Disease Phenotype Research Articles (Page 10)

Background: Chronic mast cell–mediated angioedema (MC-AE) and chronic spontaneous urticaria (CSU) both involve mast cell activation but may differ in long-term systemic outcomes. Limited data exist comparing their comorbidity profiles over extended follow-up. Objective: To compare systemic comorbidities in patients with chronic MC-AE versus CSU using a large, population-based dataset. Methods: We conducted a retrospective matched case–control study using electronic health records from Leumit Health Services, a nationwide Israeli health maintenance organization. Patients diagnosed with chronic MC-AE between 2005 and 2023 (n = 2133) were matched 1:1 by age, sex, and year of diagnosis to patients with CSU (n = 2133). Comorbidities were assessed at diagnosis and after a mean follow-up of 10.2 ± 2.9 years. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multivariable logistic regression was used to assess the association between medications and MC-AE diagnosis. Results: MC-AE patients exhibited significantly higher baseline rates of hypertension (23.8% vs. 18.5%), ischemic heart disease (5.67% vs. 3.84%), and type 2 diabetes (10.45% vs. 6.42%) compared to CSU. These differences persisted or increased at follow-up, including myocardial infarction (4.13% vs. 2.25%) and chronic kidney disease (4.13% vs. 2.91%). CSU patients had consistently higher rates of atopic dermatitis, viral infections, and herpes zoster. Statin use was inversely associated with MC-AE (adjusted OR = 0.63; 95% CI: 0.44–0.90). Conclusions: Chronic MC-AE is associated with a distinct and sustained cardiometabolic and renal comorbidity burden compared to CSU, supporting its classification as a systemic disease phenotype requiring differentiated long-term care.

ABSTRACT Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system characterized by recurrent inflammation, primarily targeting the optic nerves and spinal cord. The presence of anti‐aquaporin 4 antibodies has revealed core aspects of its immunopathology, but growing evidence suggests that genetic factors also contribute to individual susceptibility, clinical heterogeneity, and treatment response. Recent advances in genome‐wide association studies (GWAS), whole exome sequencing (WES), and Mendelian randomization (MR) have identified genetic variants associated with NMOSD. These findings span human leukocyte antigen (HLA) class II alleles, non‐HLA immune‐related genes, and somatic mutations acquired by clonal hematopoiesis. Importantly, genetic associations vary by ethnicity and may underlie the disparities seen in disease prevalence and phenotype. In addition, MR studies are revealing potential causal pathways involving immune mediators, cytokines, and metabolites, providing a new perspective on the disease mechanism. These genomic findings are accelerating our understanding of NMOSD and are expected to lead to risk stratification, refinement of diagnostic classification, and development of targeted therapies. This review provides an integrated overview of current genetic research in NMOSD and identifies implications for future precision medicine.

Phenotype-driven approaches identify disease-counteracting compounds by analysing the phenotypic signatures that distinguish diseased from healthy states. Here we introduce PDGrapher, a causally inspired graph neural network model that predicts combinatorial perturbagens (sets of therapeutic targets) capable of reversing disease phenotypes. Unlike methods that learn how perturbations alter phenotypes, PDGrapher solves the inverse problem and predicts the perturbagens needed to achieve a desired response by embedding disease cell states into networks, learning a latent representation of these states, and identifying optimal combinatorial perturbations. In experiments in nine cell lines with chemical perturbations, PDGrapher identifies effective perturbagens in more testing samples than competing methods. It also shows competitive performance on ten genetic perturbation datasets. An advantage of PDGrapher is its direct prediction, in contrast to the indirect and computationally intensive approach common in phenotype-driven models. It trains up to 25× faster than existing methods, providing a fast approach for identifying therapeutic perturbations and advancing phenotype-driven drug discovery.

BACKGROUNDThe number of population-based studies on unclassified inflammatory bowel disease (IBD-U) is very limited.AIMTo evaluate the long-term incidence, disease course and surgery rates of IBD-U in a prospective population-based cohort.METHODSThe present study is a continuation of the well-established Veszprem IBD cohort with patient inclusion between 1977 and 2018. Both in-hospital and outpatient records were collected. The source of age- and gender-specific demographic data was derived from the Hungarian Central Statistical Office. Medical therapy, surgery and change in disease phenotype were analyzed.RESULTSData of 119 incident IBD-U patients were analyzed [male/female: 55/64; median age at diagnosis: 34 years (interquartile range: 24-47.5)]. Adjusted mean incidence rate was 0.76 (95%CI: 0.63-0.9)/105 person-years in the total study period. Disease extent at diagnosis was extensive (pancolitis) in 56.3%. Twenty-two of 119 (18.5%) patients were reclassified to Crohn’s disease during follow up, the probability of developing terminal ileum involvement was 6.8%, while perianal disease developed in 5% (n = 6). The probability of receiving biological therapy in patients diagnosed after the year 2000 (n = 62), was 15.5% (SD: 4.8) at 5 years. The overall resective surgery rate was 16.8%. Segment resection was performed in 5.0% of the patients, and 11.8% underwent subtotal or total colectomy. The cumulative probability of resective surgery was 7.6% (SD: 2.4) at 1 year, 9.3% (SD: 2.7) at 5 years, 13.5% (SD: 3.3) at 10 years, and 18.5% (SD: 3.9) at 20 years.CONCLUSIONThese data extend our knowledge on the overall burden of IBD-U. Colonic involvement was extensive in a high proportion of IBD-U. Disease reclassification to Crohn’s disease was relatively high. High rates of biological therapy and surgery rates support a relatively severe disease course of IBD-U.

In patients with inflammatory bowel disease (IBD), social determinants of health contribute to health inequalities. We aimed to compare patients with IBD treated at a private nonprofit vs public hospital in New York City. We performed a retrospective study of adult patients with Crohn's disease or ulcerative colitis with established IBD care. Patient demographics, disease characteristics, healthcare utilization, treatment modalities, and clinical outcomes were collected. Using a series of linear mixed and logistic models, the differences between care at a private nonprofit vs public hospital were assessed while controlling for factors that differed between them. Our study included 418 patients with IBD, 209 from each hospital. Compared with public hospital patients, private hospital patients were more likely to be White, be non-Hispanic, and have private insurance (all P = .0005) and less likely to face housing instability (P < .0001), face unemployment (P = .0004), be current smokers (P = .03), or be foreign born (P < .0001). Patients at the private hospital were more likely to have multiple anti-tumor necrosis factor (P = .0001) and biologic use (P < .0001). Public hospital patients were less likely to be considered endoscopically adherent (odds ratio [OR], 0.377; P = .001) and more likely to visit the emergency department (OR, 5.01; P < .0001) and be hospitalized (OR, 1.92; P = .05). Our study is the first to identify significant differences in patient demographics, disease phenotype, treatments and clinical outcomes between patients treated for IBD at a private nonprofit vs public hospital. Our data suggest that social determinants of health drive disparities in the utilization of healthcare facilities.

Cilia, evolutionarily conserved organelles on eukaryotic cell surfaces, depend on the intraflagellar transport (IFT) system for their assembly, maintenance, and signaling. The IFT system orchestrates bidirectional trafficking of structural components and signaling molecules through coordinated actions of protein complexes and molecular motors. IFT complexes assemble into anterograde trains at the ciliary base and undergo structural remodeling at the ciliary tip to form retrograde trains, with bidirectional motility regulated by modifications on the trains per se and the microtubule tracks. The BBSome rides with the IFT train and serves as a pivotal adaptor linking membrane cargos to the IFT train primarily for cargo exit from the cilia. Mutations in cilium-related genes from human ciliopathies contribute to the understanding of the IFT machinery. This review comprehensively delineates the molecular architecture, transport mechanisms, and regulatory networks of IFT complexes, bridging their functional dysregulation to disease phenotypes and advancing mechanistic insights.

IntroductionMuscle eye brain disease (MEB) is a rare, multi-systemic autosomal recessively inherited disorder of relevance to ophthalmologists. The aim of this report is to describe a novel ocular phenotype for a genetically confirmed MEB patient using retinal multi-modal imaging.Case descriptionWe report a case of 18-year-old male patient that was referred to our tertiary unit for management of retinal detachment. Fundoscopic examination indicated optic nerve and macula hypoplasia, retinal hypo-pigmentation, and unilateral retinal detachment. There were no retinal breaks found in association with retinal detachment affecting the left eye. A well demarcated temporal pigmentary retinopathy with a 'ghost' retinal vessel in fundus autofluorescence image suggested spontaneous retinal reattachment of the retina in the right eye. Fundus autofluorescence and optical coherence tomography images revealed the novel features of internal limiting membrane disruption and sub-retinal opacity in association with neurosensory separation of the left retina, which is consistent with histopathology in the human eye and the mouse models of the disease.ConclusionsOur case suggests that retinal detachment in MEB disease should be managed conservatively in the absence of retinal breaks as spontaneous reattachment can occur. Extensive areas of non-perfusion should be treated with laser photo-coagulation to avoid the sequelae of retinal neovascularization. The mechanism for the development of retinal detachment without breaks is unknown.

IntroductionPatients with frequent exacerbator phenotype in chronic obstructive pulmonary disease (COPD) tend to experience a progressive decline in lung function, a gradual deterioration of the disease, and even a serious threat to their lives. However, current treatment measures still need further improvements to reduce the frequency of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Therefore, our team developed Bufei Yishen (BFYS) granules specifically for patients with frequent exacerbator phenotype in COPD and is conducting a randomized controlled trial (RCT) to validate their effectiveness.MethodsA multi-center, randomized, double-blind, placebo-controlled trial will be conducted. A total of 848 patients will participate in the study, with a treatment duration of 1 year. The participants will be randomly assigned to the experimental group and the control group in a 1:1 ratio. Both groups will receive health education and conventional drugs. In addition, the experimental group will receive BFYS granules, while the control group will be given the corresponding BFYS placebo. The primary outcome is the frequency of AECOPD. The secondary outcomes include the frequency of AECOPD leading to hospitalization, the mortality rate, lung function, six-minute walk distance (6MWD), clinical symptoms and signs scores, and quality of life. Safety outcomes include vital signs and laboratory tests. Statistical analysis will be conducted using SPSS software (version 25.0). Furthermore, the health economics evaluation of the BFYS granules will use cost-effectiveness analysis methods.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine (No. 2024HL-043-01). Written informed consent will be obtained from all participants. The results will be published in a peer-reviewed journal after the end of the study. The data of this trial will be disseminated publicly through conferences and publications.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT06326658.

IntroductionCombination antiretroviral therapy (cART)-mediated immune reconstitution can establish a tumor-permissive microenvironment. In addition, compromised immune surveillance may contribute to more aggressive disease phenotypes in HIV patients; however, clinical evidence remains limited.MethodsWe conducted a retrospective analysis of clinical data of newly diagnosed Hodgkin lymphoma (HL) patients from 2014 to 2024 treated at four medical centers in China. The authors conducted clinical and immune function analysis of HIV-positive HL patients with special emphasis on prognosis and immune factors.ResultsIn total, 19 patients were diagnosed as HIV positive. HIV-positive HL patients (HIV-HL) had more advanced stage disease, ECOG-PS, bulky disease, and B symptoms compared to HL patients without HIV (n=130). HIV-positive HL patients had decreased CD4 cell count, CD4/CD8, and GZMB. Lower CD4 count was associated with more bulky disease and B symptoms and higher IL-2R and IL-6 levels in HIV-HL patients. And HIV-HL patients with bulky disease had less GZMB compared to non-bulky disease patients. The enrichment impact of gene alterations on bulky disease demonstrated that PI3K/AKT, thyroid hormone signaling, NF−kappa B signaling pathway, and EBV infection were involved. Immune dysfunction (CD4, CD8, and CD4/CD8), on the other hand, showed no association with survival in both HIV-positive and negative HL patients. There were similar outcomes in patients with and without HIV treated by ABVD chemotherapy.ConclusionHIV-associated Hodgkin lymphoma (HIV-HL) often presents with more aggressive clinical features, although outcomes are similar to those observed in HIV-negative HL patients. Impaired immune function may contribute to an increased tumor burden through multiple mechanisms. However, it was not associated with outcomes. HL treatment approaches might not necessarily require adjustment solely due to HIV status, but additional clinical evidence is needed to support this assertion.

ObjectivesAccurate characterization of patients with congenital heart disease is fundamental to research, outcomes reporting, quality improvement, and clinical decision-making. Here we present an approach to computing the anatomy of patients with congenital heart disease based on the whole of their diagnostic and surgical codes.Materials and MethodsAll diagnostic and procedure codes for patients cared for between 1981 and 2020 at Boston Children’s Hospital were extracted from a database containing diagnostic codes from echocardiograms, and procedural codes from surgical and catheterization procedures. The pipeline sequentially (1) mapped each of the 7500 native codes to algorithm codes; (2) computed the parent anatomy for each study using a pre-defined hierarchy; (3) computed the parent anatomy for the patient, based on highest ranking parent anatomy; and (4) computed the subcategories and mandatory co-variate findings for each patient. Thereafter, diagnostic accuracy of 500 unseen patients was adjudicated against clinical documentation by clinical experts.ResultsA total of 514 541 echocardiograms on 161 735 patients were available for this study. Phenotypes of congenital cardiac diseases were assigned in 84 285 patients (52%), and the remainder were computed to have normal anatomy. Clinicians agreed with algorithm assignments in 96.4% (482 of 500 patients), with disagreements most often representing definitional differences. An interactive dashboard enabled by the output of this algorithm is presented.ConclusionsThe computation of detailed congenital heart defect phenotypes from raw diagnostic and procedure codes is possible with a high degree of accuracy and efficiency. This framework may enable tools to support interactive outcomes reporting and clinical decision support.

To assess the relation between the proportion of myeloid-derived suppressor cells (MDSCs), monocyte subsets, and the clinical phenotypes and disease activity of psoriatic disease (PsD), including psoriasis (PsO) and psoriatic arthritis (PsA). We carried out a cross-sectional study including 47 patients with PsD and 10 age and sex-paired healthy controls. Using multiparametric flow cytometry, we evaluated the granulocytic (G) and monocytic (M) MDSCs, classical, intermediate and non-classical monocytes in peripheral blood. We compared these cell populations according to the clinical features, phenotype of PsD, and treatment groups. We evaluated their capability to predict disease activity measured by Psoriasis Area and Severity Index (PASI) and Disease Activity in Psoriatic Arthritis (DAPSA) by multivariate logistic and linear regressions. In comparison to healthy donors, PsD patients displayed lower mature G-MDSCs (5.88% vs 60.97%), increased M-MDSCs (0.62% vs 0.02%), decreased expression of arginase-1 and PDL1, and expansion of non-classical monocytes (12.2% vs 4.68%). Increased mature G-MDSCs and decreased arginase-1 expression were seen in patients with cutaneous features. G-MDSCs were associated with cutaneous disease activity (PASI (β 5.05, p= 0.05)), whilst non-classical monocytes were related to active PsA (DAPSA (β 0.68, p= 0.004)), highlighting their potential as disease activity biomarkers. In PsD, G-MDSCs relate to cutaneous disease activity, whereas non-classical monocytes correlate with musculoskeletal features, highlighting their role as potential biomarkers of disease activity in PsD. Further prospective studies addressing the function of these cell subtypes would confirm their relationship with PsD activity status.

Small signaling peptides (SSPs) play a crucial role in various plant biological processes. However, the involvement of SSPs in plant immunity, particularly during host and nonhost bacterial infection remains largely unexplored. We established a pipeline using transcriptomics and genetic experimental validation and identified 243 upregulated and 194 downregulated SSPs upon host and nonhost bacterial pathogen inoculation in Arabidopsis. Four novel upregulated SSPs with previously uncharacterized roles in plant immunity were experimentally validated, including a defensin-like small cysteine-rich secreted peptide termed S-LOCUS CYSTEINE-RICH LIKE 7 (SCRL7), A DOMAIN of UNKNOWN FUNCTION 538 (DUF538) and two dirigent-like SSPs, termed DIR20 and DIR25. Based on the disease phenotypes of mutants and upon synthetic peptide treatments, we determined that SCRL7 plays a negative role while DUF and DIR peptides have a positive role in plant immunity. We established an efficient pipeline to discover pathogen responsive SSPs that could play an important role in plant immunity. This method can also be applied to identify SSPs in other plant physiological processes. These findings contribute to a better understanding of the role of SSPs mediating plant pathogen responses and pave the way for developing new strategies to enhance disease resistance in agriculturally important crops.

AAV delivery of full-length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders.

In the diagnostic process of monogenic genetic disorders, identifying pathogenic variants is a crucial step. Thanks to the widespread adoption of Next-Generation Sequencing (NGS) technology, diagnostic efficiency has been significantly enhanced. However, with the increasing demand for diagnostic accuracy in clinical practice for monogenic genetic diseases, accurately and swiftly pinpointing pathogenic variants among numerous candidate variants remains a significant challenge. The complexity of data analysis and interpretation continues to limit both the efficiency and accuracy of diagnosis. In this study, we have developed an innovative phenotype-driven algorithm, geneEX. This algorithm integrates large language model technology to accurately extract phenotypes from clinical information and automatically acquire Human Phenotype Ontology (HPO) information through a semantic vector representation model, thereby identifying HPO-associated genes. Additionally, it supports semantic matching between patients' free-text phenotypic descriptions and disease phenotypes, further enhancing the identification of pathogenic genes. The algorithm can rank candidate causative variants, enabling rapid and precise identification of potential pathogenic variants in rare genetic disorders. geneEX demonstrates commendable performance in ranking pathogenic variants across both virtual and clinical datasets. The supplementary matching of phenotypes in free-text form significantly enhances the precision of candidate variant prioritization for samples. geneEX has achieved automated HPO acquisition through its independently developed phenotype extraction and standardization methods, thereby enabling the full-process automated identification from clinical samples to pathogenic variants. Additionally, by integrating free-text phenotypic descriptions with disease phenotype matching, it enhances the accuracy of pathogenic gene identification. This innovative approach significantly improves the precision and efficiency of identifying pathogenic variants in rare genetic disorders, providing robust support for the diagnosis of monogenic diseases.

Evolution of Mycobacterium tuberculosis transcription regulation is associated with increased transmission and drug resistance.

The growth in detailed multi-omic profiling has created new opportunities to tailor clinical care and therapy to patient-level variations in disease phenotype. However, efforts towards precision medicine and personalised therapeutics are hampered by limitations in identifying biologically relevant signals that correlate with and underlie disease activity and therapeutic response from these growing arrays of data. These complexities are accentuated further when attempting to translate the new insights in disease pathobiology into new drug targets for treatment. Additionally, understanding how best to reposition existing drugs in the context of new data on disease pathogenesis remains a challenge. Network medicine provides one approach to comprehend these large data sets and identify better the key molecular and phenotypic signals that can function as disease and treatment biomarkers and that can be targeted for therapy. In this review, we discuss basic concepts in the application of network science to biological systems and then build on these concepts to discuss network-based approaches for identifying novel disease biomarkers, elucidating new drug targets and repositioning existing drugs for new indications.

Actg2D245G Mutation Causes Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome by Impairing Smooth Muscle Contractility.

Leishmaniasis in the United Kingdom: Experience of a national multidisciplinary team meeting in a non-endemic setting.

408P Cardiac imaging and disease phenotypes in UK biobank breast cancer survivors

Induced pluripotent stem cell-based modelling of disease evolution in myeloid leukemia: MDS to AML.