Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I).

BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. The objective of this trial was to evaluate the efficacy and safety of baricitinib in patients with active SLE in a 52-week phase 3 study. METHODS: In a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase 3 study, SLE-BRAVE-I, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, 2 mg, or placebo once daily for 52 weeks with standard of care. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was the proportion of patients reaching an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on a modified intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT03616912. FINDINGS: 760 participants were randomly assigned and received at least one dose of baricitinib 4 mg (n=252), baricitinib 2 mg (n=255), or placebo (n=253). A significantly greater proportion of participants who received baricitinib 4 mg (142 [57%]; odds ratio 1·57 [95% CI 1·09 to 2·27]; difference with placebo 10·8 [2·0 to 19·6]; p=0·016), but not baricitinib 2 mg (126 [50%]; 1·14 [0·79 to 1·65]; 3·9 [-4·9 to 12·6]; p=0·47), reached SRI-4 response compared with placebo (116 [46%]). There were no significant differences between the proportions of participants in either baricitinib group reaching any of the major secondary endpoints compared with placebo, including glucocorticoid tapering and time to first severe flare. 26 (10%) participants receiving baricitinib 4 mg had serious adverse events, 24 (9%) participants receiving baricitinib 2 mg, and 18 (7%) participants receiving placebo. The safety profile of baricitinib in participants with SLE was consistent with the known baricitinib safety profile. INTERPRETATION: The primary endpoint in this study was met for the 4 mg baricitinib group. However, key secondary endpoints were not. No new safety signals were observed. FUNDING: Eli Lilly and Company.

Pathology Education Powered by Virtual and Digital Transformation: Now and the Future

[...]standing on the crest of yet another wave of change, driven by artificial intelligence (AI) and machine learning,2 pathology educators may soon be challenged to convey the best ways to apply these tools to the problems of diagnostic pathology for the coming generation of learners and the present corps of practitioners.3 Hence, this collaborative effort aims to describe the genetic code governing the transmission of pathology knowledge to subsequent generations of medical professionals.4 We aim to expose not just the code but also the supporting array of catalysts, enhancers, and other cofactors now in place to ensure we have a robust and potent supply of pathologists. APPLYING DP IN UNDERGRADUATE MEDICAL, DENTAL, VETERINARY, AND ALLIED HEALTH EDUCATION Beginning in 1985, this technology has been progressively more widely implemented in undergraduate medical, dental, veterinary, and allied health (nursing, pharmacy, medical technology, etc) education platforms in the United States and internationally.5,11-26 As noted above, virtual microscopy laboratories, available on personal devices or in school-based computer labs, have replaced fixed laboratories housing gross specimens, boxes of glass slides, and student microscopes. WSI with links to supplementary resources, such as gross and radiologic images and additional study material, provide enrichment for the teaching and learning experience in the new virtual environment. [...]significant exposure to microanatomy and the laboratory methods of pathology underpinning so much of diagnosis, therapy, and management is foundational.

A Qualitative Exploration of COVID-19 Vaccine Hesitancy Among Hispanic/Latine and African American and Black Middle-Aged and Older Adults in South Florida.

Racial and ethnic health disparities are more conspicuous in the United States since the start of the coronavirus disease 2019 (COVID-19) pandemic. While the urgency of these disparities was already alarming, the pandemic has exacerbated longstanding issues in health equity, disproportionate impacts, and social determinants of health. Vaccine hesitancy was a crucial factor during the U.S. COVID-19 vaccination campaign. We conducted a qualitative exploration of vaccine hesitancy through thematic analysis of four focus groups with Hispanic/Latine and African American/Black adults and senior citizens (N=23). The focus groups were conducted between February and April of 2021, in both English and Spanish. All participants (mean age=66.2, female 78.3%) were recruited by community-based organizations in the South Florida area. We explored six categories: (1) barriers to prevention and preventive behaviors, (2) barriers to vaccination against COVID-19, (3) facilitators of prevention and preventative behaviors, (4) facilitators of vaccination against COVID-19, (5) trusted sources of information, and (6) suggested macrolevel measures. These categories are discussed vis-à-vis COVID-19 disparities among racial and ethnic minorities. Implications for public health policy and future vaccination campaigns are outlined and discussed.

Course and predictors of eating disorder symptoms, anxiety symptoms, and pandemic-related eating disorder concerns among adults with eating disorders during the first year of the COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic and public health mitigation measures have negatively impacted individuals with eating disorders (ED). We evaluated changes in and predictors of ED symptoms, pandemic-related ED concerns, and anxiety symptoms across the first 12 months of the COVID-19 pandemic among individuals with self-reported EDs in the United States (US), Sweden (SE), and the Netherlands (NL). METHOD: Participants in the US (N = 510), SE (N = 982), and NL (N = 510) completed an online survey assessing ED symptoms (binge eating, restriction, compensatory behaviors, and anxiety about being unable to exercise), general anxiety symptoms, and pandemic-related ED concerns about accessing food, lack of structure and social support, being in a triggering environment, and food and treatment costs. In the US and NL, respondents completed surveys beginning April 2020 and continuing monthly for a year. In SE, respondents completed baseline surveys in May 2020, a six-month follow-up around December 2020, and a 12-month follow-up in May 2021. RESULTS: Three patterns emerged: (1) a curvilinear course with the highest level of symptoms at baseline, declining through November 2020, and increasing through the rest of the year; (2) a linear declining course over time; and (3) a stable course with no changes. Worries about COVID-19 infection, lockdown, concerns about lack of structure and social support, and concerns about accessing food consistent with one's recovery meal plan predicted increases in ED symptoms. DISCUSSION: ED symptoms tracked with pandemic-related concerns in people with EDs. Conceptualizing predictors of symptoms may inform therapy and public health resources that reduce the impact of pandemics on mental health. PUBLIC SIGNIFICANCE: Our findings suggest that the COVID-19 pandemic had negative impacts on people with eating disorders, including amplification of mental health symptoms and stressors around peak periods of infection and COVID-19 restrictions. These findings inform medical providers, policy-makers, and community-based supports about the information and resource needs of this group to ensure efficient dissemination in future public health emergencies and during the ongoing COVID-19 pandemic.

Longer-term impact of COVID-19 among individuals with self-reported eating disorders in the United States, the Netherlands, and Sweden.

OBJECTIVE: We assessed eating disorder (ED) illness status, symptomatology, treatment access, anxiety, and depression in the first year of the COVID-19 pandemic among individuals with a pre-existing ED in the United States (US), the Netherlands (NL), and Sweden (SE). METHODS: Participants completed online surveys in April-July 2020, at the early stage of the pandemic, and one year later. At one-year follow-up, we added questions addressing retrospective changes in ED symptoms, treatment, and anxiety/depression since the start of the COVID-19 pandemic. We present descriptive statistics and assess change in ED symptomatology, treatment, and anxiety/depression among those with an active or lingering ED. RESULTS: Participants (US n = 132; NL n = 219; SE n = 702) were mostly young and female with a history of anorexia nervosa (>60% in all three countries). Across countries, respondents reported impact of COVID-19 on ED symptoms at both time points, with improvement in US and NL at one-year follow-up, and stable but less impact on ED symptoms in SE. Furthermore, at one-year follow-up, roughly half of those in treatment reported reduced treatment access and quality, and the majority of the sample reported increased anxiety and depressive mood since the start of the pandemic. DISCUSSION: Our findings suggest that the self-perceived impact of COVID-19 changed over time but remained concerning even one year after the start of the pandemic. Clinicians, community organizations, and policy makers are encouraged to address potentially changing treatment needs in the face of public health emergency events. PUBLIC SIGNIFICANCE: Our findings suggest that the impact of COVID-19 on individuals with eating disorders decreased over time but remained concerning even one year after the start of the pandemic and that the impact differed across countries. Clinicians, community organizations, and policy makers are encouraged to incorporate this knowledge to address potentially changing treatment needs in the face of public health emergency events.

A Randomized, Placebo-Controlled Phase III Extension Trial of the Long-Term Safety and Tolerability of Anifrolumab in Active Systemic Lupus Erythematosus.

OBJECTIVE: To explore long-term safety and tolerability of anifrolumab 300 mg compared with placebo in patients with systemic lupus erythematosus (SLE) who completed a Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trial and enrolled in the placebo-controlled 3-year long-term extension (LTE) study (ClinicalTrials.gov identifier: NCT02794285). METHODS: In the blinded LTE study, patients continued anifrolumab 300 mg, switched from anifrolumab 150 mg to 300 mg, or were re-randomized from placebo to receive either anifrolumab 300 mg or to continue placebo, administered every 4 weeks. Primary comparisons in the LTE study were between patients who received anifrolumab 300 mg or placebo throughout the TULIP and LTE studies. For rare safety events, comparisons included patients who received any anifrolumab dose during TULIP or LTE. When exposure differed, exposure-adjusted incidence rates (EAIRs) per 100 patient-years were calculated. RESULTS: In the LTE study, EAIRs of serious adverse events (SAEs) were 8.5 with anifrolumab compared with 11.2 with placebo; likewise, EAIRs of AEs leading to treatment discontinuation were 2.5 versus 3.2, respectively. EAIRs of non-opportunistic serious infections were comparable between groups (3.7 with anifrolumab versus 3.6 with placebo). Exposure-adjusted event rates of COVID-related AEs, including asymptomatic infections, were 15.5 with anifrolumab compared with 9.8 with placebo. No COVID-related AEs occurred in fully vaccinated individuals. EAIRs of malignancy and major acute cardiovascular events were low and comparable between groups. Anifrolumab was associated with lower cumulative glucocorticoid use and greater mean improvement in the SLE Disease Activity Index 2000, compared with placebo. CONCLUSION: This LTE study represents the longest placebo-controlled clinical trial performed in SLE to date. No new safety findings were identified in the LTE study, supporting the favorable benefit-risk profile of anifrolumab for patients with moderate-to-severe SLE receiving standard therapy.

Nonfatal opioid-related overdoses treated by emergency medical services in Florida, before and during the COVID-19 pandemic.

Previous studies have found increases in nonfatal opioid overdoses during the COVID-19 pandemic, which created difficult conditions for people with substance use disorders. We assessed changes in nonfatal opioid-related overdoses in Florida during the onset of the COVID-19 pandemic. Emergency medical service data was obtained from the Florida Department of Health. Naloxone administration with documented improvement was used as a proxy for nonfatal opioid-related overdoses. Age-adjusted rates were estimated per 100,000 population for April-September 2020 (n = 9,377) and compared to the same time period during 2019 (n = 6,765) using rate ratios. Age-adjusted rates were estimated by sex, race/ethnicity, and metro/nonmetro county classification, as well as county-level measures of medications for opioid use disorder (MOUD) availability, rates of COVID-19 deaths, and unemployment during 2020. The age-adjusted rate of nonfatal opioid-related overdoses increased from 32.41 (95 % CL: 31.64-33.19) during 2019 to 45.35 (95 % CL: 44.42-46.27) during 2020 (RR = 1.40; 95 % CL: 1.36-1.44). The rate for males increased most in metro counties (RR = 1.47, 95 % CL: 1.41-1.53); the rate for females increased most in nonmetro counties (RR = 1.51, 95 % CL: 1.10-2.06). The largest increases were observed among Hispanics (males: RR = 1.56, 95 % CL: 1.37-1.78; females: RR = 1.44, 95 % CL: 1.14-1.81), counties with no MOUD treatment options (RR = 1.66, 95 % CL: 1.14-2.44) and counties with the lowest rates of buprenorphine prescribers (RR = 1.70, 95 % CL: 1.29-2.22). Nonfatal opioid-related overdoses increased in Florida during the first six months of the COVID-19 pandemic. Expanding access to services that support treatment and recovery is critical to addressing the ongoing opioid crisis in Florida.

Author Correction: A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Preliminary Analysis of COVID-19 Vaccination Factors among Native and Foreign-Born Hispanic/Latine Adults Residing in South Florida, U.S.A.

This study explored barriers, motivators, and trusted sources of information regarding COVID-19 vaccination among Hispanic/Latine individuals. Hispanic/Latine is a broad social construct that encompasses people from heterogeneous countries and cultures. In the U.S., foreign-born Hispanics/Latines tend to have better health outcomes than U.S.-born individuals. Thus, the study examined whether nativity is a significant factor in COVID-19 vaccine hesitancy. Binary logistic regression and linear regression analyses were employed and revealed that, regardless of nativity, Hispanic/Latine participants face similar barriers and find similar sources of information trustworthy. Controlling for age and race, vaccination rates or perceived likelihood of getting vaccinated did not differ between the two groups. The two groups significantly differed in specific motivators for vaccination: foreign-born Hispanic/Latine individuals were more motivated to get the vaccine to keep themselves, their families, and their community safe, and more often believed vaccination is needed for life to return to normal. Study results provide important insights into similarities and differences in barriers, motivators, and trusted sources of information regarding COVID-19 vaccination among native and foreign-born Hispanic/Latine individuals.

A Latent Profile Analysis of COVID-19 Trusted Sources of Information among Racial and Ethnic Minorities in South Florida.

By the spring of 2021, most of the adult U.S. population became eligible to receive a COVID-19 vaccine. Yet, by the summer of 2021, the vaccination rate stagnated. Given the immense impact COVID-19 has had on society and individuals, and the surge of new variant strains of the virus, it remains urgent to better understand barriers to vaccination, including the impact of variations in trusted sources of COVID-19 information. The goal of the present study was to conduct a cross-sectional, community-engaged, and person-centered study of trusted sources of COVID-19 information using latent profile analysis (LPA). The aims were to (1) identify the number and nature of profiles of trusted sources of COVID-19 information, and (2) determine whether the trust profiles were predictive of COVID-19 vaccination attitudes and various demographic categories. Participants included mostly racial and ethnic minority individuals (82.4%) recruited by various community-based agencies in South Florida. The LPA evidenced an optimal 3-class solution characterized by low (n = 80)-, medium (n = 147)-, and high (n = 52)-trust profiles, with high trust statistically significantly predictive of vaccination willingness. The profiles identified could be important targets for public health dissemination efforts to reduce vaccine hesitancy and increase COVID-19 vaccination uptake. The general level of trust in COVID-19 information sources was found to be an important factor in predicting COVID-19 vaccination willingness.

A Whole Genome Sequencing Analysis of a Multi-unit Long-term Care Facility COVID-19 Outbreak

Background. The coronavirus disease (COVID-19) pandemic has affected residents in long-term care facilities (LTCF) significantly. Understanding transmission dynamics in this setting is crucial to control the spread of COVID-19 in this population. Using whole genome sequencing (WGS) of SARS-CoV-2, we aimed to delineate the points of introduction and transmission pathways in a large LTCF in Quebec, Canada. Methods. Between 2020-10-28 and 2021-01-09, COVID-19 cases occurred in 102 residents and 111 HCW at a 387-bed LTCF;cases were distributed in 11 units on 6 floors. As part of outbreak analysis, SARS-CoV-2 isolates underwent WGS using the Oxford Nanopore Minion and the Artic V3 protocol. Lineage attribution and sequence types (ST, within 3 mutations) were assigned based on Pangolin classification and variant analysis. Epidemiologic data including date of positive PCR test, resident room number and HCW work location were collected. Self-reported high-risk exposures were collected by HCW questionnaire via phone interview after consent. Cases and their ST, geo-temporal relations and HCW-reported exposures were examined via network plots and geography-based epidemic curves to infer points of introduction and paths of transmission. Results. Of 170 isolates available from 100/102 residents and 70/111 HCW, 130 (76.4%) were successfully sequenced. Phylogenetic analysis revealed 7 separate introductions to the LTCF. Grouping of ST by units was observed, with temporal appearance of ST supporting HCW introduction in 7/11 units. Proportion of phone interview completion was low at 35% (26/70). Few HCW recalled specific high-risk exposures. Recalled exposures supported by genetic linkage revealed potential between-unit introductions from HCW-to-HCW transmission at work and outside the workplace (e.g. carpooling). On one unit, a wandering resident was identified as a likely source of transmission to other residents (Figure 1). Network plot of cases clustered by geographic unit, colour-coded by sequence type. Circles represent residents;addition signs represent healthcare workers. Blue lines represent identified high-risk exposures. Node labels represent floor and unit identifiers;2 units per floor. Conclusion. We demonstrate the complex genomic epidemiology of a multi-unit LTCF outbreak, putting into evidence the importance of a multi-faceted approach to limit transmission. This analysis highlights the utility of using WGS to uncover unsuspected transmission routes, such as HCW contact outside work, which can prompt new infection control measures.

Virtual town halls addressing vaccine hesitancy among racial/ethnic minorities: Preliminary findings.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic remains a public health priority, and vaccination is important for ending the pandemic. Racial and ethnic minorities are disproportionally affected by COVID-19 yet report high levels of vaccination hesitancy. OBJECTIVE: We conducted virtual town halls to address vaccine hesitancy among racial and ethnic minorities in South Florida. METHODS: Our approach used social influence and persuasion models. In a formative phase, we gathered meeting preferences from our communities and developed and tested our approach. In an implementation phase, we conducted 6 virtual town halls in partnership with minority community-based organizations. RESULTS: The town halls reached 383 participants (mean age 37.5 years; 63.4% female, 33.9% male, 2.7% nonbinary; 59% racial/ethnic minority) who completed pre- and postmeeting assessments. Among nonvaccinated participants, at the prepoll, 58% reported a high likelihood of seeking vaccination, rising to 63% at the postassessment. Unvaccinated non-hesitant and hesitant groups were compared on trusted information sources and reasons and barriers for vaccination. Nonhesitant participants reported significantly greater trust in the COVID-19 Task Force (97.3% vs. 83.3%) as a source of vaccine information than did hesitant participants. Nonhesitant participants were significantly more likely to endorse family safety (82.5% vs. 63.2%), community safety (72.5% vs. 26.3%), personal safety (85% vs. 36.8%), and wanting to return to a normal life (70% vs. 31.6%) as reasons for vaccination than were hesitant participants. Hesitant participants were significantly more likely to endorse concerns about vaccine safety doubts (63.2% vs. 17.5%) and not believing the pandemic is as bad as people say it is (21.1% vs. 5%) as barriers to vaccination than were nonhesitant participants. Qualitative data revealed high consumer satisfaction with the town halls. CONCLUSION: This study supports the feasibility, acceptability, and potential impact of virtual town halls for addressing vaccine hesitancy among racial/ethnic minorities; however, our approach was resource intensive, required an extensive community-university collaborative infrastructure, and yielded a small effect.

Design, implementation and initial findings of COVID-19 research in the Rotterdam Study: leveraging existing infrastructure for population-based investigations on an emerging disease.

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of 8 months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown.

Design, Implementation and Initial Findings of COVID-19 Research in the Rotterdam Study: Leveraging Existing Infrastructure for Population-Based Investigations on An Emerging Disease (preprint)

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8,732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of eight months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown.

When is it safe to perform abdominal transplantation in patients with prior SARS-CoV-2 infection: A case series.

BACKGROUND: The Coronavirus disease 2019(COVID-19) pandemic has negatively impacted worldwide organ transplantation. However, there is limited information on recipients transplanted after SARS-CoV-2 infection. A full understanding of this scenario is required, as transplantation is a life-saving procedure and COVID-19 remains an ongoing threat. METHODS: Abdominal organ transplant recipients diagnosed with COVID-19 prior to transplantation were identified by chart review and clinical data were collected. The primary outcome was the transplant outcome including graft loss, rejection and death, and reactivation of infection post-transplant. RESULTS: We identified 14 patients who received abdominal organ transplants after symptomatic PCR confirmed SARS-CoV-2 infection; four patients had a positive PCR at the time of admission for transplantation. The median time of follow-up was 79 (22-190) days. One recipient with negative PCR before transplant tested positive 9 days after transplant. One of 14 transplanted patients developed disseminated mold infection and died 86 days after transplant. During the follow-up, only one patient developed rejection; thirteen patients had favorable graft outcomes. CONCLUSIONS: We were able to perform abdominal transplantation for patients with COVID-19 before transplant, even with positive PCR at the time of transplant. Larger studies are needed to determine the time to safe transplant after SARS-CoV-2 infection.

Resolving the Functional Significance of BRCA1 RING Domain Missense Substitutions (preprint)

Part 1: Development and calibration of suitably accurate functional assays for BRCA1 RING domain and BRCT domain missense substitutions could dramatically accelerate clinical classification of rare missense substitutions observed in that gene. Leveraging data from 68,000 full sequence tests of BRCA1 and BRCA2, plus data from the limited number of already classified BRCA1 RING domain missense substitutions, we used logistic regression and related techniques to evaluate three BRCA1 RING domain assays. These were recently described high throughput yeast 2-hybrid and E3 ubiquitin ligase assays, plus a newly developed mammalian 2- hybrid assay. While there were concerns about the accuracy of the yeast 2-hybrid assay and the indirect nature of the ubiquitin ligase assay, the mammalian 2-hybrid assay had excellent correlation with existing missense substitution classifications. After calibration, this assay contributed to classification of one newly reported BRCA1 missense substitution. In principal, the mammalian 2-hybrid assay could be converted to a high-throughput format that would likely retain suitable accuracy. Part 2: How does one achieve clinically applicable classification of the vast majority of all possible sequence variants in disease susceptibility genes? BRCA1 is a high-risk susceptibility gene for breast and ovarian cancer. Pathogenic protein truncating variants are scattered across the open reading frame, but all known missense substitutions that are pathogenic because of missense dysfunction are located in either the amino-terminal RING domain or the carboxy-terminal BRCT domain. Heterodimerization of the BRCA1 and BARD1 RING domains is a molecularly defined obligate activity. Hence, we tested every BRCA1 RING domain missense substitution that can be created by a single nucleotide change for heterodimerization with BARD1 in a Mammalian 2-hybrid (M2H) assay. Downstream of the M2H laboratory assay, we addressed three additional challenges: assay calibration, validation thereof, and integration of the calibrated results with other available data such as computational evidence and patient/population observational data to achieve clinically applicable classification. Overall, we found that about 20% of BRCA1 RING domain missense substitutions are pathogenic. Using a Bayesian point system for data integration and variant classification, we achieved clinical classification of about 89% of observed missense substitutions. Moreover, among missense substitutions not present in the human observational data used here, we find an additional 47 with concordant computational and functional assay evidence in favor of pathogenicity; these are particularly likely to be classified as Likely Pathogenic once human observational data become available.

Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019.

BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

Breaking the chain of transmission within a tertiary health service: An approach to contact tracing during the COVID-19 pandemic.

BACKGROUND: Tertiary referral health service. INTERVENTION(S): An approach to hospital based contact tracing is described along with tools employed to streamline the process and including the development of an outbreak management team (OMT) for each contact trace. RESULTS: Forty-one OMTs occurred, involving 23 HCW and 18 patient index cases. The total furloughed HCWs arising from these contact traces was 383, with individual contact traces furloughing a mean (range) of 10 (0-80) HCWs. Importantly, 15 furloughed HCWs subsequently became COVID-19 positive during their 14-day isolation period, showing the importance of the contact tracing process and the ability to remove workers from the workplace before they become infectious. CONCLUSIONS: A standardised, streamlined contact tracing procedure in healthcare settings ensures any impacts of COVID-19 positive cases are consistently managed. This response framework may be of use to other health services and help reduce the transmission of COVID-19 in the workplace.

The Impact of COVID-19 on African American Communities in the United States.

Purpose: The purpose of this ecological study was to understand the impact of the density of African American (AA) communities on coronavirus disease 2019 (COVID-19) prevalence and death rate within the three most populous counties in each U.S. state and territory (n=152). Methods: An ecological design was employed for the study. The top three most populous counties of each U.S. state and territory were included in analyses for a final sample size of n=152 counties. Confirmed COVID-19 cases and deaths that were accumulated between January 22, 2020 and April 12, 2020 in each of the three most populous counties in each U.S. state and territory were included. Linear regression was used to determine the association between AA density and COVID-19 prevalence (defined as the percentage of cases for the county population), and death rate (defined as number of deaths per 100,000 population). The models were adjusted for median age and poverty. Results: There was a direct association between AA density and COVID-19 prevalence; COVID-19 prevalence increased 5% for every 1% increase in county AA density (p<0.01). There was also an association between county AA density and COVID-19 deaths; the death rate increased 2 per 100,000 for every percentage increase in county AA density (p=0.02). Conclusion: These findings indicate that communities with a high AA density have been disproportionately burdened with COVID-19. To help develop effective interventions and programs that address this disparity, further study is needed to understand social determinants of health driving inequities for this community.

Early impact of COVID-19 on individuals with self-reported eating disorders: A survey of ~1,000 individuals in the United States and the Netherlands.

OBJECTIVE: We evaluated the early impact of COVID-19 on people with self-reported eating disorders. METHOD: Participants in the United States (US, N = 511) and the Netherlands (NL, N = 510), recruited through ongoing studies and social media, completed an online survey that included both quantitative measures and free-text responses assessing the impact of COVID-19 on situational circumstances, eating disorder symptoms, eating disorder treatment, and general well-being. RESULTS: Results revealed strong and wide-ranging effects on eating disorder concerns and illness behaviors that were consistent with eating disorder type. Participants with anorexia nervosa (US 62% of sample; NL 69%) reported increased restriction and fears about being able to find foods consistent with their meal plan. Individuals with bulimia nervosa and binge-eating disorder (US 30% of sample; NL 15%) reported increases in their binge-eating episodes and urges to binge. Respondents noted marked increases in anxiety since 2019 and reported greater concerns about the impact of COVID-19 on their mental health than physical health. Although many participants acknowledged and appreciated the transition to telehealth, limitations of this treatment modality for this population were raised. Individuals with past histories of eating disorders noted concerns about relapse related to COVID-19 circumstances. Encouragingly, respondents also noted positive effects including greater connection with family, more time for self-care, and motivation to recover. DISCUSSIONS: COVID-19 is associated with increased anxiety and poses specific disorder-related challenges for individuals with eating disorders that require attention by healthcare professionals and carers.