Citations

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

AbstractNeutralizing antispike monoclonal antibody (mAb) therapies were highly efficacious in preventing coronavirus disease 2019 (COVID‐19) hospitalization. While severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants may harbor spike protein mutations conferring reduced in vitro susceptibility to these antibodies, the effect of these mutations on clinical outcomes is not well characterized. We conducted a case–control study of solid organ transplant recipients who received an antispike mAb for treatment of mild‐to‐moderate COVID‐19 and had an available sample from initial COVID‐19 diagnosis for genotypic sequencing. Patients whose SARS‐CoV‐2 isolate had at least one spike codon mutation conferring at least fivefold decreased in vitro susceptibility were classified as resistant. Overall, 9 of 41 patients (22%) had at least one spike codon mutation that confers reduced susceptibility to the antispike mAb used for treatment. Specifically, 9 of 12 patients who received sotrovimab had S371L mutation that was predicted to confer a 9.7‐fold reduced susceptibility. However, among 22 patients who required hospitalization, 5 had virus with resistance mutation. In contrast, among 19 control patients who did not require hospitalization, 4 also had virus‐containing resistance mutations (p > 0.99). In conclusion, spike codon mutations were common, though mutations that conferred a 9.7‐fold reduced susceptibility did not predict subsequent hospitalization after treatment with antispike mAb.

Introduction: Prior AF screening trials demonstrated low yield, highlighting the need for more targeted approaches. An AI algorithm was developed to identify ECG signatures of AF risk during normal sinus rhythm, which has been validated in diverse external populations. Hypothesis: An AI-guided, targeted screening approach could improve the diagnosis of AF. Methods We conducted a pragmatic decentralized trial to prospectively recruit patients with stroke risk factors but no prior AF. The AI algorithm was applied to the ECGs performed in routine practice and divided patients into high- or low-risk groups. The primary endpoint was AF lasting ≥ 30 seconds on a subsequent 30-day continuous cardiac rhythm monitor. In a secondary analysis, trial participants were 1:1 propensity score-matched to real-world controls derived from the eligible but unenrolled population. Results A total of 1,003 patients from 40 U.S. states completed the study, with a mean age of 74 [SD 8.8] years. Over a mean of 22.3 days of continuous monitoring, AF was detected in 6 (1.6%) of low-risk patients and 48 (7.6%) of high-risk patients (OR 4.98 [2.11-11.75], p<0.001). Compared to usual care, AI-guided AF screening was associated with increased detection of AF (high-risk group: 4.2% vs. 11.1%, p<0.001; low-risk group: 0.9% vs. 2.4%, p=0.12) over a median follow-up of 10 months. Conclusions A prospective pragmatic study found that the AI a can risk-stratify a relatively uniform population (i.e., older adults at risk for stroke) to detect AF during short-term cardiac monitoring. Furthermore, when compared with usual care, AI-guided cardiac monitoring was associated with increased AF detection. As such, an AI-guided AF screening approach, leveraging existing EHR data and infrastructure, could be effective, patient-centered, and massively scalable, thereby reducing unnecessary health utilization and diagnosis-related anxiety (Clinicaltrials.gov: NCT04208971).

Abstract Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.

Background: Our understanding of the risk factors for and effectiveness of prophylactic measures against shoulder periprosthetic joint infections (PJIs) continues to evolve. This study’s objective was to study patient characteristics, procedural characteristics, and various infection prophylactic measures and their effects on the risk of shoulder PJI after primary arthroplasty. Methods: Nine hundred and ninety-eight patients in a longitudinally maintained, single-institution shoulder arthroplasty database who had at least 2 years of clinical follow-up were retrospectively reviewed. Patient and procedural characteristics were collected. Perioperative variables, including the use of intraoperative antibiotics, topical antibiotics, antibiotic-containing irrigation solution, and a postoperative drain, were collected. Patients who developed shoulder PJI were compared with those without shoulder PJI to identify any association with patient or procedural characteristics. Results: Of the 998 patients, 20 (2.0%) met the criteria for shoulder PJI. Cutibacterium was identified as the causative organism in 19 (95%) of 20 culture-positive reoperations. On univariate analysis, patients in the PJI group were more likely to be younger (p < 0.001), to be male (p = 0.014), to have commercial insurance (p = 0.003), to use alcohol (p = 0.048), and to have had a ream-and-run or hemiarthroplasty procedure (p = 0.005). On multivariable analysis, older age was independently associated with a lower risk of PJI (odds ratio [OR] per year = 0.95; 95% confidence interval [CI], 0.91 to 0.99; p = 0.014). Reverse total shoulder arthroplasty (OR, 10.32; 95% CI, 0.92 to 116.33; p = 0.059) and hemiarthroplasty (OR, 8.59; 95% CI, 0.86.30 to 85.50; p = 0.067) trended toward a higher risk of PJI. Conclusions: Younger patients and patients undergoing procedures other than anatomic total shoulder arthroplasty are at higher risk for shoulder PJI. The majority of culture-positive reoperations were a result of Cutibacterium species. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Ream-and-run arthroplasty can improve pain and function in patients with glenohumeral arthritis while avoiding the complications and activity restrictions associated with a prosthetic glenoid component. However, stiffness is a known complication after ream-and-run arthroplasty and can lead to repeat procedures such as a manipulation under anesthesia (MUA) or open surgical revision. The objective of this study was to determine risk factors associated with repeat procedures indicated for postoperative stiffness after ream-and-run arthroplasty. Methods: We conducted a retrospective review of our shoulder arthroplasty database to identify patients who underwent ream-and-run arthroplasty and determined which patients underwent subsequent repeat procedures (MUA and/or open revision) indicated for postoperative stiffness. The minimum follow-up was 2 years. We collected baseline demographic information and preoperative and 2-year patient-reported outcome scores and analyzed preoperative radiographs. Univariate and multivariate analyses determined the factors significantly associated with repeat procedures to treat postoperative stiffness. Results: There were 340 patients who underwent ream-and-run arthroplasty. The mean Simple Shoulder Test (SST) scores for all patients improved from 5.0 ± 2.4 preoperatively to 10.2 ± 2.6 postoperatively (p < 0.001). Twenty-six patients (7.6%) underwent open revision for stiffness. An additional 35 patients (10.3%) underwent MUA. Univariate analysis found younger age (p = 0.001), female sex (p = 0.034), lower American Society of Anesthesiologists (ASA) class (p = 0.045), posterior decentering on preoperative radiographs (p = 0.010), and less passive forward elevation at the time of discharge after ream-and-run arthroplasty (p < 0.001) to be significant risk factors for repeat procedures. Multivariate analysis found younger age (p = 0.040), ASA class 1 compared with class 3 (p = 0.020), and less passive forward elevation at discharge (p < 0.001) to be independent risk factors for repeat procedures. Of the patients who underwent open revision for stiffness, 69.2% had multiple positive cultures for Cutibacterium. Conclusions: Younger age, ASA class 1 compared with class 3, and less passive forward elevation in the immediate postoperative period were independent risk factors for repeat procedures to treat postoperative stiffness after ream-and-run arthroplasty. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

AbstractBackgroundWe identify chronic rhinosinusitis (CRS) manifestations associated with how rhinologists assess CRS control, with a focus on patient perspectives (patient‐reported CRS control).MethodsFifteen rhinologists were provided with real‐world data from 200 CRS patients. Participating rhinologists first classified patients’ CRS control as “controlled,” “partly controlled,” and “uncontrolled” using seven CRS manifestations reflecting European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) CRS control criteria (nasal obstruction, drainage, impaired smell, facial pain/pressure, sleep disturbance, use of systemic antibiotics/corticosteroids in past 6 months, and nasal endoscopy findings) and patient‐reported CRS control. They then classified patients’ CRS control without knowledge of patient‐reported CRS control. Interrater reliability and agreement of rhinologist‐assessed CRS control with patient‐reported CRS control and EPOS guidelines were determined.ResultsCRS control classification with and without knowledge of patient‐reported CRS control was highly consistent across rhinologists (κw = 0.758). Rhinologist‐assessed CRS control agreed with patient‐reported CRS control significantly better when rhinologists had knowledge of patient‐reported CRS control (κw = 0.736 vs. κw = 0.554, p < 0.001). Patient‐reported CRS control, nasal obstruction, drainage, and endoscopy findings were most strongly associated with rhinologists’ assessment of CRS control. Rhinologists’ CRS control assessments weakly agreed with EPOS CRS control guidelines with (κw = 0.529) and without (κw = 0.538) patient‐reported CRS control. Rhinologists classified CRS as more controlled than EPOS guidelines in almost 50% of cases.ConclusionsThis study directly demonstrates the importance of patient‐reported CRS control as a dominant influence on rhinologists’ CRS control assessment. Knowledge of patient‐reported CRS control may better align rhinologists’ CRS control assessments and treatment decisions with patients’ perspectives.

Background: A recent subanalysis of the EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) suggests a stronger benefit of early rhythm control (ERC) in patients with atrial fibrillation and a high comorbidity burden when compared to patients with a lower comorbidity burden. Methods: We identified 109 739 patients with newly diagnosed atrial fibrillation in a large United States deidentified administrative claims database (OptumLabs) and 11 625 patients in the population-based UKB (UK Biobank). ERC was defined as atrial fibrillation ablation or antiarrhythmic drug therapy within the first year after atrial fibrillation diagnosis. Patients were classified as (1) ERC and high comorbidity burden (CHA 2 DS 2 -VASc score ≥4); (2) ERC and lower comorbidity burden (CHA 2 DS 2 -VASc score 2–3); (3) no ERC and high comorbidity burden; and (4) no ERC and lower comorbidity burden. Patients without an elevated comorbidity burden (CHA 2 DS 2 -VASc score 0–1) were excluded. Propensity score overlap weighting and cox proportional hazards regression were used to balance patients and compare groups for the primary composite outcome of all-cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction as well as for a primary composite safety outcome of death, stroke, and serious adverse events related to ERC. Results: In both cohorts, ERC was associated with a reduced risk for the primary composite outcome in patients with a high comorbidity burden (OptumLabs: hazard ratio, 0.83 [95% CI 0.72–0.95]; P =0.006; UKB: hazard ratio, 0.77 [95% CI, 0.63–0.94]; P =0.009). In patients with a lower comorbidity burden, the difference in outcomes was not significant (OptumLabs: hazard ratio, 0.92 [95% CI, 0.54–1.57]; P =0.767; UKB: hazard ratio, 0.94 [95% CI, 0.83–1.06]; P =0.310). The comorbidity burden interacted with ERC in the UKB (interaction- P =0.027) but not in OptumLabs (interaction- P =0.720). ERC was not associated with an increased risk for the primary safety outcome. Conclusions: ERC is safe and may be more favorable in a population-based sample of patients with high a comorbidity burden (CHA 2 DS 2 -VASc score ≥4).

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .