Medical students experience converging risks of emotional distress, sleep disturbance, and problematic smartphone use, but the dimension-level conditional association patterns linking these domains remain insufficiently specified. This cross-sectional study surveyed 2,587 Chinese medical students (mean age = 18.88 ± 1.01 years; 55.51% female) using the 21-item DASS-21, the PSQI, and the MPAI. Regularized Gaussian graphical models were estimated with EBICglasso for the DASS-MPAI, PSQI-MPAI, and integrated DASS-PSQI-MPAI networks. Strength, bridge strength, node predictability, bootstrapped stability, and gender-based network differences were examined. Nodes represented DASS-21 dimensions, PSQI components, and MPAI dimensions rather than individual questionnaire items. Anxiety was the most prevalent emotional distress dimension (39.89%), followed by depression (34.60%) and stress (15.58%). Sleep problems were detected in 23.42% of participants, whereas problematic smartphone use was detected in 64.71%. Across networks, nodes clustered into clearly differentiated emotional distress, sleep, and problematic smartphone use modules, with stronger within-domain than cross-domain edges. In the DASS-MPAI network, stress and withdrawal showed the highest strength, whereas depression and stress showed the highest bridge strength. In the PSQI-MPAI network, withdrawal and inefficiency were the strongest central nodes, and sleep disturbance and loss of control showed the highest bridge strength. In the integrated network, anxiety and stress showed the highest strength, followed by inefficiency and withdrawal. Bridge strength identified sleep disturbance (0.264), daytime dysfunction (0.239), and anxiety (0.235) as the most prominent cross-domain bridge nodes. Bootstrap analyses supported network stability; the integrated network centrality indices showed acceptable-to-good stability. Gender comparisons revealed no significant difference in global strength (P = 0.728), but the omnibus network structure test was significant (P = 0.010). This study provides a dimension-level map of conditional associations among emotional distress, sleep problems, and problematic smartphone use in a single-institution convenience sample of Chinese medical students. Anxiety, stress, sleep disturbance, daytime dysfunction, inefficiency, and withdrawal emerged as central or bridge nodes in the observed networks. These findings should be interpreted as exploratory cross-sectional associations rather than causal relationships or confirmed intervention targets, but they may inform hypotheses for future longitudinal and intervention studies.
Androgen receptor signaling inhibitors (ARSIs) have transformed the treatment of advanced prostate cancer, yet durable responses are limited by the emergence of therapy-resistant disease states, including neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC). Lineage plasticity has traditionally been studied from a tumor-cell-intrinsic perspective, but single-cell and spatial studies increasingly indicate that the tumor microenvironment, particularly tumor-associated macrophages (TAMs), may influence tumor-cell state transitions, immune exclusion, and therapeutic resistance. In this review, we synthesize established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity. We first summarize independently supported myeloid programs, including SPP1+/TREM2+ macrophage states and TAM-derived pathways such as IL-6/STAT3, TGF-beta, NF-kappaB, CXCL12/CXCR4, and adenosine signaling. We then discuss PLAC8+ TAMs, TNFAIP8L2, and PLAC8+ TAM/CXCL12+ iCAF/CD8+ TRM spatial aggregates as an emerging, hypothesis-generating framework that may be associated with ARSI-induced DNPC-like remodeling. Importantly, we explicitly distinguish spatial and transcriptomic associations from experimentally proven causal mechanisms. The proposed TNFAIP8L2-integrin/PI3K-Akt/beta-catenin/FOSL1-HMGA1 cascade is therefore presented as a working model that requires direct biochemical, genetic, and in vivo validation. Finally, we outline an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Exposure of cannabis to heavy metals may interfere with metabolic pathways of cannabinoid biosynthesis and compromise its medical quality. Furthermore, inflorescence contamination with heavy metals presents a critical challenge for the production of safe pharmaceutical-grade cannabis, since it poses a significant health risk to consumers. The present study therefore evaluated the hypotheses that heavy-metal exposure affects cannabinoid production, leads to inflorescence-contamination, and compromises the cannabis plant function; and that the responses are genotype-dependent and heavy-metal dose-dependent. To evaluate the hypotheses, we studied responses of four 'drug-type' medical cannabis cultivars to a cocktail of four heavy-metals (Cd, Pb, Ni, Co), in three concentrations each (0, 1, 5µM), and analyzed translocation and accumulation patterns of the heavy-metals in the plant organs, and the resulting impact on cannabinoid production and the plant's physiological integrity. The results confirmed effects of the heavy metals on cannabinoid production, with a heavy-metal concentration threshold, and genotypic variability, thus confirming the hypotheses. The roots accumulated the highest levels of heavy metals, demonstrating an avoidance strategy of exclusion from sensitive shoot organs; and the root-to-shoot translocation factor was Ni > Cd, Co > Pb demonstrating heavy-metal specificity. The accumulation patterns revealed that plant exposure to moderate-low heavy metal concentrations (5µM) poses health concerns, as the inflorescences' Cd and Ni concentrations were above the WHO-permitted threshold for medical plant consumption.
To evaluate construct validity and responsiveness of the health-related quality of life (HRQoL) instrument EQ-5D-3L (index, dimensions) and EQ VAS among patients with psoriatic arthritis (PsA). This retrospective, register-based study utilised data from the Swedish Rheumatology Quality Register. Known-groups validity was assessed by comparing EQ-5D-3L and EQ VAS results across groups with varying levels of physical function or disease activity. Convergent validity was assessed through correlations with comparator instruments. Responsiveness was assessed by analysing correlations between changes in EQ-5D-3L, EQ VAS, and comparator instruments, as well as by assessing the ability to discriminate between patients who improved and those who did not, using the area under the receiver operating characteristic curve (AUC). To confirm construct validity or responsiveness, ≥ 75% of hypotheses had to be supported. The study included 13,105 patients with PsA. EQ-5D-3L and EQ VAS demonstrated moderate to strong correlations with comparator instruments and found expected differences between groups with varying physical function or disease activity. Over 75% of the hypotheses related to construct validity were supported. Regarding responsiveness, several hypotheses for the EQ-5D-3L were not supported, and none of the AUC-related hypotheses for EQ VAS were supported. Overall, less than 75% of the hypotheses related to responsiveness for EQ-5D-3L and EQ VAS were supported. The results from this observational study support construct validity of EQ-5D-3L and EQ VAS among patients with PsA. However, responsiveness was not supported for the EQ-5D-3L dimensions which suggests that the EQ-5D-3L may not fully capture changes in HRQoL from interventions impacting other dimensions than pain/discomfort.
Purpose: This study sought to extract and characterize fucoidan from brown seaweed Padina tetrastromatica for the synthesis of fucoidan-gold nanoparticles (F-AuNPs) and to assess their physicochemical properties, as well as their antioxidant, anti-inflammatory, and anticancer activities, alongside potential molecular interactions with specific cancer-related targets. Methods: The extracted fucoidan-rich fraction was characterized for its sulfate content. Citrate-stabilized plain gold nanoparticles (plain AuNPs) were prepared and characterized as non-fucoidan nanoparticle controls. Comprehensive physicochemical characterization, including UV-Vis spectroscopy, Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), X-ray diffraction (XRD), dynamic light scattering (DLS), zeta-potential analysis, and thermogravimetric analysis (TGA), was performed on the resultant fucoidan-functionalized AuNPs (F-AuNPs). Biological activities were assessed using different techniques: antioxidant potential (Ferric Reducing Antioxidant Power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays), anti-inflammatory effects (NO inhibition in macrophages), and anticancer efficacy against HepG2 cells (MTT and flow cytometry). Potential molecular targets relevant to these activities were further explored in silico using molecular docking against key cancer-related proteins, providing hypotheses for future experimental validation. Results: The fucoidan-rich fraction showed a sulfate content of 10.08%. Strong antioxidant activity was observed, especially in FRAP (11.20 ± 0.29 mg TE g-1 DW). F-AuNPs exhibited enhanced cytotoxicity against HepG2 cells (IC50 138.1 µg mL-1) compared to plain AuNPs (IC50 271.2 µg mL-1) and the fucoidan-rich fraction (IC50 390.2 µg mL-1), inducing G1 phase arrest. In addition, F-AuNPs reduced nitric oxide production in LPS-stimulated RAW 264.7 macrophages, reaching 21.42 ± 1.29% inhibition at 100 µg mL-1. As an exploratory, hypothesis-generating step, an in silico target-prioritization screen identified HPSE and MMP-2 as the highest-scoring candidate proteins, proposed solely as targets for future experimental validation. Conclusions: F-AuNPs represent a promising multifunctional nanoplatform with antioxidant, anti-inflammatory, and antiproliferative activities. The integration of in vitro biological evaluation with in silico target prediction supports the potential biomedical relevance of F-AuNPs and generates testable hypotheses regarding their molecular targets, which require experimental validation.
Immune fitness (IF) reflects the body's ability to mount appropriate immune responses. Monitoring IF could improve tailored treatment in oncological rehabilitation. The Immune Status Questionnaire (ISQ) and the Single-Item Scale (SIS) were developed to assess IF, but their clinimetric properties in cancer rehabilitation remain unknown. To evaluate the construct validity, responsiveness, and correlation between the ISQ and the SIS in oncological rehabilitation. The study population included people participating in oncological rehabilitation during or within one year after medical treatment. Data were collected prospectively via questionnaires. Construct validity and responsiveness were assessed through predefined hypotheses, including correlations with fatigue, sleep problems, malnutrition risk, activity impairment, and physical functioning. In total, 97 individuals were included in the analyses. Median ISQ and SIS scores were 8/10 and 7/10, respectively. Correlations ranged from r = -0.21 to r = -0.50. Only the SIS correlations with fatigue and physical functioning, and the ISQ correlation with fatigue, met the predefined thresholds. Responsiveness hypotheses were not confirmed. The ISQ and the SIS demonstrated low construct validity and responsiveness in this population. IF scores were higher than expected. Correlations showed links between fatigue, physical functioning, and IF. Future research should develop tools tailored to the complex immune disturbances experienced by cancer survivors.
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious pulmonary manifestation for which multidisciplinary ILD teams balance immunomodulation with antifibrotic therapy. The 2023 ACR/CHEST guideline recommends immunosuppressive therapy as first-line treatment for autoimmune ILD, but real-world agent-level documentation alongside antifibrotic therapy is poorly characterized. We characterized immunosuppressive medication documentation among seropositive RA-ILD patients stratified by antifibrotic documentation status. Using a federated U.S. EHR network (TriNetX, academic medical centers), we identified three cohorts of seropositive adults: RA without ILD (N=31,932), coded RA-ILD without antifibrotic documentation (N=1,885), and coded RA-ILD with repeated antifibrotic documentation (N=115). Immunosuppressive medications documented within 90 days of each patient's analytic index date were compared descriptively. Methotrexate was documented in 52% of RA without ILD versus 12% of coded RA-ILD patients with repeated antifibrotic documentation. Azathioprine, mycophenolate, and rituximab were more frequently documented in coded RA-ILD. Among 98 coded RA-ILD patients with in-window antifibrotic documentation, 80.6% had at least one non-antifibrotic agent co-documented; 48 distinct medication sets were observed, with the most common set in 14.3% of patients. Medication documentation among coded RA-ILD patients with repeated antifibrotic documentation was more heterogeneous than in RA without ILD, with no dominant medication set. Methotrexate documentation was uncommon, whereas azathioprine, mycophenolate, and rituximab were more frequently documented. These descriptive findings provide agent-level reference data for interdisciplinary management of RA-ILD and identify hypotheses for future comparative-effectiveness research; they do not establish treatment indication or comparative effectiveness.
Background: Multiple sclerosis (MS) lacks a single invariant phenotypic core. Patients accumulate heterogeneous combinations of sensory, motor, cognitive, and autonomic impairments over time, reflecting lesions that are disseminated in time and space. Standard scales such as the Expanded Disability Status Scale (EDSS) distribute disability across functional systems, but do not explicitly represent MS phenotype as a mixture of latent symptom modules. Methods: We analyzed 4617 de-identified neurology progress notes from 577 patients with MS at a single academic medical center. A large language model (GPT-5.2) categorized each note with respect to 17 non-mutually-exclusive neurological phenotype features, and note-level features were aggregated to patient-level binary vectors. Non-negative matrix factorization (NMF) was applied to generate three-, four-, and five-module solutions. For each rank, we computed approximate variance captured, relative reconstruction error, and module-level feature loadings. In the preferred four-module solution, we derived patient-level module percentages, identified highly dominant (≥55%) and archetypal (≥70%) module profiles, and quantified admixture using Shannon entropy and the effective number of modules. Results: Three-, four-, and five-module NMF solutions showed similar approximate variance captured (52.7-54.3%) and reconstruction error (0.47-0.53), but the four-module solution provided the clearest clinical interpretation. The four latent modules were sensory-visual-pain, ataxic-spastic-falls, cognitive-psychologic-fatigue, and autonomic-bladder-bowel, aligning closely with established functional systems in MS. Most patients exhibited admixed phenotypes, with module entropies ranging from 0 (single-module dominance) to 1.386 (equal mixture) and effective modules spanning approximately 1 to 4. Using pre-specified thresholds, 154 patients (26.6%) were highly dominant in a single module and 72 (12.5%) were archetypal; these purer phenotypes were most often in the sensory-visual-pain module. Conclusions: MS phenotypic diversity in routine clinical practice can be parsimoniously represented as mixtures of four latent symptom modules rather than as positions along a single severity axis. Most patients show substantial admixture of sensory, motor, cognitive, and autonomic involvement, but a minority exhibit relatively pure or strongly dominant module patterns. This modular representation provides an interpretable framework for quantifying MS phenotype and for generating testable hypotheses about MS subtypes whose biological relevance remains to be established.
Clinical lipidomics can capture disease-associated molecular alterations at high resolution, yet translating complex lipid species data into interpretable biological insight remains challenging. Existing workflows often emphasize statistical discrimination while underutilizing the structural information embedded in lipid species. To address this gap, we developed LipiDecipher, a structure-oriented analytical framework designed to summarize lipidomic alterations into interpretable structural patterns and to provide database-supported biological contextualization. LipiDecipher integrates differential lipid analysis, structure-resolved summarization, multivariate discrimination, and knowledge-based lipid-to-protein/pathway contextualization. We applied this framework to a retrospective serum lipidomics dataset comprising healthy controls and patients with acute myocardial infarction or post-PCI recurrent myocardial infarction. To improve transparency and robustness, the revised analysis includes sex-disaggregated reporting, covariate-adjusted sensitivity analyses for sex and age, and internal separation stability assessment of category-specific LDA projections through resampling-based feature stability analysis, repeated cross-validation, and permutation testing. The framework identified distinct lipid alterations across study groups, including changes in phosphatidylinositols, ceramides, and triglyceride remodeling patterns. These alterations became more interpretable when summarized at the structural level, including lipid class composition, acyl-chain length, and degree of unsaturation. Internal discrimination analyses suggested separability between groups, while repeated resampling highlighted a subset of recurrently selected lipid features. Knowledge-based mapping prioritized lipid-associated biological contexts related to glycerophospholipid metabolism, sphingolipid metabolism, membrane remodeling, inflammatory signaling, and energy-related processes. Importantly, these protein- and pathway-level outputs are presented as database-supported hypotheses rather than direct evidence of target engagement or pathway activation in the studied cohort. LipiDecipher provides a structure-oriented and interpretation-focused framework for clinical lipidomics. In a retrospective acute myocardial infarction cohort, it enabled the prioritization of candidate lipid signatures and biologically plausible hypotheses from complex lipidomic data. These findings support its use as a hypothesis-generating analytical tool, while external validation and experimental follow-up remain necessary before mechanistic or clinical claims can be established.
Despite the substantial global burden of dengue, clinical management remains largely supportive. Severe disease involves viral replication, dysregulated inflammation, endothelial injury, plasma leakage, thrombocytopenia, and coagulation abnormalities. In this review, we link the traditional Chinese medicine Wei-Qi-Ying-Blood theory with stage-specific dengue pathophysiology and biomarker-guided risk assessment. We also summarize representative formulas and bioactive compounds in terms of their potential antiviral, anti-inflammatory, endothelial-protective, and hematological effects. Computational studies predict relevant targets and pathways, while preclinical studies suggest effects on viral replication, inflammation, vascular integrity, and coagulation. Limited clinical studies have reported shorter fever duration, reduced hospital stay, and improved hematological recovery, although these findings require further validation. Several proposed mechanisms are extrapolated from non-dengue models. The proposed framework is therefore intended to generate hypotheses rather than serve as a validated treatment algorithm. Future studies should focus on standardized preparations, safety assessment, mechanistic validation, and adequately powered multicenter trials.
The Kidney Disease: Improving Global Outcomes (KDIGO) CGA framework remains the essential basis for chronic kidney disease (CKD) classification, risk stratification, and guideline-based therapy. However, eGFR and albuminuria do not always explain the physiological mechanism maintaining the current filtration level or the heterogeneity of treatment responses. This narrative review proposes a hypothesis-generating functional-hemodynamic extension of KDIGO CGA that incorporates renal functional reserve (RFR), blood pressure, volume status, proteinuria phenotype, and selected tubular markers. RFR is discussed as a dynamic stress test of nephron reserve rather than as a replacement for eGFR or albuminuria. A low, zero, or negative RFR may suggest reserve exhaustion or relative hyperfiltration, but its interpretation depends on standardized testing conditions and clinical context. We distinguish established evidence-based therapy-RAAS blockade in albuminuric or hypertensive CKD, SGLT2 inhibition for kidney and cardiorenal protection, and non-steroidal MRA therapy in selected patients-from conceptual sequencing hypotheses such as RAASi-prioritized, SGLT2i-prioritized, early dual, or staged triple renoprotection. The review also summarizes albuminuria as a two-compartment phenomenon involving both glomerular passage and proximal tubular handling of filtered proteins. The proposed framework is not a validated treatment algorithm. It is intended to support physiological phenotyping, interpretation of early eGFR changes, and the design of prospective studies that test whether RFR adds independent prognostic or therapeutic value beyond KDIGO CGA.
Scapholunate dissociation is usually the result of failure of multiple wrist ligaments. With continued use other structures attenuate, which results in change in position of the carpal bones. It is presumed that load characteristics in the wrist joint change with changes in carpal bone position. This is thought to result in localized pressure overload and arthritic change. The purpose of this study was to evaluate radioscaphoid joint pressures and carpal kinematics after sectioning specific wrist ligaments. Our hypotheses are that there would be increased scaphoid flexion and ulnar deviation, increased lunate extension and radial deviation, increased contact pressure in the radioscaphoid fossa, and increased tendon forces. Eight cadaver wrists were instrumented with an electromagnetic motion tracking device and a pressure sensor was inserted into the radioscaphoid joint. Using a wrist joint motion simulator, motion and pressure data were obtained in the moving wrist in the intact state and after sectioning the dorsal radiocarpal, dorsal intercarpal, and scapholunate interosseous ligaments. After ligament sectioning there was increased scaphoid flexion, scaphoid ulnar deviation, lunate extension, and lunate radial deviation resulting in carpal instability. There was also an increase in pressure in the radioscaphoid fossa. Several specimens showed evidence of scaphoid subluxation. It is our conclusion that this combination of ligament sectioning produces scapholunate instability and increased pressures in the radioscaphoid fossa in the laboratory setting. We believe that if left untreated in the clinical setting, scapholunate advanced collapse could result.
Many molecular signals are known to be organized in subcellular regions termed microdomains. One example entails Rho GTPases, which control a range of cell behaviors through their functional patterning in spatiotemporal units. While fluorescent biosensors have allowed precise measurement of Rho GTPase activity in living cells, computational tools to delineate and track signaling microdomains in time-lapse image sequences of such biosensors do not exist. Here, we introduce a method that centers on the notion of activation time series coordination to identify signaling microdomains in space and time. After validating the algorithm with simulated microdomains, we show that our method identifies domains that support current hypotheses on the signaling architecture governing Rho GTPase organization and also respond to perturbation with optogenetics. A record of this paper's transparent peer review process is included in the supplemental information.
This phase 2 trial investigated rucaparib (PARP inhibitor) in combination with nivolumab in patients with advanced BTC without progression after 4-6 months of first-line platinum-based chemotherapy. The primary endpoint was 4-month progression-free survival (PFS) rate with null and alternative hypotheses of 63% and 85%. Secondary endpoints included PFS rate in patients with DNA damage repair (DDR) and IDH1 mutations, median PFS and overall survival (OS) from start of study treatment (PFS1, OS1) and first-line chemotherapy (PFS2, OS2), best overall response and safety; NCT03639935. Of 31 patients, 24 (77.6%) had ECOG performance status 1 and 22 (71.0%) intrahepatic cholangiocarcinoma. Nine (29%) patients had DDR or IDH1 mutations (BRCA2 (n = 3), ATM (2), FANCA (1), IDH1 (3)). 4-month PFS rate was 54.8% (95% confidence intervals (CI), 36.0-72.7) in all patients, and 83.3% and 100% in the DDR and IDH1 cohorts, respectively. Median PFS1 and OS1 were 4.6 months (95% CI, 3.7-6.2) and 15.9 months (95% CI, 9.8-24.1). Median PFS2 and OS2 were 9.9 months (95% CI, 8.3-11.3) and 21.4 months (95% CI, 14.8-26.7). Two (6.4%) patients had partial response. Most common grade ≥ 3 TRAEs included anemia (12.9%), neutropenia (9.7%) and elevated liver enzymes (12.9%). The primary endpoint of PFS rate at 4 months was not met. The PFS rate at 4 months in the DDR and IDH1 cohorts were longer than expected and support further investigation of the addition of PARP inhibitor during maintenance immune-checkpoint inhibition for DDR and IDH1 altered BTC patients.
Background/Objectives: Dental caries remains a major public health problem in childhood and disproportionately affects socioeconomically disadvantaged populations. Although toothbrushing and oral hygiene are commonly promoted as key preventive behaviours, their protective effect may be limited by structural factors such as access to dental care, fluoride exposure, and preventive services. This study aimed to compare dental caries experience, oral hygiene status, toothbrushing frequency, and sugar consumption among disadvantaged children from the Peruvian Amazon and Valencia, Spain, and to explore whether differences in hygiene behaviours were reflected in caries outcomes. Methods: An exploratory cross-sectional school-based study was conducted among 291 children aged 5-12 years attending three purposively selected schools serving socioeconomically disadvantaged communities: one rural school in the Peruvian Amazon (n = 162) and two urban schools in Valencia, Spain (n = 129). Dental caries experience was assessed using a combined global caries score derived from the dmft and DMFT (CAOD/cod) indices according to dentition type, and oral hygiene status was evaluated using the Simplified Oral Hygiene Index (OHI-S). Toothbrushing frequency and sugar consumption were collected through structured questionnaires. Group comparisons, Spearman correlation analyses, and exploratory multiple linear regression models were performed. Results: Mean global caries scores did not differ significantly between Peruvian and Spanish children (3.71 ± 2.86 vs. 4.07 ± 3.44; p = 0.596). However, severe caries experience (score ≥ 8) was more frequent among Valencian children (21.7% vs. 10.5%; p = 0.014). Peruvian children showed significantly better oral hygiene status (OHI-S-derived score: 1.25 ± 0.79 vs. 1.49 ± 0.84; p = 0.014) and higher toothbrushing frequency (p < 0.001). Frequent sugar consumption was similarly high in both groups. Within each population, poorer oral hygiene and lower toothbrushing frequency were associated with higher caries experience in bivariate analyses, although the exploratory multivariable models showed a more limited pattern of association. Conclusions: Among the participating schools, children from the Peruvian Amazon showed better oral hygiene indicators and more frequent toothbrushing than Spanish children, while no statistically significant difference in caries experience was detected. Because structural variables such as fluoride exposure, dental attendance, and access to restorative care were not directly measured, explanations involving healthcare infrastructure should be considered as candidate hypotheses to be tested in future, adequately powered and adjusted studies, rather than as confirmed mechanisms. Findings should not be generalised beyond the participating schools.
This study aimed to evaluate the adjunctive triage performance of p16/Ki-67 dual staining (DS) cytology for cervical lesions in a colposcopy-referred cohort, to analyze its correlation with lesion severity, and to explore its predictive value for persistent high-risk human papillomavirus (HR-HPV) infection. A total of 109 patients undergoing colposcopic cervical biopsy (recruited via standard HPV+TCT referral criteria) were included. We evaluated the incremental diagnostic performance of adding p16/Ki-67 dual-stain (DS) triage to the standard HPV+TCT referral workflow for detection of CIN2+ and CIN3 +. Among 66 HR-HPV-positive patients with CIN1 or lower lesions, p16/Ki-67 DS cytology was performed, and the patients were followed up for 6 months to assess the predictive value for persistent infection. The positivity rate of p16/Ki-67 DS cytology gradually increased with the progression of cervical lesion severity (P<0.001). Further triage with p16/Ki-67 DS on the basis of combined HPV+TCT cervical cancer screening yielded sensitivity, specificity, accuracy and AUC of 77.8%, 88.6%, 84.4% and 0.822 ± 0.052 (95%CI: 0.721-0.923) for the diagnosis of CIN2+, and 93.3%, 81.3%, 81.7% and 0.823 ± 0.056 (95%CI: 0.713-0.933) for CIN3+, respectively. Among HR-HPV-positive CIN1/lower lesions, 87.1% of DS-positive patients had persistent infection compared to 62.9% of DS-negative patients (P = 0.025), with an odds ratio of 4.515 (P = 0.028). In this colposcopy-referred cohort defined by HPV and/or TCT-based referral criteria, p16/Ki-67 dual-stain (DS) cytology exhibited satisfactory adjunctive triage efficacy for identifying CIN2+ and CIN3+, and independently predicted persistent HR-HPV infection among patients with ≤CIN1 lesions. Notably, all analyses in this study are limited to diagnostic efficacy in this referral cohort; any potential clinical applications, including possible reductions in unnecessary procedures, remain exploratory hypotheses that require prospective clinical validation.
To explore temporal patterns of serially measured cardiovascular-related biomarkers in patients with chronic heart failure (CHF), with the objective of identifying biomarker pathophysiological trajectories associated with clinical outcomes. These explorative analyses can generate hypotheses regarding underlying pathophysiological processes and the potential role of multi-biomarker approaches in chronic HF. The BioMEMS-study involved 334 patients with moderate to severe chronic HF in NYHA class III who received either standard of care or remote hemodynamic monitoring. Serial blood samples were collected at baseline, 3, 6, and 12 months, and biomarker levels were assessed using the Olink Cardiovascular-III panel. Joint modelling analyses were performed, integrating longitudinal biomarker trajectories and risk of the composite endpoint of all-cause mortality or HF hospitalization. In multivariable-adjusted models, 15 biomarkers were consistently and significantly associated with the composite endpoint after adjustment for confounders and multiple testing. MMP-2, ST2, IGFBP-1, IGFBP-7, and NT-proBNP exhibited the strongest associations with the composite endpoint, with hazard ratios (95% CI) of 2.72 (1.87-4.03), 2.71 (2.00-3.80), 2.70 (1.81-4.27), 2.48 (1.81-3.45), and 2.28 (1.72-3.03), respectively. These findings were robust across sensitivity analyses correcting for clinical confounders and treatment groups. Temporal trajectories revealed higher biomarker levels in patients who experienced incident events, with biomarkers showing corresponding changes in levels preceding events. Serial biomarker measurements could provide additional insights in the pathophysiology of worsening HF. Specific biomarkers reflecting myocardial stress, cardiac remodelling and fibrosis show changes in levels over time as worsening HF approaches, which highlights possible involvement of these pathophysiological pathways.
Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease and can trigger life-threatening neurological complications, yet the sequence-level physicochemical correlates of CNS involvement across globally circulating lineages remain incompletely defined. Here we screened 15,247 EV-A71 genomic entries spanning 1998-2024, retaining 267 full-length sequences (≥7,000 bp) with confirmed clinical outcomes (7 central nervous system [CNS]-involved, 260 non-CNS). This extreme 7:260 class imbalance, reflecting the scarcity of publicly available full-length CNS-associated EV-A71 genomes, is the principal limitation and interpretive premise of the study. Each polyprotein position was encoded by three Z-scale descriptors-hydrophobicity (Z1), molecular volume (Z2), and electrostatic polarity (Z3)-converting discrete residue identities into a continuous biophysical feature space. A two-stage statistical pipeline (Mann-Whitney U screening followed by odds-ratio ranking) distilled 20 significant loci down to five core positions: P2124_Z1, P997_Z2, P1246_Z3, P1743_Z2, and P1711_Z1 (all P<0.001). Leave-one-out cross-validated logistic regression achieved the highest area under the receiver operating characteristic curve (AUC = 0.889) among eight algorithms benchmarked. Because this AUC is estimated from only seven positive samples, it should be regarded as an exploratory internal performance signal rather than definitive evidence of generalisable accuracy. SHapley Additive exPlanations (SHAP) assigned the largest model contribution to P2124_Z1 (OR = 4.28; 95% CI 1.47-12.51), while P1246_Z3 was statistically associated with lower CNS odds (OR = 0.50); these model-derived quantities do not establish causal mechanisms. Reference-strain mapping linked the five polyprotein coordinates to mature-protein residues in 3D RdRp, 3C protease, 2C helicase, and 2A, thereby providing structural context for cautious biochemical hypotheses rather than confirmed mechanisms. Phylogenetic dispersion of CNS-associated strains was compatible with convergent evolution, but this inference remains limited by the seven available CNS genomes. We therefore present the five-position physicochemical signature and nomogram as hypothesis-generating tools for prioritising candidate neurovirulence markers, requiring prospective validation in larger and more balanced independent cohorts before clinical or field deployment.
The proliferation of body-technology interfaces - including wearable devices, virtual reality, augmented reality, and digital body modification applications - has significantly influenced contemporary embodied experience, raising novel questions for psychopathology research and clinical practice. This analysis examines how modern body-technology interfaces influence bodily experience and identifies proposed clinical presentations arising from these interactions, discussing their theoretical grounding and implications for assessment and treatment. We conducted a comprehensive interdisciplinary review integrating phenomenological, neuroscientific, and clinical perspectives to characterize technology-related embodiment presentations and discuss existing and potential therapeutic approaches within established clinical frameworks. Literature was identified through PubMed/MEDLINE, PsycINFO, and Google Scholar searches (1990-2025), using terms related to embodiment, body-technology interfaces, virtual and augmented reality, wearable devices, and emerging psychopathology. Sources spanning neuroscientific, clinical, phenomenological, and ethnographic perspectives were selected based on direct relevance to the review scope. Eight proposed clinical constructs are described across four domains: body image disorders (filter dysmorphia, tracking dysperception), embodiment disorders in virtual environments (virtual depersonalization disorder, avatar-body identity conflict), disorders of technologically mediated proprioception (proprioceptive lag syndrome, augmented sensorimotor confusion disorder), and behavioral addictions (self-tracking addiction, virtual embodiment addiction. These constructs are grounded in documented neurobiological mechanisms involving body representation, interoceptive processing, and reward circuits. Current evidence consists primarily of theoretical elaborations, case reports, and ethnographic observations; epidemiological data remain limited. The proposed constructs are best understood as technology-amplified variants of established conditions or as hypotheses warranting empirical investigation rather than validated independent diagnostic entities. Body-technology interfaces generate psychopathological presentations that existing clinical frameworks may not fully capture. Future research should focus on empirically validating these proposed constructs, developing standardized assessment instruments, and establishing evidence-based therapeutic protocols. Ethical dimensions, including differential access and algorithmic normalization of bodily experience, require ongoing clinical and policy attention.
Osteosarcopenia, which is the coexistence of sarcopenia and osteoporosis, is being increasingly recognized as a systemic musculoskeletal aging syndrome. However, shared molecular regulators of bone-muscle deterioration remain unclear. In this study, we integrated bulk transcriptomic datasets from sarcopenic skeletal muscle and osteoporosis peripheral blood mononuclear cells to identify shared differentially expressed genes, followed by two-sample Mendelian randomization using osteoporosis genome-wide association study summary statistics to prioritize genes with potential causal relevance. Furthermore, diagnostic performance, functional enrichment, immune infiltration, single-cell RNA sequencing, regulatory network reconstruction, compound prediction, and siRNA-mediated validation were conducted in C2C12 and MC3T3-E1 cells. Overall, 122 shared differentially expressed genes were preliminarily screened, and KAZN and SUPT3H were tentatively proposed as candidate genes genetically associated with osteoporosis risk. Both genes were upregulated in the disease groups and exhibited weak to modest diagnostic performance. Furthermore, Kazn or Supt3h knockdown promoted myogenic differentiation in C2C12 cells as well as osteogenic differentiation and mineralization in MC3T3-E1 cells, supporting their roles as negative regulators of lineage differentiation. Moreover, functional analyses linked KAZN mainly to mitochondrial-related programs and SUPT3H to immune signaling, whereas single-cell analyses localized these genes to stromal, progenitor, and immune-related compartments. These hypothesis-generating findings suggest that KAZN and SUPT3H participate in shared bone-muscle dysfunction and generate candidate genes and mechanistic hypotheses for subsequent functional validation and translational research.