Estrogen-Dependent Gene Expression in the Mouse Ovary

Estrogen (E) plays a pivotal role in regulating the female reproductive system, particularly the ovary. However, the number and type of ovarian genes influenced by estrogen remain to be fully elucidated. In this study, we have utilized wild-type (WT) and aromatase knockout (ArKO; estrogen free) mouse ovaries as an in vivo model to profile estrogen dependent genes. RNA from each individual ovary (n = 3) was analyzed by a microarray-based screen using Illumina Sentrix Mouse WG-6 BeadChip (45,281 transcripts). Comparative analysis (GeneSpring) showed differential expression profiles of 450 genes influenced by E, with 291 genes up-regulated and 159 down-regulated by 2-fold or greater in the ArKO ovary compared to WT. Genes previously reported to be E regulated in ArKO ovaries were confirmed, in addition to novel genes not previously reported to be expressed or regulated by E in the ovary. Of genes involved in 5 diverse functional processes (hormonal processes, reproduction, sex differentiation and determination, apoptosis and cellular processes) 78 had estrogen-responsive elements (ERE). These analyses define the transcriptome regulated by E in the mouse ovary. Further analysis and investigation will increase our knowledge pertaining to how E influences follicular development and other ovarian functions

Immediate effect of the COVID-19 pandemic on patient health, health-care use, and behaviours : results from an international survey of people with rheumatic diseases

Funding Information: We would like to thank all the clinicians, health-care providers, and patient organisations who helped to develop and disseminate this survey. A full list of all the contributors can be found in the appendix (pp 44?45). Preliminary results were presented at the American College of Rheumatology 2020 conference. The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology, the European League Against Rheumatism, the UK National Health Service, the National Institute for Health Research, the UK Department of Health, or any other organisation. Funding Information: JSH reports grants from Childhood Arthritis and Rheumatology Research Alliance and Rheumatology Research Alliance; and personal fees from Novartis, Pfizer, and Biogen, outside of the submitted work. JWL reports grants from Pfizer, outside of the submitted work. JAS reports grants and personal fees from Bristol-Myers Squibb; and personal fees from Gilead, Inova Diagnostics, Optum, and Pfizer, outside of the submitted work. CH reports personal fees from AstraZeneca and Aurinia Pharmaceuticals, outside of the submitted work. MJL reports grants from American College of Rheumatology during the conduct of the study and consulting fees from AbbVie, Amgen, Actelion, Boehringer Ingelheim, BMS, Celgene, Gilead, Johnson & Johnson, Mallinckrodt, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi, and UCB, outside of the submitted work. SES is supported by the Vasculitis Clinical Research Consortium and Vasculitis Foundation outside of the submitted work. KLD reports grants from Novartis, Sobi, National Institutes of Health, and Horizon Bio, outside of the submitted work. EFM reports that the Liga Portuguesa Contra as Doenças Reumaticas received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal SA, MSD, Celgene, Medac, Pharmakern, GAfPA, AMGEN, A Menarini Portugal; grants and non-financial support from Pfizer; and non-financial support from Grünenthal GmbH and Tilray, outside of the submitted work. DPR is the volunteer Vice President of the Canadian Arthritis Patient Alliance, which is primarily supported by independent grants from pharmaceutical companies. DPR reports consulting fees from NovoNordisk Canada and speaking fees and an honoraria from Eli Lilly Canada, outside of the submitted work. DPR also lives with rheumatoid arthritis. SB reports personal fees from Novartis, AbbVie, Pfizer, and Horizon Pharma, outside of the submitted work. RG reports personal fees from AbbVie New Zealand, Cornerstones, Janssen New Zealand; and personal fees and non-financial support from Pfizer New Zealand, (all <$10 000) outside of the submitted work. PMM reports personal fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and grants and personal fees from Orphazyme, outside of the submitted work. PCR reports personal fees from Abbvie, Gilead, Lilly, and Roche; grants and personal fees from Novartis, UCB Pharma, Janssen, and Pfizer; and non-financial support from BMS, outside of the submitted work. PS reports honoraria from being a social media editor for @ACR_Journals, outside of the submitted work. ZSW reports grants from National Institutes of Health, BMS, and Sanofi; and personal fees from Viela Bio and MedPace, outside of the submitted work. JY reports personal fees from Pfizer and Eli Lilly, and grants and personal fees from Astra Zeneca, outside of the submitted work. ES is a Board Member of the Canadian Arthritis Patient Alliance, which is a patient-run, volunteer-based organisation whose activities are primarily supported by independent grants from pharmaceutical companies. All other authors declare no competing interests. Publisher Copyright: © 2021 Elsevier LtdBackground: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. Methods: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. Findings: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjögren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). Interpretation: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. Funding: American College of Rheumatology.publishersversionPeer reviewe

Identification of an INa-dependent and Ito-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient

Brugada syndrome (BrS) is an inherited cardiac arrhythmia commonly associated with SCN5A mutations, yet its ionic mechanisms remain unclear due to a lack of cellular models. Here, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a BrS patient (BrS1) to evaluate the roles of Na+ currents (INa) and transient outward K+ currents (Ito) in BrS induced action potential (AP) changes. To understand the role of these current changes in repolarization we employed dynamic clamp to "electronically express" IK1 and restore normal resting membrane potentials and allow normal recovery of the inactivating currents, INa, ICa and Ito. HiPSC-CMs were generated from BrS1 with a compound SCN5A mutation (p. A226V & p. R1629X) and a healthy sibling control (CON1). Genome edited hiPSC-CMs (BrS2) with a milder p. T1620M mutation and a commercial control (CON2) were also studied. CON1, CON2 and BrS2, had unaltered peak INa amplitudes, and normal APs whereas BrS1, with over 75% loss of INa, displayed a loss-of-INa basal AP morphology (at 1.0 Hz) manifested by a reduced maximum upstroke velocity (by ~80%, p < 0.001) and AP amplitude (p < 0.001), and an increased phase-1 repolarization pro-arrhythmic AP morphology (at 0.1 Hz) in ~25% of cells characterized by marked APD shortening (~65% shortening, p < 0.001). Moreover, Ito densities of BrS1 and CON1 were comparable and increased from 1.0 Hz to 0.1 Hz by ~ 100%. These data indicate that a repolarization deficit could be a mechanism underlying BrS

A Randomized Controlled Trial on the Effects of a 6-Month Home-Based Physical Activity Program with Individual Goal-Setting and Volunteer Mentors on Physical Activity, Adherence, and Physical Fitness in Inactive Older Adults at Risk of Cognitive Decline: The INDIGO Study

This is the author accepted manuscript. The final version is available from IOS Press via the DOI in this recordBackground: Increasing physical activity (PA) in those who have memory concerns requires innovative approaches. Objective: To compare in this randomized controlled trial (RCT) the effects on PA, adherence, and fitness of two approaches to deliver a 6-month home-based PA program in older, inactive individuals at risk of cognitive decline. Methods: Individuals (n = 52) aged 60–85 years, inactive with mild cognitive impairment or subjective cognitive decline were recruited from the community and memory clinics. Randomization was to 6 months of 150 min/week moderate intensity PA with either: goal-setting with mentor support; or education and peer contact. A subset of participants (n = 36) continued for a further 6 months. PA, moderate and vigorous PA, and secondary outcomes, fitness, goal performance/satisfaction and self-efficacy were assessed at baseline, 6 and 12 months. Modelling of primary and secondary outcomes was conducted with linear mixed models. Results: Participants were mean age (±sd) 70.1 (6.4) years. Six-month retention was 88.5%(n = 46). No significant between-group differences were observed for PA or fitness. Post-hoc combined group data showed a significant, moderate-large effect size increase in PA with time. PA increased by a mean 1,662 (943, 2383) steps/day (95%CI) and 1,320 (603, 2037) steps/day at 6 and 12 months (p <  0.001). Median (quartiles Q1-Q3) 6 and 6–12 month combined group adherence was 88.9 (74.4–95.7)%and 84.6 (73.9–95.4)%respectively. Conclusion: In this target group, no differences were detected between groups both intervention strategies were highly effective in increasing PA and fitness.National Health and Medical Research Counci

Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey.

Background: We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. Methods: From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. Results: We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Conclusion: Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring

A Surveillance System to Reduce Transmission of Pandemic H1N1 (2009) Influenza in a 2600-Bed Medical Center

BACKGROUND: Concerns have been raised about how the transmission of emerging infectious diseases from patients to healthcare workers (HCWs) and vice versa could be recognized and prevented in a timely manner. An effective strategy to block transmission of pandemic H1N1 (2009) influenza in HCWs is important. METHODOLOGY/PRINCIPAL FINDINGS: An infection control program was implemented to survey and prevent nosocomial outbreaks of H1N1 (2009) influenza at a 2,600-bed, tertiary-care academic hospital. In total, 4,963 employees at Kaohsiung Chang Gung Memorial Hospital recorded their temperature and received online education on control practices for influenza infections. Administration records provided vaccination records and occupational characteristics of all HCWs. Early recognition of a pandemic H1N1 (2009) influenza case was followed by a semi-structured questionnaire to analyze possible routes of patient contact, household contact, or unspecified contact. Surveillance spanned August 1, 2009 to January 31, 2010; 51 HCWs were confirmed to have novel H1N1 (2009) influenza by quantitative real-time reverse transcription polymerase chain reaction. Prevalence of patient contact, household contact, or unspecified contact infection was 13.7% (7/51), 13.7% (7/51), and 72.5% (37/51), respectively. The prevalence of the novel H1N1 infection was significantly lower among vaccinated HCWs than among unvaccinated HCWs (p<0.001). Higher viral loads in throat swabs were found in HCWs with patient and household contact infection than in those with unspecified contact infection (4.15 vs. 3.53 copies/mL, log(10), p = 0.035). CONCLUSION: A surveillance system with daily temperature recordings and online education for HCWs is important for a low attack rate of H1N1 (2009) influenza transmission before H1N1 (2009) influenza vaccination is available, and the attack rate is further decreased after mass vaccination. Unspecified contact infection rates were significantly higher than that of patient contact and household contact infection, highlighting the need for public education of influenza transmission in addition to hospital infection control

Characteristics and Outcomes of People With Gout Hospitalized Due to COVID-19: Data From the COVID-19 Global Rheumatology Alliance Physician-Reported Registry

Objective: To describe people with gout who were diagnosed with coronavirus disease 2019 (COVID-19) and hospitalized and to characterize their outcomes. Methods: Data on patients with gout hospitalized for COVID-19 between March 12, 2020, and October 25, 2021, were extracted from the COVID-19 Global Rheumatology Alliance registry. Descriptive statistics were used to describe the demographics, comorbidities, medication exposures, and COVID-19 outcomes including oxygenation or ventilation support and death. Results: One hundred sixty-three patients with gout who developed COVID-19 and were hospitalized were included. The mean age was 63 years, and 85% were male. The majority of the group lived in the Western Pacific Region (35%) and North America (18%). Nearly half (46%) had two or more comorbidities, with hypertension (56%), cardiovascular disease (28%), diabetes mellitus (26%), chronic kidney disease (25%), and obesity (23%) being the most common. Glucocorticoids and colchicine were used pre-COVID-19 in 11% and 12% of the cohort, respectively. Over two thirds (68%) of the cohort required supplemental oxygen or ventilatory support during hospitalization. COVID-19-related death was reported in 16% of the overall cohort, with 73% of deaths documented in people with two or more comorbidities. Conclusion: This cohort of people with gout and COVID-19 who were hospitalized had high frequencies of ventilatory support and death. This suggests that patients with gout who were hospitalized for COVID-19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31–1·57]), were male compared with female (1·38 [1·05–1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23–1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50–3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49–3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology

Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

Gene expression associated with West Nile virus (WNV) infection was profiled in the central nervous system of horses. Pyrosequencing and library annotation was performed on pooled RNA from the CNS and lymphoid tissues on horses experimentally infected with WNV (vaccinated and naïve) and non-exposed controls. These sequences were used to create a custom microarray enriched for neurological and immunological sequences to quantitate gene expression in the thalamus and cerebrum of three experimentally infected groups of horses (naïve/WNV exposed, vaccinated/WNV exposed, and normal)

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry

OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants