Variation In Disease Severity Research Articles

Harnessing a Self-Regenerated Hybridization Circuit for Differentiating Heart Failure Patients of Varied Severity.

Heart failure (HF) is a globally threatening cardiovascular disease associated with poor quality of life and high mortality, therefore, timely diagnosis and risk prediction for HF disease are urgently needed. Herein, a compact yet robust self-regenerated hybridization circuit (SHC) aptasensor is developed for the amplified detection of N-terminal pro-brain natriuretic peptide (NT-proBNP), a "gold standard biomarker" for HF. The aptamer transduction module can specifically recognize NT-proBNP, thus initiating the cascade hybridization reaction with the successively self-regenerated triggers that reversely initiate the cross-hybridization reaction. Benefiting from the aptamer-specific recognition and the self-replicated signal amplification, the robust SHC aptasensor demonstrated a more impressive diagnostic performance for HF in elderly patients than the clinical fluorescence immunochromatography assay (FICA) in terms of positive predictive value (21 vs 17), specificity (39 vs 32), and diagnostic accuracy (37 vs 36). Furthermore, this approach allows for differentiation among HF patients with varying disease severities, achieving a sufficiently high accuracy of 78.3%, thus facilitating more timely and accurate therapeutic intervention. The versatile and reliable SHC system offers a new approach to analyzing low-abundance biomarkers from clinical rare specimens, which is highly important for early disease diagnosis and prognosis assessment.

UAV rice panicle blast detection based on enhanced feature representation and optimized attention mechanism

BackgroundRice blast is one of the most destructive diseases in rice cultivation, significantly threatening global food security. Timely and precise detection of rice panicle blast is crucial for effective disease management and prevention of crop losses. This study introduces ConvGAM, a novel semantic segmentation model leveraging the ConvNeXt-Large backbone network and the Global Attention Mechanism (GAM). This design aims to enhance feature extraction and focus on critical image regions, addressing the challenges of detecting small and complex disease patterns in UAV-captured imagery. Furthermore, the model incorporates advanced loss functions to handle data imbalances effectively, supporting accurate classification across diverse disease severities.ResultsThe ConvGAM model, leveraging the ConvNeXt-Large backbone network and the Global Attention Mechanism (GAM), achieves outstanding performance in feature extraction, crucial for detecting small and complex disease patterns. Quantitative evaluation demonstrates that the model achieves an overall accuracy of 91.4%, a mean IoU of 79%, and an F1 score of 82% on the test set. The incorporation of Focal Tversky Loss further enhances the model's ability to handle imbalanced datasets, improving detection accuracy for rare and severe disease categories. Correlation coefficient analysis across disease severity levels indicates high consistency between predictions and ground truth, with values ranging from 0.962 to 0.993. These results confirm the model’s reliability and robustness, highlighting its effectiveness in rice panicle blast detection under challenging conditions.ConclusionThe ConvGAM model demonstrates strong qualitative advantages in detecting rice panicle blast disease. By integrating advanced feature extraction with the ConvNeXt-Large backbone and GAM, the model achieves precise detection and classification across varying disease severities. The use of Focal Tversky Loss ensures robustness against dataset imbalances, enabling accurate identification of rare disease categories. Despite these strengths, future efforts should focus on improving classification accuracy and adapting the model to diverse environmental conditions. Additionally, optimizing model parameters and exploring advanced data augmentation techniques could further enhance its detection capabilities and expand its applicability to broader agricultural scenarios.

Co-Occurrence of Stromatinia cepivora and Fusarium proliferatum Fungi on Garlic: In Vitro Investigation of Pathogen–Pathogen Interactions and In Planta Screening for Resistance of Garlic Cultivars

Garlic (Allium sativum L.), a vital global crop, suffers significant losses from soil-borne fungal pathogens such as Fusarium proliferatum, responsible for Fusarium bulb rot, and Stromatinia cepivora, the causal agent of white rot. In May 2023, garlic fields near Makó City, Hungary, showed simultaneous yellowing and wilting symptoms of unknown fungal infestations, which appeared sporadically. The causal pathogens were later confirmed as F. proliferatum and S. cepivora through sampling of symptomatic garlic plants, incubation in humid chambers to stimulate fungal growth, and culturing on Potato Dextrose Agar (PDA) under sterile conditions. This was followed by hyphal tip isolation and purification. Molecular identification was performed using ITS1-2 sequencing, supported with morphological identification based on colony and microscopic features. This research aimed to elucidate pathogen interaction dynamics and assess the resistance of eleven garlic cultivars to both single and simultaneous inoculations by these pathogens, under in vitro and in planta tests. Dual culture assays of F. proliferatum and S. cepivora were studied at two time points: Day 8, marking the cessation of growth along the interacting fronts due to competitive coexistence, and Day 14, when single cultures reached full radial growth. On Day 8, inhibition percentages were 8.47% for F. proliferatum and 6.40% for S. cepivora, reflecting the initial effects of competitive interactions at the point of contact. By Day 14, inhibition rates increased to 25.39% and 28.61%, respectively, highlighting the cumulative effects of sustained competition and the growing difference between single and dual culture growth. Inoculation trials, involving placing fungal disks onto the basal areas of wounded garlic cloves, revealed considerable variability in disease incidence and severity. Cultivars such as ‘Aulxito’, ‘Sabadrome’, ‘Arno’, ‘Garcua’, and ‘Makói Tavaszi’ were highly susceptible to both pathogens, while ‘Flavor’ and ‘Sabagold’ exhibited only mild symptoms when inoculated with F. proliferatum and S. cepivora, respectively. Simultaneous inoculation resulted in more rapid and severe infections, exhibiting disease incidences above 96.00% across all cultivars. Remarkably, the cultivar ‘Elephant’ exhibited complete resistance to both pathogens, even under simultaneous inoculation, highlighting its potential for future garlic resistance breeding programs.

Dynamics of immune responses following duck Tembusu virus infection in adult laying ducks reveal the effect of age-related immune variation on disease severity.

Duck Tembusu virus (DTMUV), an emerging avian pathogenic flavivirus, is notably associated with neurological disorders and acute egg drop syndrome in ducks. We previously demonstrated that the susceptibility of ducks to DTMUV infection varies significantly with age, with younger ducks (4-week-old) exhibiting more severe disease than older ducks (27-week-old). However, the immunological mechanisms underlying these age-related differences in disease severity remain unclear. In this study, we investigated the dynamics of immune responses following DTMUV infection in adult laying ducks (27-week-old) and compared them to our previous findings on young ducks (4 weeks old). The numbers of T helper, cytotoxic T, B, and non-T and B lymphocytes, as well as neutralizing antibody levels, were measured in parallel with DTMUV loads in the blood and target organs. Our results revealed that the number of non-T and B lymphocytes/myeloid cells in 27-week-old adult laying ducks infected with DTMUV remained consistently stable throughout the observation period, in contrast to findings in 4-week-old younger ducks, where myeloid cell responses were implicated in disease progression. Regarding lymphocyte responses, unlike in 4-week-old younger ducks, only cytotoxic T lymphocyte responses in 27-week-old older ducks showed a significant negative correlation with the reduction of viremia and viral loads in target organs, indicating their role in controlling viral replication in older ducks. Additionally, 27-week-old adult laying ducks infected with DTMUV exhibited high levels of neutralizing antibodies, which were significantly correlated with reduced viral loads in blood and target organs. Overall, the presence of robust DTMUV-specific neutralizing antibody and CTL responses, along with a finely tuned myeloid cell response likely plays a significant role in controlling severe neurological outcomes in 27-week-old adult laying ducks. This study highlights the age-related differences in immune responses following DTMUV infection, which potentially contribute to the varying disease severity among ducks of different ages. Understanding the interplay between the host and DTMUV provides significant implications for disease management strategies and vaccine development.

P-1012. Looking Back to Move Forward: Insights into Current Coccidiomycosis Therapeutic Pathways

Abstract Background Coccidioidomycosis (cocci) poses therapeutic challenges due to the variability in disease presentation and severity, particularly for immunocompromised patients. Treatment approaches for cocci have not changed in decades. Fluconazole may remain ineffective as a first-line option in refractory cases or in more invasive disease. We aim to identify a cohort of patients diagnosed with cocci and their treatment pathways using a "real world" international global health network database.Table 1.Characterization of patients undergoing treatment for coccidiomycosis including clinical characteristics and clinical outcomes. Methods We conducted a multicenter retrospective study by querying TriNetX, a global research network, identifying patients with cocci by ICD-10-CM codes and linking to antifungal therapy. We investigated comorbidities diagnosed before infection and outcomes of interest after 1 year. Treatment pathways were assessed within 3 months post-diagnosis. A line of treatment was defined as receipt of the same medication within 3 days of cocci diagnosis, and was considered complete once absent from the patient’s record for 3 consecutive days. Graphs were designed with R Studio (3.6.0).Figure 1.Treatment pathways in coccidioidomycosis Sunburst diagram of initial treatment choices for cocci. A. Treatment pathways for the entire patient cohort diagnosed with coccidioidomycosis B. A subset of the treatment pathway analysis that removes patients with fluconazole monotherapy to better visualize other treatments that were used. Each ring represents a line of treatment. The inner side of the ring is the initial treatment choice, while subsequent rings represent switches. Each switch was defined by taking the same medication for 3 days within coccidioidomycosis diagnosis followed by the receipt of a different medication for at least 3 consecutive days. Results We captured 1909 patients diagnosed with cocci, of which 1581 (82.9%) had treatment pathway information. Most patients were white females around 51 years of age, presenting with pulmonary cocci (52%). Common comorbidities included T2DM (38.3%), CKD (30.9%), concurrent neoplasm (25.1%), and post-transplant-status (18.9%) (Table 1). Candidiasis was present in 14.9% of patients and CMV in 7.2%. Overall, 1-year mortality was 11%. Fluconazole was the most common initial therapy (87.4%) followed by amphotericin B (6.45%), echinocandins (2.34%), and itraconazole (1.83%). Of these, 11.2% of patients were switched to at least one new agent, with the most common switch being fluconazole to amB (1.6%) and amB to fluconazole (1.8%); 1.5% of patients were treated with ≥ 3 total antifungal agents (Fig 1). Conclusion Fluconazole remains the preferred initial agent to treat cocci; only 12.6% of patients received an alternative agent. Most initial switches favored amB, raising concern for treatment failure with fluconazole. Unveiling clinical characteristics of those patients may reveal possible clinical predictors of failure or situations where amB may be preferred. Disclosures George R. Thompson, III, MD, Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant

OP37 Delineating molecular and microbial signatures across disease severity in Inflammatory Bowel Disease in adult treatment naive patients through single-cell transcriptomic and microbiome profiling.

Abstract Background Inflammatory Bowel Disease (IBD), including Crohn's disease (CD) and Ulcerative Colitis (UC), is a chronic inflammatory condition with complex etiology involving genetic, immune, microbiome, and environmental factors. This study aims to elucidate the cellular and microbial landscape of adult treatment-naive IBD patients with varying disease severity to identify potential disease mechanisms and therapeutic targets, presenting one of the largest single-clinic, IBD single-cell datasets to date. Methods Tissue biopsies were collected from inflamed and non-inflamed regions of the colon in UC patients and colon + ileum in CD patients. Using 10x Genomics single-cell RNA sequencing (scRNA-seq), we analyzed 1.4 million cells from 68 treatment-naive IBD patients (38 CD, 30 UC) and 70 symptomatic healthy controls. Shotgun metagenomic sequencing was performed on 36 IBD patients with matched scRNA-seq data to explore host-microbe interactions, and a further 49 patients with paired clinical data. At presentation, standard clinical metadata, Patient Reported Outcomes, post-biopsy treatment, and 6/12-month treatment response were collected for stratification across disease severity and response. Results Our analysis revealed distinct cellular populations and gene expression profiles between IBD patients and healthy controls along the disease severity axis. Specific immune cell subsets were significantly expanded in IBD patients, with inflammatory monocytes particularly prominent in those with higher disease severity, exhibiting upregulated expression of pro-inflammatory cytokines and chemokines. Additionally, a shift from IgA to IgG antibody-producing cells was observed along the disease severity axis, indicating a dysregulated immune response associated with disease progression. Fecal microbial community typing based on pathway abundance revealed two clusters defined by low or high abundance of Bacteroidetes phylum taxa. Integration with clinical metadata and transcriptional profiles showed that Bacteroidetes-high UC patients displayed lower levels of inflammation and up-regulation of interferon signaling in B cells and myeloid cells. Conclusion This comprehensive profiling of adult treatment-naive IBD patients provides valuable insights into the cellular and microbial factors contributing to IBD prior to treatment perturbation. Our findings offer a deeper understanding of the underlying disease pathology of IBD patients at the time of presentation along the axis of disease severity, expanding the dynamic range of IBD patient profiling and informing future therapeutic strategies that may more quickly put patients on the right treatment and better address the causes of IBD in addition to the inflammatory response alone.

Phenotypic analysis of various Clostridioides difficile ribotypes reveals consistency among core processes.

C. difficile infections impact thousands of individuals every year many of whom experience recurring infections. Clinical studies have reported an unexplained correlation between some clades / ribotypes of C. difficile and disease severity / recurrence. Here, we demonstrate that C. difficile strains across the major clades / ribotypes are consistent in their core phenotypes. This suggests that such phenotypes are not responsible for variations in disease severity / recurrence and are ideal targets for the development of therapeutics meant to treat C. difficile related infections.

Elevations in D-dimer levels in patients with Plasmodium infections: a systematic review and meta-analysis

D-dimer, a byproduct of cross-linked fibrin degradation, arises during the fibrinolysis process, breaking down blood clots in circulation. This systematic review and meta-analysis aimed to synthesize evidence of D-dimer alteration in people with malaria, including variations in disease severity. The systematic review was registered in PROSPERO with registration number CRD42024528245. Searches were performed in EMBASE, Scopus, MEDLINE, PubMed, Nursing & Allied Health Premium, and Journals@Ovid on March 25, 2024, to identify original studies that reported D-dimer in patients with Plasmodium infections. The methodological quality of the included studies was assessed using the Joanna Briggs Institute critical appraisal tools. Thematic synthesis and meta-analysis were carried out to synthesize the findings of the included studies. A total of 24 studies were included in the review out of 1,115 records identified. According to the evaluated studies, patients with Plasmodium infections had higher D-dimer levels. A meta-analytic evaluation of D-dimer levels between patients with and without Plasmodium infections revealed a significant elevation of D-dimer in patients with infection, with high heterogeneity (SMD = 2.11, 95% CI = 0.59; 3.64, P = 0.007, I² = 98%, 6 studies, 1,418 participants, random-effects model). However, no significant alterations in D-dimer levels were observed following the comparison between patients with severe and uncomplicated malaria, also with high heterogeneity (SMD = 2.54, 95% CI = -1.60; 6.68, P = 0.23, I² = 99%, 3 studies, 595 participants). The findings suggested that malaria patients have significantly higher D-dimer levels compared to non-malarial individuals. However, there was no significant difference in D-dimer levels between severe and uncomplicated malaria cases. These results highlight the potential of D-dimer as a biomarker for Plasmodium infections, but its clinical utility requires further validation. Future studies should prioritize standardizing D-dimer measurement methods, including assay types, threshold values, and sample types, to ensure consistent and reliable application in clinical settings. Additionally, large, multicentric cohorts are needed to establish robust guidelines for incorporating D-dimer into malaria management practices. Further research should also explore the role of D-dimer in the pathogenesis of Plasmodium infections to deepen our understanding of their clinical significance.

Effect of Barley Yellow Dwarf Virus (BYDV) on Barley: A Precise Assessment of Reductions in Yield Components Under Variable Disease Severities.

Understanding the effects of barley yellow dwarf virus (BYDV) on crop agronomic traits and yield performance helps breeders balance their selection criteria and farmers decide if pesticides should be applied to control aphids that distribute the virus. To precisely assess the deterioration of different agronomic traits and yield components caused by different levels of BYDV infection, seeds of a BYDV-sensitive barley cultivar RGT Planet were space sown in a field plot with 10 cm between seeds and 20 cm between rows under two consecutive years. When BYDV symptoms were shown, plants with different levels (0 to 5) of BYDV infection were tagged. For accurate comparisons, the neighboring non/less-infected plants were also tagged. At maturity, different agronomic traits and yield components were measured on those tagged plants. Results showed a strong linear correlation between BYDV severity and the performance of agronomic traits and yield components. The yield reductions ranged from 30% for the least affected (score of 1) to 90% for the severely affected (score of 5). Our research confirmed previous findings that BYDV seriously affects crop yield and the prediction of yield loss due to BYDV infection should use the percentage of plants with different BYDV symptoms.

Atypical free sialic acid storage disorder associated with tissue specific mosaicism of SLC17A5.

Free sialic acid storage disorder (FSASD) is a rare autosomal recessive lysosomal storage disease caused by pathogenic SLC17A5 variants with variable disease severity. We performed a multidisciplinary evaluation of an adolescent female with suspected lysosomal storage disease and conducted comprehensive studies to uncover the molecular etiology. The proband exhibited intellectual disability, a storage disease gestalt, and mildly elevated urine free sialic acid levels. Skin electron micrographs showed prominent cytoplasmic vacuolation. Clinical exome and genome sequencing identified a maternally-inherited SLC17A5 variant: c.533delC;p.Thr178Asnfs*34. RNASeq of proband skin fibroblasts revealed exon 3 skipping, which was not detected in RNA from proband blood or parental fibroblasts. Targeted deep sequencing of proband fibroblast DNA revealed a 184bp deletion in ∼15% of reads, encompassing the 3' end of exon 3. Illumina Complete Long Read sequencing confirmed the deletion was in the paternally-inherited allele and found in a mosaic state in proband fibroblasts and muscle but not in blood or buccal cells. Functional studies, including SLC17A5 knockout cells and transient transfections of mutated SLC17A5 demonstrated pathogenicity of the identified variants. We report an adolescent female with atypical FSASD with tissue-specific mosaicism for an intragenic deletion in SLC17A5, explaining the atypical clinical course, mild biochemical abnormalities, and long diagnostic process.

Identification of novel candidate genes for Ascochyta blight resistance in chickpea

Ascochyta blight, caused by the necrotrophic fungus Ascochyta rabiei, is a major threat to chickpea production worldwide. Resistance genes with broad-spectrum protection against virulent A. rabiei strains are required to secure chickpea yield in the US Northern Great Plains. Here, we performed a genome-wide association (GWA) study to discover novel sources of genetic variation for Ascochyta blight resistance using a worldwide germplasm collection of 219 chickpea lines. Ascochyta blight resistance was evaluated at 3, 9, 11, 13, and 14 days post-inoculation. Multiple GWA models revealed eight quantitative trait nucleotides (QTNs) across timepoints mapped to chromosomes 1, 3, 4, 6, and 7. Of these eight QTNs, only CM001767.1_28299946 on Chr 4 had previously been reported. QTN CM001766.1_36967269 on Chr 3 explained up to 33% of the variation in disease severity and was mapped to an exonic region of the pentatricopeptide repeat-containing protein At4g02750-like gene (LOC101506608). This QTN was confirmed across all models and timepoints. A total of 153 candidate genes, including genes with roles in pathogen recognition and signaling, cell wall biosynthesis, oxidative burst, and regulation of DNA transcription, were observed surrounding QTN-targeted regions. Further gene expression analysis on the QTNs identified in this study will provide insights into defense-related genes that can be further incorporated into breeding of new chickpea cultivars to minimize fungicide applications required for successful chickpea production in the US Northern Great Plains.

Relation between dysbiosis and inborn errors of immunity.

Inborn errors of immunity (IEI) disorders, formerly primary immune deficiency diseases, are a heterogeneous group of disorders with variable hereditary transitions, clinical manifestations, complications and varying disease severity. Many of the clinical symptoms, signs and complications in IEI patients can be attributed to inflammatory and immune dysregulatory processes due to loss of microbial diversity (dysbiosis). For example, in common variable immunodeficiency patients, the diversity of bacteria, but not fungi, in the gut microbiota has been found to be reduced and significantly altered. Again, this was associated with a more severe disease phenotype. Compromise of the STAT3/Th17 pathway in hyper-IgE syndrome may lead to dysbiosis of the oral microbiota in these patients, causing Candida albicans to switch from commensal to pathogenic. Modification of the microbiota can be used as a therapeutic approach in patients with IEI. Prebiotics, probiotics, postbiotics and fecal microbiota transplantation can be used to restore the balance of the gut microbiota and reduce pathogenicity in IEI patients. Clinical trials are currently underway to understand the impact of this dysbiosis on the phenotype of IEI diseases and its role in their treatment.

Environmental drivers of spatial variation in myrtle rust development on a critically endangered tree species

Environmental drivers of spatial variation in myrtle rust development on a critically endangered tree species

Novel risk predictor of arrhythmias for patients with potassium channel-related congenital long QT syndrome.

Congenital long QT syndrome (LQTS) is characterized by delayed ventricular repolarization, predisposing to potentially lethal ventricular arrhythmias. The variability in disease severity among patients remains largely unexplored, underscoring the limitations of current risk stratification methods. We aimed to evaluate the potential utility of electrocardiographic markers from the exercise stress test (EST) in identifying patients with high-risk LQTS. The study, which considered patients with LQTS type 1 and LQTS type 2, comprised a discovery cohort of 695 and a validation cohort of 635 patients. The change in corrected QT (QTc) interval between rest and recovery (between rest and 3-4 minutes into the recovery period, called recovery-rest ΔQTc) was consistently greater in symptomatic patients. Sensitivity analyses performed on EST data obtained on and off β-blockers as well as upon distinguishing between patients with a baseline QTc interval below and those above 470 ms demonstrated consistent findings. The association of recovery-rest ΔQTc with cardiac events remained significant in a subanalysis focusing on future events (ie, occurring after the EST). An optimal recovery-rest ΔQTc cutoff was determined for LQTS type 1 (35 ms) and LQTS type 2 (16 ms) separately and was shown to be significantly associated with cardiac events. Our findings suggest that in patients with LQTS, dynamic QT interval measures obtained during the EST are associated with lifetime arrhythmic events and events after the EST. Such measures can be helpful in identifying a higher-risk subset of patients with LQTS in order to optimize their management. Further research may confirm these findings in larger cohorts and explore the potential benefit of combining genetic and EST data for more precise risk stratification.

Delving Into Stem Canker Disease of Potato Caused by Paramyrothecium roridum: A Morphological and Host Range Study in Iran.

In the summer of 2019, a severe stem canker disease affected potato (Solanum tuberosum) plants in a 10-hectare commercial field in Kermanshah province, Iran. Approximately 10% of the plants exhibited wilting, leaf yellowing and brown stem lesions with black sporodochia. Infected plants produced small tubers with no visible lesions. Ten fungal isolates from diseased plants were identified as Paramyrothecium roridum based on colony culture, microscopic characteristics, and analysis of the internal transcribed spacer (ITS) region and part of the β-tubulin gene. The pathogenicity of P. roridum on seedlings was confirmed by fulfilling Koch's postulates. Host range studies revealed a broad pathogenicity of the P. roridum isolate, successfully infecting various plant species with varying disease severities. Cucumis melo (melon) and Nicotiana rustica (wild tobacco) displayed susceptibility, while Triticum aestivum (wheat) and Avena sativa (oat) from the Poaceae family exhibited resistance. This study identifies P. roridum as a novel cause of potato stem canker disease in Iran.

Detailed Pathophysiology of Minimal Change Disease: Insights into Podocyte Dysfunction, Immune Dysregulation, and Genetic Susceptibility.

Minimal Change Disease (MCD) is a predominant cause of idiopathic nephrotic syndrome in the pediatric population, yet presents significant clinical challenges due to its frequent relapses and steroid resistance. Despite its relatively benign histological appearance, MCD is characterized by severe proteinuria, hypoalbuminemia, and edema, which may affect patient outcomes. Current treatment strategies primarily rely on corticosteroids, which are effective in inducing remission but are associated with high relapse rates, steroid resistance, and numerous long-term side effects, underscoring the need for more targeted and effective therapeutic approaches. This narrative review synthesizes current knowledge on the pathophysiological mechanisms underlying MCD, focusing on the following three critical areas: podocyte dysfunction, immune dysregulation, and genetic susceptibility. Podocyte dysfunction, particularly involving alterations in nephrin, plays a central role in the breakdown of the glomerular filtration barrier, leading to the characteristic proteinuria observed in MCD. Immune dysregulation, including the presence of autoantibodies against nephrin and other podocyte components, exacerbates podocyte injury and contributes to disease progression, suggesting an autoimmune component to the disease. Genetic factors, particularly mutations in the NPHS1 and NPHS2 genes, have been identified as significant contributors to disease susceptibility, influencing the variability in treatment response and overall disease severity. Understanding these mechanisms is crucial for developing targeted therapies that address the underlying causes of MCD rather than merely managing its symptoms. This review highlights the need for further research into these pathophysiological processes to pave the way for more personalized and effective treatment strategies, ultimately improving patient outcomes and reducing reliance on corticosteroids.

Abstract 4139170: Relationship between hemodynamics and oxygen consumption in hypertrophic cardiomyopathy during maximal stress testing

Background: Hypertrophic cardiomyopathy (HCM) is a global heart disease with great variability in disease severity, which can lead to significant impairment of exercise capacity. In healthy populations, oxygen consumption is related to cardiac output and arteriovenous oxygen difference. We sought to determine the relationship between hemodynamics (cardiac output and stroke volume) and oxygen consumption in HCM compared to healthy controls during maximal stress testing. Aims: To evaluate associations between the trajectories of hemodynamic function and oxygen consumption in HCM compared to healthy controls. Methods: Twenty individuals with HCM (51±15 years old, body mass index (BMI): 28±3 kg/m 2 , females, n=4) and 16 healthy controls (66±7 years old, 27±6 kg/m 2 , females, n=6) were included in the present study. Participants completed a maximal-graded stress test coupled with non-invasive hemodynamic bioreactance (cardiac output, stroke volume) and gas exchange (oxygen consumption, VO 2 ) measurements. Data were analyzed in quartiles (exercise only) and phases (rest, pre-pedalling, exercise and recovery) of the maximal-graded stress test. Results: In HCM, cardiac output declined in the fourth quartile of the exercise phase of the stress test (-0.39 L/min, p <0.001) whilst VO 2 increased (3.86 ml/kg/min, p <0.001). There was a significant difference in the gradient of cardiac output between HCM and controls in the final quartile of the test (-1.6 vs. 18.1 L/min, p<0.001). In coherence, stroke volume declined in the fourth quartile of the test (-18.4 ml, p <0.01) in response to increasing VO 2 in HCM. The rates of recovery were faster in HCM compared to the control group for VO 2 (-4.3 vs -2.6 mL/second, p<0.001), cardiac output (-0.03 vs -0.02 L/second, p<0.001), heart rate (-0.17 vs -0.10 beats/second, p<0.001), and stroke volume (-0.18 vs -0.07 L/second, p<0.001). Conclusions: In HCM, cardiac output declined during the later stages of maximal stress testing whereas in controls it continued to rise, indicating impaired maximal cardiac output responses to exercise. These findings have implications for exercise prescription and training regimens in HCM suggesting avoidance of maximal exercise levels.

Research on gut microbiota characteristics of PBC patients at different ALBI grades based on machine learning.

The Albumin-Bilirubin (ALBI) score and grade are widely used to stratify patients with primary biliary cholangitis (PBC) into different disease statuses and risk levels. Recent studies have increasingly highlighted the role of gut microbiota in autoimmune liver diseases. This study aimed to investigate the differences in gut microbiota among PBC patients with varying ALBI grades. Clinical data and stool samples were collected from outpatient and inpatient PBC patients between 2019 and 2022. Gut microbiota profiles were obtained using 16S rDNA sequencing of stool samples. We analyzed alpha diversity, beta diversity, LEfSe analysis and pathway function prediction. Additionally, various machine learning methods-including random forest (RF), lasso, gradient boosting machine (GBM) and support vector machine (SVM)-were employed to identify key features and to build and validate predictive models using bootstrap techniques. Clinical characteristics of ALBI grade 1 patients were comparatively better than those of ALBI grade 2 and 3 patients, including multiple laboratory indices. Gut microbiota analysis revealed that species richness and balance were higher in ALBI grade 1 patients. Both the comparison of the most abundant genera and the linear discriminant analysis (LDA) in LEfSe demonstrated that Lachnospira had a higher abundance and better discriminative ability in ALBI grade 1. Pathway function prediction indicated that sulfur metabolism was upregulated in higher ALBI grades. Furthermore, RF identified 10 specific genera, which were then used to build and validate models for discriminating PBC patients according to their ALBI grades. All three models, developed using different machine learning methods, demonstrated good discrimination ability (mean AUC 0.75-0.80). This study highlights significant differences in gut microbiota profiles among PBC patients with different ALBI grades. The increased abundance of Lachnospira and upregulation of sulfur metabolism pathways are notable in patients with lower ALBI grades. The machine learning models developed based on gut microbiota features offer promising tools for discriminating between PBC patients with varying disease severities, which could enhance the precision of treatment strategies.

Depression, health-related quality of life and life satisfaction in patients with heart failure

Background: The Patient Health Questionnaire 9 (PHQ9) has been recognized as an effective tool for identification of patients with heart failure (HF) at risk for lower health-related quality of life (HRQoL). We aimed to compare HRQoL levels, overall satisfaction with health and life, disease severity variables, sociodemographic variables and behavioural risk factors between patients with HF with different levels of depressive symptomatology. Methods: In a >55 years-old general population cross-sectional HF prevalence study, 1851 subjects were screened and those with NTproBNP ≥125 pg/mL (n=930) underwent detailed diagnostic visit to confirm or rule out HF as per 2016 European Society of Cardiology guidelines. HRQoL (the ShortForm 12 Health Survey, SF12; EQ5D3L), depressive symptoms (Patient Health Questionnaire, PHQ9) and satisfaction with life (Satisfaction With Life Scale, SWLS) were also assessed. Patient with HF (75±8 years, 54 % male, New York Heart Association (NYHA) functional class IIII, with mean left ventricular ejection fraction (LVEF) 56±13) were divided into three groups based on the severity of depressive symptomatology as per PHQ9 score (none: score 04, mild: score 59, and moderate-to-severe: score 1027). Multiple group comparisons and pairwise post hoc analyses were performed. Results: Results indicated significant between group differences in NYHA status (p<0.001), number of comorbidities (p=0.006), functional capacity (p=0.01), as well as HRQoL variables (p=0.05 to 0.001) and SWLS score (p<0.05), with nondepressed group generally showing better physical and subjective indicators of health and wellbeing compared with the mild and moderate-to-severe group. Conclusions: Results indicate that even patients with HF with clinically non-significant levels of depressive symptomatology show significantly impaired psychosocial status (diminished HRQoL, lower life satisfaction).

Variability in Disease Severity in Siblings With Homozygous Missense Variant of ADSSL1: Clinical Genetic Study and Review of Literatures.

Distal myopathies are genetic muscle disorders caused by mutations in various genes. A study found that mutations in adenylosuccinate synthetase-like 1 (ADSSL1) are associated with distal myopathy in nine patients from six unrelated families in South Korea. Previous research showed that affected individuals experienced distal muscle weakness starting in adolescence, along with mild facial muscle weakness, slightly elevated or normal serum creatine kinase (CK) levels, and the presence of a few rimmed vacuoles in muscle fibers or minimal chronic myopathic damage. Previously reported patients in this category exhibited an early age of symptom onset and severe muscle weakness. In this study, we present a case of two sisters who share the same mutation locus but display distinct disease phenotypes. A literature review was conducted on distal myopathies in patients with ADSSL1 mutations, alongside a retrospective analysis of disease severity variability among siblings with a homozygous missense variant of ADSSL1. The study focuses on two sisters with differing disease manifestations despite carrying the same genetic mutation. The older sister showed lower ability in running and jumping compared to her peers at age 7 and experienced notable muscle weakness and atrophy by age 27, whereas the younger sister remained free of symptoms at age 30. These findings suggest that mutations at the same locus can result in varying disease outcomes, emphasizing the complexity of predicting disease progression based solely on genetic mutations.