Citations

Abstract Background & Aims Pregnancy can be a complex and risk-filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process was used when sufficient published data were available and the RAND (Research and Development) process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

Purpose of review To synthesize the current literature regarding the evaluation and management of genitourinary fistula in women. Recent findings Genitourinary fistula are aberrant communications between the urinary tract and genital tract that present with urinary leakage per the vagina. Initial management often involves conservative measures, such as urethral catheter or ureteral stent placement, progressing to surgical repair when needed. Key surgical principles include a tension-free, watertight closure with well-vascularized tissue including tissue interposition as appropriate, and postoperative urinary drainage. When surgical management of vesicovaginal fistula is necessary, a transvaginal repair is the most common. Other minimally invasive approaches are increasing and result in similarly high success rates with lower patient morbidity compared to open abdominal surgeries. The initial management of ureterovaginal fistula commonly includes ureteral stent placement. When not feasible or in persistent fistula, laparoscopic and robotic surgical repair with ureteral reconstruction offers high success rates with lower morbidity than an open approach. Summary Successful management of genitourinary fistula ranges from conservative urinary tract drainage to surgical interventions based on etiology, location, and complexity. Approaches to repair are shifting toward less invasive procedures. With optimal technique and surgical planning, high success rates can be achieved, particularly in primary repairs.

Sindbis virus (SINV), a prototype of the Alphavirus genus (family Togaviridae), is a globally distributed arbovirus causing febrile rash and debilitating arthritis in humans. Viral structural proteins—capsid (C), E1, and E2—are fundamental to the virion’s architecture, mediating all stages from assembly to host cell entry and pathogenesis, thus representing critical targets for study. This review consolidates the historical and current understanding of SINV structural biology, tracing progress from early microscopy to recent high-resolution cryo-electron microscopy (cryo-EM) and X-ray crystallography. We detail the virion’s precise T = 4 icosahedral architecture, composed of a nucleocapsid core and an outer glycoprotein shell. Key functional roles tied to protein structure are examined: the capsid’s dual capacity as a serine protease and an RNA-packaging scaffold that interacts with the E2 cytoplasmic tail; the E1 glycoprotein’s function as a class II fusion protein driving membrane fusion; and the E2 glycoprotein’s primary role in receptor binding, which dictates cellular tropism and serves as the main antigenic target. Furthermore, we connect these molecular structures to viral evolution and disease, analyzing how genetic variation among SINV genotypes, particularly in the E2 gene, influences host adaptation, immune evasion, and the clinical expression of arthritogenic and neurovirulent disease. In conclusion, the wealth of structural data on SINV offers a powerful paradigm for understanding alphavirus biology. However, critical gaps persist, including the high-resolution visualization of dynamic conformational states during viral entry and the specific molecular determinants of chronic disease. Addressing these challenges through integrative structural and functional studies is paramount. Such knowledge will be indispensable for the rational design of next-generation antiviral therapies and broadly protective vaccines against the ongoing threat posed by SINV and related pathogenic alphaviruses.

This review explores how multimodal foundation models (MFMs) are transforming biliary tract cancer (BTC) research. BTCs are aggressive malignancies with poor prognosis, presenting unique challenges due to difficult diagnostic methods, molecular complexity, and rarity. Importantly, intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal bile duct cholangiocarcinoma (dCCA) represent fundamentally distinct clinical entities, with iCCA presenting as mass-forming lesions amenable to biopsy and targeted therapies, while pCCA manifests as infiltrative bile duct lesions with challenging diagnosis and primarily palliative management approaches. MFMs offer potential to advance research by integrating radiological images, histopathology, multi-omics profiles, and clinical data into unified computational frameworks, with applications tailored to these distinct BTC subtypes. Key applications include enhanced biomarker discovery that identifies previously unrecognizable cross-modal patterns, potential for improving currently limited diagnostic accuracy—though validation in BTC-specific cohorts remains essential—accelerated drug repurposing, and advanced patient stratification for personalized treatment. Despite promising results, challenges such as data scarcity, high computational demands, and clinical workflow integration remain to be addressed. Future research should focus on standardized data protocols, architectural innovations, and prospective validation studies. The integration of artificial intelligence (AI)-based methodologies offers new solutions for these historically challenging malignancies. However, current evidence for BTC-specific applications remains largely theoretical, with most studies limited to proof-of-concept designs or related cancer types. Comprehensive clinical validation studies and prospective trials demonstrating patient benefit are essential prerequisites for clinical implementation. The timeline for evidence-based clinical adoption likely extends 7–10 years, contingent on successful completion of validation studies addressing current evidence gaps.

Background Birt–Hogg–Dubé syndrome (BHD) is a rare autosomal dominant disease characterised by the development of lung cysts, skin fibrofolliculomas and an increased risk for renal cancer. The progression of cystic lung disease with ageing in BHD has not been well characterised. Objectives To assess the severity of lung involvement in patients with BHD aged 50 years or older. Methods A retrospective computer-assisted search was performed to identify patients with BHD seen at Mayo Clinic in Rochester, Minnesota and the First Affiliated Hospital of University of Science and Technology of China from January 2000 to May 2023. Demographic, clinical, pulmonary function and radiological parameters were extracted and analysed. Results Among 82 patients with BHD aged 50 years or older, 49 (59%) were female and the median age was 57 years (range, 50–79) at baseline. Pneumothorax occurred in 46 patients (56%). Lung cysts were observed on CT in 77 patients (94%) and were bilateral in nearly all cases. The number of cysts was≥10 for most patients (84%) and the median size of the largest cyst was 31 mm (range, 4–160 mm). Median (range) % predicted values of forced vital capacity, forced expiratory volume in 1 s and diffusion capacity of the lung for carbon monoxide were 98 (62–147), 92 (56–145) and 85 (61–133), respectively, for those with data available. During follow-up (median, 41 months; range, 3–259), 35% of patients manifested worsening in pulmonary function or cystic lung disease. Conclusion Lung involvement in older patients with BHD manifests varying severity of cystic lung disease with relatively mild functional impairment, if any, and indolent progression.

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 Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

The integration of artificial intelligence (AI) in medical imaging has revolutionized diagnostic capabilities, yet the black-box nature of deep learning models poses significant challenges for clinical adoption. Current explainable AI (XAI) approaches, including SHAP, LIME, and Grad-CAM, predominantly focus on post hoc explanations that may inadvertently undermine clinical decision-making by providing misleading confidence in AI outputs. This paper presents a systematic review and meta-analysis of 67 studies (covering 23 radiology, 19 pathology, and 25 ophthalmology applications) evaluating XAI fidelity, stability, and performance trade-offs across medical imaging modalities. Our meta-analysis of 847 initially identified studies reveals that LIME achieves superior fidelity (0.81, 95% CI: 0.78–0.84) compared to SHAP (0.38, 95% CI: 0.35–0.41) and Grad-CAM (0.54, 95% CI: 0.51–0.57) across all modalities. Post hoc explanations demonstrated poor stability under noise perturbation, with SHAP showing 53% degradation in ophthalmology applications (ρ = 0.42 at 10% noise) compared to 11% in radiology (ρ = 0.89). We demonstrate a consistent 5–7% AUC performance penalty for interpretable models but identify modality-specific stability patterns suggesting that tailored XAI approaches are necessary. Based on these empirical findings, we propose a comprehensive three-pillar accountability framework that prioritizes transparency in model development, interpretability in architecture design, and a cautious deployment of post hoc explanations with explicit uncertainty quantification. This approach offers a pathway toward genuinely accountable AI systems that enhance rather than compromise clinical decision-making quality and patient safety.

Abstract Background Dose‐driven continuous scanning (DDCS) is a type of beam delivery in Hitachi pencil beam scanning (PBS) particle therapy system. Particle beam is irradiated continuously between spots to achieve a higher effective dose rate and a shorter beam delivery time. The beam is only turned off at break spots, the end of a treatment layer and during spill change. The break spot is a unique feature of the DDCS introduced by the treatment planning system (TPS) to interrupt continuous scanning. DDCS separates the dose delivery of a spot into a move dose and stop dose components. The move dose is controlled by the scanning speed and beam current, while the stop dose delivers the remaining monitor units (MUs). Hence, rigorous quality assurance (QA) of the scanning speed and functionality of break spot are required to ensure safe and successful DDCS delivery. Purpose We aim to report for the first time the QA methodology and result for DDCS, focusing on the scanning speed and break spot validation. Methods A rectangular spiral irradiation pattern with different degree of break spots were irradiated on a 2D strip ionization chamber (CROSSmini) detector using 50 time resolution to validate the break spots. Four methods of measuring scanning speeds were proposed. Using a spiral irradiation pattern, methods one and two applied linear regression to the scanning time measured by the CROSSmini for different inter‐spot distances, with measurements taken at sampling rates of 5 and 20 kHz, respectively. Methods three and four measured the scanning time of single inter‐spot distances in the X and Y directions. Method three measured the scanning time with the CROSSmini while method four measured the rise and fall time of the scanning magnet (SCM) current. All measurements were performed with 70.2, 150.2 and 228.7 MeV proton beam energies and three different beam currents of 8, 14 and 20 MU/s. Lastly, the scanning speed tolerance limit was calculated analytically under the requirement of avoiding a beam abort when the stop dose was less than zero. Results The data recorded by the CROSSmini under the spiral irradiation patterns with break spots was reconstructed into a 2D dose, and the break spots’ operations were visually validated for all the energies and beam currents. There were no statistically significant difference in the measured X and Y scanning speeds across the four methods. However, the last method involving the SCM current yielded the largest type A uncertainty of up to 25% () due to the noisy signal. The first method with the linear regression and 5 kHz acquisition rate was preferred due to a smaller type A uncertainty of up to 2.0% and a lower false negative rate in detecting the rising and falling edges during scanning. The calculated tolerance limit based on our current DDCS setting was found to be 0.50 times of the expected scanning speed. Conclusion We have introduced QA protocols for DDCS, designed to ensure complete and safe beam delivery without interruptions caused by move doses exceeding planned spot doses.