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Showing papers in "Social Science Research Network in 2021"


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TL;DR: Nearly 50% COVID-19 patients could not reach obvious clinical and radiological remission within 10 days after hospitalization, and the patients with male sex, anorexia and no fever on admission predicted poor efficacy.
Abstract: South Australia is presently in the throes of major changes to its regulatory system governing land use, development of land and the development of planning policy against which development assessment decisions are to be made. Eventually the planning and development control system established under the Development Act 1993 (SA) will be replaced by a new system implemented by the Planning, Development and Infrastructure Act 2016 (SA) (the new Act).

568 citations


Journal ArticleDOI
TL;DR: It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more symptoms, and there is a need for studies to stratify by sex, age, previous comorbidities, severity of COVID-19 (including asymptomatic), and duration of each symptom.
Abstract: Background: COVID-19, caused by SARS-CoV-2, can involve sequelae that last weeks to months after initial recovery. The objective of this systematic review and meta-analysis is to identify studies assessing the long-term effects of COVID-19 and estimate the prevalence of each symptom, sign, or laboratory parameters of patients at a post-COVID-19 stage. Methods: In this systematic review and meta-analysis, LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. Studies published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using the I2 statistics. PRISMA guidelines were followed. Findings: A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). In order to have a better understanding, there is a need for studies to stratify by sex, age, previous comorbidities, severity of COVID-19 (including asymptomatic), and duration of each symptom. Interpretation: From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address after-COVID-19 care. Funding: National Institute for Neurological Disorders and Stroke (NINDS), and Houston Methodist Research Institute, Houston, TX. Declaration of Interests: SLL is an employee of Novartis Pharmaceutical Company; the statements presented in the paper do not necessarily represent the position of the company. The remaining authors have no competing interests to declare.

438 citations


Journal ArticleDOI
TL;DR: A further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses are presented.
Abstract: Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, MHRA, with a regimen of two standard doses given with an interval of between 4 and 12 weeks The planned rollout in the UK will involve vaccinating people in high risk categories with their first dose immediately, and delivering the second dose 12 weeks laterHere we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered Methods: We present data from phase III efficacy trials of ChAdOx1 nCoV-19 in the United Kingdom and Brazil, and phase I/II clinical trials in the UK and South Africa, against symptomatic disease caused by SARS-CoV-2 The data cut-off date for these analyses was 7th December 2020 The accumulated cases of COVID-19 disease at this cut-off date exceeds the number required for a pre-specified final analysis, which is also presented As previously described, individuals over 18 years of age were randomised 1:1 to receive two standard doses (SD) of ChAdOx1 nCoV-19 (5x1010 viral particles) or a control vaccine/saline placebo In the UK trial efficacy cohort a subset of participants received a lower dose (LD, 22x1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose All cases with a nucleic acid amplification test (NAAT) were adjudicated for inclusion in the analysis, by a blinded independent endpoint review committee Studies are registered at ISRCTN89951424 and ClinicalTrialsgov; NCT04324606, NCT04400838, and NCT04444674 Findings: 17,177 baseline seronegative trial participants were eligible for inclusion in the efficacy analysis, 8948 in the UK, 6753 in Brazil and 1476 in South Africa, with 619 documented NAAT +ve infections of which 332 met the primary endpoint of symptomatic infection >14 days post dose 2The primary analysis of overall vaccine efficacy >14 days after the second dose including LD/SD and SD/SD groups, based on the prespecified criteria was 667% (574%, 740%) There were no hospitalisations in the ChAdOx1 nCoV-19 group after the initial 21 day exclusion period, and 15 in the control groupVaccine efficacy after a single standard dose of vaccine from day 22 to day 90 post vaccination was 76% (59%, 86%), and modelled analysis indicated that protection did not wane during this initial 3 month period Similarly, antibody levels were maintained during this period with minimal waning by day 90 day (GMR 066, 95% CI 059, 074)In the SD/SD group, after the second dose, efficacy was higher with a longer prime-boost interval: VE 824% 95%CI 627%, 917% at 12+ weeks, compared with VE 549%, 95%CI 327%, 697% at <6 weeks These observations are supported by immunogenicity data which showed binding antibody responses more than 2-fold higher after an interval of 12 or more weeks compared with and interval of less than 6 weeks GMR 219 (212, 226) in those who were 18-55 years of age Interpretation: ChAdOx1 nCoV-19 vaccination programmes aimed at vaccinating a large proportion of the population with a single dose, with a second dose given after a 3 month period is an effective strategy for reducing disease, and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term Trial Registration: Studies are registered at ISRCTN89951424 and ClinicalTrialsgov; NCT04324606, NCT04400838, and NCT04444674 Funding: UKRI, NIHR, CEPI, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’OR, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and Astra Zeneca Conflict of Interest: Oxford University has entered into a partnership with Astra Zeneca for further development of ChAdOx1 nCoV-19 SCG is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine TL is named as aninventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project PMF is a consultant to Vaccitech AJP is Chair of UK DeptHealth and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in discussions on COVID-19 vaccines, and is a member of the WHO’sSAGE AJP and SNF are NIHR Senior Investigator The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR or WHO AVSH reports personal feesfrom Vaccitech, outside the submitted work and has a patent on ChAdOx1 licensed to Vaccitech, and may benefit from royalty income to the University of Oxford from sales of this vaccine by AstraZeneca and sublicensees MS reports grants from NIHR, non-financial support fromAstraZeneca, during the conduct of the study; grants from Janssen, grants fromGlaxoSmithKline, grants from Medimmune, grants from Novavax, grants and non-financialsupport from Pfizer, grants from MCM, outside the submitted work CG reports personal fees from the Duke Human Vaccine Institute, outside of the submitted work SNF reports grants from Janssen and Valneva, outside the submitted work ADD reports grants and personal fees from AstraZeneca, outside of the submitted work In addition, ADD has a patent manufacturingprocess for ChAdOx vectors with royalties paid to AstraZeneca, and a patent ChAdOx2 vector with royalties paid to AstraZeneca The other authors declare no competing interests

428 citations


Journal ArticleDOI
TL;DR: The authors found that correcting for the bias induced by the staggered nature of policy adoption frequently impacts the estimated effect from standard difference-in-difference studies, in many cases, the reported effects in prior research become indistinguishable from zero.
Abstract: Difference-in-differences analysis with staggered treatment timing is frequently used to assess the impact of policy changes on corporate outcomes in academic research. However, recent advances in econometric theory show that such designs are likely to be biased in the presence of treatment effect heterogeneity. Given the pronounced use of staggered treatment designs in applied corporate finance and accounting research, this finding potentially impacts a large swath of prior findings in these fields. We survey the nascent literature and document how and when such bias arises from treatment effect heterogeneity. We apply recently proposed methods to a set of prior published results, and find that correcting for the bias induced by the staggered nature of policy adoption frequently impacts the estimated effect from standard difference-in-difference studies. In many cases, the reported effects in prior research become indistinguishable from zero.

302 citations


Journal ArticleDOI
TL;DR: In this paper, the authors used geolocation data from smartphones to study whether political beliefs inhibit compliance with government orders and found that residents in Republican counties are less likely to completely stay at home after a state order has been implemented relative to those in Democratic counties.
Abstract: We use the state-mandated stay-at-home orders during the coronavirus pandemic as a setting to study whether political beliefs inhibit compliance with government orders. Using geolocation data sourced from smartphones, we find residents in Republican counties are less likely to completely stay at home after a state order has been implemented relative to those in Democratic counties. Debit card transaction data shows that Democrats are more likely to switch to remote spending after state orders are implemented. Heterogeneity in factors such as Covid-19 risk exposure, geography, and county characteristics do not completely rule out our findings, suggesting political beliefs are an important determinant in the effectiveness of government mandates. Political alignment with officials giving orders may partially explain these partisan differences.

264 citations


Journal ArticleDOI
TL;DR: For example, this paper found that 20 percent of full workdays will be supplied from home after the pandemic ends, compared with just 5 percent before, and that the shift to WFH will directly reduce spending in major city centers by at least 5-10 percent relative to the pre-pandemic situation.
Abstract: COVID-19 drove a mass social experiment in working from home (WFH). We survey more than 30,000 Americans over multiple waves to investigate whether WFH will stick, and why. Our data say that 20 percent of full workdays will be supplied from home after the pandemic ends, compared with just 5 percent before. We develop evidence on five reasons for this large shift: better-than-expected WFH experiences, new investments in physical and human capital that enable WFH, greatly diminished stigma associated with WFH, lingering concerns about crowds and contagion risks, and a pandemic-driven surge in technological innovations that support WFH. We also use our survey data to project three consequences: First, employees will enjoy large benefits from greater remote work, especially those with higher earnings. Second, the shift to WFH will directly reduce spending in major city centers by at least 5-10 percent relative to the pre-pandemic situation. Third, our data on employer plans and the relative productivity of WFH imply a 5 percent productivity boost in the post-pandemic economy due to re-optimized working arrangements. Only one-fifth of this productivity gain will show up in conventional productivity measures, because they do not capture the time savings from less commuting.

236 citations


Journal ArticleDOI
TL;DR: It is shown how choices and assumptions made—often implicitly—to justify the use of prediction-based decision-making can raise fairness concerns and a notationally consistent catalog of fairness definitions from the literature is presented.
Abstract: A recent wave of research has attempted to define fairness quantitatively. In particular, this work has explored what fairness might mean in the context of decisions based on the predictions of sta...

212 citations


Journal ArticleDOI
TL;DR: There was a signal toward increased severity associated with B.1.617.2 with lower Ct value and longer viral shedding providing a potential mechanism for increased transmissibility, and these findings provide a strong impetus for the rapid implementation of vaccination programmes.
Abstract: Background: The impact of SARS-CoV-2 variants of concern (VOCs) on disease severity is unclear. In this retrospective cohort study, we compared outcomes of patients infected with B.1.1.7, B.1.351, and B.1.617.2 with those with wild-type strains from early 2020. Methods: National surveillance data from 1-January-2021 to 22-May-2021 were obtained from the Ministry of Health, and outcomes in relation to VOC were explored. Detailed patient level data from all SARS-CoV-2 patients with VOC infection admitted to our centre between 20-December-2020 and 12-May-2021 were analysed. Outcomes were compared with a cohort of 846 patients admitted January-April 2020. Findings: There were 838 VOC infections in Singapore in the study period. After adjusting for age and gender, B.1.617.2 infection was associated with higher odds of oxygen requirement, ICU admission, or death (adjusted odds ratio (aOR) 4·90, [95% CI 1·43-30·78]. 157 patients with VOCs were admitted to our centre. After adjusting for age, gender, comorbidities, and vaccination, aOR for pneumonia with B.1.617.2 was 1·88 [95% CI 0·95-3·76]) compared with wild-type. B.1.617.2 was associated with significantly lower PCR Ct values and significantly longer duration of Ct value ≤30 (estimated median duration 18 days for B.1.617.2, 13 days for wild-type). Vaccine breakthrough cases were less severe. Interpretation: There was a signal toward increased severity associated with B.1.617.2. The association of B.1.617.2 with lower Ct value and longer viral shedding provides a potential mechanism for increased transmissibility. These findings provide a strong impetus for the rapid implementation of vaccination programmes. Funding Information: National Medical Research Council grants COVID19RF-001 and COVID19RF-008. Declaration of Interests: BEY reports personal fees from Roche and Sanofi, outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: Informed consent for retrospective data collection was waived as approved by the institutional review board (NHG-DSRB reference number 2020/01122).

201 citations


Journal ArticleDOI
TL;DR: A phase 3 clinical trial conducted in healthcare professionals in Brazil demonstrated that the inactivated CoronaVac vaccine has a good safety profile and is efficacious against any symptomatic SARS-CoV-2 infections and highly protective against moderate and severe COVID-19.
Abstract: Background: Vaccines are urgently needed to tackle the unprecedented morbidity and mortality of COVID-19. Administration of inactivated viruses are the common and mature platform of developing new vaccines. CoronaVac is an inactivated vaccine that has undergone preclinical tests and phase I/II clinical trials. Methods: We conducted a randomised, double-blind, placebo-controlled phase 3 clinical trial with CoronaVac among healthy healthcare professionals in 16 centres in Brazil. Participants received two doses of vaccine (3 μg in 0.5 mL) vaccine or placebo at day 0 and 14. The primary efficacy endpoint was the number of symptomatic COVID-19 cases confirmed by RT-PCR 14 days after the second dose of the vaccine. Prevention of disease severity was a major secondary efficacy endpoint, and adverse events incidence up to seven days after immunization was the primary safety outcome. The trial was registered at ClinicalTrials.gov, NCT04456595. Findings: Between July 21 and Dec 16, 2020, 12 396 participants were enrolled and received at least one vaccine or placebo dose. There were 9,823 participants who received the two doses and were followed for at least 14 days and had, therefore, reached the final efficacy analysis. There were 253 confirmed COVID-19 cases in the cohort: 85 cases (11.0/100 person-year) among 4,953 participants in the vaccine group, and 168 cases (22·3/100 person-year) among 4,870 participants in the placebo group. The primary efficacy against symptomatic COVID-19 was 50·7% (95%CI 36·0-62·0). The secondary efficacy against cases requiring assistance (score ≥3) and moderate and severe cases (score ≥4) were 83·7% (95%CI 58·0-93.7) and 100% (95%CI 56·4-100.0) respectively. All 6 cases of severe COVID-19 occurred in the placebo group. The incidence of adverse reactions, which was mainly pain at the administration site, was higher in the vaccine group (77·1%) than in the placebo group (66·4%). There were 67 serious adverse events reported by 64 participants and all were determined to be unrelated to vaccination, including two fatal cases. In a subset of participants, neutralizing antibody assays showed similar seroconversion and geometric mean titres against B.1.128, P.1, and P.2 variants. Interpretation: A phase 3 clinical trial conducted in healthcare professionals in Brazil demonstrated that the inactivated CoronaVac vaccine has a good safety profile and is efficacious against any symptomatic SARS-CoV-2 infections and highly protective against moderate and severe COVID-19.

152 citations


Journal ArticleDOI
TL;DR: This observational study highlights that while both mRNA COVID-19 vaccines strongly protect against infection and severe disease, further evaluation of mechanisms underlying differences in their effectiveness such as dosing regimens and vaccine composition are warranted.
Abstract: Although clinical trials and real-world studies have affirmed the effectiveness and safety of the FDA-authorized COVID-19 vaccines, reports of breakthrough infections and persistent emergence of new variants highlight the need to vigilantly monitor the effectiveness of these vaccines. Here we compare the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna (mRNA-1273) and Pfizer/BioNTech (BNT162b2) in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. We defined cohorts of vaccinated and unvaccinated individuals from Minnesota (n = 25,589 each) matched on age, sex, race, history of prior SARS-CoV-2 PCR testing, and date of full vaccination. Both vaccines were highly effective during this study period against SARS-CoV-2 infection (mRNA-1273: 86%, 95%CI: 81-90.6%; BNT162b2: 76%, 95%CI: 69-81%) and COVID-19 associated hospitalization (mRNA-1273: 91.6%, 95% CI: 81-97%; BNT162b2: 85%, 95% CI: 73-93%). However, in July, the effectiveness against infection was considerably lower for mRNA-1273 (76%, 95% CI: 58-87%) with an even more pronounced reduction in effectiveness for BNT162b2 (42%, 95% CI: 13-62%). Notably, the Delta variant prevalence in Minnesota increased from 0.7% in May to over 70% in July whereas the Alpha variant prevalence decreased from 85% to 13% over the same time period. Comparing rates of infection between matched individuals fully vaccinated with mRNA-1273 versus BNT162b2 across Mayo Clinic Health System sites in multiple states (Minnesota, Wisconsin, Arizona, Florida, and Iowa), mRNA-1273 conferred a two-fold risk reduction against breakthrough infection compared to BNT162b2 (IRR = 0.50, 95% CI: 0.39-0.64). In Florida, which is currently experiencing its largest COVID-19 surge to date, the risk of infection in July after full vaccination with mRNA-1273 was about 60% lower than after full vaccination with BNT162b2 (IRR: 0.39, 95% CI: 0.24-0.62). Our observational study highlights that while both mRNA COVID-19 vaccines strongly protect against infection and severe disease, further evaluation of mechanisms underlying differences in their effectiveness such as dosing regimens and vaccine composition are warranted. Declaration of Interests: AP, PJL, ES, MJN, JC, AJV, and VS are employees of nference and have financial interests in the company. nference is collaborating with Moderna, Pfizer, Janssen, and other bio-pharmaceutical companies on data science initiatives unrelated to this study. These collaborations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JCO receives personal fees from Elsevier and Bates College, and receives small grants from nference, Inc, outside the submitted work. ADB is supported by grants from NIAID (grants AI110173 and AI120698), Amfar (#109593), and Mayo Clinic (HH Shieck Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). ADB is a paid consultant for Abbvie, Gilead, Freedom Tunnel, Pinetree therapeutics Primmune, Immunome and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals, Equilium, and Excision Biotherapeutics, has received fees for speaking for Reach MD and Medscape, owns equity for scientific advisory work in Zentalis and nference, and is founder and President of Splissen Therapeutics. MDS received grant funding from Pfizer via Duke University for a vaccine side effect registry. JH, JCO, AV, MDS and ADB are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. Ethics Approval Statement: This study was reviewed and approved by the Mayo Clinic Institutional Review Board (IRB 20-003278) as a minimal risk study. The approved IRB was titled: Study of COVID-19 patient characteristics with augmented curation of Electronic Health Records (EHR) to inform strategic and operational decisions with the Mayo Clinic. The study was deemed exempt by the Mayo Clinic Institutional Review Board and waived from consent. The following resource provides further information on the Mayo Clinic Institutional Review Board and adherence to basic ethical principles underlying the conduct of research, and ensuring that the rights and well-being of potential research subjects are adequately protected: www.mayo.edu/research/institutional-review-board/overview.

148 citations


Journal ArticleDOI
TL;DR: It is suggested that text-based nudges can substantially increase and accelerate COVID-19 vaccinations at almost zero marginal cost, highlighting the promising role of behavioral science in addressing a critical component of the CO VID-19 pandemic response.
Abstract: Enhancing vaccine uptake is a critical public health challenge. Overcoming vaccine hesitancy and failure to follow through on vaccination intentions requires effective communication strategies. Here we present two sequential randomized controlled trials to test the effect of behavioural interventions on the uptake of COVID-19 vaccines. We designed text-based reminders that make vaccination salient and easy, and delivered them to participants drawn from a healthcare system one day (first randomized controlled trial) (n = 93,354 participants; clinicaltrials number NCT04800965) and eight days (second randomized controlled trial) (n = 67,092 individuals; clinicaltrials number NCT04801524) after they received a notification of vaccine eligibility. The first reminder boosted appointment and vaccination rates within the healthcare system by 6.07 (84%) and 3.57 (26%) percentage points, respectively; the second reminder increased those outcomes by 1.65 and 1.06 percentage points, respectively. The first reminder had a greater effect when it was designed to make participants feel ownership of the vaccine dose. However, we found no evidence that combining the first reminder with a video-based information intervention designed to address vaccine hesitancy heightened its effect. We performed online studies (n = 3,181 participants) to examine vaccination intentions, which revealed patterns that diverged from those of the first randomized controlled trial; this underscores the importance of pilot-testing interventions in the field. Our findings inform the design of behavioural nudges for promoting health decisions, and highlight the value of making vaccination easy and inducing feelings of ownership over vaccines.

Journal ArticleDOI
TL;DR: In pwMS, therapy with anti-CD20 and fingolimod led to a reduced humoral response to SARS-CoV-2 vaccines, and mRNA-1273 vaccine resulted in a systematically 3·5-fold higher antibody level than the BNT162b2 vaccine.
Abstract: Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) are known to affect immune response to antigens and possibly to SARS-CoV2 vaccine. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech, Inc or mRNA-1273, Moderna Tx, Inc). A blood collection for the measure of SARS-CoV-2 antibody before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche Diagnostics). Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariate analysis, the antibody levels of patients on ocrelizumab (178-fold decrease, p<0·001), fingolimod (26-fold decrease, p<0·001) and rituximab (17-fold decrease, p<0·001) were significantly reduced as compared to untreated patients. mRNA-1273 vaccine resulted in a systematically 3·5-fold higher antibody level than the BNT162b2 vaccine (p<0·001). Interpretation: In pwMS, therapy with anti-CD20 and fingolimod led to a reduced humoral response to SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·5-higher antibody titers than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 or fingolimod. Since it is still unknown the role of T-cells vaccine response, further information is required about the role of cellular immunity triggered by vaccination to better define the most appropriate strategy to vaccinate pwMS under specific DMTs. Funding Information: FISM [2021/Special-Multi/001]; the Italian Ministry of Health grant ‘Progetto Z844A 5x1000’. Declaration of Interests: MPS reports grants from Roche, during the conduct of the study; personal fees from Biogen, Merck, Roche, Sanofi, personal fees from Novartis, Medday, Geneuro, Celgene, Mylan, outside the submitted work; MI reports consulting fees from Roche, Merck-Serono, Novartis, Sanofi-Genzyme, Biogen; AL has received personal compensation from Novartis, Sanofi Genzyme, Biogen, Merck, and Roche for public speaking and advisory boards. AL received funding for research by Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, and the Italian Ministry of University; CC reports personal fees from Novartis, personal fees from Biogen Idec, personal fees from Almirall, personal fees from Merck Serono, outside the submitted work; DL reports consulting fees Roche, Biogen, Teva, Mylan, Sanofi-Genzyme, fess for advisory boards from Bristol-Celgene, Merck, Novartis, JF reports consulting fees fromSanofi, Biogen, Admirall; ADS reports personal consulting fees from Biogen, Novartis, Genzyme; MS reports research support and personal consulting fees from Merk, Sanofi, Novartis, Biogen, Roche; AU has received personal compensation from Novartis, Biogen, Merck, Roche and Sanofi Genzyme for public speaking and advisory boards. AU received funding for research by Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health and the European Community. IS, LC, CL, GDR, CS, IG, TT, GP, PG, GPB, AM, MLS, MC, ES, MTF, LP, MU, FM, GC, RI, GL, AMR, FC, SC, MAB, DF, have nothing to dislcose. Ethics Approval Statement: The study is done in compliance with the principles of the Declaration of Helsinki. The protocol is approved by the regional (CER Liguria: 5/2021 - DB id 11169- 21/01/2021) and the centralized national ethical committee AIFA/Spallanzani (Parere n 351, 2020/21). Written informed consent was obtained from all participants before starting any study procedures.

Journal ArticleDOI
TL;DR: The mRNA BNT162b2 vaccination elicits a strong systemic immune response by drastically boosting neutralizing antibodies development in serum, but not in saliva, indicating that at least oral mucosal immunity is poorly activated by this vaccination protocol, thus failing in limiting virus acquisition upon its entry through this route.
Abstract: Background: Although the BNT162b2 COVID-19 vaccine is known to induce IgG neutralizing antibodies in serum protecting against COVID-19, it has not been studied in detail whether it could generate specific immunity at mucosal sites, which represent the primary route of entry of SARS-CoV-2. Methods: Samples of serum and saliva of 60 BNT162b2-vaccinated healthcare workers were collected at baseline, two weeks after the first dose and two weeks after the second dose. Anti-S-protein IgG and IgA total antibodies titres and the presence of neutralizing antibodies against the Receptor Binding Domain in both serum and saliva were measured by quantitative and by competitive ELISA, respectively. Findings: Complete vaccination cycle generates a similar serum IgG antibody titre as a single dose in previously infected seropositive individuals. Serum IgA concentration reaches a plateau after a single dose in seropositive individuals and two vaccine doses in seronegative subjects. After the second dose IgA level was higher in seronegative than in seropositive subjects. In saliva, IgG level is almost two orders of magnitude lower than in serum, reaching the highest values after the second dose. IgA concentration remains low and increases significantly only in seropositive individuals after the second dose. Neutralizing antibody titres were much higher in serum than in saliva. Interpretation: The mRNA BNT162b2 vaccination elicits a strong systemic immune response by drastically boosting neutralizing antibodies development in serum, but not in saliva, indicating that at least oral mucosal immunity is poorly activated by this vaccination protocol, thus failing in limiting virus acquisition upon its entry through this route. Funding Information: This study was funded by our public Institution, Department of Medicine and Surgery, University of Insubria. Declaration of Interests: None to declare. Ethics Approval Statement: The clinical protocol for sample and data collection and the informed consent were approved by the Institutional Ethics Committee (Comitato Etico dell’Insubria, n° 165/2020).

Journal ArticleDOI
TL;DR: It is found that reviews are typically informative but that negative experiences are underreported, and that social considerations also cause information loss in reputation systems.
Abstract: Reputation systems are used by nearly every digital marketplace, but designs vary and the effects of these designs are not well understood. We use a large-scale experiment on Airbnb to study the causal effects of one particular design choice — the timing with which feedback by one user about another is revealed on the platform. Feedback was hidden until both parties submitted a review in the treatment group and was revealed immediately after submission in the control group. The treatment stimulated more reviewing in total. This is due to users' curiosity about what their counterparty wrote and/or the desire to have feedback visible to other users. We also show that the treatment reduced retaliation and reciprocation in feedback and led to lower ratings as a result. The effects of the policy on feedback did not translate into reduced adverse selection on the platform.

Journal ArticleDOI
TL;DR: The study demonstrates that the BNT162b2 vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults; this cohort was vaccinated when the dominant variant in circulation was B1.1.
Abstract: Background: BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK. We determined the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in our healthcare worker (HCW) cohort study of staff undergoing regular asymptomatic testing. Methods: The SIREN study is a prospective cohort study among staff working in publicly funded hospitals. Baseline risk factors, vaccination status (from 8/12/2020-5/2/2021), and symptoms are recorded at 2 weekly intervals and all SARS-CoV-2 polymerase chain reaction (PCR) and antibody test results documented. A mixed effect proportional hazards frailty model using a Poisson distribution was used to calculate hazard ratios to compare time to infection in unvaccinated and vaccinated participants to estimate the impact of the BNT162b2 vaccine on all (asymptomatic and symptomatic) infection. Findings: Vaccine coverage was 89% on 5/2/2021. Significantly lower coverage was associated with prior infection (aOR 0.59 95% confidence interval [CI] 0.54-0.64), female (aOR 0.72, 95% CI 0.63-0.82), aged under 35 years, being from minority ethnic groups (especially Black, aOR 0.26, 95% CI 0.21-0.32), porters/security guards (aOR 0.61, 95% CI 0.42-0.90),or midwife (aOR 0.74, 95% CI 0.57-0.97), and living in more deprived neighbourhoods (IMD 1 (most) vs. 5 (least) (aOR 0.75, 95% CI 0.65-0.87). A single dose of BNT162b2 vaccine demonstrated vaccine effectiveness of 72% (95% CI 58-86) 21 days after first dose and 86% (95% CI 76-97) seven days after two doses in the antibody negative cohort. Conclusion: Our study demonstrates that the BNT162b2 vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults; this cohort was vaccinated when the dominant variant in circulation was B1.1.7 and demonstrates effectiveness against this variant. Trial Registration: IRAS ID 284460, REC reference 20/SC/0230 Berkshire Research Ethics Committee, Health Research Authority and Health and Care Research Wales approval granted 22 May 2020. Trial registered with ISRCTN, Trial ID: ISRCTN11041050. https://www.isrctn.com/ISRCTN11041050 Funding: The study is funded by the United Kingdom’s Department of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments. Funding is also provided by the National Institute for Health Research (NIHR) as an Urgent Public Health Priority Study (UPHP). SH, VH are supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with Public Health England (PHE) (NIHR200915). AC is supported by NIHR HealthProtection Research Unit in Behavioural Science and Evaluation at University of Bristol in partnership with Public Health England. MR, NA, AC are supported by NIHR HealthProtection Research Unit in Immunisation at the London School of Hygiene and Tropical Medicine in partnership with Public Health England. Conflict of Interest: The Immunisation and Countermeasures Division has provided vaccine manufacturers(including Pfizer) with post-marketing surveillance reports on pneumococcal andmeningococcal infection which the companies are required to submit to the UK Licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports. Ethical Approval: The study was approved by the Berkshire Research Ethics Committee, Health Research Authority (IRAS ID 284460, REC reference 20/SC/0230) on 22 May 2020; the vaccine amendment was approved on 12/1/2021.

Journal ArticleDOI
TL;DR: Vaccination with BNT162b2 induces significantly higher levels of SARS-CoV-2 specific binding and neutralizing antibody responses compared to CoronaVac and these differences are likely to result in differences in protection from infection.
Abstract: Background: COVID-19 vaccination programs are ongoing world-over using a wide array of vaccines. The performance of vaccines has been evaluated for immunogenicity and efficacy in separate clinical trials, but few head-to-head evaluations of vaccine responses have been carried out. Methods: An age-matched cohort that received 2 doses of either BNT162b2 (=49) or CoronaVac (n=49) were recruited from adults in the community in Hong Kong SAR, China. The humoral and cellular immune responses were examined to determine the levels of SARS-CoV-2 neutralizing and binding antibody in plasma and T cell reactivity in peripheral blood mononuclear cells (PBMC). Findings: At one month after second dose of vaccine, BNT162b2 vaccines elicited significantly higher 50% plaque reduction neutralization test (PRNT50), PRNT90, surrogate virus neutralization (sVNT), spike receptor binding (RBD), spike N terminal domain binding (NTD), spike S2 domain binding antibody levels compared to those vaccinated with CoronaVac. All 49 vaccinees in each group developed detectable PRNT 50 antibody. The geometric mean titers (GMT) PRNT50 in those vaccinated with BNT162b2 and CoronaVac vaccines was 251.6 and 69.45 respectively (p<0.0001). Forty-eight (98%) of 49 vaccinated with BNT162b2 and 44 (89.8%) of 49 vaccinated with CoronaVac achieved the 50% protection threshold for PRNT50. Allowing for a two-fold waning of antibody titers over time, 98% of those receiving BNT162b2 would still be protected but only 53.1% of CoronaVac recipients would remain protected. Age was negatively correlated with PRNT90 antibody titers among all vaccine recipients or either one of the vaccine subgroups separately. Both vaccines resulted in comparable levels of CD4 and CD8 T cell responses to spike protein at 1 month of post-vaccination. Interpretation: Vaccination with BNT162b2 induces significantly higher levels of SARS-CoV-2 specific binding and neutralizing antibody responses compared to CoronaVac and these differences are likely to result in differences in protection from infection. The two vaccines induce comparable CD4 and CD8 T cell responses. These findings are of relevance for decisions on the need for booster vaccines and for public health control of SARS-CoV-2. Funding Information: The Health and Medical Research Fund Commissioned Research on the Novel Coronavirus Disease (#COVID-1903003), Hong Kong SAR (see Acknowledgments for full list). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study has been approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Ref no: 2020.229) and all participants provided written consent.

Journal ArticleDOI
TL;DR: In this article, the authors administered the Zoom Exhaustion & fatigue scale to 10,591 participants from a convenience sample and tested the associations between five theoretical nonverbal mechanisms and Zoom Fatigue.
Abstract: There is little data on Zoom Fatigue, the exhaustion that follows video conference meetings. This paper administers the Zoom Exhaustion & Fatigue scale to 10,591 participants from a convenience sample and tests the associations between five theoretical nonverbal mechanisms and Zoom Fatigue – mirror anxiety, being physically trapped, hyper gaze from a grid of staring faces, and the cognitive load from producing and interpreting nonverbal cues. First, we show that daily usage predicts the amount of fatigue, and that women have longer meetings and shorter breaks between meetings than men. Second, we show that women have greater Zoom fatigue than men. Third, we show that the five nonverbal mechanisms for fatigue predict Zoom fatigue. Fourth, we confirm that mirror anxiety mediates the difference in fatigue across gender. Exploratory research shows that race, age, and personality relate to fatigue. We discuss avenues for future research and strategies to decrease Zoom fatigue.

Journal ArticleDOI
TL;DR: The data suggest that the enhancement of infectivity in mouse may lead to the spillover of 501Y.V2 to mouse, which may compromise the efficacy of monoclonal antibodies, convalescent sera and vaccines.
Abstract: The 501Y.V2 variants contain multiple mutations in the spike region. We found that they had no significant increased effect on infectivity to human cell lines and cells overexpressing human ACE2, but increased infectivity in cells overexpressing mouse ACE2 based on the pseudotyped viruses. The susceptibility of 501Y.V2 variants to many neutralizing monoclonal antibodies decreased significantly. These variants also had a significant reduced effect on the neutralization ability of convalescent and RBD protein immunized sera. The immune resistances were mainly caused by E484K and N501Y mutations located in receptor binding region. These data suggest that the enhancement of infectivity in mouse may lead to the spillover of 501Y.V2 to mouse. The immune resistance of 501Y.V2 may compromise the efficacy of monoclonal antibodies, convalescent sera and vaccines. Funding: This work was supported by General Program ofNational Natural Science Foundation of China [grant number 82073621], BILL & MELINDA GATES FOUNDATION [Investment ID INV-006379], National Science and Technology Major Projects of Drug Discovery [grant number 2018ZX09101001] and National Science and Technology Major Projects of Infectious Disease [grant number 2017ZX10304402]. Conflict of Interest: All the authors declare no competing interests. Ethical Approval: The protocol of the animal study was approved by Ethical review Committee for Animal Welfare of The National Institutes for Food and Drug Control.

Journal ArticleDOI
TL;DR: The authors found that pump-and-dump schemes can lead to short-term bubbles featuring dramatic increases in prices, volume, and volatility of cryptocurrencies, implying significant wealth transfers between insiders and outsiders.
Abstract: Pump-and-dump schemes (P&Ds) are pervasive in the cryptocurrency market. We find that P&Ds lead to short-term bubbles featuring dramatic increases in prices, volume, and volatility. Prices peak within minutes and quick reversals follow. The evidence we document, including price run-ups before P&Ds start, implies significant wealth transfers between insiders and outsiders. Bittrex, a cryptocurrency exchange, banned P&Ds on November 24, 2017. Using a difference-in-differences approach, we provide causal evidence that P&Ds are detrimental to the liquidity and price of cryptocurrencies. We discuss potential mechanisms why outsiders are willing to participate and describe how our findings shed light on manipulation theories.

Journal ArticleDOI
TL;DR: A prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection, which is the minimum likely effect as seroconversions were not included.
Abstract: Background There is an urgent need to better understand whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection. Methods A large multi-centre prospective cohort was recruited from publicly funded hospital staff in the UK. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed fortnightly questionnaires on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negative cohort (antibody negative, not previously known to be PCR/antibody positive). Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection were excluded from this analysis if infection was confirmed by antibody only. Reinfection rates in the positive cohort were compared against new PCR positives in the negative cohort using a mixed effective multivariable logistic regression analysis. Findings Between 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 person days between June and November 2020 was 3.3 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days. Interpretation A prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection. This is the minimum likely effect as seroconversions were not included. Funding Department of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments.

Journal ArticleDOI
TL;DR: In this paper, the authors investigate the interrelationships between NFT sales, NFT users (unique active blockchain wallets), and the pricing of Bitcoin and Ether, and show that a Bitcoin price shock triggers an increase in NFT Sales.
Abstract: Non-fungible tokens (NFTs) are transferrable rights to digital assets, such as art, in-game items, collectables or music. The phenomenon and its markets have grown significantly since early 2021. We investigate the interrelationships between NFT sales, NFT users (unique active blockchain wallets), and the pricing of Bitcoin and Ether. Using daily data between January 2018 and April 2021, we show that a Bitcoin price shock triggers an increase in NFT sales. Also, Ether price shocks reduce the number of active NFT wallets. The results suggest that (larger) cryptocurrency markets affect the growth and development of the (smaller) NFT market, but there is no reverse effect.

Journal ArticleDOI
TL;DR: A high antibody response without detrimental effect on viral load was revealed and this study provides support for the immunization of PLWH against COVID-19 with the BNT162b2 mRNA Covid-19 vaccine.
Abstract: Background: The immunogenicity and safety of the Pfizer-BioNTech BNT162b2 mRNA vaccine in people living with HIV-1 (PLWH) are unknown We thus aimed to assess the immunogenicity and safety of this vaccine in PLWH Methods: In this prospective open study, we enrolled 143 PLWH, aged ³18 years, who attended our clinic Patients who had recovered from COVID-19 were excluded SARS-CoV-2 receptor binding domain (RBD) IgG and neutralizing antibodies were measured and compared to those in a cohort of vaccinated health care workers (HCWs) Adverse events, viral load and CD4 cell counts were monitored Findings: At a median of 15 (IQR 14-19) days following the first dose of the BNT162b2 vaccine and 18 (IQR 14-21) days after the second dose, anti-RBD IgG was positive in 66/128 (51%) and 139/141 (98%) PLWH, respectively Among the HCWs, 235/399 (59%) and 269/272 (99%) developed anti-RBD IgG at a median of 14 (IQR 14-14) and 26 (IQR 24-27) days after first and second doses, respectively Following the second dose, immune sera neutralized SARS-CoV-2 pseudo-virus (psSARS-2) in 97% and 98% of PLWH and HCW, respectively Vaccination was associated with adverse events in 60% of PLWH, mainly pain at the injection site, fatigue, and headache AIDS-related adverse events were not reported HIV viral load increased in 3/143 (2%) patients from < 40 copies/mL to ≤ 100 copies/mL CD4+ T cell count decreased from a geometric mean of 700 (95% CI 648–757) cells/mm3 to 6338 (95% CI 588–683) cells/mm 3 (P<001) Interpretation: This study on BNT162b2 vaccination in PLWH revealed a high antibody response without detrimental effect on viral load A small decline in CD4 cell count was noted, but it was not accompanied by clinical deterioration This study thus provides support for the immunization of PLWH against COVID-19 with the BNT162b2 mRNA Covid-19 vaccine Funding Statement: None Declaration of Interests: None Ethics Approval Statement: Written informed consent was obtained from all participants and the study protocol and informed consent were approved by the Institutional review board of Sheba Medical Center

Journal ArticleDOI
TL;DR: It is suggested that early T cell and binding antibody responses, rather than either receptor-blocking or virus neutralizing activity, induced early protection against Covid-19.
Abstract: RNA vaccines against Covid-19 have demonstrated ~95% efficacy in Phase III clinical trials. Although complete vaccination consisted of two-doses, the onset of protection for both licensed RNA vaccines was observed as early as 12 days after a single dose. The adaptive immune response that coincides with this onset of protection could represent the necessary elements of immunity against Covid-19. Herein, we tracked the early adaptive immune responses after Covid-19 RNA vaccination, in a cohort of 20 healthcare workers. Our findings suggest that early T cell and binding antibody responses, rather than either receptor-blocking or virus neutralizing activity, induced early protection against Covid-19. Funding: This study was partially funded through a generousdonation from The Hourglass to support Covid-19 research in ViREMiCS. SK receives salary support from the Transition Award, RdA receives funding from the Open Research Fund Young Investigator Award, JGL and EEO receive salary support from the Clinician Scientist Award, and AB receives salary support from the Singapore Translational Research Award, all administered by the National Medical Research Council of Singapore. Conflict of Interest: Duke-NUS Medical School is in partnership with Arcturus Therapeutics to develop a self-replicating RNA vaccine against Covid-19, with EEO as the principal investigator. No monetary or personal benefits are derived from this partnership. Ethical Approval: This study was approved by the SingHealth Centralized Institutional Review Board (CIRB/F2021/2014). Healthcare workers (HCWs) from the Singapore Health Services institutions whowere eligible for Covid-19 vaccination were invited to participate in this study, and written informed consent was obtained.

Journal ArticleDOI
TL;DR: In this article, the influence of financial innovation by fintech brokerages on individual investors' trading and stock prices was studied using data from Robinhood, and they found that Robinhood investors engage in more attention-induced trading than other retail investors.
Abstract: We study the influence of financial innovation by fintech brokerages on individual investors’ trading and stock prices. Using data from Robinhood, we find that Robinhood investors engage in more attention-induced trading than other retail investors. For example, Robinhood outages disproportionately reduce trading in high-attention stocks. While this evidence is consistent with Robinhood attracting relatively inexperienced investors, we show that it can also be partially driven by the app’s unique features. Consistent with models of attention-induced trading, intense buying by Robinhood users forecast negative returns. Average 20-day abnormal returns are -4.7% for the top stocks purchased each day.

Journal ArticleDOI
TL;DR: The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.
Abstract: Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies assessing pathogenic T cell functions and inducing signals. We identified activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Age-dependent generation of C3a in severe COVID-19 induced activated CD16 + cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19. Funding: This work was supported by the German Research Foundation (DFG): SA1383/3-1 to B.S.; SFB-TR84 114933180 to L.E.S., S.B., P.G., S.H. and W.M.K. INST 37/1049-1, INST 216/981- 1, INST 257/605-1, INST 269/768-1, INST 217/988-1, INST 217/577-1, and EXC2151- 390873048 to J.L.S.; GRK 2168 – 272482170, ERA CVD (00160389 to J.L.S.; SFB 1454 – 432325352 to A.C.A. and J.L.S.; SFB TR57 and SPP1937 to J.N.; GRK2157 to A.-E.S.; and ME 3644/5-1 to H.E.M.; RTG2424 to N.B.; SFB-TRR219 322900939, BO3755/13-1 Project- ID 454024652 to P.B.; the Berlin University Alliance (BUA) (PreEP-Corona grant to L.E.S. and V.M.C.); the Berlin Institute of Health (BIH) (to L.E.S., V.M.C.,B.S. and W.M.K.); Helmholtz- Gemeinschaft Deutscher Forschungszentren, Germany (sparse2big to J.L.S.), EU projects SYSCID (733100 to J.L.S.); European Research Council Horizon 2020 (grant agreement No 101001791 to P.B.); the DZIF, Germany (TTU 04.816 and 04.817 to J.N.); the Hector Foundation (M89 to J.N.); the EU projects ONE STUDY (260687), BIO-DrIM (305147) and INsTRuCT (860003) to B.S.); German Registry of COVID-19 Autopsies through Federal Ministry of Health (ZMVI1-2520COR201 to P.B.); Federal Ministry of Education and Research (DEFEAT PANDEMICs, 01KX2021 and STOP-FSGS-01GM1901A to P.B.); the Berlin Senate to German Rheumatism Research Centre (DRFZ); the Berlin Brandenburg School for regenerative Therapies (BSRT) to C.B.; the German Federal Ministry of Education and Research (BMBF) projects RECAST (01KI20337) to B.S., V.M.C., L.E.S and M.R.; VARIPath (01KI2021) to V.M.C.; NUM COVIM (01KX2021) to L.E.S., V.M.C., F.K., J.L.S., J.N. and B.S.; RAPID to and S.H.,; SYMPATH to N.S. and W.M.K.; PROVID to S.H. and W.M.K.; ZissTrans (02NUK047E) to N.B; National Research Node ‘Mass spectrometry in Systems Medicine (MSCoresys) (031L0220A) to M.R. and N.B.; Diet–Body–Brain (DietBB) (01EA1809A) to J.L.S.; the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC), the Francis Crick Institute through the Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), the Wellcome Trust (FC001134 and IA 200829/Z/16/Z) to M.R.; a Charite 3R project (to B.S., S.H., W.M.K.); and an intramural grant from the Department of Genomics & Immunoregulation at the LIMES Institute to A.C.A. We are grateful to the patients and donors volunteering to participate in this study making this research possible in the first place and wish for a speedy and full recovery. Conflict of Interest: V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding SARS-CoV-2 diagnostics via antibody testing. A.R.S. and H.E.M. are listed as inventors on a patent application by the DRFZ Berlin in the field of mass cytometry. Ethical Approval: The study was approved by the Institutional Review board of Charite (EA2/066/20).

Book ChapterDOI
TL;DR: In this paper, the authors show that an equal-weighted portfolio has a higher total return than a value weighted portfolio, and that a considerable part of rebalancing to maintain constant weights.
Abstract: We show that an equal-weighted portfolio has a higher total return than a value-weighted portfolio. As one may expect, this is partly because the equal-weighted portfolio has higher exposure to value and size factors, but we show that a considerable part (42%) comes from rebalancing to maintain constant weights. We then demonstrate, through four applications, that inferences from asset-pricing tests are substantially different depending on whether one uses equal- or value-weighted portfolios. These four applications are tests of the: Capital Asset Pricing Model, spanning properties of the stochastic discount factor, relation between characteristics and returns, and pricing of idiosyncratic volatility.

Journal ArticleDOI
TL;DR: It is reported that the blood-brain barrier (BBB) and its microenvironment show pronounced upregulation of interferon signaling pathways in fatal COVID-19, providing direct evidence for SARS-CoV-2 brain entry across the BBB resulting in an increase in interferons signaling.
Abstract: Neurological complications are common in COVID-19 patients. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been detected in patients’ brain tissues, its entry routes and resulting consequences are not well understood. Here, we report that the blood-brain barrier (BBB) and its microenvironment show pronounced upregulation of interferon signaling pathways in fatal COVID-19. Moreover, human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) were susceptible to SARS-CoV-2 infection and recapitulated the transcriptional changes detected in vivo . While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active transcytosis of the virus across the BBB in vitro . SARS-CoV-2 entry into BCECs could be reduced by anti-spike-, anti-ACE2- and anti-NRP1-specific antibodies or the TMPRSS2 inhibitor nafamostat. Together, our data provide direct evidence for SARS-CoV-2 brain entry across the BBB resulting in an increase in interferon signaling.

Journal ArticleDOI
TL;DR: The authors synthesize the historical literature on the criminalization and incarceration of black Americans for an interdisciplinary audience, drawing on key insights from new histories in the field of race and ethnicity.
Abstract: This review synthesizes the historical literature on the criminalization and incarceration of black Americans for an interdisciplinary audience. Drawing on key insights from new histories in the fi...

Journal ArticleDOI
TL;DR: It is found that the 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly related to ribonucleocapsid (RNP) assembly during virus replication.
Abstract: In this study, cooccurring mutations R203K/G204R in the nucleocapsid protein are demonstrated adaptive and associated with the emergence of a high-transmissibility SARS-CoV-2 lineage B.1.1.7. Through comparing a R203K/G204R mutant virus, created based on the USA-WA1/2020 SARS-CoV-2 strain, with the native virus in competition experiments, we found that the 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly related to ribonucleocapsid (RNP) assembly during virus replication. Moreover, the 203K/204R virus showed increased infectivity in a human lung cell line and induced increased damage to blood vessels in infected hamster lungs. Accordingly, we observed a positive association between increased COVID-19 severity and the incidence frequency of 203K/204R. Our work suggested a contribution of the 203K/204R mutations to the increased transmission and virulence of SARS-CoV-2. In addition to mutations in the spike protein, the mutations in the nucleocapsid protein are important for viral spreading during the pandemic. Funding Information: This work was supported by grants from the National Natural Science Foundation of China, SGC's Rapid Response Funding for COVID-19 (C-0002), the National Key Research and Development Program (2019YFC1604600), the National Natural Science Foundation of China (81970008 and 31200941), the Fundamental Research Funds for the Central Universities (2021CDJYGRH-009), the Youth Innovative Talents Training Project of Chongqing (CY210102) and the National Natural Science Foundation of HeBei province (19226631D). Declaration of Interests: The authors declare no competing interests.

Journal ArticleDOI
TL;DR: Beyond demonstrating a role for histone lactylation in a neurodegenerative disease and showing how multi-layered regulatory impacts attend altered glucose metabolism in microglia, this study illustrates that disrupting a positive feedback loop may support the development of innovative AD therapies.
Abstract: The pro-inflammatory activation of microglia is a hallmark of Alzheimer’s disease (AD), and this process is known to involve a switch in energy metabolism from oxidative phosphorylation (OXPHOS) towards glycolysis. Here, we show how a positive feedback loop in microglia—comprising metabolic, histone lactylation, and transcriptional layers—drives AD pathogenesis, and we demonstrate that inhibiting this vicious cycle in microglia can ameliorate Aβ burden and cognitive deficits in AD model mice. After first detecting elevated histone lactylation in both AD model (5XFAD) mice and AD patient brains, we observed that H4K12la levels are elevated specifically in Aβ plaque-adjacent microglia. We subsequently found that this lactate-dependent histone modification is enriched at the promoters of glycolytic genes (e.g., Pkm). We confirmed that this enrichment activates transcription and thereby increases glycolysis activity, and ultimately demonstrate that a glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction in AD. Pharmacologic inhibition of PKM2 attenuated microglial activation, and microglia-specific ablation of Pkm2 improved spatial learning and memory in AD mice. Thus, beyond demonstrating a role for histone lactylation in a neurodegenerative disease and showing how multi-layered regulatory impacts attend altered glucose metabolism in microglia, our study illustrates that disrupting a positive feedback loop may support the development of innovative AD therapies.