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Clinical ethics scholarship on deepfakes has focused primarily on patients as targets of synthetic deception, in which fabricated audiovisual material alters patient beliefs about clinicians and care. This focus neglects the reverse epistemic vulnerability: clinicians themselves as recipients of synthetic, adversarially generated clinical information. To develop a conceptual analysis of clinician-facing deepfakes and their implications for clinical epistemology, diagnostic reasoning, and institutional trust. Normative and conceptual analysis drawing on virtue epistemology, philosophy of testimony, diagnostic error theory, automation bias research, and socio-technical systems theory. Clinician-facing deepfakes constitute a distinct epistemic risk category producing three primary harms: (1) diagnostic error cascades, (2) testimonial contamination of clinical knowledge transmission, and (3) institutional epistemic fragility. We introduce the concept of epistemic role reversal, defined as the systematic decoupling of perceptual reliability from epistemic justification under adversarially generated clinical inputs, resulting in the collapse of expert perceptual advantage in bounded domains. Clinical ethics must address both sides of the epistemic encounter in medicine. Clinician-facing deepfakes are not merely a symmetrical extension of patient-facing deception but a structurally distinct class of epistemic threat. While empirical prevalence remains unknown, evidence from adjacent literatures supports their plausibility. A precautionary framework of clinical epistemic hygiene is therefore warranted, combining institutional verification infrastructure, workflow-level safeguards, and professional epistemic norms adapted to adversarial information environments.

Introduction In recent years, artificial intelligence (AI)-generated prostate whole-gland segmentation has shown promise for clinical use. This study compares AI- and human-derived prostate segmentation on magnetic resonance imaging (MRI) and evaluates its practical application. Methods A retrospective study from December 2020 to December 2022 evaluated 31 randomly selected patients who had previously undergone MRI-ultrasound (US)-guided fusion biopsies. AI-generated auto-contours&#xa0;of the whole-gland prostate, seminal vesicle, and urethra were produced using the&#xa0;Prot&#xe9;g&#xe9;AI feature of the MIM Software from MRIs obtained on GE Signa HDxt 3.0T and Siemens Altea Magnetom 1.5T scanners. The same MRIs were independently contoured manually by a board-certified urologist (U) and a board-certified radiologist (R) using MIM Software contouring tools. Volumetric conformity among the three contour sets was assessed using the Dice similarity coefficient, Hausdorff distance (HD), and mean distance to agreement (MDA). Contouring time was recorded for each method, with AI timed from command execution to file generation and physicians timed from file opening to save. Pairwise Wilcoxon signed-rank tests (JMP Pro 15) compared contouring times and similarities across AI to urologist (AI-U), AI to radiologist (AI-R), and urologist to radiologist (U-R) contours. Results The average volumetric Dice similarity, HD, and MDA for the AI-U&#xa0;contours were 0.875&#xb1;0.039, 9.186&#xb1;4.004 mm, and 1.410&#xb1;0.511 mm for the whole-gland prostate, 0.283&#xb1;0.185, 18.117&#xb1;13.265 mm, and 4.907&#xb1;4.992 mm for the urethra, and 0.377&#xb1;0.244, 14.708&#xb1;9.489 mm, and 4.260&#xb1;4.092 mm for the seminal vesicle. For the AI-R contours, the values were 0.757&#xb1;0.072, 17.562&#xb1;7.240 mm, and 3.050&#xb1;1.339 mm for the prostate, 0.162&#xb1;0.105, 19.956&#xb1;11.962 mm, and 4.798&#xb1;3.879 mm for the urethra, and 0.451&#xb1;0.219, 16.069&#xb1;9.245 mm, and 4.075&#xb1;3.734 mm for the seminal vesicle. For the U-R contours, the values were 0.769&#xb1;0.070, 15.109&#xb1;6.177 mm, and 2.733&#xb1;1.265 mm for the prostate, 0.144&#xb1;0.091, 13.560&#xb1;7.087 mm, and 3.406&#xb1;1.985 mm for the urethra, and 0.471&#xb1;0.216, 12.981&#xb1;6.756 mm, and 3.264&#xb1;2.308 mm for the seminal vesicle. Using the Wilcoxon signed-rank test with statistical significance defined as p<0.01, the AI-U Dice similarity for the prostate differed significantly from both the AI-R and U-R comparisons. Similarly, AI-U demonstrated significantly different HD values than both AI-R and U-R, whereas the AI-R and U-R HD comparison was statistically insignificant. All pairwise MDA comparisons for the prostate were statistically significant. For the urethra, the AI-U Dice similarity differed from the other two comparisons, while for HD, the AI-R and U-R comparisons differed significantly from each other. No significant differences were observed among the three comparisons for the seminal vesicle across any metric. The average times to produce contours for the AI, urologist, and radiologist were 96.5 seconds, 285.8 seconds, and 217.9 seconds, respectively (p<0.01 for each time comparison). Conclusion This study suggests that AI may be a useful tool for prostate segmentation workflows in streamlining MRI-US prostate cancer diagnostics by producing similar contouring results in less time. Additional investigation should be conducted regarding the differences between the pathological outcomes of AI and non-AI contours, and the accuracy, cost analysis, and efficiency of AI technology should be elucidated.

Introduction Single-isocenter multi-target (SIMT) radiosurgery enhances efficiency by treating multiple lesions with a single plan. However, this technique is highly susceptible to patient positioning errors, particularly rotational deviations. Even minor rotations can lead to significant reductions in target dose coverage, with the degree of degradation being influenced by target size, the magnitude of rotation, and the target's distance from the treatment isocenter. While previous studies have investigated these effects through simulations, retrospective analyses, or statistical models, a robust mathematical framework for predicting these interactions is lacking. Purpose This study aims to develop and apply mathematical models to quantify the impact of rotational errors on target coverage in SIMT radiosurgery. The primary objective is to elucidate the interplay between target size, distance from the isocenter, and the magnitude of rotational error, with a view to informing individualized planning target volume (PTV) margin selection for optimized target coverage and minimized normal tissue irradiation. Methods We developed mathematical models to simulate the dosimetric consequences of rotational errors under the assumption of a dose distribution encompassing the target perfectly, in the absence of setup errors. The target and radiation fields were modeled as three-dimensional spheres, and equations were derived to calculate the volume of intersection between the rotated target and the prescribed radiation field. The percentage of target volume maintained within the prescription dose sphere was then calculated. Graphical representations of Gross Tumor Volume (GTV) coverage as a function of rotational error (ranging from 0&#xb0; to 3&#xb0;), target diameter (0.5 cm to 3.0 cm), PTV margins (0 mm, 0.5 mm, 1.0 mm), and distance from the isocenter (1.5 cm to 7.5 cm) were generated. The methodology was applied to clinical cases to demonstrate its utility in deriving customized margins. Results The mathematical analysis demonstrated that small targets located further from the isocenter are most vulnerable to coverage degradation due to rotational errors, especially with minimal or no PTV margins. For a 0.5 cm diameter target, even a 0.5&#xb0; rotation resulted in coverage below 95% at 1.5 cm from the isocenter without a margin, dropping significantly at greater distances. Conversely, larger targets maintained adequate coverage even at 2.5&#xb0; rotation without a margin. Introduction of a 1.0 mm uniform margin generally ensured over 95% GTV coverage for 1&#xb0;&#xa0;rotations across all evaluated target sizes and distances from the isocenter. Applying this framework to a clinical case, differential margins derived from our model resulted in a decreased treated volume and reduced brain V12Gy compared to a uniform 1 mm margin plan. Conclusions The findings underscore the impact of rotation based on target size and location and the critical importance of individualized PTV margin selection. By leveraging this analysis, clinicians can determine optimal, customized margins based on specific target characteristics and acceptable rotation thresholds, thereby ensuring robust target coverage while minimizing unnecessary irradiation of healthy tissue and enhancing the precision of SIMT treatments.

To develop and evaluate a stress-constrained physics-informed UNet framework for voxel-wise, multiparameter hyperelastic characterization of heterogeneous soft tissues from volumetric displacement data and accessible boundary reaction information in controlled synthetic 3D benchmarks. We introduce a physics-informed UNet (PI-UNet) that estimates voxel-wise Mooney-Rivlin parameter maps from multi-loading, strain-derived volumetric inputs. Synthetic finite-element data were generated for three benchmarks: a stiff spherical inclusion in a homogeneous matrix, an anatomically realistic gray/white matter brain embedded in a homogeneous matrix, and an embedded brain containing a synthetic tumor-like inclusion. The loss enforces static equilibrium through the divergence of the first Piola-Kirchhoff stress and incorporates boundary reaction information as face-averaged stress or an equivalent resultant force. Noise robustness was assessed using displacement perturbations and Gaussian smoothing within the loss formulation. PI-UNet reconstructed heterogeneous Mooney-Rivlin fields with high spatial fidelity across the tested synthetic configurations. In the spherical-inclusion benchmark, moderate smoothing reduced noise sensitivity while preserving inclusion geometry. In the gray/white matter benchmark, the framework recovered distinct material signatures for matrix, gray matter, and white matter. In the tumor-like benchmark, scalar fields derived from reconstructed material parameters improved unsupervised identification of the mechanically distinct lesion-like region compared with deformation-derived invariant fields alone. The proposed stress-constrained PI-UNet provides a scalable computational framework for controlled voxel-wise 3D multiparameter hyperelastic inversion from volumetric deformation fields and accessible boundary reaction measurements, supporting future experimental phantom validation, richer constitutive models, uncertainty quantification, and eventual in vivo elastography studies.

Mycobacterium abscessus complex is a rapidly growing non-tuberculous mycobacterium(NTM) associated with difficult-to-treat pulmonary and extrapulmonary infections. Clinical management is complicated by intrinsic antimicrobial resistance, inducible macrolide resistance, and genomic heterogeneity. This study characterised five clinical pulmonary M. abscessus&#xa0;isolates from India using whole-genome sequencing (WGS)-based genomic, phylogenetic, and antimicrobial resistance analysis. Five clinical isolates recovered from pulmonary specimens were sequenced using the Illumina NovaSeq platform (Illumina, Inc., San Diego, California, United States) with paired-end 151 bp chemistry. Reads were quality filtered using fastp v1.0.1. Reference-guided alignment and consensus generation were performed using Burrows-Wheeler Aligner (BWA)-Maximal Exact Match (MEM) and SAMtools-based workflows. Genome annotation was conducted using Prokka v1.14.6, functional annotation using eggNOG-mapper, variant analysis using Genome Analysis Toolkit (GATK) HaplotypeCaller and SnpEff, and antimicrobial resistance gene detection using the Comprehensive Antibiotic Resistance Database (CARD).&#xa0;Phenotypic antimicrobial susceptibility findings and GenoType NTM-drug resistance&#xa0;(DR) Line Probe Assay Version 1.0 results (Bruker Corporation, Billerica, Massachusetts, United States) were used to support the interpretation of macrolide resistance-associated findings. The isolates generated 0.92-1.24 Gb of high-quality sequencing data, with Q30 values exceeding 95%. Genome coverage at &#x2265;30&#xd7; depth exceeded 91%, and average sequencing depth ranged from 44.16&#xd7; to 149.59&#xd7;. Annotation identified 4,457-4,751 coding sequences, 45-48 tRNA genes, three rRNA genes, and one tmRNA gene per isolate. Reference alignment ranged from 24.86% to 64.22%, supporting isolate-level genomic heterogeneity. MAB &#x3b2;-lactamase (blaMab) gene was detected in all isolates, while erm(41) was detected only in LIN. WGS-enabled isolate-level characterisation of pulmonary&#xa0;M. abscessus&#xa0;isolates from India demonstrated conserved genomic features with measurable heterogeneity. blaMab supports intrinsic &#x3b2;-lactam resistance, while erm(41) in LIN was consistent with an inducible macrolide resistance pattern supported by available phenotypic antimicrobial susceptibility testing.

Objectives: A common inflammatory condition affecting oral health is periodontitis, which can lead to tooth loss if not treated early, as it destroys the supporting structures of the teeth. Fusobacterium nucleatum is an orange-pigmented bacterium commonly referred to as "the bridging species" between early and late colonizers in the oral microbiota, and it is associated with the progression of periodontal disease. This study aimed to develop an effective and precise multi-epitope vaccine against F. nucleatum, as there is currently no approved vaccine for periodontal disease. Materials and Methods: This study employed a computational method to design a multiple epitope-based vaccine against F. nucleatum using an immunoinformatics reverse vaccinology approach. FadA, a novel adhesin unique to F. nucleatum, was a suitable peptide for vaccine development. B- and T-cell epitopes were identified and assessed to design a multi-epitope vaccine. The developed vaccine construct was analyzed for potency based on its allergenicity, antigenicity, solubility, and stability. Results: The vaccine structure was non-allergenic and exhibited high antigenicity, stability, and solubility. This vaccine may be a candidate for eradicating F. nucleatum, based on predictions of immunogenicity responses. Conclusion: The designed vaccine construct could generate an effective immune response against F. nucleatum, owing to its high antigenicity and non-allergenicity.

Computer-integrated surgical navigation systems are often run in the OR with the assistance of a technician for controlling the user interface and advising on technical details of the system. In lower-resource healthcare settings, limited access to additional OR staff and technical training for operating navigation systems can represent a barrier to sustainably deploying a low-cost surgical navigation solution. Recent advancements in locally deployable large language models (LLMs) have improved their ability to answer technical questions based on source materials and safely perform limited tasks on behalf of a user. The objective of this paper is to explore the feasibility of using a network of local LLM-based agents to act as a natural language interface for a low-cost surgical navigation system, facilitating hands-free manipulation of the user interface and providing documentation-grounded technical guidance. We propose the navigation offline virtual agent (NOVA), an end-to-end architecture that integrates distinct local LLM-based agents for knowledge tasks, action tasks, and delegation between the agents. Two semisynthetic benchmark datasets were generated for ablation studies of individual agents, and a prototype was built which integrates these agents into NousNav, an open-source neuronavigation system. The agents based on local LLMs were found to perform comparably to closed-source, commercially hosted LLMs. In a user study with nine participants, NOVA facilitated hands-free patient registration with a mean end-to-end latency of 10.4 &#xb1; 2.4 &#xa0;s and an 81% command success rate. This work demonstrates that local LLM-based agents can be deployed to support users of low-cost navigation systems by providing a context-aware natural language interface, representing an important step toward reducing technician dependence in low-cost surgical navigation.

No published studies have evaluated the application of Generative Pre-trained Transformer-5 (GPT-5) in the analysis of memory clinic patient clinical notes or the interpretation of plasma phosphorylated tau (P-tau) 217 values. We compared Alzheimer's disease (AD) probability estimates generated by GPT-5 before and after incorporating plasma P-tau 217 with pre- and posttest probabilities. This was a retrospective study comprising 74 patients from a memory clinic in Queen Mary Hospital, Hong Kong. Final diagnoses were made by physicians, supported by medical history, physical examination, neuroimaging and amyloid positron emission tomography. Extracted clinical data included cognitive, functional and neuropsychiatric assessments. Pretest AD probabilities were derived from a published meta-analysis, while posttest probabilities were calculated using a Bayesian approach. These values were compared with those estimated by GPT-5. The diagnostic performance of GPT-5 and physicians was assessed using accuracy and Kappa coefficient, with final diagnosis as reference. There were 40 amyloid-positive (A+) and 34 amyloid-negative (A-) patients. In A+ patients, Bayesian posttest probabilities were higher than GPT-5 estimates (median 97.0% vs. 80.0%, P = 0.003), while those of A- patients were lower than GPT-5 estimates (median 3.0% vs. 27.5%, P < 0.001). With application of plasma P-tau 217, physicians achieved higher diagnostic accuracy than GPT-5 (81.1% vs. 45.9%, P < 0.001), while GPT-5 suggested mixed aetiologies more frequently (23.0% vs. 8.1%, P = 0.04) and inappropriate anti-amyloid therapy in 31% (11/36) of scenarios. Our findings show that GPT-5 has limitations in analysing clinical information of real-life memory clinic patients.

Healthcare systems worldwide face mounting pressure to deliver high-quality care while enhancing efficiency and sustainability. Nurse-led interventions have emerged as promising strategies to optimize care delivery, particularly within value-based health systems. However, a comprehensive understanding of their clinical impact and economic value remains limited. This systematic review conducted following PRISMA guidelines, searched nine international databases to identify and synthesize formally evaluated nurse-led interventions, programs, and strategies. Twenty-eight studies were included, encompassing diverse care settings and patient populations. Most studies reported improvements in clinical outcomes, including reduced hospital readmissions, enhanced quality of life, and improved chronic disease management. Several interventions analyzed effectiveness, particularly those involving advanced nursing roles such as nurse practitioners and case managers. Findings suggest that clinical effectiveness does not necessarily translate into increased professional authority: nurse-led interventions consistently generate value across patient, organizational, and systemic dimensions, yet nursing leadership remains structurally subordinate within healthcare governance. A systematic agenda for rigorous economic evaluation embedded in nursing research programs is urgently needed, alongside structural reforms that redistribute authority-not merely develop competencies-within healthcare organizations.

The use of digitally fabricated esthetic crowns for restoring primary molars has increased with the development of CAD/CAM systems, three-dimensional (3D) printing, and tooth-colored biomaterials. However, the available evidence remains heterogeneous, and the clinical role of customized digital crowns in comparison with conventional pediatric crowns is still unclear. This systematic review aimed to assess the available in vitro and clinical evidence on esthetic customized crowns fabricated using digital workflows for primary molars. A systematic literature search was conducted in PubMed, Scopus, and Web of Science to identify studies evaluating digitally fabricated esthetic crowns for primary molars. Eligible studies included in vitro investigations, clinical studies, randomized clinical trials, and finite element analyses assessing marginal or internal adaptation, fracture resistance, wear behavior, clinical performance, gingival health, or patient and parent satisfaction. Risk of bias was assessed using RoB 2 for clinical trials and the QUIN tool for in vitro studies. Due to heterogeneity in study designs, materials, comparators, and outcomes, a qualitative synthesis was performed. Twenty-four studies were included, 17 in vitro studies, six clinical studies, and one finite element analysis. Most studies evaluated zirconia, 3D-printed resins, PMMA, CAD/CAM composites, or hybrid ceramics. In vitro findings suggested favorable marginal and internal adaptation for several customized digital crowns and material-dependent fracture resistance. Clinical studies reported acceptable short-term performance, although follow-up was generally limited and outcomes varied across materials. Stainless steel crowns remained a highly predictable comparator, while esthetic digital crowns showed potential advantages in esthetics and customization. Digitally fabricated esthetic crowns for primary molars represent a promising restorative alternative, but current evidence does not demonstrate consistent superiority over stainless steel crowns. Further well-designed clinical trials with longer follow-up and standardized outcomes are needed.

This study aims to compare the rates of medical complication and mortality following initial bipolar hemiarthroplasty (bHA) and reoperation procedures, as well as between different causes of reoperation (nonseptic vs. septic). The retrospective study included 118 patients undergoing reoperation after bHA for femoral neck fractures between January 2002 and December 2022. The primary outcomes included in-hospital complications, readmission, and mortality events, while secondary outcomes included length of hospital stay, transfusion rates, and estimated blood loss. These outcomes were compared between each patient's initial bHA and their subsequent reoperation procedure. The two cohorts were matched using propensity scores based on age, sex, and Charlson Comorbidity Index to compare outcomes between nonseptic and septic causes of reoperation. Of the 118 patients, 64 were male and 54 were female. The mean age was 77.8 &#xb1; 7.9 years, with a range of 61 to 98 years. The in-hospital complication rate was higher after reoperation than after initial bHA (15.3% vs. 1.7%, p < 0.001). Conversely, the readmission rate was higher after the initial procedure (60.2% vs. 23.7%, p < 0.001), mainly due to surgical complications. Patients undergoing reoperation had longer hospital stays, higher transfusion requirements, and more frequently received general anesthesia compared to the initial procedure (p < 0.05). In the matched cohort, septic group had higher in-hospital complication rates than the nonseptic group (23.5% vs. 3.9%, p = 0.004), while readmission and mortality rates were comparable. Reoperations after bHA carry a higher risk of medical complications. This risk is particularly pronounced in cases related to septic conditions, underscoring the greater impact of reoperation and careful clinical attention.

Objectives: Hypericum perforatum (H. perforatum) has natural anti-inflammatory properties when used as a dressing on ulcers and burn wounds. The aim of this study was to investigate the effect of topical application of hydroethanolic gel of H. perforatum on soft tissue healing in tooth extraction sockets. Materials and Methods: This split-mouth randomized controlled clinical trial was performed on 30 patients aged 18-30 years who required simultaneous extraction of maxillary premolars bilaterally for orthodontic reasons. After tooth extraction, 2mL of 3% H. perforatum gel was injected into the extraction socket in the intervention side. Pain was measured based on a Numeric Rating Scale (NRS). Socket healing was assessed using the standardized Landry, Turnbull, and Howley index. Repeated measures ANOVA and generalized estimating equations (GEE) were employed to compare different indices between the two groups (alpha=0.05). Results: The mean age of the participants was 23.53 years. Of all, 25 were females and 5 were males. The intervention side had a significantly lower pain than the control side (P<0.05). The wound size decreased at 3 and 7 days, and it was smaller in the intervention side than the control side (P<0.05). The healing index score was significantly higher in the intervention side than the control side (P<0.001). Conclusion: The results showed that 3% H. perforatum hydroethanolic gel was effective for promoting soft tissue healing in tooth extraction sockets, decreasing pain, and improving the wound healing index.

Penile fracture is a rare and underreported urological emergency, defined as traumatic rupture of the tunica albuginea of the corpus cavernosum. Most cases result from vigorous sexual intercourse or direct blunt trauma to an erect penis. While conservative management was once standard, high rates of long-term complications - including severe penile curvature, fibrotic plaques, and permanent erectile dysfunction (ED) - have led to a universal preference for immediate surgical repair. Although anatomical and physiological outcomes after surgery are well documented, the long-term psychosexual impact remains poorly characterised. Many patients report performance anxiety, fear of recurrence, and changes in sexual habits, but these experiences are often overlooked in favour of objective hemodynamic assessments. This scoping review aims to map and synthesise current evidence on functional, sexual, and psychosexual outcomes after surgical repair of penile fractures. Specifically, it examines the impact of surgical timing on erectile function, identifies independent risk factors for postoperative ED, and evaluates psychological effects on sexual satisfaction, relationship dynamics, and ejaculatory function. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) framework. Comprehensive searches were conducted in PubMed/MEDLINE, EMBASE, the Cochrane Library, SCOPUS, and Web of Science. Data charting included patient demographics, injury mechanisms, diagnostic methods, surgical timing, and validated psychometric assessments across nine core studies. Immediate surgical intervention, ideally within 24 hours, is the gold standard and is associated with lower postoperative ED rates (6.5% to 16.5%) than delayed surgery (up to 42.9%) and conservative management (up to 52.9%). Independent predictors of poor outcomes include age over 50, urethral injury, bilateral corporal involvement, and tunical defects larger than 2 centimetres. Early repair reduces scarring and penile curvature. However, psychosexual outcomes remain complex. While erectile function is usually preserved, many patients experience psychogenic issues. Up to 77.5% report persistent fear of recurrence, and nearly 69% change their sexual habits. Changes in ejaculatory latency are also observed and correlate with higher depressive scores. Broad psychiatric screening tools do not show increased rates of clinical depression or generalised anxiety, indicating that psychological distress is specific to sexual performance and relationships. Immediate surgical repair remains the standard approach for preserving erectile function and anatomical integrity after penile fracture. However, postoperative recovery should not be assessed solely by structural or hemodynamic outcomes. The available evidence suggests that some patients experience persistent fear of recurrence, avoidance behaviours, performance anxiety, and reduced sexual confidence after repair. These findings highlight the need for more consistent assessment of psychosexual outcomes in follow-up studies. Multidisciplinary postoperative support, including psychological counselling, sexual health assessment, and partner-centred care, may be considered where clinically appropriate, but further research is needed to define optimal follow-up and rehabilitation strategies.

Cystinuria is a hereditary aminoaciduria causing recurrent cystine nephrolithiasis, impaired quality of life and potential renal function decline. Despite established treatment guidelines, real-world data reveal a persistent gap between recommended targets and clinical outcomes. Preliminary data from the EUROCYS 2024 prospective European registry (269 patients, 29 centers, 8 countries) showed that only 16.3% of patients achieved the target urinary pH range, 55.2% remained above the conventional urinary cystine threshold of 250 mg/L, and approximately 39% experienced a new stone event within the preceding 12 months, despite follow-up in specialist centers. Discontinuation rates for available thiol drugs have been reported to reach 30-50%. This narrative review, based on a structured non-systematic search of major databases and guideline repositories (2009-2026), synthesizes current evidence on cystinuria diagnosis and management and appraises emerging adjunctive interventions. Next-generation sequencing-based genetic testing and the cystine capacity assay represent key recent advances in monitoring. Thulium fiber laser lithotripsy and miniaturized percutaneous approaches offer less traumatic surgical options in this high-burden population. Oral N-acetylcysteine has mechanistic plausibility and a favorable, well-characterized safety profile in other clinical settings, making it a rational candidate for formal prospective evaluation; however, robust clinical trial evidence in cystinuria using contemporary monitoring parameters is lacking. Current standard treatment remains insufficient for a substantial proportion of patients, underscoring the need to evaluate accessible adjunctive therapies with defined mechanisms and measurable outcomes. Cystinuria is a rare inherited condition in which the kidneys cannot properly reabsorb certain amino acids, leading to the formation of kidney stones made of cystine. These stones recur frequently, often require surgery, and can cause long-term kidney damage over time. Diagnosis relies on urine and blood tests, genetic testing, and a newer urine test called the cystine capacity assay, which more accurately reflects how close a patient is to forming stones. Treatment begins with drinking large amounts of fluid, alkalinizing the urine with potassium citrate, and reducing salt and protein in the diet. When these measures are insufficient, a drug called tiopronin is added to help prevent stone formation. Despite specialist care, real-world data show that most patients still do not meet recommended treatment targets and continue to form stones. For stone removal, ureteroscopy with laser lithotripsy and percutaneous nephrolithotomy are the main surgical options; newer thulium fiber lasers show promising results for this stone type. Oral N-acetylcysteine has a plausible mechanism and known safety from other conditions, but clinical evidence in cystinuria is lacking and it cannot yet be considered a standard treatment. This review highlights a persistent gap between treatment targets and real-world outcomes, underscoring the urgent need for accessible adjunctive therapies supported by well-designed clinical trials.

FGF/FGFR alterations are recurrent but heterogeneous in head and neck cancer, and which types predict benefit from selective fibroblast growth factor receptor (FGFR) inhibition is unknown. We examined whether response to gunagratinib, a pan-FGFR1-4 inhibitor, differs by FGF/FGFR alteration type in recurrent or metastatic head and neck cancer. Patients with recurrent or metastatic head and neck cancer and fibroblast growth factor(FGF)/FGFR alterations treated with gunagratinib in two prospective trials were combined (phase I ICP-CL-00301, n = 10; phase IIa ICP-CL-00304 at the recommended phase II dose [RP2D] of 20 mg once daily, n = 27). Confirmed objective response rate (Response Evaluation Criteria in Solid Tumours [RECIST] Version 1.1, investigator assessed) was the primary endpoint. Exploratory analyses examined efficacy by alteration type, with an RP2D sensitivity analysis and post-hoc CCND1 outcomes. Among 37 patients (23 head and neck squamous cell carcinoma, 9 nasopharyngeal carcinoma, 5 other; 78.4% with three or more prior therapy lines), confirmed the objective response rate at the RP2D (n = 27) was 7.4% (95% confidence interval 0.9-24.3) and disease control rate 55.6%, with no responses among FGFR-mutant patients (0/6) and single responses among fusions (1/2) and amplifications (1/6). In the pooled cohort (N = 37, including ten treated at sub-RP2D doses), objective response rate was 13.5% (95% confidence interval 4.5-28.8), disease control rate 56.8%, median progression-free survival 4.1 months, median duration of response 11.0 months and median overall survival 7.4 months. Four of five responses arose in receptor-level FGFR alterations rather than FGF3/4/19 amplification alone; because both mutation responses occurred at sub-RP2D doses, this pattern is hypothesis generating. Grade &#x2265;3 treatment-related adverse events occurred in 35.1%, most commonly hyperphosphataemia; no treatment-related deaths occurred. At the RP2D, gunagratinib monotherapy had limited activity (0/6 among FGFR-mutant tumours). In the pooled cohort, confirmed responses concentrated among FGFR receptor-level alterations rather than the FGF3/4/19-amplified majority; because part of this signal came from sub-RP2D dosing, alteration type is a candidate enrichment criterion requiring prospective RP2D testing. ClinicalTrials.gov, NCT03758664 (registered 29 November, 2018) and NCT05372120 (registered 12 May, 2022, retrospectively).

A 32-year-old male patient presented with symptoms of gastric outlet obstruction secondary to distal gastric adenocarcinoma. A fully covered self-expanding metal stent (SEMS) measuring 20 mm &#xd7; 130 mm was placed to relieve obstruction and restore oral intake, with the aim of optimizing the patient for planned perioperative chemotherapy. The patient subsequently received neoadjuvant FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy as per recommendations of the multidisciplinary team&#xa0;and completed three cycles uneventfully. Before scheduled restaging imaging and completion of the fourth cycle, he developed sudden-onset abdominal pain with signs of generalized peritonitis. Imaging revealed pneumoperitoneum, and an emergency exploratory laparotomy was performed. Intraoperatively, a perforation was identified in the ascending colon near the hepatic flexure. A right hemicolectomy was carried out. Histopathological examination demonstrated a foreign body consistent with a migrated stent embedded at the perforation site, confirming complete transintestinal migration of the gastric stent as the cause of colonic perforation. This case highlights a rare but serious complication of fully covered gastric SEMS, particularly in patients receiving neoadjuvant chemotherapy, and emphasizes the need for clinical vigilance even in the absence of interim symptoms.

Patients with chronic hepatitis C and advanced fibrosis remain at substantial risk of hepatocellular carcinoma (HCC) and non-liver-related death even after sustained virological response (SVR) to direct-acting antivirals (DAA). Serum agalactosyl IgG (agal-IgG) reflects chronic inflammation and fibrogenic activity, but its prognostic value after SVR is unknown. We investigated whether serum agal-IgG at end of treatment (EOT) predicts HCC and all-cause mortality in DAA-treated patients with advanced fibrosis. Among 3550 patients with chronic hepatitis C treated with DAAs at Osaka University Hospital and affiliated centers, the stored sera of 136 patients with biopsy-proven F3-F4 fibrosis before DAA treatment, who achieved SVR, and had no history of HCC were available at EOT. Serum agal-IgG at EOT was measured using a 42B1-based ELISA. During a median follow-up of 68.7&#xa0;months (interquartile range, 36.8-84.9) for HCC surveillance, 15 patients developed HCC. Over a median overall follow-up of 73.7&#xa0;months (54.5-86.7), 11 patients died. Higher EOT agal-IgG levels were significantly associated with both HCC occurrence and all-cause mortality, and these associations remained independent after adjustment for age, sex, and baseline fibrosis (FIB-4 index). The adjusted hazard ratios per 1-unit increase in agal-IgG were 1.050 (95% CI, 1.008-1.094) for HCC and 1.085 (95% CI, 1.035-1.137) for all-cause mortality. Patients with EOT agal-IgG levels above the cohort median also showed significantly higher cumulative incidences of HCC and all-cause death than those with lower levels. Serum agalactosyl IgG measured at the end of DAA therapy independently predicts HCC and all-cause mortality after SVR in patients with chronic hepatitis C and advanced fibrosis. EOT agal-IgG may offer additional prognostic information for post-SVR risk stratification and help identify patients at higher risk of HCC and all-cause mortality after SVR.

CT-P16 (Vegzelma&#xae;) is a bevacizumab biosimilar approved for indications including non-squamous non-small cell lung cancer. We developed an integrated population pharmacokinetic model pooling data from two phase I studies in healthy subjects and one phase III study in patients with non-small cell lung cancer to (i) quantify the influence of the drug product on pharmacokinetic parameters within a single unified framework simultaneously evaluating CT-P16 against both EU-Avastin&#xae; and US-Avastin&#xae;; (ii) characterise covariate-driven exposure variability, including disease-status effects, across healthy subjects and patients with non-small cell lung cancer, and compare these effects with previously reported analyses of reference bevacizumab and other bevacizumab biosimilars; and (iii) contextualise simulated steady-state exposure under the approved 15 mg/kg every-3-weeks regime against a published exposure-response benchmark, thereby supporting a biosimilar assessment within the streamlined regulatory paradigm. Concentration data from one phase III trial (NCT03676192) and two phase I trials (NCT03247673; CT-P16 1.2) were pooled. The population pharmacokinetic analysis used nonlinear mixed-effects modelling in NONMEM&#xae; (Version 7.4) with first-order conditional estimation with interaction. Drug product (CT-P16, EU-Avastin&#xae;, US-Avastin&#xae;) and clinical/demographic covariates were evaluated by stepwise selection. Model adequacy was assessed by goodness-of-fit diagnostics, non-parametric bootstrap resampling (1000 replicates), and a visual predictive check. Steady-state exposure under 15 mg/kg every 3 weeks was simulated using both typical population-predicted profiles and the observed phase III patient covariate distribution with inter-individual variability. A total of 8058 serum concentrations from 834 subjects (phase I: 187 healthy male volunteers; phase III: 649 patients with non-small cell lung cancer) were analyzed. A two-compartment model with first-order elimination adequately described the pooled data. Body weight, sex, and disease status were retained as covariates on clearance; sex, baseline serum albumin, and disease status were retained on central volume of distribution. Drug product was not retained as a significant covariate, indicating no clinically meaningful difference between CT-P16 and either EU-Avastin&#xae; or US-Avastin&#xae;. The estimated body-weight exponent on clearance (0.369) was numerically indistinguishable from previously published values for reference bevacizumab (0.368 [11]) and for the bevacizumab biosimilar PF-06439535 (0.354 [24]). Across covariate-defined subgroups, the median simulated steady-state trough concentrations remained above the published progression-free-survival reference of 89.1 &#xb5;g/mL. Within a unified population pharmacokinetic framework, CT-P16 demonstrated comparable pharmacokinetics to both EU-Avastin&#xae; and US-Avastin&#xae;, with no clinically meaningful drug-product effect on clearance or central volume of distribution. Covariate effects mirrored those reported for reference bevacizumab, and simulated steady-state exposures were generally consistent with a published progression-free-survival-based exposure benchmark at the median level across covariate-defined patient subgroups. These findings extend the totality of evidence supporting CT-P16 biosimilarity and illustrate how population pharmacokinetic modelling can quantitatively inform a streamlined biosimilar assessment in the era of reduced reliance on comparative clinical efficacy trials. NCT03247673; NCT03676192.

The growing availability of public genomic repositories led to increased use of integrative and meta-analytic approaches to combine multi-omics datasets for biomarker discovery. Building on this framework, our study applies a molecular discovery approach to identify diagnostic biomarkers for cervical pre-cancer in high-risk HPV-positive women using aggregated genomic evidence across populations. This study performed a secondary analysis of publicly available DNA-methylation datasets identified through a systematic search of the Gene Expression Omnibus database to enable integrative analysis. After employing standard preprocessing methods across the selected DNA-methylation datasets, statistical analyses (specifically limma and meta-analysis with a random-effects model) were used to calculate the cumulative standardized effect sizes for all 9570 genes across the 4 selected studies. This cross-dataset analysis led to the identification of 4 promising, non-population-specific genes, that show potential for detecting precancerous cervical lesions in high-risk HPV-positive women. Collectively, these genes reflect a molecular profile associated with Cervical Intraepithelial Neoplasia lesions undergoing malignant progression. By leveraging aggregated data, our findings enhance the potential of generalization of biomarker signals and illustrate the strength of multi-data sets integration in advancing cervical pre-cancer triage screening strategies. Given their diagnostic promise, further experimental validation in large and diverse cohorts is warranted to evaluate their clinical applicability.