Pathophysiological Heterogeneity Research Articles

Comparison of GWAS results between de novo tinnitus and cancer treatment-related tinnitus suggests distinctive roles for genetic risk factors.

Tinnitus is a common sensorineural complication that can occur de novo or after cancer treatments involving cisplatin or radiotherapy. Considering the heterogeneous etiology and pathophysiology of tinnitus, the extent to which shared genetic risk factors contribute to de novo tinnitus and cancer treatment-induced tinnitus is not clear. Here we report a GWAS for de novo tinnitus using the UK Biobank cohort with nine loci showing significantly associated variants (p < 5 × 10-8). To our knowledge, significant associations in four of these loci are novel, represented by rs7336872, rs115125870, rs1532898 and rs2537, with UBAC2, NUDT9, TGM4 and MPP2 as their nearest protein coding genes, respectively. Through quantitative comparison of results from GWAS of de novo tinnitus with GWAS of radiation-induced tinnitus, two intronic variants (rs7023227 and rs3780395) from a locus within immunoregulatory gene PD-L1 (CD274) reached the replication threshold using comparison thresholds of 10-5 and 10-4, with no other shared genetic risk factors identified. We did not observe shared genetic risk factors between de novo and cisplatin-induced tinnitus. Our results suggest that genetic risk factors are mainly distinct based on etiology of tinnitus and future efforts to study, prevent or treat tinnitus are expected to benefit from strategies that allow for distinction of cases based on the primary environmental risk factor.

Abstract 4121812: Longitudinal Trajectory-Based Classification of Heart Failure with preserved Ejection Fraction: A Machine Learning Approach

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome characterized by heterogeneous pathophysiology and dynamic changes in cardiac structure and function. Current research predominantly focuses on left ventricular ejection fraction (LVEF) or left ventricular structures with predefined categories. This study hypothesized that applying unsupervised methodologies to longitudinal echocardiography will reveal distinct trajectory patterns in cardiac structure and function related to clinical outcomes in HFpEF patients. Methods: This retrospective cohort study, conducted at UC Davis Medical Center (2014 to 2022), consisted of adult patients with HFpEF. The inclusion criteria included ICD HF codes, a left ventricular ejection fraction (LVEF) ≥50%, and a Brain natriuretic peptide (BNP) ≥100 pg/ml or N-terminal-pro BNP (NT-proBNP) ≥225 pg/ml. Longitudinal data were analyzed using unsupervised machine learning, including UMAP for dimensionality reduction and Gaussian Mixture Models for clustering. Primary and secondary outcomes included all-cause mortality and changes in BNP levels, respectively. Results: The study included 1,626 patients. The cohort had a median age of 69 years, was 57.5% female, and 51.8% white. Three distinct echocardiographic trajectory patterns emerged (p&lt;.05) among the HFpEF cohort. Trajectory #1 (n=568) exhibited a high-stable pattern with the highest mortality rates, Trajectory #2 (n=512) showed a high-decreasing pattern with high mortality rates, and Trajectory #3 (n=546) had a low-increasing pattern with the lowest mortality rates. Trajectories varied significantly in baseline characteristics and longitudinal echocardiographic changes, with Trajectory #3 having a lower baseline left ventricular mass index (p&lt;.001) and a higher mean arterial pressure ( p =.001) compared to the other trajectories. Kaplan-Meier survival analysis indicated significant differences in survival among the trajectories ( p =.004). Conclusion: The study utilized unsupervised analysis of longitudinal echocardiographic data to identify three distinct HFpEF trajectories, each associated with unique clinical features and outcomes. These findings underscore the heterogeneity of HFpEF and highlight the potential trajectory-based patient stratification to improve targeted intervention strategies. Future validation in larger, multicenter cohorts is warranted to enhance HFpEF management and patient prognosis.

The Critical Role of Host and Bacterial Extracellular Vesicles in Endometriosis

Endometriosis is a chronic, inflammatory, oestrogen-dependent disorder that is defined by the presence of endometrium-like tissue in the extra-uterine environment. It is estimated to affect approximately 10% of women of reproductive age, and the cause is still largely unknown. The heterogenous nature and complex pathophysiology of the disease results in diagnostic and therapeutic challenges. This review examines the emerging role of host extracellular vesicles (EVs) in endometriosis development and progression, with a particular focus on bacterial extracellular vesicles (BEVs). EVs are nano-sized membrane-bound particles that can transport bioactive molecules such as nucleic acids, proteins, and lipids, and therefore play an essential role in intercellular communication. Due to their unique cargo composition, EVs can play a dual role, both in the disease pathogenesis and as biomarkers. Both host and bacterial EVs (HEVs and BEVs) have been implicated in endometriosis, by modulating inflammatory responses, angiogenesis, tissue remodelling, and cellular proliferation within the peritoneal microenvironment. Understanding the intricate mechanisms underlying EVs in endometriosis pathophysiology and modulation of the lesion microenvironment may lead to novel diagnostic tools and therapeutic targets. Future research should focus on uncovering the specific cargo, the inter-kingdom cell-to-cell interactions, and the anti-inflammatory and anti-microbial mechanisms of both HEVs and BEVs in endometriosis in the hope of discovering translational findings that could improve the diagnosis and treatment of the disease.

Study protocol: Cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury -CAPCOG-TBI.

Moderate-severe traumatic brain injury (msTBI) stands as a prominent etiology of adult disability, with increased risk for cognitive impairment and dementia. Although some recovery often occurs within the first year post-injury, predicting long-term cognitive outcomes remains challenging, partly due to the significant pathophysiological heterogeneity of TBI, including acute cerebrovascular injury. The primary aim of our recently funded study, cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury (CAPCOG-TBI), is to determine if acute cerebrovascular dysfunction after msTBI measured using multimodal non-invasive neuromonitoring is associated with cognitive outcome at 1-year post-injury. This longitudinal observational study will be conducted at two Level 1 trauma centers in Texas, USA, and will include adult patients with msTBI, and/or mild TBI with neuroimaging abnormalities. Multimodal cerebral vascular assessment using transcranial Doppler and cerebral near-infrared spectroscopy (NIRS) will be conducted within 7-days of onset of TBI. Longitudinal outcomes, including cognitive/functional assessments (Glasgow Outcome Scale and Patient-Reported Outcomes Measurement Information System), cerebral vascular assessment, and imaging will be performed at follow-ups 3-, 6-, and 12-months post-injury. We aim to recruit 100 subjects with msTBI along with 30 orthopedic trauma controls (OTC). This study is funded by National Institute of Neurological Disease and Stroke (NINDS) and is registered on Clinicaltrial.org (NCT06480838). We anticipate that msTBI patients will exhibit impaired cerebrovascular function in the acute phase compared to the OTC group. The severity of cerebrovascular dysfunction during this stage is expected to inversely correlate with cognitive and functional outcomes at 1-year post-injury. Additionally, recovery from cerebrovascular dysfunction is expected to be linked to cognitive recovery. The results of this study could help to understand the contribution of cerebrovascular dysfunction to cognitive outcomes after TBI and pave the way for innovative vascular-focused interventions aimed at enhancing cognitive recovery and mitigating neurodegeneration following msTB. In addition, its focus toward personalized medicine to aid in the management and prognosis of TBI patients.

Identifying methamphetamine use predictors in HIV infection: Immune-dopaminergic signatures in peripheral leukocytes and the role of COMT genotype

The pursuit of translational biomarkers is complex due to the heterogeneous human pathophysiology, but critical for disease diagnosis, prognosis, monitoring therapeutic efficacy, and for patient stratification. In HIV-associated neurocognitive impairment (NCI), biomarkers that delineate the trajectory of neuropathogenesis and neurocognitive sequelae are critical, particularly considering confounders such as substance use, including Methamphetamine (METH). METH use is a significant health concern among persons living with HIV (PWH), aggravating cognitive deficits and neuroinflammation despite of antiretrovirals, introducing elements in the microenvironment that are fundamentally differerent in relation to non-METH users, such as high levels of dopamine (DA) affecting HIV-innate immune targets. Yet, current biomarkers do not detect these differences. We hypothesized that predefined DA-induced signatures detectable in peripheral blood leukocytes, can distinguish HIV+ METH users compared to HIV-negative or PWH that are non METH users. The elevated expression of CD8A, CREBBP, CCL5, and combinations of dopaminergic pathway transcripts clustered METH users with detectable CSF viral load and major depressive disorder (MDD), indicating neuroimmune-mechanistic links. Cathecol-o-methyltransferase (COMT) gene polymorphisms affecting DA metabolism improved the identification of PWH using METH with biomarkers. The results indicate that underlying immunedopaminergic mechanisms provide signatures and genotypes that can identify PWH that are METH users and their attributes.

Challenges in the diagnosis and management of dry tamponade.

Dry tamponade is a rare complication of percutaneous coronary intervention. It encompasses a heterogenous pathophysiology and is used to describe hemodynamic compromise secondary to a coronary artery perforation, without free-flowing fluid in the pericardium. Tamponade physiology can result from compressive epicardial, intramyocardial, subepicardial hematomas, or dissecting intramyocardial hematomas. The diagnosis of dry tamponade requires hemodynamic derangement in the context of a compressive hematoma as demonstrated by imaging. Although echocardiography can often help identify dry tamponade, additional studies including right heart catheterization, computed tomography, or cardiac magnetic resonance imaging can inform the exact mechanism and help guide management. This article describes a case of dry tamponade, reviews the existing literature on the topic, and offers expert recommendations on diagnosis and management.

Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology

The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3–7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10–14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in β-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology.

A study on serum zonulin in chronic spontaneous urticaria patients

hronic spontaneous urticaria (CSU) is a widespread disease with a complicated heterogenous pathophysiology. Increased intestinal permeability i.e., leaky gut has been linked to the pathology of many diseases. Zonulin was recently used as a marker for leaky guts. This study aimed to assess the relation between serum zonulin level and CSU and its possible relationship with disease activity. This was a comparative cross-sectional study, which included 97 CSU adult patients and 87 apparently healthy controls. CSU patients had significant lower zonulin level than controls (p&lt;0.001). The median of serum zonulin level was equal to 2.93 ng/ml with interquartile range (IQR) (1.40-4.19) in the CSU group and of 3.92 ng/ml with IQR (2.97-4.69) in the control group. We found a positive correlation between serum zonulin and C-reactive protein with Pearson correlation coefficient of 0.2, (p=0.04). No significant correlation was found between serum zonulin level and urticaria activity score 7 or total immunoglobulin E level. In conclusion, this study found that serum zonulin level is lower in CSU patients than in controls which could be attributed to food restriction, severity of the CSU disease and/or drug intake in the CSU cases.

Unraveling the role of the renin-angiotensin system in severe mental illnesses: An insight into psychopathology and cognitive deficits

Severe mental illnesses (SMI), especially schizophrenia and bipolar disorder (BD), are associated with significant distress to patients, reduced life expectancy and a higher cost of care. There is growing evidence that SMI may increase the risk of dementia in later life, posing an additional challenge in the management of these patients. SMI present a complex and highly heterogeneous pathophysiology, which has hampered the understanding of its underlying pathological mechanisms and limited the success of the available therapies. Despite the advances in therapeutic approaches in psychiatry over the past decades, treatment resistance is still a common problem in clinical practice, highlighting the urgent need for novel therapeutic targets for SMI. The discovery that renin-angiotensin system (RAS) components are expressed in the central nervous system opened new possibilities for investigating a potential role for this system in the neurobiology of SMI. The safety and efficacy of AT1 receptor blockers and angiotensin-converting enzyme inhibitors in cardiovascular and metabolic diseases, common medical comorbidities among SMI patients and well-known risk factors for dementia, suggest the potential scalability of these strategies for the management of SMI outcomes including the risk of subsequent dementia. This review aimed to discuss the available evidence from animal models and human studies of the potential involvement of RAS in the pathophysiology of SMI. We also provided a reflection on drawbacks and perspectives that can foster the development of new related therapeutic strategies.

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength.

Dilated cardiomyopathy (DCM) has etiological and pathophysiological heterogeneity. Abnormal circadian rhythm (ACR) is related to the development of DCM in animal models, but exploration based on clinical samples is lacking. Sleep apnea (SA) is the most common disease related to ACR, and we chose SA as the study object to explore ACR-DCM. We included a derivation cohort (n =105) and a validation cohort (n = 65). DCM patients were divided into SA and without SA group. RT-qPCR was used to determine the change of rhythm gene expression pattern of heart samples from different timepoints. We used single-nucleus RNA sequencing (snRNA-seq) to explore the abnormal transcriptional patterns in the ACR group, and we verified the findings by pathological staining, atomic force microscopy (AFM), and Rev-erbα/β knockout (KO) mice analysis. DCM patients with SA showed decreased amplitude of rhythm gene expression. SA group showed more severe dilation of left heart chambers. From snRNA-seq, ACR-DCM lost the morning transcriptional patterns, detailly, actin cytoskeleton organization of cardiomyocytes (CMs) disrupted and hypertrophy aggravated, and the proportion of activated fibroblasts (Fibs) decreased with the reduction of fibrotic area ratio. The results of pathological staining, mechanical experiments, and transcriptional feature of Rev-erbα/β KO mice supported the above findings. Compared with the non-SA group, left ventricular (LV) wall dilation was more severe and the structural strength was lower in DCM patients with SA, and phenotypic changes in CM and Fib were involved in this process. ACR-DCM was histopathologically characterized by a structurally weak ventricular wall.

Identifying metabotypes of insulin resistance severity in children with metabolic syndrome

BackgroundInsulin resistance is a frequent precursor of typical obesity and metabolic syndrome complications. However, accurate diagnosis remains elusive because of its pathophysiological complexity and heterogeneity. Herein, we have explored the utility of insulin secretion dynamics in response to an oral glucose tolerance test as a surrogate marker to identify distinct metabotypes of disease severity.MethodsThe study population consisted of children with obesity and insulin resistance, stratified according to the post-challenge insulin peak timing (i.e., early, middle, and late peak), from whom fasting and postprandial plasma and erythrocytes were collected for metabolomics analysis.ResultsChildren with late insulin peak manifested worse cardiometabolic health (i.e., higher blood pressure, glycemia, and HOMA-IR scores) than early responders. These subjects also showed more pronounced changes in metabolites mirroring failures in energy homeostasis, oxidative stress, metabolism of cholesterol and phospholipids, and adherence to unhealthy dietary habits. Furthermore, delayed insulin peak was associated with impaired metabolic flexibility, as reflected in compromised capacity to regulate mitochondrial energy pathways and the antioxidant defense in response to glucose overload.ConclusionsAltogether, these findings suggest that insulin resistance could encompass several phenotypic subtypes characterized by graded disturbances in distinctive metabolic derangements occurring in childhood obesity, which serve as severity predictive markers.

Contemporary treatment options in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) constitutes approximately half of the heart failure population, with its prevalence markedly increasing with older age and the presence of cardio-metabolic comorbidities. Although HFpEF is associated with a high symptom- and mortality burden, historically there have been few evidence-based treatment options for patients with HFpEF. Recent randomized clinical trials have expanded evidence on pharmacological treatment options, introducing new agents for the managing HFpEF. Given the complex clinical phenotype with pathophysiological heterogeneity, evolving diagnostic standards, the evidence-based management of HFpEF remains challenging for clinicians. This review summarizes the latest evidence from contemporary randomized clinical trials and recent guideline recommendations to provide guidance for the treatment of patients with HFpEF.

Physiological Features of the Neural Stem Cells Obtained from an Animal Model of Spinal Muscular Atrophy and Their Response to Antioxidant Curcumin.

The most prevalent rare genetic disease affecting young individuals is spinal muscular atrophy (SMA), which is caused by a loss-of-function mutation in the telomeric gene survival motor neuron (SMN) 1. The high heterogeneity of the SMA pathophysiology is determined by the number of copies of SMN2, a separate centromeric gene that can transcribe for the same protein, although it is expressed at a slower rate. SMA affects motor neurons. However, a variety of different tissues and organs may also be affected depending on the severity of the condition. Novel pharmacological treatments, such as Spinraza, Onasemnogene abeparvovec-xioi, and Evrysdi, are considered to be disease modifiers because their use can change the phenotypes of the patients. Since oxidative stress has been reported in SMA-affected cells, we studied the impact of antioxidant therapy on neural stem cells (NSCs) that have the potential to differentiate into motor neurons. Antioxidants can act through various pathways; for example, some of them exert their function through nuclear factor (erythroid-derived 2)-like 2 (NRF2). We found that curcumin is able to induce positive effects in healthy and SMA-affected NSCs by activating the nuclear translocation of NRF2, which may use a different mechanism than canonical redox regulation through the antioxidant-response elements and the production of antioxidant molecules.

"Inhibitory immune checkpoints predict 7-day, in-hospital and 1-year mortality of internal medicine patients admitted with bacterial sepsis".

Sepsis is a life-threatening syndrome with complex pathophysiology and great clinical heterogeneity which complicates the delivery of personalized therapies. Our goals were to demonstrate that some biomarkers identified as regulatory immune checkpoints in preclinical studies could 1)improve sepsis prognostication based on clinical variables and 2)guide the stratification of septic patients in subgroups with shared characteristics of immune response or survival outcomes. We assayed the soluble counterparts of 12 biomarkers of immune response in 113 internal medicine patients with bacterial sepsis. IL-1 receptor-associated kinase M (IRAK-M) exhibited the highest hazard ratios (HRs) for increased 7-day (1.94 [1.17-3.20]) and 30-day mortality (1.61 [1.14-2.28]). HRs of IRAK-M and Galectin-1 for predicting 1-year mortality were 1.52 (1.20-1.92) and 1.64 (1.13-2.36), respectively. A prognostic model including IRAK-M, Galectin-1, and clinical variables (Charlson Comorbidty Index, multiple source of sepsis, and SOFA score) had high discrimination for death at 7 days and 30 days (area under the curve 0.90 [0.82-0.99]) and 0.86 [0.79-0.94], respectively). Patients with elevated serum levels of IRAK-M and Galectin-1 had clinical traits of immune suppression and low survival rates. None of the 12 biomarkers were independent predictors of 2-year mortality. Two inhibitory immune checkpoint biomarkers (IRAK-M and Galectin-1) helped identify 3 distinct sepsis phenotypes with distinct prognoses. These biomarkers shed light on the interplay between immune dysfunction and prognosis in patients with bacterial sepsis and may prove to be useful prognostic markers, therapeutic targets, and biochemical markers for targeted enrollment in targeted therapeutic trials.

Assessing the state of obesity care: Quality, access, guidelines, and standards.

An international panel of obesity medicine experts from multiple professional organizations examined patterns of obesity care and current obesity treatment guidelines to identify areas requiring updating in response to emerging science and clinical evidence. The panel focused on multiple medical health and societal issues influencing effective treatment of obesity and identified several unmet needs in the definition, assessment, and care of obesity. The panel was held in Leesburg, Virginia in September 2019. The panelists recommended addressing these unmet needs in obesity medicine through research, education, evaluation of delivery and payment of care, and updating clinical practice guidelines (CPG) to better reflect obesity's pathophysiological basis and heterogeneity, as well as the disease's health, sociocultural, and economic complications; effects on quality of life; need for standards for quantitative comparison of treatment benefits, risks, and costs; and the need to more effectively integrate obesity treatment guidelines into routine clinical practice and to facilitate more direct clinician participation to improve public understanding of obesity as a disease with a pathophysiological basis. The panel also recommended that professional organizations working to improve the care of people with obesity collaborate via a working group to develop an updated, patient-focused, comprehensive CPG establishing standards of care, addressing identified needs, and providing for routine, periodic review and updating. Unmet needs in the definition, assessment and treatment of obesity were identified and a blueprint to address these needs developed via a clinical practice guideline that can be utilized worldwide to respond to the increasing prevalence of obesity.

A multifaceted ecological approach to explore links between environmental factors and the epidemiology of disorders of gut-brain interaction.

Disorders of gut-brain interaction (DGBI) are characterized by debilitating symptoms not explained by structural or biochemical abnormalities. While functional conditions present with complex, likely heterogeneous pathophysiology, we aimed to investigate if proxy measures of sociocultural and environmental factors are associated with the prevalence of various DGBI in populations across the world. We performed an ecological study utilizing peer-reviewed published datasets reporting for 26 countries prevalence rates of DGBI (Rome Foundation Global Epidemiology Study, RFGES), with six independent variables: Helicobacter pylori prevalence and household size as proxy measures for orofecal infections, gross domestic product per capita (GDP), and median age as a proxy measures for socioeconomic development, density of fast food outlets (FFO) per 100,000 population as proxy measure for processed food exposure, and suicide mortality rate per 100,000 people, and world happiness scores were used as a proxy for psychological stress. The data were retrieved from publicly accessible datasets (United Nations, CIA World Factbook, World Bank, World Happiness Report, commercial/financial reports of a global FFO chain). We used linear regression to assess variables in univariate and multivariate analysis and report standardized β coefficients with 95% confidence intervals (CI). The regression model revealed that the overall prevalence of DGBI was inversely associated with both GDP per capita (β = -0.57, 95% CI: -0.92, -0.22, p = 0.002) and happiness scores (β = -0.433 95% CI: 0.821, -0.065, p = 0.023), while being positively associated with H. pylori prevalence (β = 0.40, 95% CI: 0.008, 0.81, p = 0.046). The prevalence of functional constipation (FC) was also inversely associated with GDP per capita (β = -0.50, 95% CI: -0.86, -0.13, p = 0.01) and happiness scores (β = -0.497, 95% CI: -0.863, -0.132, p = 0.01), while being positively associated with H. pylori prevalence (β = 0.53, 95% CI: 0.16, 0.91, p = 0.007). The Multivariate model analysis revealed that combining the factors of H. pylori prevalence, suicide rate, household size and happiness scores showed statistically significant association with FC (p = 0.039). Household size (β = -0.43, 95% CI: -0.82, 0.038, p = 0.033) and suicide rates (β = 0.55, 95% CI: 0.19, 0.90, p = 0.004) were statistically significantly associated with functional diarrhea. Irritable bowel syndrome (IBS) was associated with GDP per capita (β = -0.40, 95% CI: -0.79, -0.014, p = 0.043) and happiness scores (β = -0.390, 95% CI: -0.778, -0.003, p = 0.049). Utilizing publicly available data, the prevalence of DGBI across diverse countries is linked to various socio-cultural and environmental factors. Collectively, the data suggests that the prevalence of DGBI is increased in less prosperous regions of the world.

Pulmonary hypertension and chronic kidney disease: prevalence, pathophysiology and outcomes.

Pulmonary hypertension (PH) is common in patients with chronic kidney disease (CKD) or kidney failure, with an estimated prevalence of up to 78% in those referred for right-heart catheterization. PH is independently associated with adverse outcomes in CKD, raising the possibility that early detection and appropriate management of PH might improve outcomes in at-risk patients. Among patients with PH, the prevalence of CKD stages 3 and 4 is estimated to be as high as 36%, and CKD is also independently associated with adverse outcomes. However, the complex, heterogenous pathophysiology and clinical profile of CKD-PH requires further characterization. CKD is often associated with elevated left ventricular filling pressure and volume overload, which presumably leads to pulmonary vascular stiffening and post-capillary PH. By contrast, a distinct subgroup of patientsat high risk is characterized by elevated pulmonary vascular resistance and right ventricular dysfunction in the absence of pulmonary venous hypertension, which may represent a right-sided cardiorenal syndrome defined in principle by hypervolaemia, salt avidity, low cardiac output and normal left ventricular function. Current understanding of CKD-PH is limited, despite its potentially important ramifications for clinical decision making. In particular, whether PH should be considered when determining the suitability and timing of kidney replacement therapy or kidney transplantation is unclear. More research is urgently needed to address these knowledge gaps and improve the outcomes of patients with or at risk of CKD-PH.

Deep brain stimulation for the heterogeneous pathophysiology of Parkinson’s disease

Deep brain stimulation affects the pathophysiology of various motor disorders including essential tremor, Parkinson’s disease (PD) and dystonia. The motor deficits from PD have been explained by the firing rate and pattern models. However, due to the variability between patients’ electrophysiology, the pathophysiology for PD is difficult to sparse apart. Neither model can fully explain the spectrum of patient presentations. The localisation and stimulation of various structures including the subthalamic nucleus, globus pallidus internus and ventral intermediate nucleus lead to different effects on the patient’s motor symptoms. This group of targeted structures affects the models of PD in distinct ways. This review aims to explain the models of PD and the effects of stimulation in each structure.

Cluster approach to identifying the 5-year prognosis of patients with chronic heart failure of ischemic etiology

BACKGROUND: The phenotypic and pathophysiological heterogeneity of patients with chronic heart failure increases the interest of researchers in grouping according to similar clinical and genetic characteristics based on cluster analysis. AIM: To identify phenotypic subgroups in a multivariate cohort of patients with chronic heart failure secondary to coronary artery disease using uncontrolled cluster analysis of clinical, instrumental and genetic components. MATERIAL AND METHODS: 470 patients with chronic heart failure of functional class I–IV, stable course, ischemic etiology of both sexes at the age of 66.4±10.4 years were examined. A clinical study was conducted, genotyping single nucleotide polymorphisms rs10927875 of the ZBTB17 gene, rs247616 of the CETP gene, rs1143634 of the IL-1β gene, rs1800629 of the TNF gene, rs1800795 of the IL-6 gene was carried out, and patient outcomes were assessed for 5 years. Quantitative data were presented as mean and standard deviation or median and interquartile range; categorical — as frequencies and percentages. Categorical intergroup differences were tested using the χ2 test, and quantitative differences were tested using the Student/Mann–Whitney test. Hierarchical clustering was carried out according to 44 demographic, clinical, genetic variables, time to event was analyzed by the Kaplan–Meier method, risk ratio — by Cox regression. Statistical processing was carried out in the R4.3.1 program. RESULTS: Two clusters of patients with heart failure were identified. Cluster 1 (66%) included older patients of both sexes, predominantly functional class III–IV chronic heart failure, with enlarged heart chambers, reduced left ventricular ejection fraction, higher heart rate, atrial fibrillation and left ventricular hypertrophy. In this cluster, more carriers of the GG genotype of the rs1800795 polymorphism of the IL-6 gene (p 0.001) and the CT genotype of the rs247616 polymorphism of the CETP gene (p=0.014) were identified. Cluster 2 (34%) was represented predominantly by younger women, with a higher metabolic index, a history of myocardial infarction and coronary intervention, smokers, and a larger proportion of the TT genotype of the rs247616 polymorphism of the CETP gene (p=0.029). CONCLUSION: 2 clusters of patients with chronic heart failure, characterized by a different set of 44 variables that determine the risk of death from all causes, were identified.