Deucravacitinib, a Tyrosine Kinase 2 Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE). METHODS: Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI-4) response at week 32. Secondary outcomes assessed at week 48 included SRI-4, British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts. RESULTS: At week 32, the percentage of patients achieving SRI-4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95% CI) 1.5, 5.1]; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 [95% CI 1.0, 3.4]; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 [95% CI 0.8, 2.9]; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI-50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported. CONCLUSION: Deucravacitinib treatment elicited higher response rates for SRI-4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE.

The Impact of COVID-19 on Cancer Screening and Treatment in Older Adults: The Multiethnic Cohort Study (preprint)

Background: The Coronavirus Disease of 2019 (COVID-19) has impacted the health and day-to-day life of individuals, especially the elderly and people with certain pre-existing medical conditions, including cancer. The purpose of this study was to investigate how COVID-19 impacted access to cancer screenings and treatment, by studying the participants in the Multiethnic Cohort (MEC) study. Methods: The MEC has been following over 215,000 residents of Hawai i and Los Angeles for the development of cancer and other chronic diseases since 1993-1996. It includes men and women of five racial and ethnic groups: African American, Japanese American, Latino, Native Hawaiian, and White. In 2020, surviving participants were sent an invitation to complete an online survey on the impact of COVID-19 on their daily life activities, including adherence to cancer screening and treatment. Approximately 7,000 MEC participants responded. A cross-sectional analysis was performed to investigate the relationships between the postponement of regular health care visits and cancer screening procedures or treatment with race and ethnicity, age, education, and comorbidity. Results: Women with more education, women with lung disease, COPD, or asthma, and women and men diagnosed with cancer in the past 5 years were more likely to postpone any cancer screening test/procedure due to the COVID-19 pandemic. Groups less likely to postpone cancer screening included older women compared to younger women and Japanese American men and women compared to White men and women. Conclusions: This study revealed specific associations of race/ethnicity, age, education level, and comorbidities with the cancer-related screening and healthcare of MEC participants during the COVID-19 pandemic. Increased monitoring of patients in high-risk groups for cancer and other diseases is of the utmost importance as the chance of undiagnosed cases or poor prognosis is increased as a result of delayed screening and treatment.Funding: This research was partially supported by the Omidyar 'Ohana Foundation and grant U01 CA164973 from the National Cancer Institute.

Employees Working from Home: Do Leadership Factors Influence Work-Related Stress and Musculoskeletal Pain?

In March 2020, the COVID-19 pandemic necessitated a rapid public health response, which included mandatory working from home (WFH) for many employees. However, given the rapid change from traditional ways of working, evidence is limited on the role of leaders, managers, and supervisors in supporting their employees' physical and mental health whilst WFH. The study aimed to examine the impact of leaders through their management of psychosocial working conditions on employees' stress and musculoskeletal pain (MSP) levels whilst WFH. METHODS: Data from 965 participants (230 males, 729 females, 6 other) involved in the Employees Working from Home (EWFH) study, collected in October 2020, and April and November 2021, were analysed. Generalised mixed-effect models were used to test relationships between psychosocial leadership factors and employees' stress and MSP levels. RESULTS: Higher quantitative demands are associated with increased stress (B: 0.289, 95%CI 0.245, 0.333), presence of MSP (OR: 2.397, 95%CI 1.809, 3.177), and increased MSP levels (RR: 1.09, 95%CI 1.04, 1.14). Higher levels of vertical trust decreased stress (B: -0.094, 95%CI -0.135, -0.052) and presence of MSP (OR: 0.729, 95%CI 0.557, 0.954). Role clarity decreased stress (B: -0.055, 95%CI -0.104, -0.007) and levels of MSP (RR: 0.93, 95%CI 0.89, 0.96). Working with interruptions was associated with increased stress (B: 0.199, 95%CI 0.119, 0.280) and MSP (OR: 1.834, 95%CI 1.094, 3.072). CONCLUSION: Leaders will need to take a broad view of job design, taking into account physical and psychosocial aspects of work, to effectively support employees WFH and manage stress and MSP.

Delivery of Epinephrine by Metered-Dose Inhaler for the Treatment of Croup in Children

Study Objective: Croup, also known as laryngotracheobronchitis, is a common pediatric presentation in the emergency department. When children present with moderate or severe croup, epinephrine, either racemic or L-isomer, given by nebulization is considered standard of care. Since the beginning of the SARS-CoV-2 pandemic, many medical institutions have moved away from the delivery of medications by nebulization whenever possible in order to prevent aerosolization of the SARS-CoV-2 virus and infecting others in close proximity. Delivery of respiratory medication by metered-dose inhaler (MDI) was the most commonly adopted method to replace nebulization. Primatene MIST (Armstrong Pharmaceuticals) is an over-the-counter, L-epinephrine MDI. In February 2021, the Pediatric Service Line Pharmacy and Therapeutics Committee of the Northwell Health system approved the use of Primatene MIST in children >= 1 years old presenting to the emergency department with croup as an alternative to nebulized epinephrine. We aim to demonstrate that L-epinephrine administered by MDI is safe and effective in children presenting with moderate croup. Study Design/Methods: We conducted a single-center retrospective chart review study of children 1 to 17 years of age who presented to the emergency department at Cohen Children's Medical Center and were evaluated for suspected croup from March 2021 until May 2022. As part of a surveillance and later reapproval process by the Pediatric Service Line Pharmacy and Therapeutics Committee of the Northwell Health system for Primatene MIST, data was prospectively collected and entered into a REDCap database. This included Westley Croup Score, requirement of additional doses of epinephrine, adverse events, disposition, and return within 48 hours. During the initial rollout, eligible patients were administered 4 puffs through an attached spacer. Following safety review, dosing was increased to 6 puffs. Result(s): A total of 24 pediatric patients with croup received Primatene MIST. The mean age was 3.3 years (SD:2.3 years) and 75% were male. Of the 16 patients who had respiratory viral testing, 19% tested positive for SARS-CoV-2 virus. The median Westley Croup Scores at presentation was 3 (IQR:2,3;Range:2-5), 0 (IQR:0,1;Range:0-4) at 30 minutes and 0 (IQR:0,1;Range:0-3) at 120 minutes following Primatene MIST administration. A second dose of epinephrine (nebulized or MDI) was administered to 7 patients (29.2%;CI:14.9%-49.2%). Only 1 patient (4.2%) was admitted and 1 (4.2%) returned within 48 hours. There were no reported adverse events. Conclusion(s): Epinephrine administered by MDI is a safe and effective treatment for moderate croup. It should be considered as an alternative to nebulized epinephrine when there are concerns for infectious aerosolization. No, authors do not have interests to disclose Copyright © 2022

Promoting Intergenerational Approach in Local Governance for Inclusive, Sustainable, and Resilient Pandemic Recovery: The Case of the City of Malolos

The study aimed to find ways to promote an intergenerational approach for inclusive, sustainable, and resilient pandemic recovery of the City of Malolos by assessing the current efforts of the city and the willingness to participate of four hundred selected citizens. The findings revealed that the City of Malolos has continuously worked to prevent and mitigate the virus while considering partnerships with non-governmental and private organizations, interagency collaborations, and community inputs. The study also revealed that respondents across different generations are willing to participate and collaborate with people from different age groups towards pandemic recovery: to voice out the needs and interests of people of their age and people younger than them;to understand and be understood;to feel a sense of fulfillment and community. The researchers suggested that the city should further encourage organization and cross-sectoral collaborations, promote understanding between generations, mobilize social media platforms, conduct educational forums, and apply intergenerational lenses to recognize challenges and opportunities concerning the pandemic. [ FROM AUTHOR]

Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy.

The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

Autoimmune Skin Disease Exacerbations Following COVID-19 Vaccination.

Background: Vaccination against COVID-19 reduces the risk of severe COVID-19 disease and death. However, few studies have examined the safety of the COVID-19 vaccine in patients with autoimmune skin disease. Objectives: We sought to determine the incidence of disease exacerbation in this population following COVID-19 vaccination as well as the associated factors. Methods: We performed a chart review of all patients seen in the autoimmune skin disease clinic of the principal investigator during the study period. All patients included for analysis were systematically and prospectively asked about COVID-19 vaccination status, manufacturers, vaccine dates, autoimmune symptoms after the vaccine, and timing of symptom onset using a standardized template as part of their visit. Demographics and autoimmune disease diagnosis were also collected. Analysis used Chi-square and Fisher's exact tests. Results: 402 subjects were included for analysis. 85.6% of patients were fully vaccinated, with 12.9% unvaccinated and 1.5% partially vaccinated. 14.8% of fully vaccinated patients reported worsening autoimmune signs and symptoms after the vaccine. Fully vaccinated dermatomyositis patients were more likely to report worsening autoimmune signs and symptoms after the vaccine (22.7%) than fully vaccinated lupus erythematosus patients (8.6%) (p=0.009). Patients fully vaccinated with the Moderna vaccine trended towards an increased likelihood of reporting worsening autoimmune signs and symptoms after the vaccine (19.1%) than those with the Pfizer-BioNTech vaccine (12.0%) (p=0.076). Of the patients who had autoimmune symptoms after vaccination, 20% had symptoms after the 1st dose, 82% after the 2nd dose, and 4% after the 3rd dose with median onset (95% confidence interval) of 7 (2,14), 14 (14,21), and 18 (7,28) days later, respectively. Conclusions: More fully vaccinated dermatomyositis patients had exacerbation of autoimmune signs and symptoms after the vaccine than fully vaccinated lupus erythematosus patients. However, given the risks of COVID-19, clinicians should still promote vaccination in most patients with autoimmune skin disease.

Organizational Agility Among Selected SMEs in the Philippines during the Covid-19 Pandemic: Genesis and Implications

Keywords: organizational agility, SMEs, Covid 19 Pandemic 1.INTRODUCTION Challenges, such as globalization, fast technological advances, competition, disruptive business models, emerging new markets, constantly evolving consumer preferences demand response from firms in order to remain competitive (Zitkiene & Deksnys, 2018;Zutshi, Mendy, Sharma, Thomas, & Sarker, (2021). [...]they employ 60% of the workforce and account for more than 99% of registered businesses in the Philippines (ITC, 2020). [...]on the supply side, contact-intensive business sectors were affected by the lockdown policies and global supply chains were likewise disrupted. Organizational agility conceptual model Dyduch, etal (2021) identified organizational abilities that are important for firms to have, especially in the context of the Coronavirus crisis, namely: (a) The ability to obtain financing;(b) The ability to work in virtual teams;(c) Delegation of power and greater autonomy of employees;(d) The ability to take advantage of opportunities that appear during a crisis;(e) The ability to innovate and/or imitate;(f) The ability to differentiate between products and services offered;(g) The ability to use and develop modern technologies;(h) The ability to move resources quickly;(i) Good work organization and proper planning;(j) The ability to maintain and develop efficient IT systems;and (k) The ability to use personal relationships.

Autoimmune Skin Disease Exacerbations Following COVID-19 Vaccination

Background Vaccination against COVID-19 reduces the risk of severe COVID-19 disease and death. However, few studies have examined the safety of the COVID-19 vaccine in patients with autoimmune skin disease. Objectives We sought to determine the incidence of disease exacerbation in this population following COVID-19 vaccination as well as the associated factors. Methods We performed a chart review of all patients seen in the autoimmune skin disease clinic of the principal investigator during the study period. All patients included for analysis were systematically and prospectively asked about COVID-19 vaccination status, manufacturers, vaccine dates, autoimmune symptoms after the vaccine, and timing of symptom onset using a standardized template as part of their visit. Demographics and autoimmune disease diagnosis were also collected. Analysis used Chi-square and Fisher’s exact tests. Results 402 subjects were included for analysis. 85.6% of patients were fully vaccinated, with 12.9% unvaccinated and 1.5% partially vaccinated. 14.8% of fully vaccinated patients reported worsening autoimmune signs and symptoms after the vaccine. Fully vaccinated dermatomyositis patients were more likely to report worsening autoimmune signs and symptoms after the vaccine (22.7%) than fully vaccinated lupus erythematosus patients (8.6%) (p=0.009). Patients fully vaccinated with the Moderna vaccine trended towards an increased likelihood of reporting worsening autoimmune signs and symptoms after the vaccine (19.1%) than those with the Pfizer-BioNTech vaccine (12.0%) (p=0.076). Of the patients who had autoimmune symptoms after vaccination, 20% had symptoms after the 1st dose, 82% after the 2nd dose, and 4% after the 3rd dose with median onset (95% confidence interval) of 7 (2,14), 14 (14,21), and 18 (7,28) days later, respectively. Conclusions More fully vaccinated dermatomyositis patients had exacerbation of autoimmune signs and symptoms after the vaccine than fully vaccinated lupus erythematosus patients. However, given the risks of COVID-19, clinicians should still promote vaccination in most patients with autoimmune skin disease.

Genetic architecture of host proteins interacting with SARS-CoV-2

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid 'in silico' assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).

American College of Rheumatology White Paper on Antimalarial Cardiac Toxicity.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well-established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)-prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID-19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus-based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long-term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk-benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases.

Genetic architecture of host proteins involved in SARS-CoV-2 infection.

Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).

Genetic architecture of host proteins interacting with SARS-CoV-2.

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid 'in silico' assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).

Genetic architecture of host proteins interacting with SARS-CoV-2 (preprint)

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid in silico assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).