Disease Phenotype Research Articles

BackgroundNon-alcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), occurring in adults of normal weight, represents a unique emerging phenotype apart from obesity-related NAFLD. Notwithstanding a normal body mass index (BMI), this phenotype poses considerable metabolic and hepatic risk, undermining conventional obesity-focused paradigms of fatty liver disease.MethodsThis comprehensive review integrates global epidemiological data, molecular investigations, and clinical research to elucidate the distinct pathogenesis, risk factors, natural history, and treatment of lean NAFLD. Essential bibliographical databases were screened for research on disease prevalence, genetic determinants, metabolic characteristics, and long-term consequences.ResultsLean NAFLD impacts 5-20% of the worldwide NAFLD population, with a greater frequency in Asian cohorts (~45%). It is characterized by visceral obesity, sarcopenia, and significant genetic determinants (variants of PNPLA3, TM6SF2, and MBOAT7) in normal BMI individuals. Gut dysbiosis and modified bile acid metabolism further delineate its pathophysiology. Importantly, lean NAFLD presents similar or elevated risks for all-cause mortality (1.6-fold increase), advanced fibrosis, cirrhosis, hepatocellular carcinoma, and cardiovascular disease compared to obese NAFLD, despite a lower prevalence of metabolic comorbidities.ConclusionLean NAFLD is a clinically relevant condition necessitating customized diagnostic and therapeutic approaches. Lifestyle modifications focusing on moderate weight reduction (3-5%), fructose and cholesterol restrictions, and resistance exercise are highlighted. Future investigations should emphasize consistent classifications, non-invasive biomarkers, and medicines tailored to lean NAFLD phenotypes.

PITPNM3 has been identified as a crucial gene associated with various phenotypes of retinal disease in humans; however, detailed mechanisms through which PITPNM3 mutations result in these conditions are not fully understood. In this study, we aimed to generate such a preclinical mouse model and evaluate its relevance to human PITPNM3-related conditions. Heterozygous mice were bred to obtain a homozygous genotype, aiming to mimic the human genetic condition. Subsequent phenotyping and genetic segregation analyses were conducted along with electrophysiological studies and histological examinations. Full-field electroretinogram analysis revealed a reduced cone response although the severity was not as pronounced as observed in humans with PITPNM3-related conditions. Histologically, the retinal structure appeared largely unchanged, indicating a discordance between functional impairment and morphological changes. In our preclinical mouse model, the observed phenotypic changes were not as severe as those found in humans with PITPNM3-related conditions and this discrepancy points to a potentially different disease progression trajectory in the mouse model. These findings highlight the importance of longer follow-up periods in such studies and the need for further research to elucidate the genotype–phenotype relationship in PITPNM3.

Background:Psoriatic arthritis (PsA) is a chronic inflammatory condition characterized by joint involvement, enthesitis, dactylitis, and skin psoriasis. The pathophysiology of PsA is complex, driven by dysregulated immune responses, making targeted therapies essential for managing symptoms. Despite the success of biologic disease-modifying anti-rheumatic drugs (bDMARDs) like tumor necrosis factor (TNF) inhibitors, many patients experience suboptimal responses or adverse effects, necessitating the development of new therapies. Emerging biologics targeting interleukin (IL)-17, IL-23, and Janus kinase (JAK) pathways offer promising alternatives. This review aims to evaluate the efficacy and safety of emerging biologics for PsA.Methods:A systematic review of studies published from 2000 to December 2024 was conducted. Randomized controlled trials (RCTs), cohort studies, and clinical trials were included to assess the efficacy, safety, and adverse effects of bDMARDs and targeted synthetic DMARDs (tsDMARDs) for PsA treatment. Studies focusing on other aspects of psoriasis or nonpharmacological treatments were excluded. Key data extracted included study design, treatment type, efficacy measures (e.g., ACR response), and safety outcomes.Results:A total of 20 studies involving 77,124 participants were reviewed. Biologic DMARDs such as TNF inhibitors, IL-17 inhibitors (e.g., secukinumab, ixekizumab), and IL-23 inhibitors (e.g., guselkumab) showed high efficacy in managing both joint and skin symptoms. Emerging therapies like bimekizumab (targeting IL-17A and IL-17F) demonstrated enhanced efficacy compared to traditional biologics. Conventional DMARDs, such as cyclosporine and leflunomide, were less effective but still showed moderate benefits. Safety profiles were generally favorable, with biologics showing fewer adverse effects than conventional therapies.Conclusion:Emerging biologics have significantly advanced the management of PsA, offering greater efficacy and safety compared to conventional DMARDs. IL-17 and IL-23 inhibitors, along with newer agents like bimekizumab, present promising treatment options for patients with inadequate responses to TNF inhibitors. Personalized treatment strategies, based on disease phenotype and individual patient needs, are essential for optimizing outcomes in PsA management. Further research into long-term efficacy and safety is required to refine treatment protocols and improve patient outcomes.

Topical mutant allele-specific siRNA delivery for treatment of Meesmann epithelial corneal dystrophy and elucidation of disease biomarkers.

Despite significant vascular inflammation, the relationship between Behçet's syndrome (BS) and atherosclerotic cardiovascular (CV) disease remains unclear. This study aimed to evaluate coronary artery involvement in asymptomatic male BS patients and matched controls using coronary computed tomography angiography (CCTA). This cross-sectional study included 178 male BS patients (mean age: 40.78±7.95) and 139 male controls (mean age: 40.48±7.17). Coronary lesions were classified as stenosis, aneurysm, arteritis, or occlusion. Agatston calcium scores were calculated. All CCTA images were evaluated independently by two radiologists, with excellent inter-observer agreement. Demographic/clinical characteristics and traditional CV risk factors were also evaluated. BS patients and controls were comparable with regard to most CV risk factors. Any coronary lesion prevalence was similar between BS patients and controls (23.6% vs 25.9%, p = 0.694), as were stenosis rates (20.8% vs 25.9%, p = 0.286) and Agatston scores. However, aneurysms (5.1%), arteritis (4.0%), and total occlusions (1.7%) occurred only in BS patients. Age was an independent predictor of any coronary lesion (OR 1.113, 95% CI 1.047-1.184, p < 0.001), while venous involvement showed protective association (OR 0.275, 95% CI 0.114-0.664, p = 0.004). Clinical risk stratification identified arterial and neurological involvement as highest risk, while venous involvement showed lowest risk. BS does not appear to accelerate atherosclerosis, in contrast to other systemic rheumatic diseases. Instead, coronary involvement in BS is characterized by vasculitis-related lesions such as arteritis, aneurysms, and total occlusions. Clinical phenotypes rather than traditional CV risk factors determine coronary involvement patterns. Distinct disease phenotypes appear to confer differential risks for coronary involvement.

Background/Objectives: Fabry disease is an X-linked lysosomal storage disorder. It is characterised by impaired metabolism of glycosphingolipids whose accumulation causes irreversible organ damage and life-threatening complications. Genotype–phenotype correlations have a limited scope in Fabry disease as the disorder presents with wide-ranging clinical variability. In other X-linked disorders, epigenetic profiling has identified methylation patterns and disease modifiers that may explain clinical heterogeneity. In this narrative review and thematic analysis, the role of DNA methylation and epigenetics on the clinical phenotype in Fabry disease was investigated. Methods: Embase, PubMed, and PsycINFO were searched to identify literature on DNA methylation and epigenetics in Fabry disease. Based on the eligibility criteria, 20 articles were identified, and a thematic analysis was performed on the extracted data to identify themes. Results: Three themes emerged: (I) genetic modifiers, (II) methylation profiling, and (III) insights into X chromosome inactivation (XCI). The evidence synthesis revealed that telomere length, especially in early disease stages, bidirectional promoter (BDP) methylation by sphingolipids, epigenetic reader proteins, mitochondrial DNA haplogroups, and DNA methylation of the promoter region of the calcitonin receptor gene are potential genetic modifiers in Fabry disease. Methylation patterns also reveal episignatures in Fabry disease evolution and genes implicated in the maintenance of basement membranes. Studies on XCI further emphasise disease heterogeneity and draw attention to methodological issues in the assessment of XCI. Conclusions: This thematic review shows that DNA methylation and genetic modifiers are key factors modifying clinical variability in Fabry disease. More broadly, it underscores a crucial role for epigenetic processes in driving disease onset, progression, and severity in X-linked disorders.

In this two-part investigation, we examined whether Alzheimer's disease (AD) phenotypes are distinct clinical entities or represent positions within a graded multidimensional space. First, using a large retrospective dataset of past research participants (n = 413) from memory clinics, we examined the comparative distributions of cognitive performance in people diagnosed with typical amnestic AD (tAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA), across a broad range of disease severities. Secondly, a prospective deep phenotyping study of lvPPA (n = 18) compared to typical AD (n = 9) addressed the following questions: (1) Does the multidimensional cognitive pattern of impairment only emerge in advanced lvPPA, and how does it compare to tAD? (2) Do memory deficits in lvPPA appear in a simple clinic-level cognitive assessment or require in-depth neuropsychological investigation? (3) To what extent is performance on verbal episodic memory attributable to language impairment? (4) Do the patterns of decline in lvPPA and tAD stay categorical or multidimensional over time? We explored the associations between scores derived from a principal component analysis of cognitive measures, and grey matter volumes in key memory- and language-related brain regions, at baseline and longitudinally. The clinic-level assessment revealed similar results in both the prospective and retrospective data: (i) patients showed graded distinctions (e.g., predominant visual versus language impairment in people with PCA versus lvPPA) and overlap (e.g., shared weakness in domains such as memory); and (ii) people with lvPPA and tAD were equally impaired on both verbal and non-verbal memory tests. Longitudinal assessment showed phenotypic dispersion: (i) people with tAD showed varied patterns of phenotypic differentiation; and (ii) people with lvPPA and lvPPA + exhibited a multidimensional pattern of decline with decreasing principal component scores and worsening multi-domain cognitive performance. The results of Bayesian linear regressions showed evidence for the association of grey matter volumes in language and memory networks with principal component analysis derived scores. The graded distinctions amongst typical amnestic and atypical (language and visual) phenotypes of AD support the proposal for a transdiagnostic, multidimensional phenotype geometry that spans all AD subtypes.

The relationship between observed clinical phenotypes and underlying genotypes is blended or skewed in multiple molecular diagnoses, complicating a comprehensive molecular genetic diagnosis. We report two families with dual diagnoses, using the deafness-associated gene, COL4A6, to exemplify its contribution to blended, complex clinical presentations. This is an observational study within a large, ethnically diverse rare disease cohort, focusing on families with hearing loss and suspected dual diagnoses, followed by functional and structural studies of novel variants. Families were identified through a large rare disease sequencing initiative. Exome or genome sequencing was performed, with follow-up RNA studies for a synonymous COL4A6 variant. Spatial and temporal expression analysis in zebrafish traced col4a6 expression in the otic vesicle and ear from 1 to 5 days post-fertilization. Structural modeling was used to estimate variant impact on protein structure. We identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4:c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6:c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4:c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3:c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease phenotype. Our findings highlight the importance of recognizing dual molecular diagnoses to untangle blended phenotypes, as well as the diagnostic relevance of synonymous variants with predicted splicing effects.

Chronic bronchitis is a major phenotype of chronic obstructive pulmonary disease (COPD), characterized by a persistent productive cough and excessive mucus secretion resulting from chronic airway inflammation. In Unani medicine, the term Waram-i- shoab Muzmin has been used in later writings as a literal translation, though the clinical description more closely resembles Sūʿāl, particularly Sūʿāl Aṣlī mentioned in classical sources. The present review explores the etiopathogenesis, symptomatology, and management of chronic bronchitis in both modern and Unani frameworks. Modern medicine attributes its development mainly to cigarette smoking, air pollution, and oxidative stress, which trigger airway remodelling, mucus hypersecretion, and epithelial injury. Unani physicians described similar mechanisms in terms of Sū’-i-Mizāj, Waram, Yubūsat, and accumulation of Mawād-i-Fāsida, often precipitated by cold, dust, and irritants, especially in individuals of Balghamī Mizāj . Preventive strategies, lifestyle regulation, and holistic management form the core of Unani practice, including Ilāj bi’l-Tadbīr (regimenal therapy), Ilāj bi’l-Ghizā (dietotherapy), and Ilāj bi’l-Dawā (pharmacotherapy). Various single drugs such as Asl-us-Soos (Glycyrrhiza glabra), Arusa (Adhatoda vasica), Behidana (Cydonia oblonga), and compound formulations like Laʿūq-e-Sapistān and Joshānda-e-Munḍij are employed, along with preventive measures such as avoiding phlegm-producing foods and exposure to cold air. Importantly, recent clinical evidence has validated the efficacy of licorice-based formulations in chronic cough, further supporting the relevance of Unani interventions. These insights demonstrate that Unani intervention can be effectively applied in clinical practice as a complementary option, offering safer and more sustainable strategies for managing chronic bronchitis. Keywords: Chronic bronchitis, COPD, Sūʿāl, Unani medicine, Etiopathogenesis

A novel X-linked retinitis pigmentosa beagle dog model for ophthalmic research established rapidly by editing the RPGR gene in zygotes.

Translational failure remains a major barrier in critical illness research, with preclinical findings from animal models often failing to replicate in human trials. we hypothesize that the integration of advanced in vitro models derived from human cells-particularly those from ICU patients-prior to animal studies will enhance clinical translation in critical care research. These emerging human-relevant platforms-such as organ-on-chip microfluidic systems-recapitulate key aspects of human physiology and pathology that animal models often cannot, thereby avoiding interspecies differences, capturing patient-specific variability, and enabling the study of disease phenotypes and endotypes. We propose that advanced in vitro models should be used first to gain mechanistic insights and assess efficacy in a human-relevant setting, while subsequent animal studies would then serve to evaluate systemic effects and safety before translation to patients. By leveraging such complementary strengths, an integrated in vitro-in vivo pipeline could better bridge the bench-to-bedside gap. This approach aligns with 3Rs principles by refining and reducing animal use (screening therapeutics in human models to focus subsequent animal experiments), and potentially replacing certain animal tests pending rigorous validation and regulatory acceptance. Implementation will require regulatory support, as well as training and funding to overcome technical barriers. This hypothesis is testable through analyses of past translational failures to determine whether human in vitro models could have predicted outcomes, and through prospective studies comparing drug development pipelines with and without an in vitro prescreening step to assess improvements in clinical success rates. By harnessing the strengths of both model systems, this two-step strategy could help bridge the translational gap in critical care, improve therapeutic development, and accelerate precision medicine in sepsis and other critical illnesses.

BackgroundAccumulating evidence indicates that the occurrence, development, and treatment of inflammatory bowel disease (IBD) are closely related to the intestinal microecology. However, whether Crohn’s disease (CD) and Ulcerative colitis (UC) are characterized by distinct gut microbial signatures and associated disease phenotypes remains to be determined. The present study investigates the correlation between potential pathogenic or protective intestinal bacteria and the clinical pathological characteristics of patients with IBD.MethodsA total of 274 tissue samples from patients with IBD, including 237 formalin-fixed paraffin-embedded (FFPE) samples and 37 fresh samples, were detected by qPCR for Enterotoxigenic Bacteroides fragilis, Klebsiella pneumoniae, Listeria monocytogenes, Akkermansia muciniphila, and Mycobacterium avium subspecies paratuberculosis. The study identified significant correlations between specific bacteria and clinical features such as age, disease location, disease behavior, and immunohistochemical markers.ResultsAmong patients with CD, Enterotoxigenic Bacteroides fragilis colonization was associated with Epstein-Barr virus (EBV) infection, Ki-67 expression, disease behavior, and prognosis. Klebsiella pneumoniae colonization showed a significant association with EBV infection and lesion location. Listeria monocytogenes colonization was correlated with IgG4 levels and disease location. Moreover, as a potential probiotic, the colonization rate of Akkermansia muciniphila is significantly higher during the remission phase than in the active phase of CD. Notably, among patients with UC, these bacteria did not correlate well with clinical pathological characteristics. In addition, compared with healthy people, these bacteria in the feces of patients with CD and UC also exhibit different characteristics.ConclusionsThese findings suggest that, compared with UC, certain specific gut bacteria, such as Enterotoxigenic Bacteroides fragilis, may play a more important role in the occurrence, development and prognosis of CD. In addition, different intestinal microbiota-based therapeutic strategies should be developed for CD and UC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07095-w.

Iliac vein stenting (IVS) is an endovascular revascularization procedure for iliac venous outflow obstruction. We aimed to synthesize the efficacy and safety of IVS across iliac vein disease phenotypes and follow-up horizons. Following a pre-registered protocol (PROSPERO CRD42024606701), we systematically searched Embase, Scopus, PubMed, Web of Science, and Cochrane Library on October 5, 2024. Without restricting study design, we included English-language reports with at least 10 patients that reported at least one prespecified outcome (or convertible data) and excluded studies with additional core therapies or duplicated cohorts. Diseases were classified as non-thrombotic iliac vein compression syndrome (NIVCS), post iliac vein thrombotic syndrome (PIVTS), chronic iliac vein obstruction (CIVO, that is, NIVCS or PIVTS), and acute thrombotic iliac vein obstruction (ATIVO, that is, a CIVO patient with acute ipsilateral thrombosis). The primary outcome was cumulative primary patency (CPP); secondary outcomes comprised ulcer healing, edema and pain relief, quality-of-life improvement, revised Venous Clinical Severity Score change, and adverse events. CPPs at prespecified intervals were extracted for each disease category and pooled in separate meta-analyses. Twenty-seven studies (4,782 patients) were included; demographic, intraoperative, and outcome data were systematically abstracted. Pooled CPPs were consistently high, particularly for NIVCS, and were lower when thrombotic components were present (PIVTS and ATIVO), while other efficacy outcomes generally improved and serious complications were uncommon. In conclusion, across diverse iliac vein diseases and follow-up periods, IVS demonstrates good efficacy and safety; this unfunded study supports IVS as a prominent treatment option.

BackgroundImmune thrombocytopenia (ITP) is a common pediatric autoimmune disorder characterized by low platelet counts and heightened bleeding risk. Fc gamma receptors (FcγRs), particularly FCGR2A (131H/R) and FCGR3A (158F/V), mediate immune responses and may influence ITP susceptibility and progression. Gender-related genetic variation has been proposed but remains underexplored, particularly in Middle Eastern pediatric populations. This study aimed to perform an exploratory assessment of the prevalence and potential clinical relevance of FCGR2A and FCGR3A polymorphisms, including gender-based tendencies, in Palestinian children with ITP.MethodsA multicenter case-control study included 40 proven pediatric ITP patients (20 males, 20 females; mean age 6.76 ± 4.13 years) and 80 age- and sex-matched healthy controls. Genotyping was performed using PCR-RFLP and nested PCR. Genotype frequencies were correlated with disease phenotype and sex.ResultsNo statistically significant differences in genotype distributions were observed between ITP cases and controls for either FCGR2A (HH: 17.5%, HR: 62.5%, RR: 20.0%) or FCGR3A (FF: 25.0%, FV: 55.0%, VV: 20.0%) (p > 0.05). However, a secondary, exploratory analysis for gender-specific trends yielded noteworthy observations: FCGR2A-HH was numerically more frequent in male ITP patients (57.4%) than in females (42.8%), while HR was lower in males (48% vs. 52%). Similarly, FCGR3A-VV occurred in 62.5% of male ITP patients versus 37.5% in females. Furthermore, the combined HR/FV genotype (32.5%) showed a non-significant trend of association with chronic ITP (69.2%), while the VV/HH genotype, although rare (5%), was linked to 50% of refractory presentations.ConclusionThis exploratory study found no statistically significant association between FCGR2A and FCGR3A polymorphisms and overall ITP susceptibility in the full cohort. However, the observed trends, particularly the distinct gender-based distribution of specific genotypes and the association of combined genotypes with chronic and refractory disease, suggest that these genetic markers may play a role in disease progression. Further investigation in a larger, appropriately powered study is warranted to validate these findings and to understand their potential to guide personalized treatment approaches for pediatric ITP.

The mouse strain O20 is highly resistant to parasite Leishmania major. O20 mice differed from all resistant strains tested until now, as they harbored parasites in their organs, but upon exposure to soluble Leishmania antigen (SLA) their splenocytes did not respond by cytokine production and their macrophages did not produce NO, suggesting a novel mechanism of resistance. Another resistant strain C57BL/10 (B10) harbors similar numbers of parasites as O20 in its organs and its splenocytes respond to SLA by production of IFNγ, but not IL-4. They also produce IL-2, IL-6, IL-10 and IL-17. Macrophages respond to SLA by NO production. Strain B10.O20 was derived from a cross of these two resistant strains. B10 provided 96.4% of its genome and O20 contributed 3.6% of its genome. Unexpectedly, this very limited difference between the two strains resulted in the very large phenotypic effects. B10.O20 was susceptible to L. major, as it exhibited large skin lesions, high parasite numbers in skin and lymph nodes, and a massive spleen infiltration by CD11b+CD193+ and CD11b+Gr1+ cells. Thus, a small percentage of genes of the resistant strain O20 in the genome of the second resistant strain B10 resulted in high susceptibility to L. major. After stimulation with SLA, splenocytes of B10.O20 produced significantly higher levels of all Th1, Th2 and Th17 cytokines than both its parental strains B10 and O20. This suggested a chronic inflammation with imbalance of several arms of immune response. In summary, the responses of strains B10.O20 and O20 to L. major revealed novel disease phenotypes that have not been observed previously in mice but they were seen in several clinical studies of human leishmaniasis. The studies of heterogeneity of defensive strategies of mouse strains may guide development of effective antileishmanial therapies or vaccine development and it could serve as a basis for investigation of asymptomatic responses to other infectious diseases.

Cerebral amyloid angiopathy (CAA) is a heterogeneous small vessel disease that can occur independently or alongside Alzheimer disease (AD). CAA is diagnosed using the Boston Criteria 2.0, integrating clinical and neuroimaging features, whereas the Cerebrospinal Fluid (CSF) role in clinical practice remains under investigation. This study explores whether CSF biomarkers can identify distinct disease phenotypes, supporting hemorrhagic risk stratification. We enrolled probable patients with CAA retrospectively (Boston Criteria 2.0) from 2 institutions, collecting clinical, neuroimaging, and follow-up data alongside core CSF biomarkers (Aβ40 [amyloid β 1-40], Aβ42 [amyloid β 1-42], p-Tau181 [phosphorylated Tau], total-Tau). Patients with CAA were stratified applying the Amyloid Tau Neurodegeneration (ATN) research framework, according to the presence of CSF amyloidosis (A+CAA versus A-CAA) and tauopathy (A+T+CAA versus A+T-CAA), and using unsupervised clustering, which defined CAA subgroups based on CSF biomarker levels only. Kaplan-Meier and Cox regression analyses assessed the predictive value of CSF-based subgroups for symptomatic hemorrhages during follow-up. Seventy-one probable CAA patients (aged 71.77±8.45 years, 66% men, median follow-up 1.15 years [0.50-2.44]) were enrolled. A+CAA showed a higher prevalence of cortical superficial siderosis than A-CAA (67% versus 25%, P=0.016). A+T-CAA had a greater hemorrhagic risk than A+T+CAA during follow-up (29 versus 7 events per 100 patient-years, P=0.010; log-rank test: P=0.013). Unsupervised clustering identified 2 subgroups, which we defined as pure CAA and CAA-ADA, with pure CAA presenting more symptomatic hemorrhages during follow-up (22 versus 0 events per 100 patient-years, P=0.017; log-rank test, P=0.011). CSF-based profiling effectively stratifies CAA phenotypes, offering a promising prognostic tool alongside neuroimaging markers. Further validation is needed to confirm its role in identifying patients with CAA with different natural histories.

BackgroundDiabetes mellitus (DM) and coronary artery disease (CAD) are closely interrelated clinical conditions. However, the combination analysis based on DM related CAD diagnostic model remains a gap. The primary objective of this study was to identify diagnostic models and diagnostic markers for CAD based on the association of diabetic phenotypes and attempt to explore them further in a mouse model.MethodsWe used data integration as well as multiple datasets for both coronary artery disease and diabetes to exclude bias as well as to improve reliability. We employed the least absolute shrinkage and selection operator (LASSO) regression algorithms to construct the CAD diagnostic model. Furthermore, we established mouse CAD model (low-density lipoprotein receptor deficient mice with high fat diet) to explore the crosstalk between the screened biomarkers and severe CAD progress.ResultsThe intersecting genes from differential analysis and weighted correlation network analysis (WGCNA) results yielded 32 diabetes-related biomarkers. We then identified two diabetes-related phenotypes through the consensus clustering in CAD patients. Microenvironmental analysis revealed that phenotype 1 exhibited higher expression of most cytokines, inflammatory factors, interleukins, and related receptors. Immune cell composition in phenotype 1 showed increased infiltration compared to phenotype 2. The LASSO regression identified 16 diabetes-related genes and we further constructed a diagnostic model based on these genes, which the area under the curve (AUC) reached 0.8. Additionally, single cell immune analysis exhibited the location of these genes. KCNQ1, ATP6V1B1, MTDH, and ITPK1 were predominantly located in macrophages, indicating their potential in regulating macrophage during myocardial injury. Furthermore, We elucidated that KCNQ1 and ITPK1 exhibited high expression level in mouse CAD model in tissue level. exhibited similar expression trends with macrophage biomarkers (CD31 and CD68). The result of qPCR also indicated the elevated level of KCNQ1 and ITPK1, which exhibited crosstalk with CD31 and CD68 in mouse CAD model.ConclusionThis study delves into the microenvironmental characteristics of diabetes-related phenotypes in CAD, constructing an optimal diagnostic model and validated the significance of diagnostic markers in mouse CAD model, which may offer insights that could be beneficial for clinical management in the near future.

BackgroundChronic obstructive pulmonary disease (COPD) remains a leading global health burden. In primary care, the inconsistent availability of spirometry and symptom scores limits the detection of patients with poor disease control. There is a pressing need for scalable, data-driven tools that leverage routinely collected clinical information to support timely, equitable, and guideline-concordant interventions.ObjectiveThis study aims to validate the performance of Seleida—a fully automated, deterministic, and bijective model for COPD control assessment and phenotyping—using real-world primary care data and to evaluate its feasibility for integration into electronic health record (EHR)–based informatics systems.MethodsSeleida estimates the probability of poor control (Pr) using two objective EHR variables: (1) annual dispensations of short-acting bronchodilators—specifically short-acting β2-agonists (SABA), short-acting muscarinic antagonists (SAMA), or both, and (2) number of dispensed antibiotic courses for bronchitis or COPD exacerbations. Its bijective structure supports both forward risk estimation and reverse phenotype inference. In a retrospective cohort of 106 patients, agreement was assessed between 2 phenotyping systems (a 126-combination model and a streamlined 21-combination version) and with clinician-assigned classifications. Due to sample size limitations, a provisional risk threshold of Pr>.50 was adopted for internal stratification.ResultsSeleida showed perfect agreement between phenotyping systems (Cohen κ=1.00; P<.001) and substantial concordance with clinician-assigned profiles (Cohen κ=0.70; P<.001). The model operates transparently, without machine learning, and can be embedded into EHR platforms or applied manually using a visual framework. It enables individualized risk estimation, phenotype-driven treatment planning, and population-level case identification—particularly in settings with limited access to traditional diagnostic tools.ConclusionsSeleida provides a reproducible and interpretable framework for COPD control monitoring using high-frequency prescribing data. Its transparent logic, low data burden, and interoperability enable integration across diverse digital infrastructures, including resource-limited settings. By supporting both individualized care and population-level risk stratification, Seleida bridges predictive analytics with real-world clinical decision-making. Ongoing multicenter validation will determine its generalizability, clinical impact, and cost-effectiveness at scale.

Biobank data provide a rich source for studying the coheritability of multiple disease phenotypes, which can provide information on shared genetic etiology. However, the large number and heterogeneous types of phenotypes (e.g., continuous, discrete, time-to-event) pose significant statistical and computational challenges for estimating coheritability. In this work, we propose a unified modeling framework with latent random effects distinguishing genetic and family-shared environmental contributions to variation across multi-type phenotypes. To avoid high-dimensional integrals over many phenotypes and family members in joint likelihood approaches, we develop a computationally efficient procedure by first maximizing the marginal likelihood function for each individual phenotype and then estimating the coheritability using only pairs of phenotypes. We apply our method to analyze the heritability and coheritability of 290 phenotypes obtained from the UK Biobank. We find that a substantial number of phenotype pairs present statistically significant genetic coheritability.

Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.