Background/Objectives: Computational and artificial intelligence (AI)-enabled imaging biomarkers are increasingly being investigated for immunotherapy-response assessment in oral squamous cell carcinoma (OSCC), but the evidence is heterogeneous. This systematic review identified, critically appraised, and synthesized imaging biomarkers used to predict or assess observed immunotherapy response in OSCC. Methods: PubMed/MEDLINE, Embase, and Scopus were searched from inception to 31 July 2026, without language restrictions. The protocol was registered in PROSPERO. Eligible studies evaluated quantitative, radiomic, machine-learning, or related medical-imaging biomarkers against pathological or radiological response. Risk of bias was assessed using design-specific tools, supplemented by a radiomics-specific methodological appraisal. A structured Synthesis Without Meta-analysis was prespecified. Results: Seven reports were included, covering pretreatment prediction, early/on-treatment dynamic assessment, and post-neoadjuvant/preoperative response assessment. Pretreatment-computed tomography and magnetic resonance imaging radiomics showed discriminatory performance, whereas baseline positron emission tomography uptake alone was not consistently associated with pathological response. Longitudinal fibroblast activation protein inhibitor positron emission tomography changes were associated with a major pathological response, and magnetic resonance imaging habitat and longitudinal habitat models showed higher within-study discrimination when combined with clinical information. No computational model had independent external validation specifically in an OSCC population, and no three independent studies were sufficiently comparable for meta-analysis. Conclusions: Computational imaging is promising across several stages of immunotherapy-response assessment. However, based on current evidence, none of the reviewed imaging biomarkers or models can yet be considered ready for routine clinical use. Prospective multicenter OSCC-specific validation and standardized imaging and analytical pipelines are needed to establish generalizability and clinical utility.
Background/Objectives: Retinal artery occlusion (RAO) represents an ischemic event of the anterior circulation, driven by impaired blood flow through the ophthalmic branches of the internal carotid artery. Atrial fibrillation (AF) is an increasingly recognized cardioembolic source in patients with RAO, yet its prevalence remains poorly characterized. We conducted a systematic review and meta-analysis to estimate the pooled prevalence of AF in RAO patients and to summarize evidence on its incidence and association with this condition. Methods: Four databases were searched through April 2025, updated on 18 August 2026. Studies reporting AF prevalence, incidence, or association in adults with RAO were included. Pooled prevalence was estimated using the Freeman–Tukey double arcsine transformation with a random-effects model. Subgroup analyses, meta-regression, and sensitivity analyses were performed to explore heterogeneity. Results: Sixty-two studies were included in the qualitative synthesis, of which 58 reported AF prevalence data. Among the 36 studies comprising 139,222 patients, the pooled AF prevalence was 11.53% (95% CI: 9.41–13.82; I2 = 99.2%; prediction interval: 2.00–26.9%). AF prevalence was significantly higher in patients aged ≥70 years (15.86%) and in central RAO cohorts (16.54%). Incident AF following RAO ranged from 10.5% to 41%, increasing progressively with monitoring intensity. The pooled odds ratio for the AF–RAO association was 1.56 (95% CI: 1.06–2.29). Conclusions: AF affects approximately one in nine patients with RAO, though with substantial uncertainty across populations (prediction interval 2.00–26.9%); the extent to which this exceeds the general-population estimates independent of age, cardiovascular risk profile, and geographic factors remains uncertain. These findings support cardiac rhythm surveillance following RAO diagnosis in selected patients, although its effect on clinical outcomes remains to be established prospectively.
Background/Objectives: Myeloproliferative neoplasms are a group of clonal myeloid malignancies that affect bone marrow and include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). PV is caused in most patients by the JAK2-V617F mutation and is characterized at the phenotypic level by overproduction and accumulation of red blood cells. PV is associated with significant morbidity, including risk of thrombotic events and of hematologic evolution (myelofibrotic or leukemic transformation) and reduced survival. In addition to the JAK2-V617F mutation, PV patients display additional molecular abnormalities. The aim of this study is to review recent studies investigating molecular abnormalities observed in PV. Methods: An extensive search of the most recent literature was performed, selecting and critically analyzing the most relevant studies. Results: The studies carried out in recent years have provided an extensive molecular analysis of PV, showing its heterogeneity, characterized in many patients by the presence of additional cytogenetic and gene mutations that contribute to the disease development and evolution. Conclusions: PV is a complex disease that needs to be carefully characterized at the molecular level at diagnosis, to be monitored in time to predict the risk for thrombotic complications and hematologic evolution and to receive an adequate treatment.
Background: Brief psychotherapies have been shown to improve clinical symptoms within a limited number of sessions without compromising treatment quality. Objectives: This study aims to test the effects of the experimental Behavioral Analysis Therapy of Feelings (BATF) in a randomized controlled trial design. Methods: This randomized, controlled, assessor-blinded clinical trial compares BATF with Brief Focal Psychotherapy in individuals presenting symptoms of anxiety and/or depression. Participants with substance use disorders, tobacco or alcohol use, pregnancy, or use of oral contraceptives will be excluded. Participants will be randomized in a 1:1 ratio with stratification by clinical condition. Outcomes will be assessed at baseline, Week 4, and Week 13 using the Hamilton Anxiety Rating Scale, the Montgomery–Åsberg Depression Rating Scale, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, and the Pittsburgh Sleep Quality Index. In addition to clinical outcomes, exploratory salivary and blood biomarkers associated with stress, inflammation, and neurobiological function will be evaluated. The trial is registered in the Brazilian Clinical Trials Registry (RBR-10p45rdg) and has Universal Trial Number U1111-1313-4499. Conclusions: This protocol describes a randomized controlled trial comparing BATF with Brief Focal Psychotherapy. The study is designed to generate preliminary evidence on the effects of the intervention in anxiety and depressive symptoms.
Antibody-mediated rejection (AMR) remains a major cause of kidney allograft injury and loss. Although donor-specific antibodies against human leukocyte antigens (HLA-DSAs) are central to humoral alloimmunity, they do not explain all cases of microvascular inflammation or graft dysfunction. This review critically evaluates non-HLA antibodies as potential mediators of allograft injury and markers of dysregulated humoral immunity by integrating functional, experimental, clinicopathological, and clinical evidence. Receptor-targeting antibodies, especially those against the angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR), have the strongest evidence for direct pathogenicity. Antibodies against major histocompatibility complex class I-related chain A (MICA) and glutathione S-transferase theta-1 (GSTT1) reflect non-HLA alloimmunity, whereas antibodies targeting perlecan-derived LG3, vimentin, and injury-associated antigens may arise through secondary autoimmunity and mark broader humoral activation. We propose that selected pathogenic non-HLA antibodies participate in a feed-forward cycle of graft injury, antigen exposure, epitope spreading, and humoral amplification, although this model requires longitudinal validation. Crucially, non-HLA antibody positivity alone should neither establish AMR nor guide antibody-specific treatment. Its interpretation should be target-specific and integrated with HLA-DSAs, histopathology, molecular findings, graft function, and evidence of immune activation.
Background: Population aging is accompanied by progressive immune remodeling, chronic low-grade inflammation, and increased susceptibility to neurodegenerative diseases. Although the microbiota–gut–brain axis is increasingly recognized as a regulator of neuroimmune homeostasis, mechanisms linking age-associated dysbiosis with immunosenescence, barrier dysfunction, and brain aging remain incompletely understood. This review integrates current evidence into the proposed Gut–Immune–Brain Resilience Axis (GIBRA), a systems-level model describing how microbial signaling shapes neuroimmune resilience during aging. Methods: A structured narrative review was conducted using PubMed and the Web of Science Core Collection from database inception up to July 2026. Evidence from systematic reviews, meta-analyses, consensus statements, mechanistic and translational studies, longitudinal cohorts, randomized clinical trials, and observational studies was synthesized. Results: Current evidence supports an important role for the disruption of microbial functional signaling in neuroimmune aging, while microbial taxonomy and functional profiles provide complementary levels of biological information. Reduced short-chain fatty acid production, dysregulated tryptophan metabolism, microbial translocation, endotoxin-mediated innate immune activation, and gut-conditioned adaptive immune responses promote immunosenescence, inflammaging, barrier dysfunction, and microglial priming. The proposed Double-Barrier Hypothesis links intestinal and blood–brain barrier dysfunction as complementary mechanisms underlying chronic neuroinflammation. GIBRA highlights functional microbiome endotypes, biomarkers, multi-omics, and artificial intelligence as emerging tools for precision medicine. Conclusions: GIBRA provides an integrated systems biology perspective connecting microbial signaling, immune resilience, barrier integrity, and brain resilience during aging. Prioritizing functional resilience over microbial taxonomy may improve biomarker discovery, patient stratification, and microbiome-targeted interventions for neurodegenerative disease prevention. Prospective longitudinal studies integrating multi-omics are needed to support clinical translation.
Background: Radiation-induced sepsis resulting from intestinal inflammation and injury is a severe complication of high-dose radiation exposure. High-dose radiation compromises the integrity of the intestinal lining, causing bacterial translocation, systemic inflammation, and sepsis. Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, plays a pivotal role in the pathogenesis of inflammatory diseases and contributes to organ injury. C23, a small molecular peptide antagonist of eCIRP, has demonstrated anti-inflammatory and organ-protective effects during organ-injury indications. However, its role in radiation-induced inflammation and injury is not known. The objective of this study is to evaluate whether C23 mitigates inflammation and injury, leading to improved survival in a murine model of partial-body irradiation (PBI) combined with sepsis. Methods: Mice were exposed to 10 Gy PBI, and at 48 h, they were subjected to cecal ligation and puncture (CLP), a well-established model of sepsis. C23 (8 mg/kg body weight [BW]) or vehicle (saline) was administered subcutaneously at 24 h and 48 h after PBI. Blood and intestinal tissue samples were collected 20 h after CLP (i.e., 68 h post-PBI) for various analyses. In another set of mice after PBI–sepsis, intestinal permeability was also assessed. In an additional cohort of mice subjected to the same experimental procedure, 10-day survival was monitored. Results: Our findings demonstrate that administration of C23 attenuated systemic inflammatory responses, intestinal permeability, intestinal injury, and apoptosis; increased crypt cell proliferation and improved survival after PBI–sepsis. Conclusions: These results reveal a novel protective role of the eCIRP antagonist, C23, in mitigating PBI–sepsis-induced inflammation and injury and represents a promising therapeutic candidate for the treatment of radiation combined injury with sepsis.
Background/Objectives: Multiple sclerosis (MS) affects motor, cognitive, psychological, and social functioning that impairment-based scales do not fully capture. This systematic review evaluated the measurement properties and applications of the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 in adults with MS across research and clinical contexts. Methods: PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 25 May 2026. Eligible peer-reviewed studies reported extractable WHODAS data in adults with MS. Evidence was organized into measurement, clinical-association, participation/employment, intervention, digital-monitoring, and longitudinal streams. Design-appropriate critical-appraisal tools and outcome-specific certainty assessments were applied; quantitative pooling was assessed but was not justified. Results: Of the 677 records identified, 28 reports were included. Five reports evaluated measurement properties; moderate-certainty evidence supported reliability and construct validity, although precision differed among 12-, 32-, and 36-item forms. Associations with quality of life and clinical severity were supported by low-certainty evidence. Evidence concerning fatigue, mood, cognition, participation, and employment was of low or very low certainty because most studies were cross-sectional, used heterogeneous metrics, or involved overlapping cohorts. Intervention evidence was of very low to low certainty: WHODAS was secondary, and interventions, time points, and scoring methods were not comparable. Eight reports arose from one overlapping research program. Conclusions: WHODAS 2.0 provides a multidimensional patient-reported account of functioning in MS and may complement, but not replace, the Expanded Disability Status Scale. Evidence supports measurement use more strongly than prognostic, treatment-response, or benefit-determination claims. Standardized version selection, scoring, domain reporting, and prespecified longitudinal endpoints are required.
Background/Objectives: Wearable devices provide multidimensional measures of cardiometabolic health. We aimed to derive latent physiological dimensions from ECG and motion variables collected by a wearable device and evaluate their associations with the individual health metrics of the Longevity Check-Up 8+ (LC8+) programme. Methods: Community-dwelling adults voluntarily participating in four Longevity Check-Up 8+ (LC8+) events underwent 24-h multiparameter recording using a wearable device. Eight wearable-derived variables were entered into principal component analysis (PCA) to derive latent physiological dimensions. Component scores were subsequently evaluated for associations with overall LC8+ health, while exploratory analyses examined associations with individual health metric domains. Results: Ninety-seven participants (mean age 51.3 ± 13.4 years; 36% female) were enrolled. Among the 96 participants with complete data for the PCA, three latent physiological components were identified, explaining 70.1% of the total variance. PC1, which was characterised by high SDNN, high RMSSD, and low nocturnal heart rate, was independently associated with overall LC8+ health (LM: B = +0.402, 95% CI [+0.103, +0.700], p = 0.009). Among the eight LC8+ domains, only the association between PC1 and glycaemic health remained statistically significant after Benjamini–Hochberg correction in the primary fixed-effects analysis (95% CI [1.32, 4.62], adjusted p = 0.039). Conclusions: A wearable-derived autonomic component was associated with overall cardiometabolic health in community-dwelling adults. Among the individual LC8+ domains, the strongest association was observed for glycaemic health. These preliminary findings support further investigation of wearable device monitoring as a complementary tool for cardiovascular health assessment in preventive medicine.
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy among men in the United States and remains a leading cause of cancer-related mortality. Its marked biological, molecular, and histopathological heterogeneity creates a central diagnostic challenge: identifying clinically significant disease while limiting unnecessary biopsy and overdiagnosis of tumors unlikely to affect survival or quality of life. Although prostate-specific antigen (PSA) remains the foundation of early detection, its limited cancer specificity has driven the development of increasingly risk-adapted diagnostic pathways. Contemporary evaluation integrates clinical risk assessment and PSA-derived measures with selectively used blood- and urine-based biomarkers, multiparametric magnetic resonance imaging (mpMRI), image-guided biopsy, histopathological classification, genomic risk assessment, and molecular imaging. Biomarkers such as the Prostate Health Index, 4Kscore, IsoPSA, MiCheck, SelectMDx, and ExoDx may refine biopsy decisions in appropriately selected patients but should be interpreted according to the clinical setting, decision threshold, and surrounding diagnostic pathway. Prostate MRI and PI-RADS-based assessment have become central to pre-biopsy evaluation, while MRI-targeted biopsy improves detection of Grade Group ≥ 2 disease. Increasing use of the transperineal biopsy route offers comparable cancer detection with a lower infectious risk. Following diagnosis, Grade Group, adverse histological features, clinical risk models, and selected tissue-based genomic classifiers provide complementary prognostic information. PSMA PET/CT has further improved staging of selected patients with higher-risk disease and localization of biochemical recurrence. Precision diagnostics must also account for disease phenotypes that may not be adequately represented by conventional PSA- and imaging-based pathways, including intraductal carcinoma, cribriform architecture, ductal adenocarcinoma, and neuroendocrine prostate cancer. Emerging approaches, including artificial intelligence-assisted MRI interpretation, digital pathology, high-frequency micro-ultrasound, liquid biopsy, alternative molecular radiotracers, and multi-omic integration, show increasing potential but remain at different stages of validation and clinical adoption. This review critically examines contemporary prostate cancer diagnostics within United States clinical practice, distinguishing established guideline-supported approaches from selectively used adjuncts and emerging technologies. Particular emphasis is placed on diagnostic performance in context, clinical utility, external validation, healthcare equity, regulatory considerations, and the need to demonstrate that increasing diagnostic complexity translates into meaningful improvements in patient care.
The posterior communicating artery (PComA) aneurysm is a challenging microsurgical problem due to multiple factors. These include the technical complexity of the surgery itself, potential injury to blood vessels during surgery, recovery of cranial nerve function, and overall neurological outcome after the operation. These are all related to the area where the PComA aneurysm is located, but they have fundamentally different biological determinants. Prior methods of describing aneurysms do not adequately describe how the relationships of the internal carotid artery (ICA) and PComA/P1 configuration influence the proximity of the aneurysm to other important structures such as the perforating arteries, the anterior choroidal artery (AChA), cranial nerve III (CN III), and the surgical corridor. We created PComA-CORE, an artificial intelligence-based framework designed to evaluate whether the elements of experienced microsurgeons’ thought processes can be measured individually while still maintaining temporally valid predictions, human interpretability, and explicit estimates of predictive uncertainty. Methods: Using a highly detailed database of clinical, radiographic, anatomical, intraoperative, and longitudinal data from 687 adult patients who underwent microsurgical clipping of PComA aneurysms over the period 1997–2026, we applied PComA-CORE to predict separately: Microsurgical Complexity (C); Oculomotor Recovery (O); Neurovascular Preservation Risk (R); and Expected 90-Day Functional Outcome (E). The models used cases from 1997–2020 (n = 564) for development and cases from 2021–2026 (n = 123) for temporal evaluation. Several architectures, including penalized regression, machine-learning techniques, interpretable machine learning, and ensembles, were compared using nested cross-validation, discrimination metrics, calibration metrics, decision-curve analysis, explainability measures, uncertainty-aware prediction, inter-observer reproducibility, and model-to-score distillation. Results: Four discrete predictive architectures were identified by PComA-CORE. PComA-C was found to be highly dependent upon anatomy because the specific geometric characteristics of individual vascular segments and the presence or incorporation of branches around the aneurysm strongly influenced temporal predictions. PComA-R was found to behave as a distributed susceptibility phenotype based on neurovascular attributes rather than a deterministic injury model and achieved a temporal AUC of 0.703. Among patients with preoperative CN III palsy, PComA-O identified that recovery primarily depended upon the time course of neurological dysfunction and structural deformation of the affected nerve. Temporal validation was not feasible given the small number of recent non-recovery events. Conversely, PComA-E showed that global functional outcome continued to depend predominantly upon clinical neurological severity, with a temporally evaluated penalized model achieving an AUC of 0.878. Uncertainty-aware predictions indicated that some cases would benefit from greater caution in interpretation. High-resolution anatomical phenotypes demonstrated good inter-observer reproducibility. Score distillation demonstrated that simplification preserved predictive information, but did so differently depending on the endpoint. Conclusions: The problem of predicting the consequences of clipping a PComA aneurysm is multidimensional and does not exist as a single “risk” prediction problem. Technical complexity, neurovascular vulnerability, neural recovery, and global disability each exist within distinct predictive spaces and require different levels of anatomical detail and/or computational complexity. PComA-CORE establishes a human-supervised framework to transform expert microsurgical thought processes into explicit, reproducible, uncertainty-aware, and clinically interpretable representations. While prospective multicenter validation will be needed prior to clinical use, it has the potential to establish a basis for explainable AI, precision cerebrovascular neurosurgery, anatomy-informed risk stratification, and clinically interpretable decision-support systems in complex aneurysm surgery.
Background: Clinical remission is an emerging therapeutic goal in severe asthma treated with biologics. However, remission may evolve beyond the conventional 12-month assessment, and limited real-world data are available on patients who continue the same biologic after incomplete remission at 12 months. We evaluated longitudinal remission trajectories in patients with severe T2-high asthma continuing the same biologic therapy. Methods: This retrospective real-world single-center SANI cohort included adults with severe asthma treated with one biologic agent and followed for at least 18 months. Clinical outcomes and remission status were assessed at 12 and 18 months according to the SANI definition, distinguishing complete remission, partial remission, and no remission. Results: The cohort included 146 patients; 64.4% were female, median age was 61 years, and all had a T2-high phenotype. Maintenance oral corticosteroid use decreased from 83.6% at baseline to 6.8% at 18 months, while symptomatic patients decreased from 100.0% to 11.0%. Median ACT improved from 12.0 to 22.0, and patients with ≥1 exacerbation decreased to 4.1% at 18 months. Complete remission increased from 36.3% at 12 months to 67.1% at 18 months, while no remission decreased from 54.1% to 16.4%. Among patients not in remission at 12 months, 43.0% achieved complete remission and 26.6% achieved partial remission at 18 months. Baseline oral corticosteroid use was associated with lower remission likelihood, whereas preserved baseline FEV1 favored remission at 18 months. Conclusions: Among patients with severe T2-high asthma selected for continuing an unchanged biologic for at least 18 months, remission status was more favorable at 18 months than at 12 months. This observation describes the trajectory of biologic continuers and should not be generalized to all patients who remain outside remission at 12 months. Because patients who discontinued or switched biologics were excluded, these data do not establish that continuation is preferable to switching after an incomplete 12-month response.
Background: Objective gait speed, self-rated walking pace, and self-reported walking difficulty are consistently associated with mortality. Far less is known about the prognostic meaning of perceiving, or being told, that one has recently become slower in both walking and everyday activities. We examined whether reported slowing was associated with long-term all-cause mortality in older adults. Methods: The Neurological Disorders in Central Spain (NEDICES) study is a prospective population-based cohort of 5278 adults aged 65 years or older. At baseline (1994–1995), participants were asked whether they noticed, or had been told, that lately they walked or did things more slowly; the item was available for 3994 participants. Vital status was ascertained through 31 December 2017 by linkage to the Spanish National Population Register. Kaplan–Meier methods and Cox regression were used. The primary model included the Carey-based comorbidity score and adjusted for demographic, movement-disorder, musculoskeletal, and lifestyle covariates. Results: Reported slowing was present in 1516 participants (38.0%); 3426 deaths occurred. In the primary complete-case model (n = 3858; 3311 deaths), reported slowing was associated with mortality after multivariable adjustment (hazard ratio 1.10, 95% confidence interval 1.02–1.18; p = 0.012). The item changed Harrell’s C-index from 0.7046 to 0.7048. The estimate was attenuated after excluding deaths within five years (1.08, 0.99–1.17; p = 0.087) and after exploratory adjustment for the Pfeffer Functional Activities Questionnaire score (1.08, 1.00–1.16; p = 0.055). Conclusions: Reported slowing in walking and everyday activities was associated with a modest increase in mortality after multivariable adjustment. It may serve as a simple indicator of slightly higher mortality risk, although its incremental contribution to individual-level prognostication was limited.
Background: Cholangiocarcinoma (CCA) frequently recurs after curative-intent resection. Metabolic alterations and systemic inflammation may contribute to aggressive disease, but their combined prognostic relevance remains unclear. Methods: We retrospectively reanalyzed 88 patients with resected CCA and documented recurrence, including 37 with early and 51 with late recurrence. A metabolite-based risk score was developed from recurrence-associated serum metabolites identified previously. Model development and internal validation used all 88 patients, whereas analyses involving preoperative neutrophil-to-lymphocyte ratio (NLR), clinicopathological variables, and survival outcomes included 85 patients with complete clinical data. Performance was assessed using repeated nested cross-validation, bootstrap validation, discrimination, calibration, and survival analyses. Results: The 10-metabolite risk score (MRS-10) showed moderate internally validated discrimination for distinguishing early from late recurrence, with a pooled patient-level out-of-fold AUC of 0.828 (95% CI, 0.725–0.911), with limited calibration. High MRS was associated with shorter disease-free survival (DFS) and overall survival (OS) (both p < 0.001) and remained independently associated with DFS events (HR, 7.92; 95% CI, 3.94–15.92) and mortality (HR, 4.05; 95% CI, 2.08–7.89). High MRS was also associated with elevated NLR (p < 0.001). The combined MRS–NLR framework improved prognostic discrimination and stratified patients into groups with stepwise differences in DFS and OS. Exploratory subgroup analyses showed broadly consistent adverse associations across selected clinicopathological strata. Conclusions: In this retrospective exploratory analysis, a metabolite-based risk score combined with preoperative NLR was associated with recurrence and survival outcomes in resected CCA. This metabolic–inflammatory framework may provide complementary prognostic information alongside conventional clinicopathological factors. However, the findings remain hypothesis-generating and require validation in larger independent cohorts before clinical application.
Background: Peritoneal dialysis (PD) effluent of kidney failure patients represents an accessible liquid biopsy of the peritoneal cavity, yet the mechanisms determining its molecular composition remain poorly understood. We applied an integrative multi-omics approach to characterize the composition, transport dynamics, and molecular origin of the PD effluentome. Methods: Cell-free effluent, effluent cells, and plasma were collected from stable PD patients during standardized peritoneal equilibration tests in a randomized clinical trial. Targeted metabolomics, proteomics, and transcriptomic profiling were integrated with a reference human plasma proteome to investigate temporal molecular changes, peritoneal transport characteristics, and protein origin. Results: A total of 207 metabolites and 2970 proteins were identified in PD effluent. Metabolites exhibited distinct class-specific transport kinetics, with rapid equilibration of amino acids and biogenic amines, whereas lipids remained markedly underrepresented despite prolonged dwell times, indicating that transport is governed by physicochemical properties beyond molecular size alone. The effluent proteome underwent concordant alteration, with dwell time-dependent enrichment of pathways related to extracellular matrix organization, angiogenesis, coagulation, and tissue repair. Integrative analysis of the effluent proteome, effluent-cell transcriptome, and human plasma proteome resolved distinct plasma-associated, effluent cell-associated, resident peritoneal tissue-associated, and mixed-origin protein populations. Conclusions: This study establishes the first systems-level approach describing the composition, transport dynamics, and molecular origin of the PD effluentome. By transforming PD effluent into a biologically interpretable molecular readout of peritoneal membrane biology, this work provides a reference for the mechanistic interpretation of effluent-derived biomarkers and supports future therapeutic monitoring and precision medicine in PD.
Background: Optical coherence tomography angiography (OCTA) provides quantitative metrics of the retinal microvasculature, most prominently vessel density (VD), that are increasingly used as biomarkers in ocular, systemic, and cerebrovascular disease. Because OCTA relies on the detection of flow-related motion contrast, image quality has emerged as a pervasive determinant of these metrics, yet its effect has been reported in fragmentary and non-comparable ways across the literature. Methods: We identified OCTA studies indexed in PubMed that examined the relationship between image quality and quantitative OCTA parameters, and we summarised their methods and findings across the macular, foveal avascular zone, and peripapillary regions and across vascular layers. We integrated directly comparable per-unit scan-quality effects using random-effects meta-analysis and separately synthesized direct cross-sectional Pearson correlations between manufacturer-reported image quality and macular vessel-density outcomes from independent healthy cohorts. Results: Higher image quality was associated with higher measured vessel density in every contributing dataset. On the Optovue scan-quality (SQ, 0–10) scale, superficial macular VD increased by 3.46% (95% CI 1.85–5.07) per SQ unit in controlled signal-attenuation experiments and by covariate-adjusted observational estimates ranging from 0.90% to 2.16% per SQ unit; a combined order-of-magnitude estimate across both estimator types was 1.64% (95% CI 1.15–2.12). Peripapillary estimates were heterogeneous and derived from only two independent cohorts; they were therefore summarised descriptively rather than pooled. Across three independent externally authored healthy cohorts reporting direct cross-sectional Pearson correlations, higher image quality was strongly associated with higher macular vessel-density outcomes (random-effects pooled r = 0.64, 95% CI 0.50–0.75; I2 = 49%). Conclusions: Image quality is an important, directional confounder of VD-based OCTA metrics whose magnitude can rival the biological or physiological signal of interest. Platform-appropriate standardisation, transparent reporting, and consideration of image quality in acquisition and analysis are therefore important for the valid interpretation of vessel-density measurements, particularly in functional and longitudinal studies.
Background and objectives: Melanoma survivors may develop additional primary malignancies, but data from Eastern European hospital cohorts are scarce. We aimed to estimate the observed incidence of second primary cancers (SPCs) within a Romanian referral-centre cohort, identify associated factors, and explore the association of SPC occurrence with overall survival. Methods: We conducted a retrospective, hospital-based cohort study of 394 patients with histopathologically confirmed cutaneous melanoma followed at two referral centres in Cluj-Napoca. Additional malignancies were counted as new primaries only when clinical and/or histopathological documentation distinguished them from recurrence or metastasis. Incidence density was expressed per 1000 person-years. Multivariable logistic regression assessed age, sex, residence, and Breslow thickness. Fixed-covariate Cox and Kaplan–Meier analyses were considered exploratory because of immortal-time and competing-risk limitations. Results: Over 1848 person-years, 79 patients (20.1%) developed at least one SPC (131 events; observed incidence 70.9/1000 person-years), most frequently cutaneous (53.6/1000 person-years). SPC occurrence increased with age (Cochran–Armitage Z = 5.63, p < 0.001); the Kaplan–Meier complement estimate reached 20.7% at five years. Age independently predicted SPC (OR 1.86 per decade, p < 0.001), whereas greater Breslow thickness was inversely associated (OR 0.86, p = 0.008). Actinic keratosis showed a strong unadjusted association (OR 6.64, p < 0.001) but was not included in the adjusted model. The fixed-status Cox model showed lower mortality among patients with an SPC (HR 0.36, p < 0.001), a finding vulnerable to detection and immortal-time bias. Conclusions: SPCs were frequent in this hospital cohort and predominantly cutaneous. Older age was an independent predictor, while actinic keratosis was a strong unadjusted marker. Prospective, population-based validation is needed before surveillance intensity is individualised.
Background: Physical activity is widely recommended for preserving musculoskeletal health and managing osteoarthritis-related pain, although its benefits are commonly framed in terms of muscle strengthening, weight control, and physical performance. This narrative review aimed to examine movement more broadly as a physiological regulator of synovial joint homeostasis, sensory calibration, and functional adaptation. Methods: A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science from database inception to 1 February 2026. Experimental studies, observational studies, clinical trials, systematic reviews, meta-analyses, and selected narrative reviews addressing movement-responsive joint biology or pain regulation were considered. Evidence was synthesized across four interrelated domains: mechanical, fluidic, immune-metabolic, and sensory regulation. Results: The narrative synthesis indicates that the concept of the synovial joint as a dynamic mechano-fluidic organ in which cartilage, synovium, synovial fluid, capsule, subchondral bone, periarticular tissues, and sensory pathways interact continuously. Repeated physiological movement may promote synovial fluid exchange, lubrication, cartilage nutrition, hyaluronic acid and lubricin function, matrix turnover, anti-inflammatory signaling, proprioceptive control, and exercise-induced hypoalgesia. In contrast, inactivity and unloading may impair fluid dynamics, promote muscle inhibition, stiffness, inflammatory persistence, sensory deconditioning, and loss of function. Excessive or poorly distributed loading may also disrupt homeostasis through matrix injury, inflammation, fatigue, and nociceptive sensitization. These findings informed the proposed adaptive loading window, a hypothesis-generating conceptual framework rather than a clinically validated threshold, describing the dynamic range of movement within which joint function and pain regulation may be supported without sustained tissue or symptom aggravation. Conclusions: Movement should be viewed not only as a therapeutic intervention, but also as a continuous regulator of joint biology and perception. Its clinical value may depend on identifying an individualized loading range that supports adaptation, function, and confidence in movement while avoiding both underloading and overload.
Background/Objectives: Adrenocortical carcinoma (ACC) is a rare malignancy in which overexpression of steroidogenic factor-1 (SF-1/NR5A1) and aberrant activation of canonical Wnt/β-catenin signaling are important oncogenic events. However, the extent to which these regulatory axes converge or interact at the transcriptional level remains unclear. We investigated their relationship using bulk transcriptomic and regulatory-network approaches. Methods: Regulatory network inference using RTN/ARACNe was applied to the TCGA-ACC cohort. NR5A1 and β-catenin-associated TCF/LEF regulon activities were evaluated in perturbation datasets and tested for associations with CpG island methylator phenotype (CIMP), overall survival, and gene-level interaction effects. Candidate modulators of NR5A1 activity were assessed using the MINDy algorithm. The effects of cBAF inhibition on NR5A1 regulon activity were also evaluated in H295R and CU-ACC1 cells. Results: NR5A1 knockdown repressed steroidogenic pathways, whereas β-catenin knockdown predominantly suppressed Wnt/β-catenin signaling. In TCGA-ACC, NR5A1 regulon activity was associated with CIMP-high status and overall survival. In contrast, β-catenin-related regulons were not significantly associated with CIMP-high status after adjustment for NR5A1 activity, and no significant multiplicative interaction effects were identified. Fewer than 3% of protein-coding genes showed improved fit in models including NR5A1 × TCF/LEF interaction terms, without enrichment for steroidogenic or Wnt/β-catenin-related pathways. CTNNB1 was identified as a statistically significant but low-ranking positive modulator of NR5A1 activity, whereas CTNNBIP1 was a top-decile negative modulator. cBAF inhibition was associated with NR5A1 regulon repression in both cell models. Conclusions: These findings indicate limited detectable global transcriptional convergence between NR5A1 and canonical β-catenin-related regulons in the evaluated bulk transcriptomic frameworks. Potential relationships between these pathways may depend on more localized, chromatin-dependent, protein-level, or context-specific regulatory mechanisms. NR5A1 regulon activity showed more consistent associations with CIMP-high status and clinical outcome than the β-catenin/TCF-LEF regulons in the evaluated TCGA-ACC models. The modulation patterns associated with CTNNB1 and CTNNBIP1, together with the repression of NR5A1 regulon activity following cBAF inhibition, raise the possibility that NR5A1 acts as a context-dependent regulatory node connecting oncogenic signaling and chromatin-remodeling mechanisms in ACC. These findings support further investigation into the role of chromatin-remodeling complexes in sustaining NR5A1-driven transcriptional programs in ACC.
Background: Parkinson’s disease (PD) exhibits remarkable clinical heterogeneity, with substantial variability in motor progression, cognitive decline, and the development of non-motor manifestations. Although the propagation of pathological alpha-synuclein is considered a central mechanism of PD pathogenesis, it does not fully explain why specific neuronal populations demonstrate differential susceptibility to degeneration. Emerging evidence suggests that selective neuronal vulnerability is determined by the interaction of multiple biological domains, including calcium homeostasis, mitochondrial bioenergetic capacity, lysosomal function, axonal architecture, synaptic resilience, and neuroinflammatory responses. Methods: A structured critical narrative review was performed using PubMed/MEDLINE, Scopus, and Web of Science databases from inception to March 2025. Only full-text articles published in English and peer-reviewed journals were included. Evidence from human post-mortem studies, genetic analyses, biomarker investigations, experimental models, induced pluripotent stem cell studies, and longitudinal clinical cohorts were systematically synthesised to identify the principal mechanisms underlying selective neuronal vulnerability and their potential translational application. To capture evidence published after this electronic cut-off, a supplementary manual review of reference lists of key systematic reviews and landmark publications was conducted up to the date of manuscript submission; references with 2025 or 2026 publication dates entered through this supplementary process. The supplementary manual review was conducted as a targeted scan of reference lists of key systematic reviews and high-impact publications identified during the primary search and did not constitute an independent updated systematic search. Results: Five interconnected biological domains emerged as key determinants of neuronal susceptibility in PD: calcium-mediated metabolic stress associated with autonomous pacemaker activity, mitochondrial dysfunction and energetic failure, impaired lysosomal degradation and proteostasis (particularly involving the GBA1–glucocerebrosidase pathway), vulnerability related to extensive axonal and synaptic architecture, and neuroinflammatory mechanisms involving microglial and astrocytic activation. Among these domains, the lysosomal pathway currently provides the strongest translational link between molecular mechanisms and measurable clinical outcomes. Based on this integrated framework, we propose the Parkinson’s Vulnerability Index (PVI), a hypothesis-generating multidimensional model combining genetic, enzymatic, alpha-synuclein seeding, cognitive, olfactory, and neuroimaging biomarkers to facilitate biological stratification and improve the design of mechanism-targeted clinical trials. Conclusions: Selective neuronal vulnerability provides a complementary framework to alpha-synuclein propagation models for understanding the heterogeneity of PD. The proposed PVI is not intended as a diagnostic or prognostic clinical instrument but as a research tool requiring prospective validation. Future precision medicine approaches in PD may benefit from integrating vulnerability-related biomarkers with existing biological staging systems to identify patients most likely to benefit from targeted disease-modifying therapies.
