Citations

Abstract Objective Flares of autoimmune rheumatic diseases (AIRDs) following COVID-19 vaccination are a particular concern in vaccine-hesitant individuals. Therefore, we investigated the incidence, predictors and patterns of flares following vaccination in individuals living with AIRDs, using global COVID-19 Vaccination in Autoimmune Diseases (COVAD) surveys. Methods The COVAD surveys were used to extract data on flare demographics, comorbidities, COVID-19 history, and vaccination details for patients with AIRDs. Flares following vaccination were identified as patient-reported (a), increased immunosuppression (b), clinical exacerbations (c) and worsening of PROMIS scores (d). We studied flare characteristics and used regression models to differentiate flares among various AIRDs. Results Of 15 165 total responses, the incidence of flares in 3453 patients with AIRDs was 11.3%, 14.8%, 9.5% and 26.7% by definitions a–d, respectively. There was moderate agreement between patient-reported and immunosuppression-defined flares (K = 0.403, P = 0.022). Arthritis (61.6%) and fatigue (58.8%) were the most commonly reported symptoms. Self-reported flares were associated with higher comorbidities (P = 0.013), mental health disorders (MHDs) (P < 0.001) and autoimmune disease multimorbidity (AIDm) (P < 0.001). In regression analysis, the presence of AIDm [odds ratio (OR) = 1.4; 95% CI: 1.1, 1.7; P = 0.003), or a MHD (OR = 1.7; 95% CI: 1.1, 2.6; P = 0.007), or being a Moderna vaccine recipient (OR = 1.5; 95% CI: 1.09, 2.2; P = 0.014) were predictors of flares. Use of MMF (OR = 0.5; 95% CI: 0.3, 0.8; P = 0.009) and glucocorticoids (OR = 0.6; 95% CI: 0.5, 0.8; P = 0.003) were protective. A higher frequency of patients with AIRDs reported overall active disease post-vaccination compared with before vaccination (OR = 1.3; 95% CI: 1.1, 1.5; P < 0.001). Conclusion Flares occur in nearly 1 in 10 individuals with AIRDs after COVID vaccination; people with comorbidities (especially AIDm), MHDs and those receiving the Moderna vaccine are particularly vulnerable. Future avenues include exploring flare profiles and optimizing vaccine strategies for this group.

AbstractObjectivesTo compare pain intensity among individuals with idiopathic inflammatory myopathies (IIMs), other systemic autoimmune rheumatic diseases (AIRDs), and without rheumatic disease (wAIDs).MethodsData were collected from the COVID‐19 Vaccination in Autoimmune Diseases (COVAD) study, an international cross‐sectional online survey, from December 2020 to August 2021. Pain experienced in the preceding week was assessed using numeral rating scale (NRS). We performed a negative binomial regression analysis to assess pain in IIMs subtypes and whether demographics, disease activity, general health status, and physical function had an impact on pain scores.ResultsOf 6988 participants included, 15.1% had IIMs, 27.9% had other AIRDs, and 57.0% were wAIDs. The median pain NRS in patients with IIMs, other AIRDs, and wAIDs were 2.0 (interquartile range [IQR] = 1.0–5.0), 3.0 (IQR = 1.0–6.0), and 1.0 (IQR = 0–2.0), respectively (P < 0.001). Regression analysis adjusted for gender, age, and ethnicity revealed that overlap myositis and antisynthetase syndrome had the highest pain (NRS = 4.0, 95% CI = 3.5–4.5, and NRS = 3.6, 95% CI = 3.1–4.1, respectively). An additional association between pain and poor functional status was observed in all groups. Female gender was associated with higher pain scores in almost all scenarios. Increasing age was associated with higher pain NRS scores in some scenarios of disease activity, and Asian and Hispanic ethnicities had reduced pain scores in some functional status scenarios.ConclusionPatients with IIMs reported higher pain levels than wAIDs, but less than patients with other AIRDs. Pain is a disabling manifestation of IIMs and is associated with a poor functional status.

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p&lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was &gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was &lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

AbstractBackgroundPre‐exposure prophylaxis with tixagevimab‐cilgavimab (tix‐cil) may be associated with cardiovascular adverse events. Also, in vitro studies have reported a reduced activity of tix‐cil against emerging SARS‐CoV‐2 Omicron subvariants. Our study aimed to report the real‐world outcomes of tix‐cil prophylaxis in orthotopic heart transplant (OHT) recipientsMethodsWe retrospectively studied all OHT recipients who received one dose of tix‐cil (150–150 mg or 300–300 mg) at Mayo Clinic in Arizona, Florida, and Minnesota, between February 5, 2022 and September 8, 2022. We collected data on cardiovascular adverse events and breakthrough COVID‐19 following tix‐cil administration.ResultsOne hundred sixty‐three OHT recipients were included. The majority were male (65.6%), and the median age was 61 years (IQR 48, 69). During the median follow‐up of 164 days (IQR 123, 190), one patient presented an episode of asymptomatic hypertensive urgency that was managed with outpatient antihypertensive treatment optimization. Twenty‐four patients (14.7%) experienced breakthrough COVID‐19 at the median of 63.5 days (IQR 28.3, 101.3) after tix‐cil administration. The majority (70.8%) completed the primary vaccine series and received at least one booster dose (70.8%). Only one patient with breakthrough COVID‐19 required hospitalization. All patients survived.ConclusionsIn this cohort of OHT recipients, no patients developed severe cardiovascular events related to tix‐cil. The high incidence of breakthrough COVID‐19 could be due to the reduced activity of tix‐cil against current circulating SARS‐CoV‐2 Omicron variants. These results emphasize the need for a multimodal prevention strategy against SARS‐CoV‐2 in these high‐risk patients. image

Introduction: Medical education is trending towards an outcome-based curriculum that prepares medical graduates to excel in a rapidly evolving, team-centred healthcare delivery system. The Mayo Medical School (MMS) has recently redesigned its curriculum to introduce early clinical relevance, optimise course integration, provide flexibility and promote active learning. This study aims to evaluate the role that curricular flexibility plays in students’ perceived learning, satisfaction and performance. Materials and Methods: First-year students completed a 5-point Likert scale survey regarding satisfaction with and perceived learning from various components of the flexible curriculum during 2 different academic blocks. Students’ academic performance was assessed by a National Board of Medical Examiners (NBME) Subject Examination after each block. Results: In comparing student-rated satisfaction and perceived learning from didactics versus other curricular components for Block 3 (Pathology and Immunology) and Block 5 (Gross Anatomy and Radiology), students rated didactics higher in all cases in which there was a statistically significant difference in the ratings. There was a statistically significant positive correlation between the amount learned and satisfaction for all curricular components with the exception of Block 5 independent study. During Block 3, only interest in the subject matter correlated positively with the NBME score, while during Block 5, only time spent in class correlated negatively with the NBME score. Conclusions: Although various components of the flexible curriculum do not appear to affect satisfaction and perceived learning, their potential influence on graduate outcomes, in terms of delivering healthcare providers who are patient-centred, creative thinkers and compassionate leaders should not be discounted. Key words: Curriculum reform, Medical curriculum, Outcomes-based education, Student satisfaction

Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Signal-processing approaches are widely used for the analysis of intracardiac electrograms (iEGMs), which are collected during catheter ablation from patients with AF. In order to identify possible targets for ablation therapy, dominant frequency (DF) is widely used and incorporated in electroanatomical mapping systems. Recently, a more robust measure, multiscale frequency (MSF), for iEGM data analysis was adopted and validated. However, before completing any iEGM analysis, a suitable bandpass (BP) filter must be applied to remove noise. Currently, no clear guidelines for BP filter characteristics exist. The lower bound of the BP filter is usually set to 3–5 Hz, while the upper bound (BP¯th) of the BP filter varies from 15 Hz to 50 Hz according to many researchers. This large range of BP¯th subsequently affects the efficiency of further analysis. In this paper, we aimed to develop a data-driven preprocessing framework for iEGM analysis, and validate it based on DF and MSF techniques. To achieve this goal, we optimized the BP¯th using a data-driven approach (DBSCAN clustering) and demonstrated the effects of different BP¯th on subsequent DF and MSF analysis of clinically recorded iEGMs from patients with AF. Our results demonstrated that our preprocessing framework with BP¯th = 15 Hz has the best performance in terms of the highest Dunn index. We further demonstrated that the removal of noisy and contact-loss leads is necessary for performing correct data iEGMs data analysis.

ImportanceMorphea is an insidious inflammatory disorder of the skin and deeper tissues. Determining disease activity is challenging yet important to medical decision-making and patient outcomes.ObjectiveTo develop and validate a scoring tool, the Morphea Activity Measure (MAM), to evaluate morphea disease activity of any type or severity that is easy to use in clinical and research settings.Design, Setting, and ParticipantsThis pilot diagnostic study was conducted from September 9, 2019, to March 6, 2020, in 2 phases: development and validation. During the development phase, 14 morphea experts (dermatologists and pediatric dermatologists) used a Delphi consensus method to determine items that would be included in the MAM. The validation phase included 8 investigators who evaluated the tool in collaboration with 14 patients with pediatric morphea (recruited from a referral center [Medical College of Wisconsin]) during a 1-day in-person meeting on March 6, 2020.Main Outcomes and MeasuresDuring the development phase, online survey items were evaluated by experts in morphea using a Likert scale (score range, 0-10, with 0 indicating not important and 10 indicating very important); agreement was defined as a median score of 7.0 or higher, disagreement as a median score of 3.9 or lower, and no consensus as a median score of 4.0 to 6.9. During the validation phase, reliability (interrater and intrarater agreement using intraclass correlation coefficients), validity (using the content validity index and κ statistics as well as correlations with the modified Localized Scleroderma Severity Index and the Physician Global Assessment of Activity using Spearman ρ coefficients), and viability (using qualitative interviews of investigators who used the MAM tool) were evaluated. Descriptive statistics were used for quantitative variables. Data on race and ethnicity categories were collected but not analyzed because skin color was more relevant for the purposes of this study.ResultsAmong 14 survey respondents during the development phase, 9 (64.3%) were pediatric dermatologists and 5 (35.7%) were dermatologists. After 2 rounds, a final tool was developed comprising 10 items that experts agreed were indicative of morphea activity (new lesion in the past 3 months, enlarging lesion in the past 3 months, linear lesion developing progressive atrophy in the past 3 months, erythema, violaceous rim or color, warmth to the touch, induration, white-yellow or waxy appearance, shiny white wrinkling, and body surface area). The validation phase was conducted with 14 patients (median age, 14.5 years [range, 8.0-18.0 years]; 8 [57.1%] female), 2 dermatologists, and 6 pediatric dermatologists. Interrater and intrarater agreement for MAM total scores was good, with intraclass correlation coefficients of 0.844 (95% CI, 0.681-0.942) for interrater agreement and 0.856 (95% CI, 0.791-0.901) for intrarater agreement. Correlations between the MAM and the modified Localized Scleroderma Severity Index (Spearman ρ = 0.747; P &amp;lt; .001) and the MAM and the Physician Global Assessment of Activity (Spearman ρ = 0.729; P &amp;lt; .001) were moderately strong. In qualitative interviews, evaluators agreed that the tool was easy to use, measured morphea disease activity at a single time point, and should be responsive to changes in morphea disease activity over multiple time points.Conclusions and RelevanceIn this study, the MAM was found to be a reliable, valid, and viable tool to measure pediatric morphea activity. Further testing to assess validity in adults and responsiveness to change is needed.

Abstract CD4+ T cells are crucial to control pulmonary tuberculosis, but also favor uncontrolled inflammation in severe disease. Effective CD4+ T cell response to tuberculosis is related to tissue location: Lung-resident CD4+ T cells display higher effector function in comparison to circulating cells. Among the factors favoring T cell residency in non-lymphoid tissues, extracellular ATP sensing via P2RX7 is crucial for the generation of virus-specific resident memory CD8+ T cells. Yet, its role in CD4+ T cell non-lymphoid tissue residency has not been defined. Moreover, mycobacterial infection induces high extracellular ATP levels due to lung tissue damage, which is increased in response to hypervirulent strains. Here, we used P2rx7 ablation models to test the role of P2RX7 in CD4+T cell function in tuberculosis. In response to the hypervirulent Mycobacterium bovis MP287/03 strain, lung-resident WT CD4+ T cells express higher P2RX7 levels compared to circulating CD4+ T cells. Compared to WT mice, P2RX7-deficient (P2rx7−/−) mice display reduced numbers of antigen-specific (I-AbESAT-64-17) and IFN-γ-producing CD4+ T cells in the lung parenchyma. Using cell adoptive transfers, while recipient CD4-deficient mice transferred with CD4+ WT T cells are protected, mice that received CD4+P2rx7−/− T cells develop severe tuberculosis. Mechanistically, CD4+P2rx7−/− T cells have poorer accumulation and IFN-γ production in the lung parenchyma; moreover, they show reduced proliferation in situ. This defect in proliferation is exclusively observed in the lung, with no differences observed in draining lymph nodes. Together, our results show that P2RX7 promote the accumulation of protective CD4+ T cells in the lung during severe tuberculosis.

Abstract Objective COVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs); however, hesitancy continues to persist among these patients. Therefore, we studied the prevalence, predictors and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys. Methods The first and second COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analysed using regression models in different groups. Results We analysed data from 18 882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) (OR: 0.26; 95% CI: 0.24, 0.30, P &lt; 0.001). However, concerns/fear over long-term safety had increased (OR: 3.6; 95% CI: 2.9, 4.6, P &lt; 0.01). We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs (OR: 1.8; 95% CI: 1.08, 3.2, P = 0.023) and HCs (OR: 4; 95% CI: 1.9, 8.1, P &lt; 0.001), as well as more long-term safety concerns/fear (IIMs vs AIRDs – OR: 1.9; 95% CI: 1.2, 2.9, P = 0.001; IIMs vs HCs – OR: 5.4 95% CI: 3, 9.6, P &lt; 0.001). Caucasians [OR 4.2 (1.7–10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8–0.97)]. Conclusion Vaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.