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Introduction: Intracranial atherosclerosis (ICAS) is a leading cause of ischemic stroke (IS) worldwide and carries a high risk of recurrence. Current guidelines favor 90 days of dual antiplatelet therapy (DAPT) for severe symptomatic ICAS, but recurrence remain high. Limited data suggest possible benefit of single antiplatelet plus anticoagulation (SAPT+AC). We compared the effectiveness and safety of DAPT versus SAPT+AC. We hypothesized that DAPT would lower 90-day recurrent IS risk without significantly increasing bleeding. Methods: This substudy of the Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) included patients from 35 centers (Jan 2019–Jun 2024) with symptomatic 50–99% ICAS in the intracranial internal carotid, vertebral, basilar, or M1 segment of the MCA, presenting ≤72 hours from last known well. The primary efficacy outcome was recurrent IS in the same vascular territory at 90 days; the primary safety outcome was severe bleeding (symptomatic intracranial hemorrhage or major extracranial bleeding). Categorical variables were compared using χ 2 and continuous variables with the Student's t test; multivariable Cox regression adjusted for key covariates. Results: Of 2050 BIORISK-ICAS patients, 1658 met criteria (DAPT n=1499; SAPT+AC n=159). Mean age was 67 vs. 73 years, and 44% were women. At 90 days, recurrent IS occurred in 121 DAPT patients (8.07%) vs. 13 SAPT+AC patients (8.17%); unadjusted HR 0.83 (95% CI, 0.50–1.36; p=0.46). After adjustment for age, diabetes, coronary heart disease, atrial fibrillation, active smoking, and borderzone infarct, the adjusted HR was 0.99 (95% CI, 0.52–1.86; p=0.97). Severe bleeding occurred in 34 DAPT patients (2.26%) and 5 SAPT+AC patients (3.14%); unadjusted HR 0.79 (95% CI, 0.28–1.85; p=0.50), adjusted HR 0.66 (95% CI, 0.21–2.09; p=0.47). Conclusions: In patients with symptomatic ICAS, DAPT and SAPT+AC were associated with similar risks of 90-day recurrent ischemic stroke and severe bleeding. Well-powered randomized trials are needed to determine the optimal antithrombotic regimen in this high-risk population.

Background and Objectives: Cervical artery dissection (CeAD) is a common cause of ischemic stroke in young adults. We aim to identify age-based differences in clinical presentation, imaging findings, and outcomes after CeAD. Methods: This was a sub-study using the STOP-CAD registry, a multicenter cross-sectional international retrospective study of patients diagnosed with CeAD and treated with an antithrombotic from January 1, 2015 to December 31, 2021. Baseline clinical and imaging characteristics were compared between younger and older adults with CeAD (≤45 versus >45 years of age) using multivariable logistic regression. We chose this age cut off due to its frequent usage in stroke in the young literature. Multiple logistic regression models were used to determine association between young age and outcomes after CeAD (ischemic stroke at 180 days, excellent functional outcome with modified Rankin Scale of 0-1 at 90 days, and mortality) after adjusting for sex, vascular risk factors, CeAD characteristics, and NIHSS on presentation. Results: Among 4023 CeAD patients included in the study, 1901 (47.3%) were ≤45 years of age. Patients were followed for a median of 307 days (IQR 102-831). Young adults with CeAD were more likely to be women (Odds Ratio [OR], 2.4; 95% CI, 2.1-2.9; p<0.001), of Hispanic ethnicity (OR, 1.8; 95% CI 1.3-2.5; p<0.001), have a history of migraines (OR, 1.6; 95% CI, 1.3-2.0; p<0.001) and recent neck trauma (OR, 1.6; 95% CI, 1.3-1.9; p<0.001) while having fewer traditional vascular risk factors. Young adults with CeAD had higher odds of a non-ischemic presentation (OR, 1.3; 95% CI, 1.1-1.5; p=0.013), vertebral artery dissection (OR 2.5; 95% CI, 2.2-3.0; p<0.001), and multivessel involvement (OR 1.5; 95% CI, 1.1-1.9; p=0.004). In adjusted analysis, younger age was not associated with an increased risk of recurrent ischemic stroke (adjusted Hazard Ratio [HR], 0.48; 95% CI 0.2-1.2; p=0.119). Younger age was associated with significantly greater odds of excellent functional outcome at 90 days (aOR, 1.48; 1.20-1.84, p<0.001) and lower risk of death at follow up (aHR, 0.37; 95% CI, 0.17-0.81; p=0.012) after CeAD. Conclusion: In a large international cohort, young adults with CeAD had a distinct clinical phenotype with higher odds of non-ischemic presentation, vertebral artery dissection, and multivessel involvement while having fewer traditional vascular risk factors. Young adults had a decreased odds of disability and mortality after CeAD.

ABSTRACT The goal of this radiomic analysis is to quantify the sensitivity of radiomic features on computed tomography (CT) image pre‐processing parameters and use machine learning (ML) techniques to identify the radiomic features that are highly predictive of shoulder arthroplasty outcomes. An ML framework auto‐segmented 3D masks of the deltoid muscle and scapula bone from pre‐operative CT images of 1949 primary anatomic total shoulder arthroplasty (aTSA)/reverse total shoulder arthroplasty (rTSA) patients. Radiomic features were extracted after various image pre‐processing protocols and assessed for reproducibility. The radiomic features deemed robust to image pre‐processing were used to train ML predictive outcomes models. Feature importance data were rank‐ordered to identify the radiomic features that were highly predictive of pain, motion, and function before and after aTSA/rTSA. A sensitivity analysis identified 37 deltoid muscle and 38 scapular bone radiomic features that were robust, reproducible, and unique across image pre‐processing parameters. The most predictive deltoid muscle radiomic measurements were normalized volume, elongation, flatness, fat percentage, sphericity, and max 2D diameter column. The most predictive scapular bone radiomic measurements were flatness, sphericity, elongation, max 2D diameter column, and max 2D diameter slice. Radiomic data of the deltoid and scapula were highly predictive of pain, motion, and function before and after aTSA and rTSA. Radiomic data were more predictive than patient comorbidities, diagnosis, and implant type/size data, but less predictive than pre‐operative active range of motion measurements and patient reported outcome measures, 3D measurements from planning software, or patient demographic data. Future work is required to clinically validate these radiomic features before they can be deployed in clinical decision support tools. Level of Evidence Level III, Retrospective Comparative Outcome Study.

Background While SARS-CoV-2 vaccines are highly effective in healthy individuals, the magnitude and durability of humoral and cellular responses in patients with solid malignancies receiving chemotherapy remain understudied. Previous reports suggest that patients with cancer may not mount adequate immune response after SARS-CoV-2 vaccination. Additionally, most studies focused on humoral responses, while data regarding cellular immune responses are scarce. In this study, we evaluated humoral and cellular responses in patients with solid tumors receiving chemotherapy compared to healthy individuals up to one year after vaccinations. Methods Patients aged ≥18 who were willing to receive the SARS-CoV-2 vaccine were enrolled. Anti-SARS-CoV-2 immunoassays were used to detect antibodies against nucleocapsid and spike proteins. Human IFN-γ Fluorospot assay was used to determine antigen−specific T-cell responses. Data were compared between groups using Mann−Whitney test for continuous variables and Fisher’s exact test for categorical variables. Results A total of 67 subjects (47 patients with cancer and 20 healthy individuals) were included. 1–3 months following the second vaccine doses, 96% of patients with cancer and 100% of healthy individuals demonstrated a positive humoral response. While the positivity rate was not significantly different, patients with cancer had significantly lower spike IgG antibodies than healthy individuals. However, this difference diminished at 6 months when patients with cancer had increased antibodies compared to decreased antibodies in the healthy cohort and no difference was noticed at 12-month. Patients with cancer developed a similar antigen-specific T-cell response as healthy individuals at 1–3 months, 6 months and 12 months. There were no significant differences when comparing patients aged ≤ 55 years vs. &gt;55 years, stages I-III vs. IV, single vs. multiple chemotherapy, and BNT162b2 vs. mRNA-1273 vaccines. There was a significant moderate correlation between neutralization and antibody levels at 12 months. However, despite patients with cancer having a significantly higher COVID risk score, there were no significant differences in COVID-19 infection and hospitalization between patients with cancer and healthy individuals. Conclusion Despite initial impaired antibody responses to SARS-CoV-2 vaccinations, patients with solid malignancies receiving chemotherapy effectively generated long-term cellular and humoral responses by 6 and 12 months, leading to similar infection and hospitalization rates compared to healthy individuals.

ABSTRACT This manuscript summarizes over 30 years of research that began with the novel concept of using intra‐articular gene transfer to treat joint diseases. A notable milestone in this journey was the first‐in‐human transfer of an exogenous gene to a joint, accomplished by the ex vivo delivery of cDNA encoding the interleukin‐1 receptor antagonist (IL‐1Ra) to joints of patients with rheumatoid arthritis. Responding to lessons learned from this study and the prevailing clinical landscape we next developed an in vivo gene delivery system based on adeno‐associated virus (AAV) with osteoarthritis (OA) as the target disease. The safety and efficacy of this vector, sc‐rAAV2.5IL‐1Ra, was demonstrated in the joints of rats and horses leading to a successful IND application to the FDA. In this clinical trial (ClinicalTrials. gov Identifier: NCT02790723) sc‐rAAV2.5IL‐1Ra was injected at escalating doses into the knee joints of nine patients with OA who were followed for 1 year. This trial met its primary outcome measure, safety, and demonstrated that sustained expression of transgenic IL‐1Ra was possible after a single injection of the vector. Patient‐reported outcomes improved, but without a control group it is not possible to determine the influence of a placebo effect. This and other unresolved matters are addressed in a recently‐completed Phase Ib trial (ClinicalTrials. gov Identifier: NCT05835895). Beyond OA, sc‐rAAV2.5IL‐1Ra has potential therapeutic value in a variety of degenerative, inflammatory, fibrotic and autoimmune conditions. More generally, gene therapy holds much promise in the field of regenerative medicine, including regenerative orthopaedics. Trial Registration: (ClinicalTrials. gov Identifier: NCT02790723, NCT05835895).

ABSTRACT Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) can reduce seizures in patients with drug-resistant epilepsy. However, seizure freedom is rare, and there is no early response biomarker to predict long-term seizure suppression. To evaluate a short-term biomarker of therapeutic response to DBS, we studied 18-minute trials of ANT stimulation in patients with drug-resistant epilepsy undergoing intracranial electroencephalography. We compared a standard high-frequency periodic versus a non-periodic pulse pattern. We found that short-term ANT stimulation within the clinically used amplitude range preferentially altered the first 150 ms of anterograde ANT to anterior cingulate and superior frontal connectivity. Non-periodic ANT stimulation selectively modified early cortico-cortical evoked potentials more than periodic stimulation, and these changes were driven by the response phase. These pattern-specific changes in connectivity between the ANT and spatially restricted cortical areas suggest differing mechanisms and are a promising biomarker for patients being treated with ANT-DBS.

PURPOSE Hot flashes are a common side effect reported by men receiving androgen-deprivation therapy (ADT) for the treatment of prostate cancer. We sought to determine whether oxybutynin could improve hot flash symptoms in men with prostate cancer. PATIENTS AND METHODS Patients with prostate cancer receiving a stable regimen of ADT with at least 28 hot flashes per week were randomly assigned to receive either oxybutynin 2.5 mg twice daily, oxybutynin 5 mg twice daily, or matching placebo for 6 weeks. The primary end point was the change in patient-reported hot flash scores since baseline at 6 weeks. Additional outcomes included incidence of adverse events (AEs), changes since baseline in Hot Flash–Related Daily Interference Scale (HFRDIS) scores, and patient-reported symptoms. RESULTS Eighty-eight patients were enrolled, with the 81 participants eligible for final analysis reporting an average of 10.1 (standard deviation [SD], 5.55) hot flashes per day and an average daily hot flash score of 18.2 (SD, 13.5) included in final analysis. On average, patients on the placebo arm, 2.5 mg oxybutynin arm, and 5 mg oxybutynin arm had reductions in hot flashes/day of 2.15, 4.77 ( P = .02), and 6.89 ( P < .001), respectively. Daily hot flash scores for placebo, 2.5 mg oxybutynin, and 5 mg oxybutynin reduced by an average of 4.85, 9.94 ( P = .07), and 13.95 ( P = .002) points, respectively. No treatment-related grade 3+ AEs occurred. HFRDIS total scores improved by 14.2 and 20.7 points in the 2.5 mg ( P = .042) and 5 mg ( P < .01) oxybutynin arms, respectively, compared with a 3.1-point improvement with placebo. CONCLUSION Oxybutynin is superior to a placebo for the management of ADT-associated hot flashes in men with prostate cancer.

Background: Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare, high-grade, and aggressive tumor of the sinonasal tract. Due to the rarity of this malignancy, current treatment guidelines are based on small and often/mainly single-center retrospective datasets. In the absence of a universally accepted standard of care for SNUC, treatment approaches vary across countries and institutions, reflecting real-world clinical practice. The primary aim of this study was to describe real-world treatment and outcomes for patients with confirmed SNUC. Methods: This was an international, multi-center, retrospective, observational cohort study that pooled patients into the largest SNUC dataset to date. Fifteen centers were enrolled to contribute data, including seven from Europe, four from the United States, three from the United Kingdom, and one from Canada. In the absence of a universally accepted standard of care for SNUC, treatment approaches varied across countries and institutions, reflecting real-world clinical practice. Patients included were those with histologically confirmed SNUC who were treated between 1997 and 2021. Results: This study yielded 485 patients treated for SNUC. The median age at diagnosis was 55.6 years (IQR: 44.5–67.6), and 63.7% were male. Most cases presented at advanced stages, with 70.8% as T4a or T4b. Overall survival (OS) outcomes were available for 412 patients, with a median follow-up of 26.0 months. The 5- and 10-year OS were 47.2% (95% CI: 40.8–53.3%) and 39.6% (95% CI: 32.5–46.6%), respectively. Advanced age, dichotomized T-stage (T4a/b vs. T1–3), M-stage, and orbital involvement were significant poor prognostic factors on univariable analysis (p’s < 0.01). On multivariable analysis, orbital involvement (HR: 2.73, 95% CI: 1.42–5.27, p = 0.003) and distance metastasis stage (HR: 3.00, 95% CI: 1.25–7.21, p = 0.014) were both independently associated with worse OS. Conclusions: This observational study presents the largest multi-center cohort analysis of SNUC to date, providing new insights into prognostic factors for a rare cancer treated at global centers of excellence. Orbital involvement and the presence of metastases are candidate independent risk factors associated with poorer OS.

Variability and persistent gaps in reporting have been consistently observed across studies evaluating adverse events in healthcare, dating back to the early days of the patient safety movement. Incomplete descriptions—particularly missing details regarding study design, conduct, methodologies and applied definitions—impede interpretation, hinder critical appraisal and limit reproducibility. These deficiencies not only obstruct a shared understanding of findings but also diminish the overall impact such studies may have on patient safety initiatives and policy development. To address these challenges and enhance the quality of reporting, we developed the SESAME (Standard Elements in Studies of Adverse Events and Medical Error) reporting guideline. SESAME is a 44-item checklist designed to support comprehensive and standardised reporting in studies evaluating potential patient harm. The guideline was developed over a 2-year period by an international, multidisciplinary panel through a consensus-driven process aligned with Enhancing the QUAlity and Transparency Of Health Research Network standards.