Journal of Translational Medicine

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterised by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

Background: Alpha-1 antitrypsin deficiency (AATD) caused by the PI*ZZ mutation (Glu342Lys) results in hepatic accumulation of misfolded AAT-Z protein and reduced circulating AAT levels, leading to progressive liver disease and emphysema. Gene correction therapy represents a potentially curative approach by directly correcting the underlying genetic defect. We report the first case of successful hepatic gene correction with early histological and functional assessment. Methods/Case presentation: We report the case of a 66-year-old male patient with PI*ZZ AATD who underwent gene correction therapy within the YOLT-202 phase I/Ia clinical trial (clinical trial.gov ID NCT07193615). Ten weeks post treatment a liver biopsy was performed to re-evaluate pre-existing F2 liver fibrosis as measured by elastography before entering the study. Serum samples allowed functional assessment of the AAT-mediated elastase inhibition. Results: Liver biopsy did not show signs of hepatic inflammation and demonstrated 54% (Sanger) and 57% (Illumina) gene correction rate of the PI*ZZ variant on the DNA level with no bystander edits or off-target effects. Following a transient elevation of transaminases during the early post-treatment period, liver enzymes normalized. Monthly serum AAT measurements demonstrated biologically active and stable therapeutic levels throughout follow-up. Conclusions: This case demonstrates efficient and precise hepatic gene correction without concerning histological alterations and with substantial improvement of functional parameters, supporting the feasibility and safety of gene editing approaches for AATD.

Background: Obesity is becoming a global health crisis, and it leads to various metabolic disorders. Body mass index fails to differentiate fat mass from lean mass and systematically misclassifies adiposity risk - a limitation particularly pronounced in South Asian adults, who exhibit characteristically elevated visceral adiposity and reduced appendicular lean mass at a normal BMI. The 2025 Lancet Commission explicitly recommends direct adiposity measurement beyond BMI for obesity diagnosis. Weight loss interventions - whether dietary, behavioural, or pharmacological - are consistently associated with concurrent reductions in both fat mass and lean mass, making body composition monitoring essential beyond scale weight alone. Although DEXA is globally accepted as a gold standard for body composition analysis, the accessibility of DEXA is limited, particularly in resource-constrained low and middle-income countries such as India. BIA devices are a convenient low-cost option to DEXA and can be used for body composition analysis more frequently than a DEXA scan to provide longitudinal data. The aim of this study is to validate 8 electrode BIA devices as a viable alternative to DEXA scan for the South Asian population. Methods: A prospective cross-sectional validation study was conducted following ethics committee approval, with a priori sample size estimation ( = 0.05, power = 80%). Fifty-eight healthy adults (n=58) underwent three BIA measurements and one DEXA scan each. To ensure statistical independence, the three BIA readings per participant were averaged, yielding 58 final measurements for validation. Body fat percentage, lean mass and fat mass were evaluated using Python with statistical analyses like Bland Altman analysis, Pearson correlation, ICC and regression analysis. Results: In this BIA vs DEXA study, the Pearson correlation was strong across all three outcomes (fat%: r = 0.97; fat mass: r = 0.98; lean mass: r = 0.96), with ICC (2,1) values of 0.94, 0.97, and 0.91 confirming excellent absolute agreement. Mean absolute error was 3.40% for fat percentage, 1.96 kg for fat mass, and 3.37 kg for lean mass. BIA systematically underestimated body fat percentage (bias -1.96%, 95% CI: -2.91% to -1.01%; LoA: -9.04% to +5.12%) and fat mass (bias -0.72 kg, 95% CI: -1.38 to -0.07 kg; LoA: -5.59 to +4.14 kg), while overestimating lean mass by +3.08 kg (95% CI: +2.34 to +3.82 kg; LoA: -2.46 to +8.62 kg). Conclusions: The 8-electrode BIA device shows clinically acceptable agreement with DEXA for body composition assessment in healthy Indian adults. It offers a radiation-free, cost-effective, accessible, and portable alternative to DEXA, making it suitable for longitudinal monitoring and trend detection. The device is particularly valuable for obesity screening and for tracking body composition changes during weight loss interventions at the population level, addressing the critical need for accessible body composition assessment in resource-limited settings.

Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [≤] 96 hours, and experienced symptom onset [≤] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.

Background: Chronic diseases and symptom syndromes often develop after prolonged biological changes that may precede formal diagnosis. RNA-based metatranscriptomics captures active microbial and human gene expression and may provide a functional layer for disease risk evaluation. To address this translational gap, we developed and validated a Disease Risk Score (DRS) framework that integrates metatranscriptome-derived pathway activity scores from stool, saliva, and blood samples, and evaluated its potential clinical utility as an adjunct risk-evaluation tool. Methods: DRS uses disease-specific sets of pathway activity scores derived from stool and saliva microbial functions, stool and saliva microbial taxa, and blood human gene expression. For each disease, 'not optimal' pathway scores are aggregated into a normalized cumulative odds ratio, or cOR, using score-level odds ratios, statistical significance, and literature-supported biological relevance derived from a Development Cohort of 22,369 individuals. A cOR [≥] 5 is defined as high risk. Performance is evaluated in an independent Validation Cohort of 15,908 individuals using self-reported diseases as the reference. Disease support requires both significant cOR separation between self-reported and not-reported (Cohen's d [≥] 0.2) and risk ratio enrichment of self-reported disease among individuals classified as high risk (95% CI of Risk Ratio > 1). Results: Of 20 initially evaluated diseases, 15 meet the prespecified validation criteria on the independent validation cohort: ADHD, anxiety, chronic fatigue syndrome, depression, GERD, hypertension, inflammatory bowel disease, IBS-C, IBS-D, insomnia, MASLD, obesity, obstructive sleep apnea, Sjogren's syndrome, and type 2 diabetes. Five selected clinical scenarios illustrate how DRS can support clinician-mediated decision making, including IBS subtype reclassification, improved diagnostic acceptance in IBS-D, personalized lifestyle counseling in MASLD and early type 2 diabetes, and diagnostic uncertainty in atypical GERD. Conclusions: DRS is a metatranscriptomics-based risk-stratification framework that aggregates active microbial and human pathway signals into interpretable disease-specific risk estimates across a wide range of disease conditions. Validation against self-reported disease labels in an independent cohort shows significant risk enrichment for each of 15 diseases. DRS is intended as an adjunct to clinical evaluation: a decision support tool in situations where routine care encounters uncertainty, delay, or low patient engagement. Future prospective studies using clinically adjudicated endpoints are needed to assess calibration and clinical outcomes.

Background and Aims: Fatigue is a prevalent and disabling symptom in inflammatory bowel disease (IBD), yet its underlying biological mechanisms remain poorly understood. We aimed to characterize fatigue-associated molecular signatures in IBD patients by integrating DNA methylation and mRNA expression analyses. Methods: Peripheral blood was collected from 40 patients with Crohn's disease (CD), 29 with ulcerative colitis (UC), and 10 healthy controls. Fatigue severity was assessed continuously using the Multidimensional Fatigue Inventory (MFI). Epigenome-wide DNA methylation profiling and mRNA sequencing were performed, identifying differentially methylated regions (DMRs) and differentially expressed genes (DEGs) for active and quiescent CD and UC, adjusting for age, sex, and smoking status. Pathway enrichment analysis was performed on genes with differential methylation and expression. Results: In active CD, more severe fatigue was associated with transcriptional suppression of immune and metabolic pathways (246 DMRs; 1,090 DEGs), versus upregulation of mitochondrial and metabolic processes in quiescent CD (200 DMRs; 1,619 DEGs). In active UC, fatigue was associated with anabolic pathway upregulation and epigenetic silencing of neuroactive pathways (6,927 DMRs; 343 DEGs; 56 concordant genes). Quiescent UC showed transcriptional changes without significant epigenetic pathway enrichment (1,710 DMRs; 3,224 DEGs). Healthy controls exhibited a distinct profile spanning metabolic, immune, and neuronal pathways (8,621 DMRs; 395 DEGs). Fatigue-associated signatures were largely non-overlapping across all five groups. Conclusions: Fatigue-associated molecular profiles differed substantially by disease subtype and activity state, highlighting the biological heterogeneity of IBD-related fatigue and laying the foundation for multi-omics approaches to identify biomarkers and potential therapeutic targets.

Objective To verify the reliability of a self developed bowel sound monitoring device under real biological tissue acoustic propagation conditions using a controllable sound source, and to establish quantitative evidence for its translational applicability. Methods Freshly euthanized six month old Bama miniature pigs were used as an experimental model. A high fidelity Bluetooth audio playback device was implanted into the abdominal cavity to deliver manually annotated bowel sound recordings as controllable acoustic stimuli. A self developed bowel sound monitoring device was fixed on the abdominal surface for continuous signal acquisition. Playback timestamps were defined as the ground truth, and event level matching was performed within a predefined temporal tolerance window. Four performance indicators were evaluated: (1) bowel sound acquisition and energy amplification, (2) event matching accuracy, (3) acoustic feature consistency, and (4) subjective agreement assessed by blinded auscultation from gastroenterologists with different levels of clinical experience. Results The monitoring device exhibited stable detection capability and effectively covered the full spectral range of the original signals. It significantly enhanced bowel sound energy while preserving temporal and spectral characteristics, demonstrating high consistency in time and frequency domain features. Blinded clinician assessments showed a subjective agreement rate of 88.9% between original and surface recorded bowel sound events. Conclusions Under real tissue acoustic propagation conditions, the self-developed bowel sound monitoring device reliably captures bowel sound events with high temporal accuracy, acoustic fidelity, and clinical perceptual consistency. This controllable sound source based validation provides robust technical evidence for subsequent in vivo studies and clinical translation, supporting the development of objective and continuous gastrointestinal function monitoring.

The increasing availability of portable ultrasound systems motivates exploration of novel approaches to respiratory signal assessment. In this in-vitro study, we investigate whether pulsed-wave (PW) Doppler ultrasound can capture structured spectral patterns from replayed lung sound recordings. Digitized respiratory sounds were replayed through a tissue-mimicking ultrasound phantom, generating 1,478 PW Doppler spectral images from recordings associated with healthy subjects and several externally labeled disease categories. Exploratory classification experiments using a ResNet-18 architecture demonstrated that these Doppler representations contain learnable differences under controlled conditions. These findings motivate further investigation into PW Doppler as a potential representation of respiratory acoustics.

Introduction: Synthetic oligopeptides provide a rapid and cost-efficient approach to developing antibodies and diagnostics for emerging viral variants. Methods: This study computationally and experimentally characterized a synthetic peptide analog of the SARS-CoV-2 spike subdomain 2 major disulfide loop (SD2MDL), designated S621 (CPVAIHADQLTPTWRVYSTC). Binding affinity was computationally estimated using the Heuristic Affinity Prediction Tool for Immune Complexes (HAPTIC), while experimental validation was performed using enzyme-linked immunosorbent assay (ELISA) with rabbit-derived antipeptide antibodies. Clinical diagnostic accuracy testing was done using plasma samples from RT-PCR-confirmed COVID-19 patients and pre-COVID-19 controls. Results: S621 demonstrated nanomolar binding affinity (Kdapp = 1.14 nM) and high avidity (3.67 nM), closely matching HAPTIC predictions (3.54 nM). Diagnostic evaluation yielded a sensitivity of 89.92% and specificity of 27.79%, corresponding to an overall accuracy of 71.79%. Discussion: These findings demonstrate that a single synthetic peptide derived from a conserved spike subdomain can function as a high-affinity surrogate for full-length antigens, supporting its potential application in rapid peptide-based immunodiagnostics.

Background: Unstructured data represent about 80% of total electronic health records (EHR) data. Structuring this free text is essential for advancing clinical research, including cohort selection for trials, retrospective studies, and the development of disease registries. While manual chart review (MCR) remains the gold standard for extracting this clinical data, the process is inherently slow, resource-intensive, and susceptible to errors from human fatigue. We evaluated the extraction accuracy, safety, and efficiency of the HeLIX (Hepatology Logic-Integrated Extraction) framework, a Large Language Model (LLM) protocol using Google Gemini 3 Pro, compared to a gold-standard Manual Chart Review (MCR). Methods: A prospective validation study was conducted using 50 high-complexity, simulated hepatology discharge summaries designed to replicate the real-world heterogeneity of EHRs. The HeLIX framework employed a Zero-Shot, Structured Chain-of-Thought (CoT) prompting strategy enforced by a three-layer architecture: Clinical Reasoning Trace, Schema Enforcement, and Evidence Verification. The model extracted 45 distinct clinical variables. Performance was benchmarked against a consensus MCR. Results: Across 2,250 evaluated data points, the model achieved an overall Extraction Accuracy of 99.24% (95% CI: 98.8%-99.5%), with perfect concordance in 35/45 (77.8%) variables. For binary diagnostic variables, the model demonstrated an overall F1-score of 0.98, Recall of 0.99 and substantial inter-rater reliability (Cohens {kappa} = 0.97). Hallucinations were exceptionally rare (2/2250; 0.08%). Critical errors affecting clinical management occurred in only 2 instances (<0.1% of total data), both involving etiological misattribution in complex multifactorial diagnoses. The AI workflow was 13.4-fold faster and 95.1% more cost-effective than manual extraction. Conclusion: The HeLIX framework demonstrates physician-level accuracy and reliability in extracting complex hepatology data. It offers a scalable, efficient, and economical alternative to manual chart review. Such frameworks could accelerate clinical research, enabling healthcare systems globally to build comprehensive patient registries for a fraction of the traditional cost.

PURPOSE: To develop and validate an artificial intelligence-enabled platform that converts unstructured cancer trial eligibility criteria into structured queries and quantifies trial eligibility across advanced/metastatic cancer trials. METHODS: We downloaded actively recruiting US interventional treatment trials for advanced/metastatic breast cancer, colon cancer, and non-small cell lung cancer from ClinicalTrials.gov. Medical oncologists created 24 synthetic patient vignettes. A large language model converted trial eligibility criteria into Structured Query Language (SQL) code and patient information into structured records, enabling automated matching. Cancer details and treatment history were considered, but not laboratory results or comorbidities. Validation included physician editing of generated eligibility code for 30 trials, and blinded physician eligibility assessment for five trials. We then evaluated how age, ECOG performance status, sex, and ZIP code affected the number of eligible trials. RESULTS: Of 833 candidate trials, 746 met inclusion criteria. In physician review of 30 trials, edits to generated SQL did not change any of 720 trial-patient eligibility determinations for 24 synthetic patients. In blinded validation across 120 trial-patient pairs, automated matching achieved 97% accuracy. Across synthetic patients, eligible trials ranged from 31 to 258 when there were no geographic restrictions. Eligibility decreased markedly with worse performance status and with geographic restriction (both p<0.001). Later-phase, randomized, and molecularly selective trials had fewer eligible patients. CONCLUSION: AI-based structuring of trial eligibility criteria can support accurate, scalable measurement of potential cancer trial eligibility. In this demonstration, performance status, geography, and age were major determinants of eligibility across the active metastatic trial landscape.

Background and Aims: MASLD has become the most prevalent chronic liver disease globally. Although MVPA and plasma fatty acids have been individually studied in relation to metabolic health, their independent and combined associations with MASLD incidence remain unclear. We aimed to investigate these associations. Methods: This study included 51,717 UK Biobank participants free of liver disease at baseline, with MVPA measured using wrist-worn accelerometers and plasma fatty acids quantified via NMR. Multivariable-adjusted Cox models and restricted cubic splines were used. Results: Over a median follow-up of 7.8 years, 472 incident cases were identified. In fully adjusted models, meeting recommended MVPA levels together with higher n-6 PUFA concentrations was associated with a 71% lower risk (HR 0.29, 95% CI 0.18-0.45). The MVPA-MASLD association was nonlinear, with risk reduction plateauing at approximately 189 minutes per week. Higher n-6 PUFA was associated with reduced risk, whereas n-3 PUFA showed no significant association. Conclusions: These findings suggest that behavioral and metabolic factors may jointly influence MASLD risk. Further studies in diverse populations are needed to confirm these associations.

Background: Low-intensity focused ultrasound (LIFU) is an emerging noninvasive neuromodulation technique capable of targeting deep cortical and subcortical structures with high spatial precision. In healthy human volunteers, LIFU has demonstrated a favorable safety and tolerability profile across multiple studies. However, its safety and tolerability in clinical populations remains poorly characterized, representing a critical barrier to clinical translation. Here, we prospectively evaluate the safety and tolerability of LIFU targeting the left dorsal anterior insula (dAI) in patients with fibromyalgia (FM). Methods: In a single-blind, sham-controlled, within-subjects crossover design, 13 individuals with FM (43.1 +/- 13.2 years; 12 female) received 10 minutes of active LIFU (500 kHz, 1 kHz PRF, 36% duty cycle, 4.2 W/cm2 Isppa; 100 x 1-second pulse trains with a 5-second inter-train interval) targeting the left dorsal anterior insula (dAI) or sham on separate visits. Safety was evaluated through neuroradiological review of post vs. pre LIFU FLAIR MRI, quantitative voxel-wise FLAIR analysis, and patient report of symptoms (ROS). Tolerability was assessed using an experience assessment. Efficacy of the LIFU intervention was assessed using quantitative sensory testing (QST) including temporal summation of pain (TSP) and conditioned pain modulation (CPM). Results: Neuroradiological review identified no new evidence of edema, microhemorrhage, acute ischemia, or white matter injury on post-LIFU structural imaging. Quantitative FLAIR analysis using contralateral-mirror-referenced relative FLAIR (rFLAIR) showed no significant within-subject change in the stimulated beam volume (delta rFLAIR = 0.002 +/- 0.025, t(12) = 0.30, P = 0.769, Cohen's dz = 0.08). No serious adverse events were documented and ROS indicated no change due to LIFU sonication. Participants rated the procedure as comfortable and could not distinguish active from sham LIFU. LIFU did not result in statistically significant changes for TSP (p = 0.797) or CPM (p = 0.465). Conclusions: Ten minutes of LIFU targeting the left dAI was safe and well tolerated in individuals with FM, with no neuroradiological or quantitative MRI evidence of tissue effects and no serious adverse events. Blinding was preserved, and participants rated the procedure as comfortable. Although no significant changes were observed in experimental pain measures, these findings support the feasibility of targeting deep salience and pain amplification circuitry with LIFU in patients with FM and provide a foundation for adequately powered efficacy trials.

Background: Histological examination of mucosal tissue in inflammatory bowel diseases (IBD) is a sensitive tool to measure disease activity, and histological remission is emerging as a potentially important treatment target. There are several existing histopathological indices, but they often encompass caveats such as not primarily having been designed to measure the degree of inflammation, encompassing subjective components with poor intra- and interindividual reproducibility, and requiring expert pathologists who are scarce, thus resulting in extended response times. Aim: To construct a new computerized, automated index to objectively measure histological disease activity in the ileal and colonic mucosa, applicable to both Crohn's disease (CD) and ulcerative colitis (UC). Materials and methods: Ileocolonic biopsies were collected from control subjects and patients with CD or UC. A group of CD patients was sampled before and after 12 weeks of anti-TNF therapy. Another group of CD and UC patients functioned as a small validation cohort. Epithelial cells, neutrophils, macrophages, and T cells were immunohistochemically stained, followed by digitalization of the color signal and computerized delineation of the epithelial and lamina propria compartments. The various immune cell types within the epithelium and the lamina propria, respectively, were enumerated, and the numbers were compared between control subjects and patients with CD or UC. Results: The numbers of neutrophils and macrophages in the epithelium, and neutrophils in the lamina propria, showed the highest sensitivity and specificity for distinguishing control-subject tissues from CD and UC tissues. These three parameters were thus chosen to construct a new index, named QiC3 1.0, that could separate tissues from control subjects and patients with CD or UC with high precision. It performed equally well in a small validation cohort of patients. The QiC3 index correlated well with previously described histopathological indices, fecal calprotectin, and endoscopic scores in UC, but showed worse correlation with endoscopic scores in CD and symptomatic scores. When applying the new index to tissues from CD patients before and after therapy, it showed good responsiveness, demonstrating a distinct amelioration in the microscopic inflammatory status that corresponded well to improvements in histopathological scores. Conclusion: We describe a new quantitative, computerized, automated, non-subjective, and response-sensitive immunohistological index (QiC3) for measuring disease activity in ileal and colonic mucosal biopsies, suitable for both CD and UC.

**Abstract** **Background:** Transcatheter edge-to-edge repair (TEER) is an established treatment for mitral regurgitation but remains highly dependent on operator experience and complex transesophageal echocardiography (TEE)-guided intraprocedural imaging. Artificial intelligence (AI)-based semantic segmentation may improve procedural reproducibility and intraprocedural guidance; however, no TEER-specific segmentation framework has been reported. **Objectives:** To develop and evaluate AutoClip, a clinician-driven AI-guided TEE semantic segmentation model designed for simultaneous delineation of mitral valve anatomy and in-vivo TEER device components. **Methods:** A retrospective proof-of-concept study was conducted using 987 intraprocedural TEE frames derived from 10 video clips in 3 patients undergoing MitraClip G4 implantation. Seven semantic labels, including mitral leaflets and device components, were manually annotated using ITK-SNAP. Following standardized preprocessing and region-of-interest extraction, an Attention U-Net architecture was trained frame-wise on bicommissural and corresponding X-plane TEE views. Model performance was assessed using mean intersection-over-union (IoU) and Dice coefficient on an independent test set. **Results:** The Attention U-Net demonstrated improved sensitivity to small device structures compared with conventional U-Net architectures. Preliminary training performance achieved a mean IoU of approximately 0.93, while independent test performance reached a mean IoU of 0.46 across foreground classes. Qualitative assessment demonstrated feasible simultaneous segmentation of mitral leaflets, clip arms, grippers, and delivery shaft during TEER procedures. **Conclusions:** AutoClip represents a proof-of-concept TEER-specific TEE semantic segmentation framework initiated through a clinician-oriented workflow without formal computer science expertise. Although preliminary accuracy remains modest due to limited sample size, this study establishes a reproducible pathway for future AI-assisted intraprocedural guidance systems and larger multicenter development efforts in structural heart interventions.

Background Pulse-field ablation (PFA) is regarded as a non-thermal ablation modality, but there is an increasing range of complications that could be due to thermal effects. Methods The hydrogel undergoes permanent colour change when a target temperature is reached allowing direct visualisation of the surface thermal footprint and depth. Comparative lesion sets using a variable loop circular catheter (VP), circular over-the-wire catheter (PS) and pentaspline catheter (FP) were performed. Protocols included single and stacked applications with variation of force, irrigation, and voltage. The hydrogel lesions were analysed en-face and by section using digital image analysis. Results All 3 PFA catheters tested had significant thermal footprints. The VP catheter had the largest mean surface footprint (156.1mm2) and thermal depth (1.31mm) compared to the other two catheters (PS 55.4mm2 & 1.1mm, FP 29.8mm2 & 1.05mm, p<0.005). Increasing irrigation showed a trend to reduce thermal footprint but did not achieve statistical significance. Increasing voltage increased thermal footprint, but increasing force had negligible effect. Stacked lesions incrementally increased thermal lesion footprint and depth in all catheters. Thermal depths of up to 2.4mm were observed. Areas of darkening and degradation of the hydrogel were observed with the VP and FP catheters, consisting of up to 47% of lesion area. No darkening was observed with the PS catheter. Conclusions There are significant thermal footprints in all the systems tested. Temperatures exceeding 60oC have been demonstrated, comparable to radiofrequency ablation, and this may explain the mechanism of injury in some reports of collateral damage during PFA.

Background. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and irritable bowel syndrome (IBS) frequently co-occur following infection, yet shared genetic architecture at the locus level has not been systematically characterised. Aims. To estimate global and local genetic correlations between ME/CFS (including infection-onset subgroup), IBS, major depressive disorder (MDD) and loneliness/isolation, and characterise ME/CFS cell-type heritability enrichment. Method. GWAS summary statistics: DecodeME (15,579 ME/CFS; 9,738 infection-onset), FinnGen R9 (9,296 IBS), PGC MDD Wave 2 (45,396) and UK Biobank loneliness (N=455,364). LDSC for global correlations; LAVA for local correlations across 2,495 loci; MAGMA for cell-type enrichment (Descartes Human atlas); coloc.abf for colocalisation. Results. All pairwise global correlations were significant after Bonferroni correction, including ME/CFS-all-MDD (rg=0.598, 95% CI 0.46-0.74) and ME/CFS-all-IBS (rg=0.573, 0.39-0.75). Of 4,232 local tests, 16 reached FDR<0.05; two lonelinessxMDD loci were Bonferroni-significant. ME/CFS-MDD showed three FDR-significant local correlations, but all were boundary-estimated and non-Bonferroni-significant. A borderline infection-onset ME/CFS-IBS signal occurred at chr12q24.22 ({rho}=1.000, FDR=0.046), but colocalisation did not support a shared causal variant (PP.H4=0.007). ME/CFS heritability was enriched in inhibitory neurons (P=1.210x-7) and enteric nervous system neurons (FDR=0.004), with no FDR-significant peripheral immune cell-type enrichment in the atlas used. Conclusions. High global ME/CFS-MDD correlation was accompanied by limited, boundary-estimated, non-Bonferroni-robust local sharing; the data do not support reducing ME/CFS to depression at the genetic-architecture level. Neural enrichment, including enteric nervous system neurons, supports involvement of neural components in ME/CFS susceptibility without excluding immune mechanisms. A borderline ME/CFS-IBS signal at a NOS1-containing region generated hypotheses requiring replication.

Background Endometrial cancer exhibits marked molecular and immune heterogeneity that is only partially explained by established genomic biomarkers. We investigated whether T cell receptor (TCR) repertoire architecture captures complementary dimensions of antitumor immunity beyond conventional molecular classification. Methods Paired tumor and peripheral blood samples from eight patients with molecularly characterized endometrial cancer underwent TCR repertoire profiling. Diversity, clonality, and tumor blood overlap metrics were integrated with genomic variables, including tumor mutational burden (TMB), genomic instability metric (GIM), and POLE status. Principal component analysis and correlation analyses were used to identify major dimensions of repertoire organization. Composite Immune Focusing and Immune Sharing Scores were derived to summarize dominant repertoire patterns. Results The first two principal components explained 70.1% of total repertoire variance and revealed substantial heterogeneity independent of histological subtype. TMB was strongly associated with reduced repertoire diversity and increased clonal dominance, resulting in a robust association with the Immune Focusing Score ({rho} = 0.88, p = 0.004). POLE mutated tumors occupied the extreme end of this focusing continuum. In contrast, genomic instability was associated with increased tumor blood repertoire overlap and preserved diversity, reflected by a strong correlation between GIM and the Immune Sharing Score ({rho} = 0.76, p = 0.027). The two immune scores showed minimal correlation with each other ({rho} = -0.24, p = 0.57), indicating that they capture largely independent aspects of immune organization. Conclusion Integrative analysis of TCR repertoire architecture and tumor genomics identifies distinct immunogenomic states in endometrial cancer that are not fully captured by conventional molecular classification. If validated in larger cohorts, immune focusing and immune sharing metrics may provide complementary biomarkers for patient stratification and immunotherapy-oriented precision oncology

As genetic testing becomes increasingly integrated into Parkinson disease (PD) research, including targeted testing for variants in LRRK2 and GBA1, the return of individual research results is becoming more common. However, limited qualitative data exists regarding how research participants experience genetic results disclosure and post-test genetic counseling in PD research settings. We conducted semi-structured qualitative interviews with participants (n=13) enrolled in the Parkinson Precision Medicine Initiative (formerly Parkinson Progression Markers Initiative; PPMI) who had received PD-related genetic test results and post-test genetic counseling. Interviews were conducted 1 to 3 weeks following result disclosure and analyzed using thematic analysis with a primarily deductive coding approach informed by study aims and inductive identification of emergent themes. Four primary themes were identified: (1) personal connection and motivations for participation, (2) centrality of result disclosure and information preferences, (3) emotional experiences and support needs, and (4) communication quality and alignment with participant needs. Overall, our findings underscore the importance of person-centered genetic counseling within PD research. As return of genetic and biomarker results in research and clinical trial contexts expand, thoughtful integration of relational, informational, and communication-focused practices will be essential to support participant engagement and trust.

This cross-sectional study aimed to examine the prevalence of alcohol use and its sociodemographic correlates among adults with cardiovascular disease (CVD). We analyzed data from two large US cohorts: the All of Us Research Program (2017-2023) and the National Health and Nutrition Examination Survey (NHANES, 1999-2016). Both CVD diagnosis and past-year alcohol consumption were self-reported. Risky drinking was defined as exceeding moderate drinking or binge drinking (All of Us), or moderate/heavy drinking (NHANES). Multivariable logistic regression was used to exam associations with sociodemographic and lifestyle factors. Among 32,788 current drinkers with CVD in the All of Us cohort, 15% exceeded moderate drinking thresholds and 26% reported binge drinking. Older age, female sex, and higher socioeconomic status were inversely associated with risky drinking, while smoking was positively associated. In NHANES, moderate drinking rose from 47.3% to 57.2% and heavy drinking from 6.7% to 7.2%. Moderate/heavy drinking was positively associated with age <65 but inversely with age [&ge;]65. Higher education and income were linked to moderate drinking, while current smoking was strongly associated with heavy drinking. These results highlight the need to integrate holistic screening for alcohol use, tobacco use, and social context into routine cardiovascular care.