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Abstract Background Recurrent pericarditis (RP) patients report that painful, debilitating flares negatively impact their health-related quality of life (HRQoL). RHAPSODY, the Phase 3 trial of rilonacept (IL-1α/IL-1β cytokine trap), included a daily pain diary and patient-reported outcome SF-36v2 to measure HRQoL throughout the trial. Purpose The purpose of this research is to evaluate the effect of rilonacept on HRQoL in relation to changes in pain for RP patients who have a recurrence. Methods RHAPSODY enrolled 86 patients with acute symptomatic RP to receive weekly rilonacept for a 12-week run-in (RI) period and randomized 61 patients (1:1) to receive placebo (n=31) or continue rilonacept (n=30) for the event-driven randomized-withdrawal (RW) period. Patients on placebo who experienced a qualifying recurrence during RW (return of pericarditis pain and increase in C-reactive protein) were rescued with bailout rilonacept. Patients reported daily pericarditis pain electronically, using a 0–10 numeric rating scale (NRS), and completed the SF-36v2 at study visits prior to clinician interaction. Scores from RI Baseline (BL), RI Week 12 (RW BL), Recurrence visit, and RW up to Week 24 (or end of study; EOS) were evaluated for patients who experienced recurrence in RW. Analyses exclude one patient randomized to placebo who had a recurrence after Week 24 of the RW period. Results Analyses focused on the 22 of 30 patients (73%) in the placebo group who experienced a recurrence before Week 24 of RW (median time from RW BL to recurrence: 8.6 weeks). During RI, daily pain scores decreased while on rilonacept (Cohen's effect size [ES] d=−2.0), and SF-36v2 scores improved, with scores at RI BL (Fig. 1 red line) below the general population average of 50 and near or above average at RI Week 12 (Fig. 1 blue line); ES were all large (d>0.8), ranging from 0.917 (Mental Component Summary) to 2.021 (Bodily Pain). At recurrence, pain scores increased (d=6.5; Fig. 2) and SF-36v2 scores were below the population average (Fig. 1 orange line), with largest reductions between RI Week 12 (RW BL) and recurrence for Bodily Pain (−13.4) and Physical Component Summary (−10.6). Following rilonacept bailout, average pain decreased (d=−2.1; Fig. 2), and by RW Week 24/EOS, SF-36v2 scores returned to similar levels as at the end of the RI period (Fig. 1 green line). Conclusion Impaired RI BL SF-36v2 scores indicate negative impact of RP on HRQOL in RP patients. While receiving rilonacept, HRQoL scores improved to near or above population averages, in conjunction with patient-reported pain. After discontinuing rilonacept during RW, HRQoL scores worsened at recurrence and improved upon receipt of bail-out rilonacept, similar to pain. These results provide support for the broader benefit of rilonacept treatment beyond pain, when administered on top of conventional therapies and as mono-therapy, providing evidence of its potential to improve HRQoL in this patient population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Kiniksa Pharmaceuticals, Ltd.

Background: Question prompt lists (QPLs) are structured sets of disease-specific questions intended for patient use, enhancing the patient-physician communication by encouraging patients to ask relevant questions during a consultation. Recently, a preliminary 78 question gastroesophageal reflux disease (GERD) specific QPL was created by 12 esophageal experts through a modified Delphi (RAND/University of California, Los Angeles) technique. Patients’ perspectives and opinions on each question, however, had not been accounted for in the preliminary expert’ version. Aim: The aim was to modify a preliminary experts’ QPL, specific to adults with GERD, following patient perspectives and opinions. Methods: A preliminary GERD QPL was modified through patient input and opinions. Thirty-eight patients with a clinical diagnosis of GERD followed at Stanford University Esophageal Clinic between January and November 2019 were consented to modify the preliminary 78 question expert QPL version. After receiving the QPL in Qualtrics (Provo, UT) by a direct e-mail invitation, patients independently rated questions on a 5-point Likert scale, where 1=“should not be included,” 2=“unimportant,” 3=“don’t know/depends,” 4=“important,” and 5=“essential.” Questions were accepted for inclusion in the QPL with an a priori interagreement of 80% ranking in the range of 4 to 5. At the end, patients were encouraged to propose additional questions to incorporate into the QPL by open-endedly asking “Are there questions we didn’t ask, that you think we should?” Results: Twenty-three patients with GERD (19 female, median age 64) fully participated and modified the existing QPL (60.5%). Of the 78 questions from the preliminary GERD QPL, 66 questions (84.6%) were accepted for inclusion. The question with the highest agreement among patients rating a question as essential consisted of “what habits, food, and drinks do I have to avoid?” (82.6%). Questions eliminated because of disagreement included “What is the natural history of GERD,” “Do I have a high chance to die from my Barrett’s?,” and “Why are you prescribing an antidepressant to treat my GERD?” Nine patients suggested additional questions totaling to 16 separate questions, including “What type of surgeries are there to help GERD?,” “What stage is my GERD?,” “What are the odds/percentage of getting cancer from GERD?” Incorporating the suggested questions, the final GERD QPL—created by esophageal experts and modified by patients—consisted of 82 questions. Conclusion: Esophageal experts and GERD patients have a high level of agreement on important questions, though there is some variation in perspective. Future studies can simplify this list and measure the impact of a shared GERD QPL on patients’ decisional conflict and perceived involvement in care.

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life threatening severe cutaneous drug reaction. Most patients develop eosinophilia, a rash, a fever, lymphadenopathy and variable visceral organ involvement 2–6 weeks following exposure to the inciting medication. Unlike other severe cutaneous drug reactions, internal organ involvement that leads to high mortality is a unique feature of DRESS syndrome. While the liver is the most common internal organ involved, literally every other visceral organ can be affected in this syndrome. The lesser-known gastrointestinal manifestations of this syndrome include esophagitis, gastritis, enteritis, colitis, pancreatitis and a late autoimmune sequela due to pancreatic injury such as fulminant type 1 diabetes mellitus, autoimmune type 1 diabetes mellitus and type 2 diabetes mellitus. While these entities are less common, they are associated with equally severe complications and adverse patient outcomes. In this review, we synthetize data on these rare manifestations using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The liver, the most common visceral organ involved, has been described as part of DRESS elsewhere and is not included in the scope of this article.

Abstract The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.

With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD); 2-SE in diastolic heart failure (SEDIA); 3-SE in hypertrophic cardiomyopathy (SEHCA); 4-SE post-chest radiotherapy and chemotherapy (SERA); 5-Artificial intelligence SE evaluation (AI-SEE); 6-Environmental stress echocardiography and air pollution (ESTER); 7-SE in repaired Tetralogy of Fallot (SETOF); 8-SE in post-COVID-19 (SECOV); 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE); 10-SE for mitral ischemic regurgitation (SEMIR); 11-SE in valvular heart disease (SEVA); 12-SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021–2025) ≥10,000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time, and in any patient.

Abstract Aims The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis. Methods Imaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy. Results We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post‐mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non‐spatial memory test seen in epileptic mice not depleted of microglia. Conclusions These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Abstract OBJECTIVES This study sought to evaluate the long-term differences in survival between multiple arterial grafts (MAG) and single arterial grafts (SAG) in patients who underwent coronary artery bypass grafting (CABG) in the SYNTAX study. METHODS The present analysis included the randomized and registry-treated CABG patients (n = 1509) from the SYNTAX Extended Survival study (SYNTAXES). Patients with only venous (n = 42) or synthetic grafts (n = 1) were excluded. The primary end point was all-cause death at the longest follow-up. Multivariable Cox regression was used to adjust for differences in baseline characteristics. Sensitivity analysis using propensity matching with inverse probability for treatment weights was performed. RESULTS Of the 1466 included patients, 465 (31.7%) received MAG and 1001 (68.3%) SAG. Patients receiving MAG were younger and at lower risk. At the longest follow-up of 12.6 years, all-cause death occurred in 23.6% of MAG and 40.0% of SAG patients [adjusted hazard ratio (HR) 0.74, 95% confidence interval (CI) (0.55–0.98); P = 0.038], which was confirmed by sensitivity analysis. MAG in patients with the three-vessel disease was associated with significant lower unadjusted and adjusted all-cause death at 12.6 years [adjusted HR 0.65, 95% CI (0.44–0.97); P = 0.033]. In contrast, no significance was observed after risk adjustment in patients with the left main disease, with and without diabetes, or among SYNTAX score tertiles. CONCLUSIONS In the present post hoc analysis of all-comers patients from the SYNTAX trial, MAG resulted in markedly lower all-cause death at 12.6-year follow-up compared to a SAG strategy. Hence, this striking long-term survival benefit of MAG over SAG encourages more extensive use of multiple arterial grafting in selected patients with reasonable life expectancy. Trial registration SYNTAXES ClinicalTrials.gov reference: NCT03417050; SYNTAX ClinicalTrials.gov reference: NCT00114972.