnant women eligible for COVID-19 vaccination, less than one third accepted COVID-19 vaccination during pregnancy and they experienced similar pregnancy outcomes. There was lower uptake among younger women, non-white ethnicity, and lower socioeconomic background. This study contributes to the body of evidence that having COVID-19 vaccination in pregnancy does not alter perinatal outcomes. Clear communication to improve awareness among pregnant women and healthcare professionals on vaccine safety is needed, alongside strategies to address vaccine hesitancy. This includes post-vaccination surveillance to gather further data on pregnancy outcomes, particularly after first trimester vaccination, as well as long-term infant follow-up.

Am J Obstet Gynecol2021       LitCov and CORD-19
297Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1  

N Engl J Med2020       LitCov and CORD-19
298A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster  

BACKGROUND: An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. METHODS: In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done. FINDINGS: From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36–66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3–6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6–10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats. INTERPRETATION: Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions. FUNDING: The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).

Lancet2020       LitCov and CORD-19
299Assessing the Impact of the COVID-19 Pandemic in Spain: Large-Scale, Online, Self-Reported Population Survey  

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

J Med Internet Res2020       LitCov and CORD-19
300Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor  


Nature2020       LitCov and CORD-19

(1) COVID-19 Open Research Dataset (CORD-19). 2020. Version 2022-06-02. Retrieved from Accessed 2022-06-05. doi:10.5281/zenodo.3715506
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(3) Currently tweets of May 15th to May 21st 2022 have been considered.

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