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Importance The Implantable Neurostimulator for the Treatment of Parkinson’s Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). Objective To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. Design, Setting, and Participants This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson’s Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. Intervention Bilateral STN-DBS for moderate to advanced PD. Main Outcomes and Measures Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. Results A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-II improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. Conclusions and Relevance Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.

Abstract Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

Abstract Background Breast cancer genome-wide association studies (GWAS) have identified more than 200 susceptibility loci, but most studies are dominated by European and East Asian populations. Methods We analyzed breast cancer GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR), and Hispanic/Latina (H/L) samples (159,297 cases and 212,102 controls). We estimated logit-scale SNP-based heritability, polygenicity, and cross-ancestry genetic correlation, partitioned heritability across functional annotations, and integrated GWAS results with the Tabula Sapiens single-cell atlas using scDRS+. Results The logit-scale heritability of breast cancer ranged from ℎ 2 =0.47 (SE = 0.07) in EAS to AFR ℎ 2 =0.61 (SE = 0.10), with no significant differences across ancestries (p=0.63). The estimated number of susceptibility markers in a sparse normal-mixture effects model also varied from 4,446 (SE = 3,100) in EAS to 8,308 (SE = 2,751) in AFR, but differences were not significant across ancestries (p=0.55). Cross-sample genetic correlations varied, with the strongest correlation between EUR and EAS (𝜌 = 0.79, SE = 0.08) and weakest between AFR and H/L (𝜌 = 0.26, SE = 0.24). Regulatory annotations were enriched for breast cancer heritability across samples. Integration with single-cell expression profiles implicated ancestry-shared associations with innate immune, secretory epithelial, and stromal cell types. Conclusion These results indicate substantial cross-ancestry sharing of breast cancer polygenic architecture, highlight a consistent contribution of regulatory variation, and identify convergent cellular contexts that motivate functional follow-up and inform expectations for the transferability and attainable performance of common-variant risk prediction across populations.

Abstract Background and Aims The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy vs medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. Methods The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR, and randomized 2:1 to TTVR (n = 267) or control (n = 133). In a post hoc analysis, patients were stratified into severe TR (n = 172) and massive/torrential TR (n = 220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan–Meier estimates for all-cause mortality and heart failure (HF) hospitalization assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. Results One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe {1.64 [95% confidence interval (CI): 1.11, 2.43]} and massive/torrential [2.20 (1.55, 3.14)]. At 18 months, TTVR patients had similar mortality to controls [rate difference: severe 0.2% (−11.6, 11.9), massive/torrential −5.8% (−17.6, 6.0)], whereas HF hospitalization rates favoured TTVR in the massive/torrential cohort [vs control, severe 9.8% (−3.0, 22.7), massive/torrential -15.2% (−28.9, −1.5)]. Conclusions Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.

BACKGROUND: This individual participant data meta-analysis aimed to determine whether time to treatment influences the effect of intraarterial thrombolysis (IAT), intravenous thrombolysis, and conservative standard therapy on visual outcomes in nonarteritic central retinal artery occlusion. METHODS: We searched MEDLINE, CENTRAL, and Embase up to June 2023 for studies reporting treatment modality and peri-treatment best-corrected visual acuity (BCVA) for ≥5 participants, excluding patients with nonsevere vision loss (BCVA <1.0 logarithm of the minimum angle of resolution [logMAR]) or treated after 24 hours of symptom onset. The primary outcome was recovery from severe vision loss (final BCVA <1.0 logMAR). We used mixed-effect models and local polynomial regression to investigate nonlinear relationships between time to treatment and recovery from severe vision loss. RESULTS: Of 4074 screened studies, individual participant data were sought from 52, with 35 contributing individual participant data for 1038 participants. In total, 783 patients met inclusion criteria (age, 64.8±13.3 years; 35.5% female; baseline BCVA, 2.3±0.5 logMAR). For every hour decrease in time to treatment, thrombolysis was associated with greater improvement in BCVA (intraarterial, 0.02 logMAR [95% CI, 0–0.04]; intravenous, 0.04 logMAR [95% CI, 0.00–0.07]) than conservative standard therapy (0.01 logMAR [95% CI, 0–0.02]). A nonlinear relationship was detected for intraarterial thrombolysis with a changepoint at 8 hours (95% CI, 6.7–9.4). Thrombolysis was associated with increased recovery from severe vision loss compared with conservative standard therapy (intraarterial within 6 hours: odds ratio, 2.72 [95% CI, 1.02–7.28], 27.2% versus 12.0%; intravenous within 4.5 hours: odds ratio, 3.32 [95% CI, 1.24–8.92], 28.8% versus 11.1%). Findings were consistent in subgroup analysis restricted to patients receiving recombinant tissue-type plasminogen activator. Monte-Carlo simulations showed that a randomized controlled trial would require 95 participants per group to achieve 80% power to detect an odds ratio of 3.0 for recovery from severe vision loss. CONCLUSIONS: Early intervention in nonarteritic central retinal artery occlusion is associated with improvement in visual recovery, with intraarterial thrombolysis and intravenous thrombolysis outperforming nonthrombolytic treatments. These findings warrant confirmation in sufficiently powered randomized controlled trials.

Background/Objectives: Transcatheter aortic valve replacement (TAVR) has been introduced as an optimal treatment for patients with severe aortic stenosis, offering a minimally invasive alternative to surgical aortic valve replacement. Predicting these outcomes following TAVR is crucial. Artificial intelligence (AI) has emerged as a promising tool for improving post-TAVR outcome prediction. In this systematic review and meta-analysis, we aim to summarize the current evidence on utilizing AI in predicting post-TAVR outcomes. Methods: A comprehensive search was conducted to evaluate the studies focused on TAVR that applied AI methods for risk stratification. We assessed various ML algorithms, including random forests, neural networks, extreme gradient boosting, and support vector machines. Model performance metrics—recall, area under the curve (AUC), and accuracy—were collected with 95% confidence intervals (CIs). A random-effects meta-analysis was conducted to pool effect estimates. Results: We included 43 studies evaluating 366,269 patients (mean age 80 ± 8.25; 52.9% men) following TAVR. Meta-analyses for AI model performances demonstrated the following results: all-cause mortality (AUC = 0.78 (0.74–0.82), accuracy = 0.81 (0.69–0.89), and recall = 0.90 (0.70–0.97); permanent pacemaker implantation or new left bundle branch block (AUC = 0.75 (0.68–0.82), accuracy = 0.73 (0.59–0.84), and recall = 0.87 (0.50–0.98)); valve-related dysfunction (AUC = 0.73 (0.62–0.84), accuracy = 0.79 (0.57–0.91), and recall = 0.54 (0.26–0.80)); and major adverse cardiovascular events (AUC = 0.79 (0.67–0.92)). Subgroup analyses based on the model development approaches indicated that models incorporating baseline clinical data, imaging, and biomarker information enhanced predictive performance. Conclusions: AI-based risk prediction for TAVR complications has demonstrated promising performance. However, it is necessary to evaluate the efficiency of the aforementioned models in external validation datasets.

Pancreatogenic or type 3c diabetes, which occurs as a consequence of pancreatitis, may have several mechanisms. Mechanisms overlapping with those of type 2 diabetes have been explored, including insulin resistance and insulin deficiency. However, autoimmune mechanisms in response to unmasking β-cell antigens, similar to those of type 1 diabetes (T1D), have not been thoroughly examined. We performed cross-sectional T1D autoantibody profiling in a large prospective cohort (N = 927) of adults with acute, recurrent acute, or chronic pancreatitis. We examined correlations of prevalence of autoantibodies against GAD (GAD antibody), IA-2 (IA-2 antibody), zinc transporter 8 (ZnT8; ZnT8 antibody), and insulin (insulin autoantibody [IAA]) with clinical and demographic features, including presence of diabetes, diabetes treatment, and family history of diabetes. Diabetes was present in 11 (12%) of 94 participants with acute pancreatitis, 69 (27%) of 273 with recurrent acute pancreatitis, and 235 (43%) of 560 with chronic pancreatitis. Among these groups, islet autoantibodies were respectively found in five (5.3%) of 94, 48 (17.6%) of 273, and 127 (22.6%) of 560. The proportions of individuals with diabetes who were autoantibody positive were 45%, 70%, and 54%, respectively (most commonly IAA, which may reflect exogenous insulin use). However, across the entire cohort, 27 participants (2.9%) had two, two (0.2%) had three, and one (0.1%) had four T1D-associated autoantibodies, respectively, suggesting a potential pathogenic link that should be further explored. ARTICLE HIGHLIGHTS Type 1 diabetes–associated autoimmune mechanisms have not been thoroughly examined in pancreatitis-associated diabetes. We assessed the prevalence of four islet autoantibodies in serum from a large prospective cohort of patients with acute, recurrent acute, or chronic pancreatitis. Diabetes was present in 11 (12%) of 94 participants with acute pancreatitis, 69 (27%) of 273 with recurrent acute pancreatitis, and 235 (43%) of 560 with chronic pancreatitis. Excluding those with only insulin autoantibody positivity, which is confounded by insulin treatment, islet autoantibodies were identified in 51 (5.5%) of 927 participants, and 30 (3.2%) of 297 were positive for two or more autoantibodies. Our findings suggest pancreatitis may elicit islet autoimmunity in a subset of patients, necessitating prospective longitudinal follow-up.

Similar to the general population, people with epilepsy (PWE) will often have multiple medical issues that may impact their care. It is therefore important for epilepsy clinicians to be aware of these issues to optimize treatment and quality of life outcomes. In this review, we discuss cardiovascular and respiratory as well as infectious disorders in PWE. We also examine autoimmune disorders and outline reproductive and sexual health issues.