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PubMed2026

Evaluation of a cornea-specialized large language model for diagnostic and management accuracy in complex corneal cases.

PURPOSE: To evaluate whether a cornea-specialized large language model (LLM) enhanced with retrieval-augmented generation (RAG) improves clinicians' diagnostic and management accuracy in complex corneal cases compared to a general-purpose GPT-4o model and unaided clinician performance. METHODS: This prospective, randomized, masked evaluation study involved three cornea trainees who each independently reviewed 39 real-world corneal cases under three experimental conditions: unaided, GPT-4o-assisted, and assisted by a cornea-specialized GPT-4o model. The cornea-specialized model was constructed by embedding over 200 publicly available Wikipedia articles into GPT-4o's RAG framework. Participants provided open-ended diagnoses and selected the next-step management options (multiple choice). They were allowed up to three GPT-4o queries per case, and the AI-assisted arms were randomized to minimize bias. Accuracy for both tasks was compared against expert reference standards using McNemar's test. RESULTS: Diagnostic accuracy was 48.7%, 20.5%, and 38.5% unaided, improving to 69.2%, 46.2%, and 59.0% with general GPT-4o (p<0.04). The cornea-specialized GPT-4o further improved accuracy to 71.8%, 48.7%, and 74.4%, with improvements over unaided performance for all clinicians (p<0.01). For next-step decisions, unaided accuracy was 76.9%, 87.2%, and 59.0%. With the specialized model, Ophthalmologist 3 improved to 71.8% (p<0.05), Ophthalmologist 1 remained high at 82.1%, and Ophthalmologist 2 declined to 64.1% (p<0.05). CONCLUSIONS: A cornea-specialized LLM enhanced with RAG improved diagnostic accuracy in complex corneal cases, particularly among clinicians with lower baseline performance. Effects on management accuracy were inconsistent. Future studies should explore the use of open-ended management tasks and examine whether smaller, curated retrieval corpora yield better model performance.

Humans↗

PubMed2026

Preoperative intramuscular testosterone and urethrocutaneous fistula formation after primary hypospadias repair.

INTRODUCTION: Preoperative androgen stimulation is widely used before hypospadias repair to increase penile dimensions and optimise surgical conditions. However, its impact on postoperative complications, particularly urethrocutaneous fistula formation, remains controversial. OBJECTIVE: To evaluate the association between preoperative intramuscular testosterone therapy and urethrocutaneous fistula formation in children undergoing primary hypospadias repair. STUDY DESIGN: This was a retrospective comparative analysis of prospectively collected clinical data from 111 boys undergoing primary hypospadias repair at a single tertiary pediatric urology center. Patients were divided into two groups: those who did not receive hormonal therapy (Group 1, n = 55) and those who received intramuscular testosterone enanthate (2 mg/kg administered 5 and 2 weeks before surgery; Group 2, n = 56). Preoperative penile measurements, operative characteristics, and postoperative complications were compared. The primary outcome was urethrocutaneous fistula formation. The mean follow-up duration was 11.9 months (median 7 months). RESULTS: Preoperative testosterone therapy was associated with significant increases in glans diameter and stretched penile length at the time of surgery. The hormone-treated group had a significantly higher proportion of proximal hypospadias (p = 0.001), underwent more complex urethroplasty procedures, and had longer operative times (p = 0.007). Postoperative edema and local inflammatory changes were more frequently observed in the hormone-treated group. Despite these differences, urethrocutaneous fistula occurred in four patients in each group (7.3% vs 7.1%, p = 0.357), with no statistically significant difference between groups. DISCUSSION: Despite greater baseline anatomical severity and operative complexity in the hormone-treated group, preoperative testosterone administration was not associated with an increased risk of urethrocutaneous fistula. These findings suggest that improved tissue bulk and vascularity may offset the potential adverse effects of transient inflammatory changes. CONCLUSION: Selective preoperative intramuscular testosterone therapy was not associated with increased urethrocutaneous fistula risk and may be considered a reasonable adjunct in appropriately selected patients undergoing primary hypospadias repair. CLINICAL/TRANSLATIONAL APPLICABILITY: These findings provide clinical reassurance that preoperative testosterone can be used selectively in patients with smaller penile dimensions or anticipated technical difficulty without increasing fistula risk, thereby supporting shared decision-making in clinical practice.

Humans↗

PubMed2026

Physical reconfiguration of limb electrodes for Precordial Bipolar Lead acquisition: Morphological validation against digital subtraction.

BACKGROUND: The V2 - V1 Precordial Bipolar Lead (PBL) selectively evaluates the right-to-left retrosternal axis and has shown diagnostic value beyond the standard 12‑lead electrocardiogram. However, its use has been limited by the need for raw electrocardiographic data and post-processing software. This study evaluated whether a simple physical reconfiguration of limb electrodes could reproduce the digitally derived V2 - V1 morphology with sufficient accuracy for clinical application. METHODS: Thirty-seven subjects underwent two sequential 10-s 12‑lead recordings using a Cardiovit FT-1 electrocardiograph sampled at 1000 Hz. In the standard recording, the digital PBL was calculated as V2 - V1. In the second recording, the right-arm and left-arm electrodes were repositioned to the V1 and V2 sites so that Lead I directly recorded the retrosternal dipole. Signals were filtered, synchronized, and analyzed using median beats. Morphological agreement was assessed with Pearson correlation on Z-normalized signals, while absolute agreement was evaluated using Lin's concordance correlation coefficient (CCC), intraclass correlation coefficient (ICC (Lewis, 1931; Nehb, 1938 [1,2])), root mean square error (RMSE), and Bland-Altman analysis. RESULTS: Mean Pearson correlation between digital and physical PBL was 0.955 (SD 0.043), with segment-specific correlations of 0.953 (SD 0.054) for QRS and 0.967 (SD 0.052) for ST-T. Lin's CCC and ICC(2,1) were both 0.871 (SD 0.110), and RMSE was 0.091 (SD 0.049) mV. Bland-Altman analysis showed minimal bias (-0.008 mV). CONCLUSIONS: Physical acquisition of the V2 - V1 PBL achieved high agreement with the digitally derived signal, supporting a simplified analog method for broader clinical implementation.

Humans↗

PubMed2026

Incidence and risk factors for malignancy in patients with incidental solitary pulmonary nodules: a systematic review and meta-analysis.

BACKGROUND: The increasing use of chest imaging has led to a higher detection rate of incidental solitary pulmonary nodules (SPNs), often causing patient anxiety. Determining the malignancy rate and associated risk factors is crucial for developing appropriate follow-up strategies to prevent overdiagnosis, overtreatment, or missed diagnoses. This meta-analysis aims to investigate the malignancy rate and risk factors in patients with incidental SPNs. METHODS: A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted up to June 30, 2025. Data on malignancy rates and potential risk factors were extracted from eligible studies. All pooled analyses were performed using a random-effects model. RESULTS: Fifty-four studies involving 19,985 patients were included. The pooled malignancy rate for incidental SPNs was 56.7% (95% CI: 51.5-62.0), with significant between-study heterogeneity (I2 = 98.5%, p < 0.001). The pooled effect size showed a minimal change after adjustment for potential publication bias using the non-parametric Trim-and-Fill method (54.7%; 95%CI: 50.9-58.8). Risk factor analysis identified that older age, history of cancer, cigarette smoker, larger nodule diameter, spiculation, upper lobe location, lobulation, pleural indentation, vascular convergence, solid nodules, family history of cancer, and irregular or ill-defined margins were significantly associated with an increased risk of malignancy. Conversely, male sex, presence of calcification, and clear borders were significantly associated with a reduced risk of malignancy. CONCLUSION: This meta-analysis provides a comprehensive assessment of malignancy rates and risk factors in incidental SPNs. The high pooled malignancy rate should be interpreted considering the significant heterogeneity and the inclusion of a high proportion of retrospective studies and populations from high-risk regions. Nonetheless, these findings offer essential evidence for clinical risk stratification, supporting optimized follow-up and informed decision-making.

Humans↗

PubMed2026

Effects of Progressive Inspiratory Muscle Training on Lung Volume and Respiratory Strength in Patients With Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Chronic kidney disease can present changes in thoracic cavity volume and respiratory muscle weakness, even in the pre-dialysis stage. However, there is little evidence on the effects of inspiratory muscle training in these patients. METHODS: This was a randomized clinical trial which comprised patients with Chronic Kidney Disease in stages 3, 4, and 5 undergoing conservative treatment, allocated experimental group (EG) with progressive loading (up to 50% of maximal inspiratory pressure [MIP]) and control group (CG) with a fixed load (5 cmH2O) and no load progression performed daily for 8 weeks. The outcomes assessed were thoracic cavity volumes, as measured by optoelectronic plethysmography, and inspiratory and expiratory respiratory muscle strength. RESULTS: A total of 30 patients completed the study. All volumes significantly increased at the end of the protocol with a large effect size, but only the pulmonary thoracic cavity volume showed a significant interaction (F = 3.698; p = 0.042). There was an increase in inspiratory muscle strength in the EG (73.88-90.35 cmH2O; p < 0.001) and in the CG (70.85-86.92 cmH2O; p = 0.001), as well as in expiratory muscle strength in the EG (97.71-108.53 cmH2O; p = 0.001) and in the CG (80.69-94.77 cmH2O; p = 0.004). CONCLUSION: Daily IMT increased thoracoabdominal volumes, particularly pulmonary rib cage volume in the progressive-load group, as well as respiratory muscle strength in patients with pre-dialysis CKD. However, progressive-load IMT was not superior to minimal-load training.

Humans↗

PubMed2026

In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.

Hyperoxaluria, Primary↗

PubMed2026

Application of musculoskeletal ultrasound in postoperative rehabilitation assessment and monitoring after rotator cuff repair: A systematic review.

BACKGROUND: The development of rehabilitation protocols after rotator cuff repair has long lacked objective benchmarks. Traditional time‑based regimens are limited by considerable inter‑individual variability and an increased risk of re‑tear. Musculoskeletal ultrasound allows dynamic assessment of tendon healing and muscle morphology, yet evidence for directly linking its use to rehabilitation decisions remains scarce. OBJECTIVE: To systematically synthesize the evidence on the use of musculoskeletal ultrasound monitoring to inform rehabilitation decision‑making after rotator cuff repair. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidelines, we searched PubMed, China National Knowledge Infrastructure (CNKI), and Wanfang Data from January 2020 to April 2026. Original studies were included if they involved patients who had undergone rotator cuff repair, used musculoskeletal ultrasound (including gray‑scale ultrasound, elastography, etc.) to evaluate the rotator cuff tendons or shoulder muscles, and reported at least one parameter related to rehabilitation decision-making or functional outcomes. RESULTS: Eleven studies were included. Shear wave velocity (SWV), cross‑sectional area (CSA), and echo intensity (EI) were the most frequently reported ultrasound parameters. Available evidence indicated that SWV increased progressively after surgery, with an overall increase of approximately 22% to 25% from one week to 12 months postoperatively. This dynamic trajectory may serve as a reference baseline for judging rehabilitation progress. An abnormally elevated SWV in the early postoperative period was associated with an increased risk of re‑tear, suggesting that a more conservative rehabilitation strategy should be adopted. Tendon stiffness measured at 12 weeks after surgery independently predicted long‑term return to sport. Regarding muscle parameters, changes in CSA and EI were positively correlated with shoulder function scores, and the combination of these two parameters effectively identified patients with rehabilitation bottlenecks. CONCLUSION: Musculoskeletal ultrasound parameters are associated with the initiation of active movement, adjustment of exercise load, prediction of return‑to‑sport prognosis, and identification of retear risk. Among these, SWV shows particular promise as an objective monitoring parameter for supporting rehabilitation assessment after rotator cuff repair. Future randomized controlled trials are needed to determine whether ultrasound-informed assessment can improve rehabilitation outcomes compared with traditional time-based regimens, and to establish standardized measurement protocols and clinically applicable reference values. Key findings of this review are summarized in S1 File.

Humans↗

PubMed2026

Acute Performance, Mechanical and Thermal Effects of Isometric Conditioning Versus Standardized Volleyball Pre-Training Activation in Highly Trained Male Players.

This study compared acute performance, neuromuscular, and thermal responses to a maximal isometric conditioning activity (ICA) versus a standardized volleyball pre-training activation (VPA) in highly trained male volleyball players, and to explore putative mechanisms underpinning post-activation performance enhancement (PAPE) considering training load. In a randomized crossover, 14 men (27 ± 3 y) completed two sessions: VPA (mobility/plyometric drills; 9 min), and ICA comprising 3×5×3-s maximal isometric back-squat contractions (knee angle 120°; 3-min inter-set rest). Countermovement jump (CMJ) height (primary), relative peak power (PP), RSImod, and contraction time (CT) were recorded pre and 3, 6, 9, and 12 min post. Rectus femoris muscle viscoelastic properties and skin surface temperature (SST) were assessed at matched time points. Analyses used repeated-measures ANOVA, responder analysis, correlations, and regression. Period×Sequence interactions favored ICA for CMJ and PP when delivered in Period 2 (lower training volume): ∆CMJ was higher under ICA versus VPA (p = 0.005, d = 1.20); PP likewise greater (p = 0.026, ηp2 = 0.35). ICA yielded more beneficial responders than VPA (9/14 vs 1/14; McNemar exact p = 0.021). In Period 2, reductions in rectus femoris muscle stiffness independently predicted CMJ gains (β_std = -0.495, p = 0.005), whereas SST changes did not (p = 0.974). RSImod and CT showed no differences. A brief, high-effort isometric squat protocol was associated with superior acute improvements in jump performance compared with a standard volleyball warm-up, but this advantage emerged specifically when the preceding training volume was reduced (Period 2), suggesting that residual fatigue from training may reduce the effects of PAPE. Gains align with neuro-mechanical rather than thermal mechanisms, supporting ICA as a practical, equipment-minimal priming strategy for elite volleyball.

Humans↗

PubMed2026

Dual-Reporter Gene-Based Multimodal Imaging for Tracking Mesenchymal Stem Cells in Diabetic Skin Wound Repair.

BACKGROUND: Diabetic foot ulcer (DFU) is a clinically challenging complication characterized by poor healing outcomes, and conventional therapies provide limited benefit. Mesenchymal stem cell (MSC) transplantation offers a promising strategy for DFU repair. However, the low survival of transplanted MSCs in the hostile wound microenvironment, coupled with the lack of real-time, non-invasive methods to track these cells in vivo, severely hampers their therapeutic efficacy and clinical translation. METHODS: We engineered MSCs to co-express a dual reporter system comprising near-infrared fluorescent protein (iRFP) and ferritin heavy chain (FTH1). These modified cells were then integrated with a fibrin glue (FG) scaffold to create a unified platform that supports both multimodal imaging and therapeutic function within skin wounds. First, FTH1 overexpression enhances the antioxidant capacity of MSCs, while the FG scaffold provides structural support; this combination enhances cell survival and retention. Second, the iRFP/FTH1 dual reporter enables near-infrared fluorescence imaging and MRI-based localization, establishing a multimodal platform for real-time cell tracking. RESULTS: In a full-thickness skin defect model in diabetic mice, multimodal imaging revealed that transplanted cells persisted in the wound area for approximately seven days. Treatment with iRFP/FTH1-MSCs/FG significantly accelerated wound closure and promoted hair follicle regeneration and angiogenesis. Additionally, local iron deposition resulting from FTH1 expression enhanced fibroblast migration and collagen synthesis, further facilitating extracellular matrix remodeling. Mechanistic studies demonstrated that this therapy drives macrophage polarization toward the anti-inflammatory M2 phenotype and activates the PI3K-AKT-VEGF signaling pathway. These complementary effects synergistically enhance tissue regeneration and systematically improve diabetic wound healing. CONCLUSIONS: Collectively, this multimodal stem cell-scaffold system effectively integrates dynamic cell tracking with stem cell therapy during skin wound repair. It addresses a critical technical gap in visualizing stem cells within the wound microenvironment and provides valuable methodological and theoretical foundations for optimizing regenerative strategies for diabetic skin wounds.

Animals↗

PubMed2026

Clinical Trial: Effectiveness and Safety of a Novel Anal Insert Device for Treatment of Faecal Incontinence.

BACKGROUND: Treatment options for medically-refractory faecal incontinence (FI)-including anorectal biofeedback, dextranomer injection, and sacral nerve stimulation-are limited and outcomes are often suboptimal. Anal or vaginal insert devices are infrequently used. AIMS: We evaluated the safety and effectiveness of a new anal insert device (StaySure) in patients with FI. METHODS: Patients with FI for ≥ 6 months and ≥ 4 moderate or large FI episodes during a 4-week baseline entered a 2-4 week fitting/run-in period to individualise device size (10 or 13 mm) followed by a 4-week treatment period. Outcomes included effectiveness, safety, and quality of life (QoL). The primary outcome was the proportion achieving a ≥ 50% reduction in FI frequency. RESULTS: Of 124 enrolled patients, 98, 71, and 61 progressed through the baseline, fitting/run-in, and treatment phases respectively, with few exclusions due to device intolerance. In the intent-to-treat cohort of 59 participants (93% women), mean (SD) number of days with FI declined from 13.2 (7.0) to 6.3 (6.9), and FI weekly episodes declined from 5.4 (6.9) to 2.1 (5.1) (69% reduction; p < 0.001) with similar results for both device sizes. The primary endpoint was achieved in 76.3% of participants; 54.2% achieved ≥ 75% reduction. The FIQoL overall score increased from a mean (SD) of 1.9 (0.6) to 2.3 (0.6) (p < 0.001), indicating improved QoL. Improvements in FI frequency, FIQoL exceeded minimal clinically important difference thresholds, confirming clear clinical benefit. No treatment-related serious adverse events were reported. CONCLUSIONS: The StaySure anal insert device is safe, well tolerated, and effective in reducing FI in patients with moderate to severe symptoms refractory to conservative therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03898778.

Adult↗

PubMed2026

Comparison between measured and synthesized posterior lead electrocardiograms during percutaneous coronary intervention-induced myocardial ischemia.

BACKGROUND: Posterior/inferolateral myocardial ischemia is frequently underrecognized on standard 12‑lead electrocardiography (ECG). Synthesized posterior leads derived from the standard 12‑lead ECG have been proposed as an alternative to directly measured posterior leads; however, their accuracy under controlled ischemic conditions has not been fully validated. METHODS: We prospectively enrolled 26 consecutive patients undergoing percutaneous coronary intervention (PCI) in whom simultaneously recorded measured and synthesized posterior lead ECGs (V7-V9) were obtained during balloon-induced myocardial ischemia. ST-segment deviation was measured at the ST junction (STJ), 40 ms (ST1), and 80 ms (ST2) thereafter. Agreement between measured and synthesized posterior leads was assessed using Pearson correlation and Bland-Altman analyses. As an exploratory patient-level analysis, diagnostic performance was compared with reciprocal anterior ST-segment depression (V1-V4). RESULTS: Strong correlations were observed between measured and synthesized posterior lead ST-segment deviations (V7: r = 0.89; V8: r = 0.86; V9: r = 0.83; all P < 0.001). Bland-Altman analysis demonstrated minimal systematic bias (within ±0.004 mV) and narrow limits of agreement. Synthesized posterior leads showed higher diagnostic performance than reciprocal anterior ST-segment depression (AUC 0.917 vs. 0.708), although the difference was not statistically significant (DeLong test, P = 0.197). Using a 0.05 mV threshold, synthesized posterior leads demonstrated 83.3% sensitivity, 100% specificity, and 96.2% overall accuracy. CONCLUSIONS: Synthesized posterior leads closely reproduced measured posterior lead ST-segment deviations during percutaneous coronary intervention (PCI)-induced myocardial ischemia, supporting the technical validity of posterior lead reconstruction. Larger prospective studies are warranted to determine whether synthesized posterior leads provide incremental diagnostic value beyond careful interpretation of the standard 12‑lead ECG.

Humans↗

PubMed2026

Skin barrier repairing and anti-aging effects evaluation of a comprehensive topical regimen incorporating niacinamide, Pro-Xylane, and panthenol after PicoWay laser: a randomized controlled study.

Pro-Xylane is a potent anti-aging ingredient; however, there is limited knowledge regarding whether a comprehensive post-procedure regimen incorporating a combination of Pro-Xylane, niacinamide, and panthenol alongside other active agents can deliver synergistic benefits for both skin barrier repair and anti-aging. This study assesses the effectiveness of the REGENMEDIC cream (anti-aging cream) and REGENMEDIC serum (anti-aging serum) in promoting skin barrier recovery and enhancing anti-aging effects following PicoWay laser treatment. A 112-day randomized controlled trial was conducted with 88 Chinese females, who were divided into two groups: the test group, using REGENMEDIC cream and Serum following PicoWay laser treatment, and the control group, using standard care regimen consisting of a standard cream. Skin barrier-repairing effects were assessed during the initial 14 days following a single use of REGENMEDIC cream, while skin elasticity, firmness, wrinkles and skin tone were evaluated over the 112-day study period after the combined use of REGENMEDIC cream and Serum. The test group exhibited lower transepidermal water loss (TEWL) and higher hydration after 14 days compared to the control group, along with a more significant reduction in skin redness. After 112-day use of REGENMEDIC cream and serum, test group showed increased skin elasticity and firmness, reduced wrinkles, and an overall improvement in skin tone and texture. Dermatologists reported excellent tolerability, with minimal adverse events. Initial application of the REGENMEDIC cream facilitated rapid skin barrier repair, while the subsequent sequential regimen incorporating the serum yielded significant long-term anti-aging benefits following PicoWay laser treatment. This study demonstrates that targeting multiple physiological pathways-specifically hydration, barrier integrity, and cellular senescence-provides a robust therapeutic option for amplifying the anti-aging outcomes of aesthetic procedures.

Humans↗

PubMed2026

Mortality of Individuals With PRNP Variants Associated With Prion Disease in the United States, 1998-2024.

BACKGROUND AND OBJECTIVES: To characterize the survival of individuals with pathogenic PRNP variants-including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. METHODS: In this single-center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center (NPDPSC), including both diagnostic tests in symptomatic individuals, and predictive tests in asymptomatic individuals. Genetic test and autopsy results were queried from the NPDPSC database, and public record searches were conducted using online tools. RESULTS: Four hundred four individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated 92.6% sensitivity. We evaluated the age-dependent penetrance of the reportedly highly penetrance variants D178N and E200K and the reportedly low-penetrance variant V210I. Among 99 initially asymptomatic individuals with the pathogenic E200K variant, more than 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. For the pathogenic D178N variant, the median age at death was 57, which was numerically later, but not significantly different from, that seen in retrospective data. For V210I, just 2 deaths occurred, both after age 90, consistent with minimal penetrance. DISCUSSION: Our data support high penetrance of PRNP D178N and E200K variants and low penetrance of V210I. For E200K, the age at onset distribution appears to be shifted slightly later, and lifetime risk slightly lower, than previously reported. Autopsy data and public death records in combination were sensitive and concordant for determining long-term outcomes, but additional prospective data should be gathered to support future preventive trials.

Journal Article↗

PubMed2026

Pembrolizumab-Chemotherapy Versus Pembrolizumab in Head and Neck Squamous Cell Carcinoma: A PD-L1 CPS-Stratified Analysis of Updated KEYNOTE-048 Data.

Based on KEYNOTE-048, pembrolizumab monotherapy and pembrolizumab-chemotherapy are established category 1 first-line treatments for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1. We compared their efficacy using updated trial data. We analyzed 4-year progression-free survival on next-line therapy (PFS2) and 5-year overall survival (OS) data from KEYNOTE-048 by reconstructing time-to-event data using KMSubtraction. Efficacy was compared in CPS 1-19 and CPS ≥ 20 subgroups using Kaplan-Meier estimates, Cox models, restricted mean survival time (RMST), and landmark analyses. Among 499 patients with CPS ≥ 1, 240 (48.1%) had CPS 1-19 and 259 (51.9%) had CPS ≥ 20. In the CPS 1-19 subgroup, pembrolizumab-chemotherapy showed numerically longer median PFS2 (10.1 vs. 8.0 months; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.62-1.06) and OS (12.8 vs. 10.8 months; HR: 0.87; 95% CI: 0.67-1.15) versus monotherapy, without statistical significance. For CPS ≥ 20 patients, efficacy was comparable between regimens, with similar median PFS2 (11.3 vs. 11.7 months; HR: 0.95) and OS (14.7 vs. 14.9 months; HR: 0.96). RMST and landmark analyses showed an early PFS2 benefit and a trend toward OS benefit with pembrolizumab-chemotherapy in CPS 1-19, with comparable outcomes in CPS ≥ 20. Pembrolizumab-chemotherapy showed a trend toward improved outcomes in the CPS 1-19 subgroup, with comparable efficacy in the CPS ≥ 20 subgroup, supporting a refined first-line strategy: monotherapy for CPS ≥ 20 to minimize toxicity, and combination therapy for CPS 1-19 to potentially enhance disease control.

Humans↗

PubMed2026

Diagnostic utility of high-risk HPV polymerase chain reaction-based testing in head and neck FNA specimens with indeterminate cytomorphology.

BACKGROUND: Fine-needle aspiration (FNA) is critical in the initial diagnosis of many high-risk human papillomavirus (HR-HPV)-associated, metastatic oropharyngeal squamous cell carcinomas. Updated guidelines recommend HR-HPV-specific polymerase chain reaction (PCR) analysis over p16 immunohistochemistry on FNA specimens because p16 performs poorly on cytology material. PCR-based assays on liquid cytology material have demonstrated excellent analytic performance; however, the diagnostic utility of a positive HR-HPV PCR result in specimens with indeterminate cytomorphology remains uncharacterized. METHODS: The authors retrospectively identified 279 head and neck FNA specimens that had paired HR-HPV PCR testing on residual liquid cytology material over a 5-year period. The positive predictive value for histopathologically confirmed squamous cell carcinoma on surgical follow-up was calculated within each cytologic interpretive category. RESULTS: The HR-HPV PCR results were positive in 50.2% of specimens, negative in 40.9%, and indeterminate in 9.0%. The HR-HPV positivity rate ranged from 0% in specimens categorized as negative for malignancy to 57.3% in cytologically positive specimens, with 19.0%, 41.2%, and 50.0% positivity in the atypical, suspicious, and nondiagnostic categories, respectively. Among cytologically indeterminate specimens with positive HR-HPV PCR results (n = 14), the positive predictive value was 100% (95% confidence interval, 78.5%-100.0%). Blinded slide review additionally identified 15 cytologically positive specimens in which the definitive malignant interpretation depended substantially on HR-HPV positivity; all 15 were confirmed as squamous cell carcinoma. CONCLUSIONS: A positive HR-HPV PCR result on liquid cytology material carries a positive predictive value of 100% for malignancy in cytologically indeterminate head and neck FNA specimens. These findings support integrating HR-HPV PCR analysis into routine cytologic interpretation with the potential to upgrade some indeterminate specimens to malignant when HR-HPV is detected, expediting definitive treatment and sparing patients additional, invasive sampling.

Humans↗

PubMed2026

Effects of exercise on muscle strength and characteristics in rheumatic diseases and sarcopenia: Protocol for the Care for Muscle (C4M) Study.

OBJECTIVE: Muscle weakness is prevalent in rheumatoid arthritis (RA), osteoarthritis (OA) and sarcopenia (SARC). Endurance exercises may improve mitochondrial function and oxidative capacity, while strength exercises are thought to stimulate myofibrillar protein synthesis. This study aims to compare the effects of strength and endurance exercise and explore the association between muscle characteristics and exercise outcomes in patients with RA, OA and SARC. We hypothesize that responses to endurance and strength exercises in patients with muscle weakness are influenced by intramuscular pathology including muscle morphology, mitochondrial function, and systemic inflammation, based on their disease pathology, potentially requiring personalized training schedules. METHODS: This two-arm, parallel-group exploratory trial will enroll 69 patients (23 RA, 23 OA, 23 SARC), randomized to endurance (n = 35) or muscle strength exercises (n = 34), using minimization to balance disease type and gender. The 8-week intervention includes two supervised sessions per week using a controlled cable pulley device (Reforter™) and fitness equipment, plus one weekly home-based session. The primary outcome is isokinetic muscle strength (peak torque), measured with the Biodex system®. Secondary outcomes include muscle morphology, mitochondrial function, systemic inflammation and muscle endurance (by Biodex and 6 Minute Walk test). Muscle morphology will be assessed via 3D ultrasound imaging of the vastus lateralis. Mitochondrial function will be analyzed using high-resolution respirometry on muscle biopsies. Systemic inflammation will be measured using multiplex assays or ELISA on serum samples. DISCUSSION: This study will explore differential responses to muscle endurance and muscle strength exercises in patients with RA, OA, and SARC, offering novel insights into the molecular mechanisms of muscle weakness. The findings may help identify potential mechanisms underlying variability in exercise response and provide effect size estimates to guide future confirmatory studies and more targeted exercise interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT06480643 (date of registration28-06-24).

Humans↗

PubMed2026

A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS. METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic. RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant. CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier CRD420251076035.

Humans↗

PubMed2026

Therapeutic-drug-monitoring-based ATG Targeted Dosing Strategy in Unmanipulated Haploidentical Haematopoietic Stem Cell Transplantation: a randomized, multicenter, phase 3 clinical trial.

Anti-thymocyte globulin (ATG) has been a standard prophylaxis for graft-versus-host disease (GVHD). However, the pharmacokinetics of ATG in vivo vary significantly, and weight-based fixed dosing may not optimize efficacy while minimizing toxicity. We investigated the clinical results of a therapeutic-drug-monitoring (TDM)-based, dose-optimized ATG strategy versus weight-based fixed dosing in haploidentical haematopoietic stem cell transplantation (NCT05166967). Patients were randomly assigned in a 1:1 ratio to receive a targeted dose of ATG or a fixed dose of 10 mg/kg. The primary endpoint was the 365-day graft-versus-host disease-free and relapse-free survival (GRFS). From January 1, 2022, to January 16, 2024, 204 patients were enrolled, with 102 patients in each group. The 365-day GRFS was higher in the targeted dose group (66.7%) than in the fixed dose group (50.0%; hazard ratio [HR], 0.666; 95% confidence interval [CI], 0.4456 to 0.9954; P = 0.048). The cumulative incidence of moderate to severe chronic GVHD at day 365 was significantly lower in the targeted dose group (9.8%; 95% CI, 5.0 to 16.5) compared with the fixed dose group (22.5%; 95% CI, 15.0 to 31.1; P = 0.026). Fewer grade 3-5 infections were reported in the targeted dose group (44.1%) than in the fixed dose group (70.6%; P < 0.001). More patients in the targeted dose group achieved optimal ATG exposure (P = 0.007) and superior CD4+ T-cell reconstitution (P = 0.002). These findings support the clinical utility of a TDM-based individualized ATG dosing strategy that balances efficacy and toxicity for GVHD prophylaxis in allogeneic stem cell transplantation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05166967.

Humans↗