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SARS-CoV-2, depends on host cell components for replication, therefore the identification of virus-host dependencies offers an effective way to elucidate mechanisms involved in viral infection. Such host factors may be necessary for infection and replication of SARS-CoV-2 and, if druggable, presents an attractive strategy for anti-viral therapy. We performed genome wide CRISPR knockout screens in Vero E6 cells and 4 human cell lines including Calu-3, Caco-2, Hek293 and Huh7 to identify genetic regulators of SARS-CoV-2 infection. Our findings identified only ACE2, the cognate SARS-CoV-2 entry receptor, as a common host dependency factor across all cell lines, while all other host genes identified were cell line specific including known factors TMPRSS2 and CTSL. Several of the discovered host-dependency factors converged on pathways involved in cell signalling, lipid metabolism, immune pathways and chromatin modulation. Notably, chromatin modulator genes KMT2C and KDM6A in Calu-3 cells had the strongest impact in preventing SARS-CoV-2 infection when perturbed. Overall, the network of host factors that have been identified will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate the development of host-directed therapies. Funding Information: This work was supported by the University of Toronto COVID-19 Action Initiative Fund to J.M., B.J.B., S.G.O., J.G., K.M., and S.M.. Indirect support was also received from the University of Toronto and the Temerty Foundation to support enhanced capacity and operations of the Toronto Combined Containment Level 3 Facility during the COVID-19 pandemic. This work was also partially supported from a Canadian Institutes for Health Research Project Grant to J.M. (MOP142375). J.M. is a Tier 2 Canada Research Chair in Function Genomics. Declaration of Interest: None to declare.

The California Department of Fair Employment and Housing (DFEH) sued Cisco Systems, Inc. regarding its discriminatory treatment of its employee John Doe, a Dalit (this group was formerly known as “outcastes” or “untouchables”). Before the summer of 2020, asserting an employment discrimination claim of intentional caste discrimination based on untouchability would have been very contestable. However, the legal analysis utilized by Justice Neil Gorsuch, for the Supreme Court’s decision of June 15, 2020 in Bostock v Clayton County appears tailored to the issue of whether the alleged employment discrimination suffered by Dalits fits within the prohibitions of Title VII and 42 USC $1981. Applying a textual analysis of Title VII, the Supreme Court concluded that discrimination against gays, lesbians and transgendered individuals meets the definition of sex discrimination because a person’s status as gay, lesbian or transgendered is inextricably entwined with their sex. Thus, while being homosexual or transgendered is a “but for” cause of their discrimination, their sex is another one. Caste discrimination based on untouchability derives from the dominant version of Hinduism that stems from India’s 3,000-year-old caste system. For simplification, in orthodox Hinduism the “caste system” consists of four distinct ‘varnas’ or major occupational groupings, also known as castes, with Dalits constituting a fifth caste outside the four-fold system. Dalits, who make up about 16.5 percent of India’s population, have traditionally occupied the very bottom levels of the caste structure and thus, India’s social-economic structure. The status of Dalits is associated with occupations historically regarded as ritually impure. For thousands of years, Hindus believed that Dalits were religiously polluted and this pollution was contagious. In the modern parlance of the COVID-19 era, Caste Hindus engaged in extreme social distancing measures to avoid contact with Dalits, including staying far enough away so that a Dalit’s shadow (six feet) did not touch them. Since this religious pollution stemmed from birth, Daltis, even today, cannot escape it by deed, increase in educational credentials or rise in social or economic standing. Caste discrimination is a mostly hidden form of discrimination in the US. As Indians emigrated from South Asia to other parts of the world, including the US, they brought their beliefs with them, including those about the caste system. There are now over 4 million people of Indian descent in the US. However, experts estimate that Dalits make up less than 2 percent of those of Indian descent. Nevertheless, as the number of Indian immigrants has increased, so have the incidences of caste discrimination based on untouchability. Dalit activists and their supporters throughout the world have advocated for global recognition of the discrimination they face not just in India, but other countries where they reside. But, caste discrimination does not fit neatly into the normal categories of discrimination of race, ethnicity, national origin or religion. As a result, a number of western countries have struggled to find legal protection for the discrimination Dalits encounter. And, India does not provide legal protection against caste discrimination by private employers. This article is the first major work to address the issue of caste discrimination based on untouchability under Title VII and Section 1981 in the aftermath of Bostock. In doing so, it asserts that caste discrimination based on untouchability is now illegal under both Title VII and Section 1981. Because of the prodigious international weight of US law, from a global perspective for the 200 million plus Dalits in India alone and the Dalit diaspora, a determination that US federal employment discrimination law now bans caste discrimination based on untouchability will have incalculable global ramifications. Thus, this article will also quickly draw huge international attention.

Adults receiving heterologous prime-boost COVID-19 immunisation schedules with mRNA (Pfizer-BioNTech) or adenoviral-vector (ChAdOx1-S/nCOV-19) vaccines had higher reactogenicity rates and were more likely to seek medical attention after their second dose than homologous schedules. Reactogenicity rates were generally higher among ≤50 than >50 year-olds and in adults with prior symptomatic or confirmed COVID-19. Adults receiving heterologous schedules because of severe first-dose reactions had lower reactogenicity after the second dose following ChAdOx1-S/Pfizer-BioNTech (93.4%[90.5-98.1] vs. 48%[41.0-57.7]) but not Pfizer-BioNTech/ChAdOx1-S (91.7%[77.5-98.2] vs. 75.0%[57.8-87.9]).

Background: In England, the reopening of universities in September 2020 coincided with a rapid increase in SARS-CoV-2 infection rates in university aged young adults. This study aimed to estimate SARS-CoV-2 antibody prevalence in students attending universities that had experienced a COVID-19 outbreak after reopening for the autumn term in September 2020. Methods: A cross-sectional serosurvey was conducted during 02-11 December 2020 in students aged ≤ 25 years across five universities in England. Blood samples for SARS-CoV-2 antibody testing were obtained using a self-sampling kit and analysed using the Abbott SARS-CoV-2 N antibody and/or an in-house receptor binding domain (RBD) assay. Findings: SARS-CoV-2 seroprevalence in 2,905 university students was 17.8% (95%CI, 16.5-19.3), ranging between 7.6%-29.7% across the five universities. Seropositivity was associated with being younger likely to represent first year undergraduates (aOR 3.2, 95% CI 2.0-4.9), living in halls of residence (aOR 2.1, 95% CI 1.7-2.7) and sharing a kitchen with an increasing number of students (shared with 4-7 individuals, aOR 1.43, 95%CI 1.12-1.82; shared with 8 or more individuals, aOR 1.53, 95% CI 1.04-2.24). Seropositivity was 49% in students living in halls of residence that reported high SARS-CoV-2 infection rates (>8%) during the autumn term. Interpretation: Despite large numbers of cases and outbreaks in universities, less than one in five students (17.8%) overall had SARS-CoV-2 antibodies at the end of the autumn term in England. In university halls of residence affected by a COVID-19 outbreak, however, nearly half the resident students became infected and developed SARS-CoV-2 antibodies.

Background: Extended-interval Covid vaccination regimens are now used widely in order to accelerate population coverage but the relative immunogenicity of different vaccines in older people remains uncertain. Methods: We recruited 165 participants aged 80+ years who had received a single dose of either BNT162b2 mRNA or ChAdOx1 adenovirus vaccine and studied adaptive immune responses after 5 weeks. Findings: Antibody responses against spike protein were detectable in 93% and 87% of mRNA or ChAdOx1 recipients respectively with median antibody titres of 19.3 and 19.6 U/ml (p=0.41). Spike-specific T cell responses were observed in 12% and 31% of mRNA and ChAdOx1 recipients respectively and median responses were 3-fold higher in ChAdOx1 vaccinees at 2 vs 6 spots/million respectively (p=

Background: We estimated the effectiveness of BNT162b2 and mRNA-1273 vaccines among residents of Ontario, Canada, where a policy to use an up to 16-week interval between doses was adopted in March 2021. Methods: We conducted a test-negative design study using linked province-wide laboratory, vaccination, and health administrative datasets. We included symptomatic individuals tested for SARS-CoV-2 by RT-PCR between 14 December 2020 and 19 April 2021. Study outcomes included symptomatic infection and associated severe outcomes (hospitalization or death). We estimated adjusted vaccine effectiveness (aVE) using multivariable logistic regression. Findings: Among 324,033 symptomatic tested individuals, 53,270 (16·4%) were positive for SARS-CoV-2 and 21,272 (6·6%) had received ≥1 dose of mRNA vaccine. Among test-positive cases, 2,479 (4·7%) had a severe outcome. aVE against symptomatic infection ≥14 days after receiving only 1 dose was 60% (95%CI, 57–64%), increasing from 48% (95%CI, 41–54%) at 14–20 days after the first dose to 71% (95%CI, 63–78%) at 35–41 days. aVE ≥7 days after receiving 2 doses was 91% (95%CI, 89–93%). Against severe outcomes, aVE ≥14 days after receiving 1 dose was 70% (95%CI, 60–77%) and aVE ≥7 days after receiving 2 doses was 98% (95%CI, 88–100%). We observed lower aVE against both outcomes after receiving 1 dose for adults aged ≥70 years, but aVE estimates for older adults were comparable to younger adults after 28 days. After 2 doses, we observed high aVE against E484K-positive variants. Interpretation: Our findings suggest that 2 doses of BNT162b2 and mRNA-1273 vaccines are highly effective against both symptomatic infection and associated severe outcomes for all circulating variants, with effectiveness lower after only a single dose, particularly for older adults shortly after the first dose. Funding Information: Canadian Institutes of Health Research, Public Health Agency of Canada, Ontario Ministries of Health and Long-Term Care. Declaration of Interests: KW is CEO of CANImmunize and serves on the data safety board for the Medicago COVID-19 vaccine trial. SMM has received unrestricted research grants from Merck, GlaxoSmithKline, Sanofi Pasteur, Pfizer, and Roche-Assurex for unrelated studies. SMM has received fees as an advisory board member for GlaxoSmithKline, Merck, Pfizer, Sanofi Pasteur, and Seqirus. CHR has received an unrestricted research grant from Pfizer for an unrelated study. The other authors declare no conflicts of interest. Ethics Approval Statement: ICES is a prescribed entity under Ontario’s Personal Health Information Protection Act (PHIPA). Section 45 of PHIPA authorizes ICES to collect personal health information, without consent, for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, the allocation of resources to or planning for all or part of the health system. Projects that use data collected by ICES under section 45 of PHIPA, and use no other data, are exempt from REB review. The use of the data in this project is authorized under section 45 and approved by ICES’ Privacy and Legal Office.

Background: Many countries re-opened schools after national lockdown but little is known about the risk of SARS-CoV-2 infection and transmission in educational settings. Public Health England conducted six-month prospective surveillance in primary schools across England. Methods: The COVID-19 Surveillance in School KIDs (sKIDs) study included two arms: weekly nasal swabs for ≥4 weeks following partial reopening during the summer half-term (June to mid-July 2020) and blood sampling with nasal and throat swabs at the beginning and end of the summer half-term, and, following full reopening in September 2020, at the end of the autumn term (end-November 2020). Results: In round 1, 12,026 participants (59.1% students, 40.9% staff) in 131 schools had 43,091 swabs taken. Weekly SARS-CoV-2 infection rates were 3.9 (1/25,537; 95% CI, 0.10-21.8) and 11.3 (2/17,554; 95% CI, 1.4-41.2) per 100,000 students and staff. At recruitment, N-antibody positivity in 45 schools was 11.1% (91/817; 95%CI, 9.2-13.5%) in students and 15.1% (209/1381; 95%CI, 13.3-17.1%) in staff, similar to local community seroprevalence. Seropositivity was not associated with school attendance during lockdown or staff contact with students. Round 2 participation was 73.7% (1,619/2,198) and only five (4 students, 1 staff) seroconverted. In round 3, when 61.9% (1,361/2,198) of round 1 participants were re-tested, seroconversion rates were 3.4% (19/562; 95%CI, 2.0-5.2) in students and 3.9% (36/930; 95%CI, 2.7-5.3) in staff. Conclusions: SARS-CoV-2 infection rates, assessed using nasal swabs for acute infection and serum antibodies for prior infection, were low following partial and full reopening of primary schools in England. Funding Statement: This surveillance was funded by the Department of Health and Social Care (DHSC). Declaration of Interests: None to declare. Ethics Approval Statement: The surveillance protocol was approved by the Public Health England Research Ethics Governance Group (R&D REGG Ref: NR0209, 16 May 2020).

Background: Mandatory social and physical distancing measures (SPDM) were introduced in the UK on the 23rd March 2020. A multi-tiered surveillance system based on influenza surveillance, was adopted from the early stages of the COVID-19 Epidemic to monitor different stages of disease. We describe how the impact SPDM was detected through each surveillance system and how these systems may be applied to detect increases in COVID-19 activity as SPDM are eased. Methods: Data from national population surveys, web-based indicators, syndromic surveillance, sentinel swabbing, respiratory outbreaks, secondary care admissions, and mortality indicators from the start of the epidemic to Week 20 2020 were used to identify timing of peaks in the indicator relative to the introduction of SPDM. This was compared to median time from symptom onset to different stages of illness or interactions with healthcare services. Results: The impact of SPDM was detected within 1 week through population symptom surveys, web search indicators and through GP sentinel swabbing reported by onset date. There were detectable impacts on syndromic surveillance indicators for difficulty breathing, influenza-like illness and COVID-19 coding at 2, 7 and 12 days respectively. This was followed by hospitalisations and critical care admissions (both 12 days), laboratory positivity (14 days), deaths (17 days) and care home outbreaks (4 weeks). Interpretation: There was a clear impact of SPDM on COVID-19 activity which was detectable within 1 week through community indicators highlighting their importance in early detection of changes in activity. Community swabbing surveillance will be increasingly important as a specific indicator when circulation of seasonal respiratory viruses increases. Funding Statement: There was no specific funding for this report. Declaration of Interests: None declared. Ethics Approval Statement: The surveillance collections included here are approved as Health Protection, under Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002.

Background: We investigated six London care homes experiencing a COVID-19 outbreak and found very high rates of SARS-CoV-2 infection among residents and staff. Here we report follow-up investigations including antibody testing in the same care homes five weeks later. Methods: Residents and staff involved in the initial investigation had a repeat nasal swab for SARS-CoV-2 RT-PCR and a blood test for SARS CoV-2 antibodies using ELISA based on SARS-CoV-2 native viral antigens derived from infected cells and virus neutralisation. Findings: Of the 518 residents and staff in the initial investigation, 208/241 (86.3%) surviving residents and 186/254 (73.2%) staff underwent repeat testing. Almost all SARS-CoV-2 RT-PCR positive residents and staff were also antibody positive five weeks later, whether symptomatic (residents 35/35, 100%; staff, 22/22, 100%) or asymptomatic (residents 32/33, 97.0%; staff 21/22, 95.1%). Symptomatic but SARS-CoV-2 RT-PCR negative residents and staff also had high seropositivity rates (residents 23/27, 85.2%; staff 18/21, 85.7%) as did asymptomatic RT-PCR negative individuals (residents 62/92, 67.3%; staff 95/143, 66.4%). Neutralising antibody was present in 118/132 (89.4%) seropositive individuals and was not associated with age or symptoms. Ten residents (10/108, 9.3%) remained RT-PCR positive but with lower RT-PCR cycle threshold values; all 7 tested were seropositive. New infections were detected in three residents and one staff. Interpretation: RT PCR provides a point prevalence of SARS-CoV-2 infection but significantly underestimates total exposure in outbreak settings. In care homes experiencing large COVID-19 outbreaks, most residents and staff had neutralising SARS-CoV-2 antibodies, which was not associated with age or symptoms. Funding: None Declaration of Interests: None. Ethics Approval Statement: The research protocol was approved by the PHE Research Ethics and Governance Group (REGG Ref: NR0204, 07 May 2020).

Background: The COVID-19 pandemic in the UK began in late January 2020 and peaked in mid-April before declining. Children typically develop only very mild symptoms and it remains unclear what role children play in the spread of COVID-19. The aim of this study was to report the prevalence of SARS-CoV-2 antibodies in healthy children of healthcare workers. Methods: Healthy children of healthcare workers, were recruited in London during May 2020. Participants had nose and throat swabs tested for SARS-CoV-2 infection via RT-qPCR and blood serums samples for SARS-CoV-2 immunoglobulin G (IgG) antibodies. Findings: A total of 215 children from 126 families took part and 25(12%) were seropositive for SARS-CoV-2. Children of clinical healthcare workers were significantly more likely to be seropositive 23/133(17%) than those of non-clinical healthcare workers 2/83(2%); p=0.001.In children of parents with confirmed COVID-19, seropositivity was 19/47(40%) compared to 3/44(7%) in children of parents with suspected COVID-19 and 3/124(2%) in children of asymptomatic parents (p

Recurrent glioblastoma (rGBM) remains vastly understudied with few biological targets for therapeutic development. Using a highly specific antibody panel for all Eph receptor tyrosine kinases, we identify that EphA2 and EphA3 co-expression marks a highly tumorigenic cell population in rGBM that is enriched in cancer stem cell marker expression. Knockdown of EphA2 and EphA3 together blocks this tumorigenicity, and is marked by an increase in the expression of differentiation marker GFAP. Treatment with a bispecific antibody (BsAb) that co-targets EphA2 and EphA3 reduces the tumorigenic potential of rGBM by down regulating Akt and Erk signaling pathways and increasing differentiation. For the first time, we show that strategic co-targeting of both EphA2 and EphA3 in GBM CSCs presents a novel and rational therapeutic approach for recurrent GBM.

One might assume that the most important decision for an academic at the beginning of their career is deciding in what area of law to specialise, but a more fundamentally important decision is what approach to the law to adopt. The choice will be shaped by the individual’s experiences, education, and worldview. The decision need not be final and many academics’ approaches develop over time, although for the most part not dramatically. Academics like others are creatures of habit. A particular approach becomes second nature; it is how we see the law. It is therefore worth reminding ourselves on occasion that our particular perspective is one of many and that there is much to be gained from having an appreciation of the alternative approaches to legal research and teaching to be found in academia.

Educational theorists have long recognised the limitations of the traditional didactic lecture as a basis for student learning and engagement with degree-level problems. Nonetheless, such lectures still dominate timetables within UK law schools. A common criticism of the lecture as a mode of teaching is that there is little scope for interaction between the student body and the lecturer, a marked change in educational environment for students fresh from secondary-level education. In an effort to address this issue, we undertook an action-research project using TurningPoint classroom response technology to generate interaction between the lecturer and students during large-cohort law lectures. This system allowed students to respond in real-time to multiple-choice questions posed in a lecture, thereby offering an alternative to more traditional methods of encouraging class participation in lectures, such as the Socratic method. In our study the use of these devices was trialled in first and second year undergraduate law lectures at Newcastle University (UK). Subsequently, students’ views on the use and benefits of the technology were investigated through questionnaires and focus groups. The results of these surveys suggest that such technology can enhance the student experience of large-cohort lectures.

As part of the recent deposit insurance reform legislation, Congress directed the FDIC to study the methodology and accounting practices the Corporation has used for maintaining and establishing reserves for loss contingencies associated with insured-institution failures. Specifically, Congress made four requests of this study. It asked the Corporation to (1) study the overall effectiveness and accuracy of the methodology used in establishing and maintaining reserves and estimating and accounting for losses at insured depository institutions during the period 1992–2004; (2) study the appropriateness and reliability of the information and criteria used in determining whether an institution was in a troubled condition and the amount of any loss anticipated at such institution; (3) analyze the actual historical loss experience for the period 1992–2004 and the causes of the exceptionally high rate of losses in the final three years of that period (2002–2004); and (4) rate the efforts of the Corporation to reduce losses in that three-year period to minimally acceptable levels and to historical levels.

Nonaudit services performed by auditors for their audit clients have long been a focus of concern for regulators. The SEC has mandated disclosure of fees for both audit and nonaudit services in order to provide investors with a more transparent representation of the auditor-client relationship. The purpose of this study is to investigate whether nonaudit service fees influence the value relevance of accounting numbers. We find that nonaudit fees have a positive effect on the value relevance of accounting numbers. This result suggests that the provision of auditor's nonaudit services increases the value relevance of accounting information. This result is contrary to the prevailing belief that nonaudit services impair auditor independence. We also find that investors' perception of nonaudit fees has changed. In particular, investors perceive nonaudit service as more value enhancing even after the enactment of Sarbanes-Oxley.