Citations

Objective Polypharmacy management of recurrent pericarditis (RP) often involves long-term therapies, often with negative effects. Slow tapering of oral therapies is often required to avoid recurrence. A post hoc analysis of the phase III trial Rilonacept inHibition of interleukin-1 Alpha and beta for recurrent Pericarditis: a pivotal Symptomatology and Outcomes Study (RHAPSODY) evaluated investigator approaches to transitioning to IL-1 blockade monotherapy with rilonacept, which was hypothesised to allow accelerated withdrawal of common multidrug pericarditis regimens. Methods RHAPSODY was a multicentre (Australia, Israel, Italy, USA), double-blind, placebo-controlled, randomised-withdrawal trial in adults and adolescents with RP. Investigators initiated rilonacept at the labelled dose level and discontinued oral pericarditis therapies during the 12-week run-in; randomised patients received study drug as monotherapy. Time to rilonacept monotherapy was quantified in patients receiving multidrug regimens at baseline who achieved rilonacept monotherapy during run-in. Results In 86 enrolled patients, mean time to rilonacept monotherapy was 7.9 weeks, with no recurrences. Of these, 64% (n=55) entered on multidrug regimens: non-steroidal anti-inflammatory drugs (NSAIDs) plus colchicine (44% (24/55)), colchicine plus glucocorticoids (24% (13/55)), or NSAIDs, colchicine, plus glucocorticoids (33% (18/55)). Investigators transitioned patients receiving colchicine and glucocorticoids at baseline to rilonacept monotherapy without recurrence regardless of taper approach: sequential (n=14; median, 7.7 weeks) or concurrent (n=17; median, 8.0 weeks). Median time to rilonacept monotherapy was similar regardless of glucocorticoid dose and duration: ≤15 mg/day (n=21): 7.3 weeks; >15 mg/day (n=18): 8.0 weeks; long-term (≥28 days): 7.6 weeks. Conclusions Rapid discontinuation of oral RP therapies while transitioning to rilonacept monotherapy was feasible without triggering pericarditis recurrence. Trial registration number NCT03737110.

Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish ( Danio rerio ) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for discovering essential genes for heart rhythm disorders such as sick sinus syndrome (SSS). SSS is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart’s primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. From 609 GBT lines screened, we generated a collection of 35 zebrafish insertional cardiac (ZIC) mutants in which each mutant traps a gene with cardiac expression. We further employed electrocardiographic measurements to screen these 35 ZIC lines and identified three GBT mutants with SSS-like phenotypes. More detailed functional studies on one of the arrhythmogenic mutants, GBT411 , in both zebrafish and mouse models unveiled Dnajb6 as a novel SSS causative gene with a unique expression pattern within the subpopulation of sinus node pacemaker cells that partially overlaps with the expression of hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4), supporting heterogeneity of the cardiac pacemaker cells.

Background Recurrent pericarditis is characterized by painful flares and inflammation, which negatively impact health‐related quality of life. RHAPSODY (rilonacept inhibition of interleukin‐1 alpha and beta for recurrent pericarditis: a pivotal symptomatology and outcomes study) evaluated the efficacy and safety of rilonacept (IL‐1α and ‐β cytokine trap) in recurrent pericarditis. A secondary analysis of these data evaluated the patient‐reported outcome questionnaire score change during the trial. Methods and Results Participants completed 5 patient‐reported outcome (PRO) questionnaires assessing pericarditis pain, health‐related quality of life, general health status, sleep impact, and overall symptom severity. PRO score changes during the treatment run‐in period (12 weeks) and the blinded randomized withdrawal period (up to 24 weeks) were evaluated using descriptive statistics and mixed model repeated measures analyses. Participants with PRO data from the run‐in period (n=84) and the randomized withdrawal period (n=61; 30 rilonacept, 31 placebo) were included in analyses. Run‐in baseline PRO scores indicated that pericarditis symptoms during pericarditis recurrence impacted health‐related quality of life. All PRO scores significantly improved ( P <0.001) on rilonacept treatment during the run‐in period. For the randomized withdrawal period, PRO scores were maintained for participants receiving rilonacept. For those receiving placebo and who experienced a recurrence, PRO scores deteriorated at the time of recurrence and then improved following rilonacept bailout. At randomized withdrawal Week 24/End of Study, scores of participants who received bailout rilonacept were similar to those of participants who had continued rilonacept. Conclusions These results demonstrate the burden of pericarditis recurrences and the improved physical and emotional health of patients with recurrent pericarditis while on rilonacept treatment. These findings extend prior rilonacept efficacy results, demonstrating improvements in patient‐reported health‐related quality of life, sleep, pain, and global symptom severity while on treatment. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03737110.

Abstract CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing &gt;3200 variants in &gt;470 genes from &gt;3100 publications.

Abstract Background Graves' disease (GD) is associated with atrial fibrillation (AF) with a prevalence ranging between 16% and 60%, but its risk factors are not well-defined. We aimed to describe the incidence, risk factors and outcomes of GD-related AF. Methods Patients diagnosed with GD between 2009 and 2019 were included retrospectively. We defined GD-related AF as AF diagnosed within 30 days before or any time after diagnosis of GD. Late onset AF was defined as GD-related AF diagnosed more than 90 days after GD diagnosis. Observed AF events were compared to the expected events in the general population utilizing published data of age and sex-specific rates of AF. Results Of 1371 patients with GD, AF occurred in 139 (10.1%) patients. Late onset AF occurred in 32 (23%), of which 50% had attained euthyroidism. The observed incidence of AF was higher in GD than that expected in the general population (p&lt;0.001), Figure 1. When comparing the incidence of only late AF to that in the general population, late AF still happened more frequently in GD although not achieving statistical significance (p=0.06), Figure 1. Independent risk factors were age [HR 1.05 (1.03–1.06) per year], overt hyperthyroidism [HR 2.71 (1.35–5.44)], and male gender [HR 2.42 (1.57–3.71)] for early AF and age [HR 1.06 (1.02–1.09) per year], BMI [1.07 (1.01–1.12) per unit], COPD [3.33 (1.08–10.27)), heart failure [HR 4.19 (1.39–17.42)], and treatment with thionamide [vs. radioiodine ablation HR 2.94 (1.38–6.27)] for late AF. AF was associated with higher rates of mortality [HR 16.32 (4.66–56.58)], acute coronary syndrome/stable angina events [HR 3.89 (1.23–12.31)], and cardiac hospitalizations [HR 15.39 (8.17–29.00)] when adjusted to age, sex, and previous AF. Conclusion AF occurred in 10.1% of GD patients. Late onset AF is an important entity comprising a quarter of GD-related AF cases and requires surveillance even after restoring euthyroidism. Risk factors for AF in GD are similar to those in general population, although overt hyperthyroidism conferred the highest risk, especially for early AF. Treatment with thionamide was associated with late AF. Funding Acknowledgement Type of funding sources: None.

PURPOSE:High-dose methotrexate (HDMTX; > 500 mg/m2) is an important component of lymphoma therapy. Serum MTX monitoring at 48 hours is the standard approach to identify those at increased risk of developing MTX toxicity. Our aim was to characterize the incidence of complications and their association with MTX levels.METHODS:A retrospective review of our institutional electronic medical record was conducted to identify patients with lymphoma who received HDMTX between January 1, 2002, and December 31, 2018. We characterized the incidence of acute kidney injury (AKI), intensive care unit (ICU) admission, length of hospital stay (LOS), and 30-day mortality across 48-hour MTX levels. To establish an association between 48-hour MTX levels and the complications listed, we performed chi-square analysis for dichotomous variables and Kruskal-Wallis for nonparametric data. Receiver operator characteristic curve analysis was performed to identify the MTX level where AKI grade ≥ 2 was more likely. Multivariate logistic regression analysis was performed to identify risk factors for this MTX level.RESULTS:We identified 642 patients with 2,804 cycles of HDMTX. The incidence of AKI was 19.1% with AKI grade ≥ 2 making up 21% of cases. Rates of AKI, ICU admission, and 30-day mortality are associated with elevated 48-hour MTX levels. There was a significant increase in median LOS with elevated MTX levels ( P < .001). Receiver operator characteristic curve analysis for AKI grade ≥ 2 demonstrated a 48-hour MTX level threshold of 1.28 μmol/L. Multivariate logistic regression analysis revealed age, male sex, elevated body surface area, higher MTX dose, monotherapy, and first cycle as independent factors.CONCLUSION:Elevated MTX levels are associated with a significant increased rate of AKI, ICU admission, prolonged LOS, and 30-day mortality. Elevated 48-hour MTX levels, particularly > 1.28 μmol/L, should alert clinicians for complications and to initiate measures to reduce MTX levels.

AbstractPatients with multiple myeloma (MM) have a lower efficacy from COVID‐19 vaccination and a high rate of mortality from COVID‐19 in hospitalized patients. However, the overall rate and severity of COVID‐19 infection in all settings (including non‐hospitalized patients) and the independent impact of plasma cell‐directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID‐19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one‐fourth of the COVID‐19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID‐19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID‐19 infection, without any COVID‐related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID‐19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2–0.8); p = .008].

AbstractPurposeMetallic implants have been correlated to local control failure for spinal sarcoma and chordoma patients due to the uncertainty of implant delineation from computed tomography (CT). Such uncertainty can compromise the proton Monte Carlo dose calculation (MCDC) accuracy. A component method is proposed to determine the dimension and volume of the implants from CT images.MethodsThe proposed component method leverages the knowledge of surgical implants from medical supply vendors to predefine accurate contours for each implant component, including tulips, screw bodies, lockers, and rods. A retrospective patient study was conducted to demonstrate the feasibility of the method. The reference implant materials and samples were collected from patient medical records and vendors, Medtronic and NuVasive. Additional CT images with extensive features, such as extended Hounsfield units and various reconstruction diameters, were used to quantify the uncertainty of implant contours.ResultsFor in vivo patient implant estimation, the reference and the component method differences were 0.35, 0.17, and 0.04 cm3for tulips, screw bodies, and rods, respectively. The discrepancies by a conventional threshold method were 5.46, 0.76, and 0.05 cm3, respectively. The mischaracterization of implant materials and dimensions can underdose the clinical target volume coverage by 20 cm3for a patient with eight lumbar implants. The tulip dominates the dosimetry uncertainty as it can be made from titanium or cobalt–chromium alloys by different vendors.ConclusionsA component method was developed and demonstrated using phantom and patient studies with implants. The proposed method provides more accurate implant characterization for proton MCDC and can potentially enhance the treatment quality for proton therapy. The current proof‐of‐concept study is limited to the implant characterization for lumbar spine. Future investigations could be extended to cervical spine and dental implants for head‐and‐neck patients where tight margins are required to spare organs at risk.

Background: Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes COL4A1/COL4A2 encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats. Methods: We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2–8.3 years) and older (17.0–22.7 years) primates ( M mulatta ) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10–12 months). Results: Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: −0.427, P =0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD ( P <0.017), including age as a covariate and either clinical hypertension ( P <0.030) or neuropathological SVD diagnosis ( P <0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals ( P =0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV. Conclusions: Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV.