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OBJECTIVE Tobacco smoking is among the factors known to significantly augment the risk of untreated intracranial aneurysm (IA) growth and rupture. Smoking appears to have a variable effect on different endovascular treatment modalities. The impact of smoking on the safety, efficacy, and outcomes of Woven EndoBridge (WEB) device use for wide-neck IAs has not been evaluated. This study aimed to investigate the outcomes of WEB devices by smoking status. METHODS A retrospective multicenter analysis was conducted on the data of patients from 36 sites worldwide treated with the WEB device for intracranial saccular aneurysms. Patients were stratified based on smoking status (current, former, and never smokers). The Student t-test and chi-square test were performed for continuous and categorical variables, respectively. Multivariable logistic regression was used to adjust for confounders. RESULTS Of 1376 patients with available smoking status, 504 were current smokers, 358 were former smokers, and 514 were never smokers. Upon adjusting for significant confounders, no association was found between smoking and recurrence outcomes (OR 1.39, 95% CI 0.69–2.80; p = 0.36), thromboembolic and hemorrhagic complications, and mortality among IAs treated with the WEB device. There was no statistically significant difference in outcomes between former and never smokers (OR 1.23, 95% CI 0.70–2.18; p = 0.46). The location of aneurysms differed between smoking groups, with former smokers having more anterior circulation aneurysms compared with current and never smokers (99.0% vs 96.9% vs 95.3%; p = 0.01). In terms of clinical symptoms, headache and dizziness were more common in the never smokers compared with current and former smokers (13.9% vs 8.9% vs 7.7%, p = 0.01). CONCLUSIONS This large-scale study suggests no significant correlation between smoking and the recurrence of IAs treated with the WEB device. Biological studies are warranted to better understand the biological impact of smoking on the growth and rupture of treated IAs.

AbstractBackgroundExternal‐beam radiation (EBRT) is a noninvasive therapeutic alternative to transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The objective of this study was to conduct a systematic review and meta‐analysis of prospective randomized clinical trials to assess the clinical efficacy of EBRT versus TACE for HCC as either a definitive monotherapy or as a bridge to transplantation/surgery.MethodsA systematic review and meta‐analysis were performed to include prospective randomized trials comparing EBRT versus TACE. Data was analyzed with random and fixed‐effects models. The inconsistency index (I2) was chosen to assess heterogeneity. Three publications were included with a total of 142 patients. Outcomes included local control (LC), overall survival (OS), progression‐free survival (PFS), and occurrences of grade ≥3 toxicity. Comparisons are reported as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).ResultsThere were three randomized trials that met inclusion criteria. The EBRT was delivered in three to 15 fractions with a total dose between 30 and 75 gray(Gy). EBRT was associated with significantly improved LC (HR, 0.16; 95% CI, 0.08–0.34; I2 = 0%) and PFS (HR, 0.37; 95% CI, 0.23–0.60; I2, 0%) compared with TACE. There was no significant difference between EBRT and TACE in OS (RR, 0.79; 95% CI, 0.51–1.22; I2 = 0%) or grade ≥3 toxicity (RR, 0.86; 95% CI, 0.31–2.37; I2 = 57%). None of the analyses had statistically significant heterogeneity.ConclusionsCompared with TACE, EBRT yields superior LC and PFS without providing a survival benefit in early and intermediate stage HCC. Additional larger prospective randomized controlled trials should be conducted to further investigate differences in clinical outcomes amongst patients with more advanced disease.

Abstract Recent clinical trials on slowing dementia progression have led to renewed focus on finding safer, more effective treatments. One approach to identify plausible candidates is to assess whether existing medications for other conditions may affect dementia risk. We conducted a systematic review to identify studies adopting a data‐driven approach to investigate the association between a wide range of prescribed medications and dementia risk. We included 14 studies using administrative or medical records data for more than 130 million individuals and 1 million dementia cases. Despite inconsistencies in identifying specific drugs that may modify Alzheimer's or dementia risk, some themes emerged for drug classes with biological plausibility. Antimicrobials, vaccinations, and anti‐inflammatories were associated with reduced risk, while diabetes drugs, vitamins and supplements, and antipsychotics were associated with increased risk. We found conflicting evidence for antihypertensives and antidepressants. Drug repurposing for use in dementia is an urgent priority. Our findings offer a basis for prioritizing candidates and exploring underlying mechanisms. Highlights We present a systematic review of studies reporting association between drugs prescribed for other conditions and risk of dementia including 139 million people and 1 million cases of dementia. Our work supports some previously reported associations, for example, showing decreased risk of dementia with drugs to treat inflammatory disease and increased risk with antipsychotic treatment. Antimicrobial treatment was perhaps more surprisingly associated with decreased risk, supportive of recent increased interest in this potential therapeutic avenue. Our work should help prioritize drugs for entry into adaptive platform trials in Alzheimer's disease and will serve as a useful resource for those investigating drugs or classes of drugs and risk of dementia.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

ImportanceDetermining spectacle-corrected visual acuity (VA) is essential when managing many ophthalmic diseases. If artificial intelligence (AI) evaluations of macular images estimated this VA from a fundus image, AI might provide spectacle-corrected VA without technician costs, reduce visit time, or facilitate home monitoring of VA from fundus images obtained outside of the clinic.ObjectiveTo estimate spectacle-corrected VA measured on a standard eye chart among patients with diabetic macular edema (DME) in clinical practice settings using previously validated AI algorithms evaluating best-corrected VA from fundus photographs in eyes with DME.Design, Setting, and ParticipantsRetrospective cross-sectional evaluation of deidentified fundus photographs matched to spectacle-corrected VA determined by technicians on eye charts among patients with a history of DME based on optical coherence tomography and at least 2 visits within 1 to 6 months of each other at a university-based clinic between January 2014 and December 2022. Data were analyzed from January 2023 to October 2024.ExposurePreviously validated AI algorithm evaluation of fundus photographs.Main Outcomes and MeasuresAI-determined VA mean absolute error (MAE) compared with actual spectacle-corrected VA.ResultsAmong 141 patients, the mean (SD) age was 63 (13) years, 71 (50%) were male, 2 (1%) were Asian, 42 (30%) were Black or African American, and 88 (63%) were White. Among 282 eyes at visit 1, 66 had nonproliferative diabetic retinopathy (NPDR) and DME, 38 had proliferative diabetic retinopathy (PDR) and DME, 101 had NPDR and no DME, and 77 had PDR and no DME. Among 564 images (282 eyes) at both initial and follow-up visits, MAE (SD) among eyes with NPDR, with or without center-involved DME (CI-DME), was 1.16 (1.00) lines on the eye chart for VA between 20/10 and 20/20 (67 images), and 1.44 (1.15) lines for between VA 20/25 and 20/80 (231 images). MAE (SD) among eyes with PDR, with or without CI-DME, was 1.92 (1.08) lines for VA between 20/10 and 20/20 (50 images), and 1.42 (0.97) lines for spectacle-corrected VA between 20/25 and 20/80 (150 images). Only 65 images had VA 20/100 or worse, precluding meaningful analyses.Conclusions and RelevanceIn this cross-sectional study, AI evaluation of fundus photographs among patients with DME and VA 20/80 or better estimated spectacle-corrected VA within approximately 1 to 1.5 lines of actual spectacle-corrected VA. These results support use of AI evaluation of fundus photographs to determine spectacle-corrected VA among patients with DME globally, beyond ophthalmology offices.

Abstract Cholecystectomy (CCY) is the standard treatment for acute cholecystitis. For non-surgical patients, percutaneous cholecystostomy tube (PT-GBD) is recommended but is associated with high readmission rates and poor quality of life. Endoscopic gallbladder decompression techniques, including endoscopic transpapillary gallbladder drainage (ET-GBD) and endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), are alternatives. Studies comparing ET-GBD and EUS-GBD have shown EUS-GBD to have superior outcomes. However, these studies assessed ET-GBD mostly via single transcystic stent placement (SSET-GBD). This study aimed to compare outcomes of dual transcystic stents (DSET-GBD) and EUS-GBD in non-surgical candidates with acute cholecystitis. A multicenter analysis was conducted on patients who underwent ET-GBD or EUS-GBD between January 2019 and January 2023. Data were extracted from electronic medical records and outcomes including technical success, success, adverse events (AEs), and recurrence rates of cholecystitis were measured. Of 129 procedures (56 EUS-GBD; 73 ET-GBD), technical success was achieved in 87.5% of EUS-GBD and 86.3% of ET-GBD attempts. Immediate clinical success was achieved in 98.1% for EUS-GBD and 100% for DSET-GBD. AE rates were similar between the groups. Recurrent cholecystitis rates were 5.3% for EUS-GBD and 8.2% for DSET-GBD (P = 0.692). This study demonstrates that DSET-GBD has similarly low rates of recurrent acute cholecystitis compared with EUS-GBD. DSET-GBD should be considered as an alternative management strategy for management of acute cholecystitis in patients who are unable to undergo CCY.

Abstract The prevalence of clonal hematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. We previously reported gene specific fitness effects in two longitudinal cohorts of aging. We now set out to define fitness effects across three longitudinal cohorts of aging in a total of 713 participants. We found that fitness correlates with timing of mutations, which needs to be taken into account when predicting health outcomes. We show that fitness and the time of mutations are superior predictors of outcomes such as all-cause mortality compared to the commonly used clone size (variant allele frequency). Our new predictor even outperforms age, the most important predictor for the onset of age-related disease thus far. In conclusion, the fitness landscape of mutations and their context in terms of clonal composition and timing of mutation acquisition are important parameters to bring CH predictors into the clinic.

ABSTRACTBackgroundThe role of Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) is still unclear in patients with STEMI undergoing PCI in the current second‐generation DES era.AimsThis study aimed to evaluate the trends and outcomes of IVUS‐guided PCI in patients with STEMI.MethodsWe used the National Inpatient Sample (NIS) database from 2016 to 2021. The primary endpoint of this study is all‐cause in‐hospital mortality. Secondary endpoints include trends of PCI hospitalizations, trends of mortality, length of stay, and cost of hospitalization.ResultsThere were data for 819,645 hospitalizations for STEMI, of which 91.2% (n = 74,7860) utilized angiography‐guided PCI, 8.4% (n = 68,985) utilized IVUS‐guided PCI and 0.3% (n = 2800) utilized OCT‐guided PCI. In‐hospital mortality for IVUS‐guided PCI was 4.6% (n = 3190) versus 6.0% (n = 44,935) for angiography‐guided PCI with an adjusted OR 0.75 (0.68–0.81, p < 0.001). In‐hospital mortality for OCT‐guided PCI was 3.4% (n = 95) versus 6.0% (n = 44,935) for angiography‐guided PCI with an adjusted OR 0.67 (0.43–1.06, p = 0.09).ConclusionsIVUS/OCT‐guidance was increasingly utilized over the years and was associated with a significantly reduced adjusted odds of in‐hospital mortality. Large‐scale, long‐term randomized data are needed to better ascertain where IVUS/OCT may be best utilized for optimization of PCI for STEMI.