Disease Association Research Articles

Advancing miRNA cancer research through artificial intelligence: from biomarker discovery to therapeutic targeting.

MicroRNAs (miRNAs), a class of small non-coding RNAs, play a vital role in regulating gene expression at the post-transcriptional level. Their discovery has profoundly impacted therapeutic strategies, particularly in cancer treatment, where RNA therapeutics, including miRNA-based targeted therapies, have gained prominence. Advances in RNA sequencing technologies have facilitated a comprehensive exploration of miRNAs-from fundamental research to their diagnostic and prognostic potential in various diseases, notably cancers. However, the manual handling and interpretation of vast RNA datasets pose significant challenges. The advent of artificial intelligence (AI) has revolutionized biological research by efficiently extracting insights from complex data. Machine learning algorithms, particularly deep learning techniques are effective for identifying critical miRNAs across different cancers and developing prognostic models. Moreover, the integration of AI has led to the creation of comprehensive miRNA databases for identifying mRNA and gene targets, thus facilitating deeper understanding and application in cancer research. This review comprehensively examines current developments in the application of machine learning techniques in miRNA research across diverse cancers. We discuss their roles in identifying biomarkers, elucidating miRNA targets, establishing disease associations, predicting prognostic outcomes, and exploring broader AI applications in cancer research. This review aims to guide researchers in leveraging AI techniques effectively within the miRNA field, thereby accelerating advancements in cancer diagnostics and therapeutics.

Computational analysis of MYC gene variants: structural and functional impact of non-synonymous SNPs.

The MYC proto-oncogene encodes a basic helix-loop-helix leucine zipper (HLH-LZ) transcription factor, acting as a master regulator of genes involved in cellular proliferation, differentiation, and immune surveillance. Dysregulation of MYC is implicated in over 70% of human cancers, driving oncogenic processes through altered gene expression and disrupted cellular functions. Non-synonymous single nucleotide polymorphisms (nsSNPs) within coding regions can significantly impact protein structure and function, leading to abnormal cellular behaviours. This study employed 29 in silico tools to systematically evaluate the deleteriousness of nsSNPs within the MYC gene. These tools assessed the variants' effects on protein structure, disease association, functional domains, and post-translational modification sites. This study investigated if these variants may disrupt protein-protein interactions, critical for MYC's oncogenic roles and normal cellular functions. Our analysis identified 21 nsSNPs that were predicted to be deleterious and pathogenic. These variants correspond to residues D63H, D63Y, P74L, P75L, N375D, N375I, E378K, E378Q, E378A, E378G, E378V, R379P, R381K, R381T, R382W, L392P, R393C, R393H, R393P, L411H, and L411P. Stability assessments indicated that these variants could destabilise the MYC protein. None of the variants affected post-translational modifications. Protein-protein interaction and docking analysis revealed that variants within bHLH and LZ domains may disrupt MYC/MAX binding, potentially impacting MYC's oncogenic activity and transcriptional regulation. This computational assessment enhances our understanding of genetic variations within the MYC gene and prioritises candidate nsSNPs for experimental validation and therapeutic exploration.

Open label vancomycin in primary sclerosing cholangitis-inflammatory bowel disease: improved colonic disease activity and associations with changes in host-microbiome-metabolomic signatures.

We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD); NCT05376228. Fifteen patients with PSC and active colitis (median faecal calprotectin 459µg/g; median total Mayo score 5) were treated with OV (125mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics and metabolomics) were collected at weeks 0, 2, 4 and 8. The primary efficacy outcome measure was induction of clinical remission. OV resulted in clinical remission in 12/15 patients and significant reductions in faecal calprotectin. OV was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia and Escherichia. OV treatment was associated with downregulation of multiple metatranscriptomic pathways (including short chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. OV use resulted in loss of specific faecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending towards baseline. Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis.

Cell-type-resolved chromatin accessibility in the human intestine identifies complex regulatory programs and clarifies genetic associations in Crohn's disease.

Crohn's disease (CD) is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial, and environmental factors. Cell-type-specific contributions to CD etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type- resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from patients with active and inactive CD and healthy controls. Using this atlas, we identified cell-type-, anatomic location-, and context-specific cCREs and characterized the regulatory programs underlying inflammatory responses in the intestinal mucosa of CD patients. Genetic variants that disrupt binding motifs of cell-type-specific transcription factors significantly affected chromatin accessibility in specific mucosal cell types. We found that CD heritability is primarily enriched in immune cell types. However, using fine- mapped non-coding CD variants we identified 29 variants located within cCREs several of which were accessible in epithelial and stromal cells implicating cell types from additional lineages in mediating CD risk in some loci. Our atlas provides a comprehensive resource to study gene regulatory effects in CD and health, and highlights the cellular complexity underlying CD risk.

Association of Metabolic Diseases and Moderate Fat Intake with Myocardial Infarction Risk.

Myocardial infarction (MI) can range from mild to severe cardiovascular events and typically develops through complex interactions between genetic and lifestyle factors. We aimed to understand the genetic predisposition associated with MI through genetic correlation, colocalization analysis, and cells' gene expression values to develop more effective prevention and treatment strategies to reduce its burden. A polygenic risk score (PRS) was employed to estimate the genetic risk for MI and to analyze the dietary interactions with PRS that affect MI risk in adults over 45 years (n = 58,701). Genetic correlation (rg) between MI and metabolic syndrome-related traits was estimated with linkage disequilibrium score regression. Single-cell RNA sequencing (scRNA-seq) analysis was performed to investigate cellular heterogeneity in MI-associated genes. Ten significant genetic variants associated with MI risk were related to cardiac, immune, and brain functions. A high PRS was associated with a threefold increase in MI risk (OR: 3.074, 95% CI: 2.354-4.014, p < 0.001). This increased the risk of MI plus obesity, hyperglycemia, dyslipidemia, and hypertension by about twofold after adjusting for MI-related covariates (p < 0.001). The PRS interacted with moderate fat intake (>15 energy percent), alcohol consumption (<30 g/day), and non-smoking, reducing MI risk in participants with a high PRS. MI was negatively correlated with the consumption of olive oil, sesame oil, and perilla oil used for cooking (rg = -0.364). MI risk was associated with storkhead box 1 (STOX1) and vacuolar protein sorting-associated protein 26A (VPS26A) in atrial and ventricular cardiomyocytes and fibroblasts. This study identified novel genetic variants and gene expression patterns associated with MI risk, influenced by their interaction with fat and alcohol intake, and smoking status. Our findings provide insights for developing personalized prevention and treatment strategies targeting this complex clinical presentation of MI.

Associations of chronic liver disease and liver cancer with glyphosate and its metabolites in Thailand.

Glyphosate [N-(phosphonomethyl) glycine], a systemic herbicide, is used globally (825 million kg/year) in 750+ formulations. The International Agency for Research on Cancer classified glyphosate is a probable human carcinogen (Group 2A), but epidemiological studies have been lacking for its association with liver cancer and chronic liver disease. We analyzed urine specimens from 591 patients with newly diagnosed liver cancer, chronic liver disease (CLD), and healthy individuals from five different medical centers between 2011 to 2016 in Thailand. Gas chromatography electrospray ionization mass spectrometry (GC-ESI/MS) was used to quantify glyphosate and its metabolites, aminomethylphosphonic acid (AMPA) and phosphoric acid (PPA) to study their levels in urine of hepatocellular carcinoma (HCC) and CLD patients in comparison to matched healthy individuals. Significantly higher levels of glyphosate were found in CLD patients compared to HCC cases and hospital controls, while significantly elevated levels of both AMPA and PPA were observed in HCC and CLD patients compared to hospital controls. Glyphosate and its metabolites were also detected at low to moderately high levels in convenience samples of food products and drinking water. These results raise concerns about the potential role of glyphosate in chronic liver disease and liver cancer risk.

High KIR diversity in Uganda and Botswana children living with HIV.

Killer-cell immunoglobulin-like receptors (KIRs) are essential components of the innate immune system found on the surfaces of natural killer (NK) cells. The KIRs encoding genes are located on chromosome 19q13.4 and are genetically diverse across populations. KIRs are associated with various disease states including HIV progression, and are linked to transplantation rejection and reproductive success. However, there is limited knowledge on the diversity of KIRs from Uganda and Botswana HIV-infected paediatric cohorts, with high endemic HIV rates. We used next-generation sequencing technologies on 312 (246 Uganda, 66 Botswana) samples to generate KIR allele data and employed customised bioinformatics techniques for allelic, allotype and disease association analysis. We show that these sample sets from Botswana and Uganda have different KIRs of different diversities. In Uganda, we observed 147 vs 111 alleles in the Botswana cohort, which had a more than 1 % frequency. We also found significant deviation towards homozygosity for the KIR3DL2 gene for both rapid (RPs) and long-term non-progressors (LTNPs)in the Ugandan cohort. The frequency of the bw4-80I ligand was also significantly higher among the LTNPs than RPs (8.9 % Vs 2.0%, P-value: 0.032). In the Ugandan cohort, KIR2DS4*001 (OR: 0.671, 95 % CI: 0.481-0.937, FDR adjusted Pc=0.142) and KIR2DS4*006 (OR: 2.519, 95 % CI: 1.085-5.851, FDR adjusted Pc=0.142) were not associated with HIV disease progression after adjustment for multiple testing. Our study results provide additional knowledge of the genetic diversity of KIRs in African populations and provide evidence that will inform future immunogenetics studies concerning human disease susceptibility, evolution and host immune responses.

DVGEDR: a drug repositioning method based on dual-view fusion and graph enhancement mechanism in heterogeneous networks

Drug repositioning, the discovery of new therapeutic uses for existing drugs, is increasingly gaining attention as a cost-effective and high-yield drug discovery strategy. Existing methods integrate diverse biological information into heterogeneous networks, providing a comprehensive framework for understanding complex drug–disease associations, which also will introduces noise into the data and affect the performance of the model. In this paper, first, a novel drug repositioning method, namely DVGEDR, is proposed, which generates two subgraphs of the target drug–disease pair to fuse biological information and integrate drug–disease associations from two distinct perspectives: drug–disease heterogeneous network and similarity networks. Next, a Multiple Attention Graph encoder (MAGencoder) module is designed to learn subgraph features and explore relationships between entities, which also improve the interpretability of the model. Finally, a graph enhancement mechanism is devised to improve the perception of critical information of model, enabling the model to flexibly process different graph structures. Performance comparisons with baseline models on three public datasets validate the state-of-the-art performance of DVGEDR in the field of drug repositioning. In case study, DVGEDR identifies 10 new candidate drugs for breast cancer and COVID-19, demonstrating not only superior performance in experimental settings but also potential therapeutic advantages in clinical environments. Furthermore, we select two sets of instances and further analyzed the attention distribution of the different nodes in the subgraph to explain the decision process of the model.

A study of impulsivity and adverse childhood experiences in a population health setting.

As complex mental health traits and life histories are often poorly captured in hospital systems, the utility of using the Barratt Impulsivity Scale (BIS) and Adverse Childhood Experiences (ACEs) for assessing adult disease risks is unknown. Here, we use participants from the Healthy Nevada Project (HNP) to determine if two standard self-assessments could predict the incidence and onset of disease. We conducted a retrospective cohort study involving adult participants who completed the Behavioral and Mental Health Self-Assessment (HDSA) between September 2018 and March 2024. Impulsivity levels were measured using the BIS-15, and retrospective self-reports of ACEs were collected through a standardized questionnaire. In total, 17,482 HNP participants completed the HDSA. Our findings indicate that ACEs were significantly associated with impulsivity. Disease associations with impulsivity and ACEs were evaluated using a phenome-wide association study, identifying 230 significant associations with impulsivity. Among these, 44 were related to mental health diagnoses, including major depressive disorder (MDD). Kaplan-Meier survival estimates characterized the differences in the lifetime predicted probability between high and low impulsivity for major depressive disorder and essential hypertension. This analysis showed that having both high ACEs and high impulsivity confer substantial risk of MDD diagnosis (hazard ratios 2.81, 2.17, respectively). Additionally, lifetime predicted probability of MDD was approximately 40% higher for high ACEs and high impulsivity compared to no ACEs and low impulsivity. Essential hypertension demonstrated similar trends, with an approximate 20% increase in predicted lifetime probability of diagnosis. These results demonstrate that high ACES and elevated impulsivity scores are associated with a range of negative health outcomes and a simple self-assessment of complex traits and life history may significantly impact clinical risk assessments.

Pheno-Ranker: a toolkit for comparison of phenotypic data stored in GA4GH standards and beyond

BackgroundPhenotypic data comparison is essential for disease association studies, patient stratification, and genotype–phenotype correlation analysis. To support these efforts, the Global Alliance for Genomics and Health (GA4GH) established Phenopackets v2 and Beacon v2 standards for storing, sharing, and discovering genomic and phenotypic data. These standards provide a consistent framework for organizing biological data, simplifying their transformation into computer-friendly formats. However, matching participants using GA4GH-based formats remains challenging, as current methods are not fully compatible, limiting their effectiveness.ResultsHere, we introduce Pheno-Ranker, an open-source software toolkit for individual-level comparison of phenotypic data. As input, it accepts JSON/YAML data exchange formats from Beacon v2 and Phenopackets v2 data models, as well as any data structure encoded in JSON, YAML, or CSV formats. Internally, the hierarchical data structure is flattened to one dimension and then transformed through one-hot encoding. This allows for efficient pairwise (all-to-all) comparisons within cohorts or for matching of a patient’s profile in cohorts. Users have the flexibility to refine their comparisons by including or excluding terms, applying weights to variables, and obtaining statistical significance through Z-scores and p-values. The output consists of text files, which can be further analyzed using unsupervised learning techniques, such as clustering or multidimensional scaling (MDS), and with graph analytics. Pheno-Ranker’s performance has been validated with simulated and synthetic data, showing its accuracy, robustness, and efficiency across various health data scenarios. A real data use case from the PRECISESADS study highlights its practical utility in clinical research.ConclusionsPheno-Ranker is a user-friendly, lightweight software for semantic similarity analysis of phenotypic data in Beacon v2 and Phenopackets v2 formats, extendable to other data types. It enables the comparison of a wide range of variables beyond HPO or OMIM terms while preserving full context. The software is designed as a command-line tool with additional utilities for CSV import, data simulation, summary statistics plotting, and QR code generation. For interactive analysis, it also includes a web-based user interface built with R Shiny. Links to the online documentation, including a Google Colab tutorial, and the tool’s source code are available on the project home page: https://github.com/CNAG-Biomedical-Informatics/pheno-ranker.

Association of Coronary Artery Disease with Carotid Intima-Media Thickness in Women Population Presenting to Fauji Foundation Hospital, Rawalpindi

bstract Objective: To determine the association of coronary artery disease (CAD) with carotid intima-media thickness (CIMT) in women population presenting to Fauji Foundation Hospital, Rawalpindi. Methodology: With ethical approval, a descriptive, cross-sectional study was carried out from June 2023 to November 2023 at the Fauji Foundation Hospital, Rawalpindi. After obtaining informed consent, 200 female patients with CAD were included using nonprobability convenient sampling. These patients then underwent primary percutaneous coronary intervention to diagnose CAD and also determine its severity. The SYNTAX score and the number of diseased vessels were used to determine the disease’s severity. The CIMT of the patients was estimated using the B-mode ultrasound. Version 25 of the Statistical Package for the Social Sciences (SPSS) was used to carry out the analysis. Results: The participants had a mean CIMT of 0.85+0.14 mm. The mean CIMT was significantly higher in triple vessel disease (0.97+0.16 mm) versus double vessel disease (0.85+0.11 mm) and single vessel disease (0.78+0.10 mm). The CIMT value was much higher in patients with SYNTAX score &gt;33 (0.96+0.14 mm) compared to score 23-32 (0.85+0.15 mm) and &lt;22 (0.80+0.10 mm). The CIMT was higher in patients with increased age and those with diabetes mellitus and hypertension, with statistical significance. However, the association between CIMT and smoking was insignificant. Conclusion: According to the SYNTAX score and the number of diseased vessels, patients with severe CAD had higher CIMT in our study. Thus, an authentic, safe and noninvasive way of determining the severity of CAD is the carotid intima-media thickness.

Naturally occurring human antibodies associated with AD and normal cognition

AbstractBackgroundAnti‐ Aβ monoclonal antibodies are the first FDA‐approved treatments for AD that slow cognitive decline and lower Aβ plaques. Our goal is to identify the epitope specificities of antibodies in human blood that are associated with AD and NC and determine the predicted protein targets of these antibodies.Method101 AD (MMSE &lt; 27) and 98 NC (MMSE &gt; 27) serum samples were obtained from the UCI tissue repository. Epitomic profiling was conducted on the blood samples to define the epitopes for the antibodies in the samples by immunoselecting random 12 amino acid sequences from a phage display library. The resulting unique sequences are identified and their frequency counted. The 12mer sequences are tiled into tetramers and the resulting antibody‐specific tetramers are compared by Mann‐Whitney U test to identify differentially expressed epitope segments (DEES) that are upregulated in the AD and NC populations.ResultA large number of DEES (range 300 – 14,000 out of a total of 160,000 tetramers) was observed for AD and NC populations in both samples. Some of the DEES map to amyloids known to occur in AD, such as Aβ, tau, a‐synuclein, TDP43 and Tmem106b, but the actual epitopes are different in AD and NC. Both AD and NC populations’ data was then processed using UMAP for visualization and cluster analysis. Cluster analysis indicates that there are two clusters in the AD population: One large group that partially overlaps with the NC population and includes antibodies against the N‐terminus of Aβ and a well separated minor group that is defined by immunoreactivity to a heptameric linear epitope of currently unknown origin. The NC population includes several groups that contain anti amyloid antibodies.ConclusionHuman blood contains a large number of antibodies that are differently expressed in AD that recognize distinct amyloid and non‐amyloid epitopes. These antibodies may be protective for disease, predictive for presymptomatic disease onset and progression or antibodies in response to amyloid deposition that could be protective depending on the concentration or predictive of disease subtype. Further work is aimed at determining the significance of the different antibodies and validating their disease association

A clinical and hematologic approach to basophilia in dogs, cats, and horses.

Basophils are the rarest blood leukocyte in most healthy domestic mammals and the clinical significance of basophilia is poorly understood. To empirically determine magnitude thresholds for basophilia, identify its hematologic correlates, and identify associations between breeds, specific diseases, disease categories, organ systems, and basophilia in dogs, cats, and horses. CBCs and clinical information from dogs, cats, and horses were collected from the University of California-Davis School of Veterinary Medicine between 2000 and 2020. Relationships between basophil concentration and other CBC parameters were evaluated by computing Pearson's correlation (r). Magnitude thresholds for basophilia (ie, mild, moderate, severe) were determined by evaluating the distribution of basophil counts for each species. For severe cases of basophilia, the clinical diagnoses were categorized by the organ system affected and the underlying pathomechanism. Basophilia groups were compared to a time-matched, randomly selected control group, and chi-square analyses were performed to evaluate associations with disease. A total of 143 841 (dog), 32 576 (cat), and 44 887 (horse) CBCs were collected. For all three species, basophilia was over-represented in some breeds. Basophilia was associated with respiratory disease in both dogs and cats. In dogs, lymphoma and mast cell neoplasia were associated with basophilia. In horses, an increased incidence of basophilia was not associated with any disease category or organ system. This is the largest study evaluating the hematologic correlations and disease associations with basophilia in dogs, cats, and horses. While basophilia was reported alongside many diseases, certain associations may aid clinicians in narrowing down underlying causes.

The association of telomere length and coronary heart disease: a systematic review and dose-response meta-analysis.

The association of telomere length and coronary heart disease: a systematic review and dose-response meta-analysis.

Do patients with axial spondyloarthritis with active disease suffer from greater disease burden and work impairment? Results from the International Map of Axial Spondyloarthritis (IMAS)

BackgroundTo assess the prevalence of clinically active disease in axial spondyloarthritis (axSpA) and its associated factors in a large global sample of patients from the International Map of Axial Spondyloarthritis (IMAS) study. MethodsIMAS is a cross-sectional online survey (2017–2022) of 5557 axSpA patients. Patients were divided between those with active disease (BASDAI ≥4) and without active disease (BASDAI <4). The factors evaluated were sociodemographic, lifestyle, patient-reported outcomes, employment, disease characteristics, extra-musculoskeletal manifestations, and treatment. Logistic regression analysis stratified by gender were used to evaluate the relationship between investigated factors and active disease. ResultsIn the present study, 5295 patients who had responded to the BASDAI scale were included in the present study: 3231 were from Europe, 770 from North America, 600 from Asia, 548 from Latin America, and 146 from Africa. The mean age was 43.8±12.9 years and 55.4% were females. Patients reported a mean BASDAI of 5.4 (±2.1) with 75% having active disease (BASDAI ≥4). In South Africa, 87.0% of patients reported having active disease, compared to 68.5% in Asia. Multivariable logistic regression showed an association of active disease with higher functional limitation, greater spinal stiffness, difficulty finding a job due to axSpA and worse mental health in both genders. For males, younger age and shorter diagnostic delay, and for females, no physical activity and presence of inflammatory bowel disease were associated with active disease. ConclusionsThree quarters of patients with axSpA reported clinically active disease, with higher proportion of patients with active disease in South Africa and lower proportion in Asia. Our results underline the complexity of the clinical disease activity concept in axSpA and the need for a holistic approach in the patient management, care and treatment.

Neuroticism and cerebral small vessel disease: A genetic correlation and Mendelian randomization analysis.

The association of neuroticism and cerebral small vessel disease (CSVD) development remains unclear. In this study, we used Mendelian randomization (MR) to explore the potential role of neuroticism in CSVD development. We collected data on ischemic stroke (IS); small vessel stroke (SVS); three neuroimaging markers altered in CSVD, including white matter hyperintensity (WMH), fractional anisotropy (FA), and mean diffusivity (MD); and three neuroticism clusters, including depressed affect, worry, sensitivity to environmental stress and adversity (SESA), from large-scale genome-wide association studies (GWAS). Bidirectional MR analyses were used to evaluate the association between neuroticism and CSVD, primarily estimated using the inverse variance weighted (IVW) method. The linkage disequilibrium score (LDSC) regression was employed to assess the association between various phenotypes. LDSC analysis unveiled a noteworthy genetic correlation between depressed affect and IS (rg=0.111, p=0.001) as well as between worry and SVS (rg=-0.111, p=0.032). Our study revealed a causal correlation between SESA and FA using both forward and reverse MR analyses (SESA on FA, odds ratio (OR)=0.186 (0.071 to 0.483), p=5.50×10-4; FA on SESA, OR = 0.996 (0.9916 to 0.9997), p=0.035). Meanwhile, FA also exerted a statistical causal influence on depressed affect cluster (OR = 0.992 (0.987 to 0.997), p=0.001). This research suggests a potential correlation between certain aspects of neuroticism and CSVD, with further studies needed to better understand the causal relationship and its implications for patient intervention.

Clinical Outcomes in Atrial Fibrillation Patients Undergoing Transcatheter Aortic Valve Replacement With Contemporary Devices.

Atrial fibrillation (AF) has been identified as a marker of advanced cardiac damage in aortic stenosis patients. However, the factors associated with poorer outcomes among AF patients in contemporary TAVR practice, particularly regarding mortality and heart failure (HF)-related hospitalizations, remain largely unknown. Multicenter study including consecutive patients with a history of AF, evaluating the clinical outcomes and predictors of mortality, and HF-related hospitalization, who underwent TAVR with newer-generation devices using balloon or self-expandable valves. A total of 3,476 patients were included. After a median follow-up of 2 (1-4) years, 36.4% had died, with 51.5% of deaths being cardiovascular-related, including 15.6% from HF. HF-related hospitalizations post-TAVR accounted for 34.8% of all hospitalizations and exhibited a significantly higher mortality risk (HR:1.54;95%CI:1.32-1.81;P<0.001). Permanent AF emerged as an independent predictor of all-cause death or HF-related hospitalizations (HR:1.25; 95%CI:1.10-1.40;P<0.001), as did other baseline characteristics, including chronic kidney disease (HR:1.23;95%CI:1.09-1.38;P=0.001), anemia (HR:1.21; 95%CI:1.07-1.36;P=0.002), and New York Heart Association class III or IV (HR:1.13; 95%CI:1.01-1.27;P=0.045). Additionally, early post-procedural complications, including stroke and bleeding also significantly increased the risk of mortality and HF-related hospitalizations (HR:5.52;95%CI:3.12-9.79;P<0.001 & HR:1.17;95%CI:1.03-1.33;P=0.014, respectively). AF patients exhibited a high risk of HF-related hospitalizations in a contemporary TAVR cohort. Several baseline co-morbidities and periprocedural complications, along with permanent (vs. paroxysmal) AF were associated with poorer outcomes. These findings confirm the negative impact of AF despite the continued improvements in TAVR technology and underscore the importance of early intervention and optimization of HF management to improve outcomes in this high-risk population.

Three Fields Allelic Haplotype Frequencies of HLA‐DPA1 and ‐DPB1 Typed by Next Generation Sequencing of 563 Families in Chinese Han Population

ABSTRACTThe present study investigated the HLA‐DPA1 and ‐DPB1 allele and haplotype frequencies in the Chinese Han population. A total of 563 families, which have been typed for the purpose of haematopoietic stem cell transplantation, were included, and three‐field allelic resolution typing of HLA‐DPA1 and ‐DPB1 of all individuals were defined by the next‐generation sequencing method. HLA‐DPA1~DPB1 haplotypes were determined by allele segregation within a nuclear family. A total of 9 HLA‐DPA1 and 39 HLA‐DPB1 alleles, and 62 HLA‐DPA1~DPB1 haplotypes were identified. The three most frequent alleles at HLA‐DPA1 locus are HLA‐DPA1*02:02:02 (46.581%), HLA‐DPA1*01:03:01 (36.456%) and HLA‐DPA1*02:01:01 (12.167%); and the three most frequent HLA‐DPB1 alleles are HLA‐DPB1*05:01:01 (34.014%), HLA‐DPB1*02:01:02 (18.428%) and HLA‐DPB1*04:01:01 (10.124%). The three most frequent haplotypes are HLA‐DPA1*02:02:02~DPB1*05:01:01 (32.327%), HLA‐DPA1*01:03:01 ~ DPB1*02:01:02 (14.654%) and HLA‐DPA1*01:03:01~DPB1*04:01:01 (9.458%). The HLA‐DPA1*02:01~DPB1*02:02 and HLA‐DPA1*04:01~DPB1*05:01 haplotypes appear to be unique in Han Chinese. Strong global linkage disequilibrium (LD) between HLA‐DPA1 and ‐DPB1 was confirmed (D′ = 0.848, Wn = 0.684). Moreover, the haplotype frequencies based on the family study were compared with the frequencies estimated by the expectation–maximisation algorithm, and the equivalent results were obtained except for haplotypes with very low frequencies. Our data provide a solid base for HLA‐DP dimer association studies and useful information for transplantation and disease association studies.

Scleritis and Episcleritis in Patients with Idiopathic Small Fiber Neuropathy

PurposeTo report the prevalence of scleritis and episcleritis in patients with idiopathic small fiber neuropathy (SFN). MethodsThe Mass General Brigham (MGB) hospital database was queried for patients with SFN, scleritis and episcleritis using diagnostic codes and natural language processing. Electronic medical chart review of patients diagnosed with SFN and episcleritis/scleritis who had at least one ophthalmology visit was conducted. The prevalence of scleritis and episcleritis in patients diagnosed with SFN was compared to those without SFN using logistic regression to adjust for covariates. All statistical analyses were performed in RStudio 4.2.1. ResultsFrom the 2100 SFN patients with an eye exam in the MGB database, 23 patients had episcleritis or scleritis (1.1%) confirmed by chart review. Ten patients had episcleritis (0.48%) and thirteen patients had scleritis (0.62%). Of the episcleritis and scleritis patients, 16 (69.6%) were women and 7 (30.4%) were men. Ten (43.5%) had bilateral ocular disease. The mean age of ocular diagnosis was 51.0 years (range, 22-77 years). Out of the 507,128 controls without SFN in the MGB database, 1,481 (0.29%) had scleritis and 1,430 (0.28%) had episcleritis. Episcleritis and scleritis were more prevalent in patients with SFN than in those without SFN: 0.48% vs. 0.28% for episcleritis and 0.62% vs 0.29% for scleritis (P values = 0.32 and 0.02, respectively). Conclusionsand Importance: There were higher rates of scleritis in SFN patients compared to non-SFN patients. This potential systemic disease association had not been previously reported.

Associations of small-airway disease with exercise intolerance and long-term outcomes in patients with heart failure and reduced or preserved ejection fraction

Associations of small-airway disease with exercise intolerance and long-term outcomes in patients with heart failure and reduced or preserved ejection fraction