Citations

Abstract Objectives To compare the efficacy and safety of pharmacologic therapies for spontaneous epistaxis in hereditary hemorrhagic telangiectasia (HHT). Data Sources PubMed, Scopus, Embase, Web of Science, and the Cochrane Library were systematically searched up to August 2025. Review Methods Eligible randomized controlled trials evaluating bevacizumab, doxycycline, tranexamic acid, or β‐blockers versus placebo or standard care were included. Outcomes included epistaxis frequency and duration, hemoglobin (Hb), epistaxis severity score (ESS), transfusion or emergent‐care requirements, quality of life (QOL), and adverse events. Results Tranexamic acid did not significantly reduce epistaxis duration or frequency or improve Hb, and it did not change transfusion or emergent‐care needs, but it increased diarrhea (odds ratio 3.8, 95% confidence interval [CI] [1.7; 8.5]). Bevacizumab produced a modest reduction in epistaxis frequency (standardized mean difference −0.25, 95% CI [−0.47; −0.02]), without significant effects on duration, ESS, Hb, or QOL. Doxycycline showed no significant benefit for duration or frequency. Topical or systemic β‐blockers did not significantly affect ESS, QOL, Hb, or overall adverse events. Across agents, between‐study heterogeneity was generally low to moderate and CIs were wide, reflecting limited sample sizes. Conclusion No pharmacologic agent demonstrated consistent, clinically robust superiority over placebo across primary endpoints. Bevacizumab may modestly reduce bleeding burden, whereas tranexamic acid increases gastrointestinal toxicity without clear efficacy. Pharmacologic control of HHT‐related epistaxis remains suboptimal, underscoring the need for adequately powered trials with standardized outcome measures and optimized dosing and delivery strategies.

Background. The VPS35 p.D620N variant causes autosomal dominant Parkinson's disease (PD) and has been shown to activate the LRRK2 kinase pathway, resulting in increased Rab substrate phosphorylation in peripheral immune cells and elevated urinary bis(monoacylglycero)phosphate (BMP) levels. Recently, a VPS35 variant of unknown significance (c.959C>T; p.A320V) was described in two late-onset sporadic PD patients. Methods. We ascertained a family from the Canary Islands in which six siblings were chronically exposed to high doses of pesticides. Three siblings developed levodopa-responsive, akinetic-rigid PD, while the other three remained unaffected. Whole-exome sequencing was performed in the three affected siblings. The frequency of the resulting candidate variant was assessed in 23,327 PD patients and 9,235 controls from four independent cohorts. Members of this pedigree and unrelated controls were assessed for LRRK2 kinase activity in monocytes and neutrophils and BMP levels in urine. Results. The three affected siblings were all heterozygous for p.A320V, whereas the three unaffected siblings did not carry the variant. In the combined PD case-control cohort, p.A320V was identified in six patients and one control. However, unlike p.D620N, heterozygous carrier status for p.A320V was not associated with increased LRRK2 kinase activity or elevated urine BMP levels. Conclusions. While VPS35 p.A320V co-segregated with PD in this family, it did not exhibit the characteristic LRRK2-associated biomarker signature observed in VPS35 p.D620N carriers. It is possible that p.A320V exerts a subtle effect on VPS35 function that was not captured by the assays performed and that chronic pesticide exposure contributed to disease penetrance in this pedigree.

ABSTRACT Many real‐world patients with advanced biliary tract cancer (BTC) are excluded by TOPAZ‐1 criteria; this study assessed cisplatin and gemcitabine plus durvalumab (CGD) efficacy and safety in these patients. Data from 1358 patients with advanced BTC treated with first‐line CGD across 55 international centers were retrospectively analyzed. Patients were classified as TOPAZ‐1‐in (meeting all inclusion criteria) or TOPAZ‐1‐out (meeting ≥ 1 exclusion criterion). Primary endpoints were overall survival (OS) and progression‐free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Furthermore, OS and PFS of the TOPAZ‐1‐out cohort were compared with reconstructed survival data from the phase III trial. 912 (67.1%) patients were classified as TOPAZ‐1‐in , and 446 (32.9%) as TOPAZ‐1‐out . After a median follow‐up of 14.5 months (95% CI: 13.7–36.5), OS was 16.1 months in TOPAZ‐1‐in and 12.5 months in TOPAZ‐1‐out (HR 0.69, 95% CI: 14.6–16.5, p = 0.0001); PFS was 8.2 versus 6.5 months (HR 0.73, 95% CI: 7.1–8.1, p < 0.0001). Median OS in the TOPAZ‐1‐out cohort (12.5 months) was nearly identical to the phase III trial experimental arm (12.9 months; HR 1.15, p = 0.13); for PFS the HR was 1.12 (95% CI 0.93–1.42; p = 0.09). Among TOPAZ‐1‐out patients, active infection, elevated bilirubin, and ECOG PS > 1 were linked to poorer OS, while no detrimental impact emerged for ALT/AST abnormalities, corticosteroid use, renal or hematologic parameters, or prior surgery within 6 months, suggesting treatment effectiveness was broadly maintained across clinical subgroups. Furthermore, TOPAZ‐1‐out patients experienced no significant increase in adverse events compared with the TOPAZ‐1‐in group. Real‐world data suggest CGD may be effective in TOPAZ‐1‐out patients, with no evident increase in toxicity, supporting the potential expanded use of the regimen in clinical practice.

Background/Objectives: The objective of this study was to evaluate age-specific effects of intraoperative platelet-rich plasma (PRP) administration on postoperative pain, wound healing, and bleeding after tonsillectomy. Methods: PubMed, Embase, Scopus, Google Scholar, and Cochrane databases were searched from inception to October 2025. Randomized controlled trials comparing intraoperative PRP with placebo or no treatment in patients undergoing tonsillectomy were included. Data on postoperative pain, wound healing, and bleeding were extracted and analyzed using standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses were performed by age (adults versus children) and by postoperative day. Results: Nine randomized controlled trials comprising 442 participants were included. In adults, PRP significantly reduced postoperative pain (SMD = −1.26 [−1.70 to −0.81]) and improved wound healing (SMD = −1.43 [−2.65 to −0.22]). The analgesic effect was greatest during the early recovery period (postoperative days 0–5) and diminished thereafter. There were no significant differences in primary postoperative bleeding (OR = 0.49 [0.04 to 5.61]) or secondary postoperative bleeding (OR = 0.23 [0.02 to 2.16]) between the PRP and control groups. In children, PRP did not significantly affect pain or bleeding outcomes. Conclusions: Intraoperative PRP may reduce early postoperative pain and may promote mucosal recovery in adults. However, its clinical efficacy in children remains unclear. Further well-designed, age-stratified trials are warranted to clarify the role of PRP in enhancing postoperative recovery.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

ABSTRACT Surgery after response to first‐line chemoimmunotherapy may offer a potential curative option for patients with locally advanced biliary tract cancer (BTC) initially considered unresectable. However, robust real‐world evidence in this setting remains limited. We retrospectively analyzed patients with locally advanced BTC treated with first‐line cisplatin, gemcitabine, and durvalumab (CGD) across 55 centers in 12 countries. Endpoints included overall survival (OS), progression‐free survival (PFS), disease‐free survival (DFS) among resected patients, objective response rate (ORR), and the prognostic impact of surgery. A multivariable logistic regression model was developed to predict surgical conversion using baseline clinical and laboratory variables. Among 1358 screened patients, 219 had locally advanced disease and were included in the analysis. Median follow‐up was 14.5 months. ORR was 34.6%, with median PFS and OS of 10.0 and 20.7 months, respectively. Twenty‐four patients (10.9%) underwent surgical resection after systemic therapy. Median OS was 22.5 months in resected patients versus 19.9 months in those who did not undergo surgery. Median DFS after resection was 15.8 months. Pathological lymph node involvement was independently associated with shorter DFS. Larger baseline tumor size correlated with higher odds of radiological response but not with OS. An exploratory elastic‐net model retained four baseline variables and showed moderate discriminative ability for surgical conversion, with an apparent AUC of 0.72 and an optimism‐corrected AUC of 0.65. First‐line CGD enabled secondary resection in approximately 11% of patients with locally advanced BTC. A simple baseline model may support patient selection for conversion surgery, although prospective validation is needed.

An exhalation delivery system for fluticasone (EDS-FLU) is designed to deposit drug into sinonasal regions above the inferior turbinate, particularly sinus drainage pathways not reached by standard nasal steroid sprays. We evaluated the efficacy and safety of EDS-FLU for chronic rhinosinusitis (CRS). We reviewed four independent randomized controlled trials derived from three published articles identified through searches of PubMed, Embase, SCOPUS, Google Scholar, Web of Science, and the Cochrane Library up to April 2024. Outcomes included 22-item Sinonasal Outcome Test (SNOT-22) scores, nasal symptom scores, nasal polyp scores, patient global impression of change (PGIC), responder and surgical indication rates, and adverse events. Compared with EDS-placebo, EDS-FLU produced greater reductions in nasal polyp scores and SNOT-22 scores over 6 months. At 3 months, nasal congestion, facial pain, rhinorrhea, and olfactory dysfunction improved more with EDS-FLU, and PGIC responder and complete response rates were higher at 3 and 6 months. EDS-FLU reduced surgical indication and increased overall responder rates at 3 months but not at 6 months. Epistaxis and nasal septal erosion or ulceration occurred more frequently with EDS-FLU, whereas rates of headache, nasal congestion, nasopharyngitis, and upper respiratory infection were similar between groups. EDS-FLU provides clinically meaningful improvements in subjective and objective outcomes in CRS but is associated with an increased risk of local nasal adverse events, warranting individualized risk-benefit assessment.

Diagnosing rare genetic diseases remains a major challenge despite widespread clinical testing. Long-read RNA sequencing (RNA-seq) offers a powerful approach to capturing the effects of genetic variants on the transcriptome, yet challenges with sequencing coverage, cost, tissue selection, and scalability have limited its clinical adoption. To address this, we developed STRIPE (Sequencing Targeted RNAs Identifies Pathogenic Events), a targeted long-read RNA-seq–based strategy for rare disease diagnosis and variant interpretation. STRIPE enables deep sequencing of full-length transcripts for any customized disease-specific gene panel such that a wide range of clinically informative readouts, including transcript aberrations and sequence variants, can be detected at haplotype-level resolution. Applying STRIPE to 88 individuals spanning two major rare disease groups, we accurately reidentified known pathogenic variants and revealed their transcript consequences, including many unexpected ones. For 8 of 15 splice site region variants, we observed more complex RNA processing defects beyond single exon skipping or cryptic splice site activation. Notably, we find that donor splice site variants frequently activate cryptic intronic polyadenylation sites, leading to premature transcript termination. Leveraging unique strengths of long-read RNA-seq, STRIPE also resolved variants of uncertain significance and uncovered disease-causing variants in five previously undiagnosed individuals. Overall, STRIPE is a powerful, adaptable, and scalable strategy with broad potential to improve clinical variant interpretation and advance genetic diagnosis of rare diseases.

Abstract Background Electronic health record (EHR)–based prognostic modeling is increasingly used in oncology, yet incorporating pharmacogenomic (PGx) knowledge derived from experimental systems into clinical prediction frameworks remains challenging. This gap is driven by fundamental mismatches between controlled drug–mutation assays and heterogeneous, incomplete real-world clinical data. Methods We propose a representation transfer framework that integrates PGx embeddings learned from large-scale in vitro pharmacogenomic screens into patient-level EHR models. A frozen pharmacogenomic encoder is used to generate interaction-aware embeddings from patient mutation profiles and administered therapies, which are aggregated into a fixed-length PGx Complementarity Representation. These representations are incorporated into multimodal survival prediction models alongside standard clinical features. Performance was evaluated using systematic modality ablation analyses, attribution analyses, and exploratory unsupervised representation analyses. Results Integrating PGx embeddings yielded consistent performance improvements across all evaluated modality combinations. Relative gains were largest in modality-sparse settings, where baseline EHR features encode limited biological context, and were attenuated—but remained significant—in biologically enriched configurations. Attribution analyses indicated that PGx embeddings contributed non-redundant predictive signal beyond standard clinical features. Exploratory unsupervised analyses further demonstrated that the learned representations exhibit interpretable association patterns aligned with known therapeutic exposures and pathway-level associations. Conclusion These findings suggest that externally learned pharmacogenomic representations can be transferred into real-world EHR models as a context-dependent, non-redundant augmentation. By framing PGx knowledge as an interaction-aware representation rather than a mechanistic model, this work provides an informatics framework for integrating experimental pharmacogenomic data into clinical prediction tasks in a reproducible and interpretable manner.