Etiology Of Disease Research Articles

The German National Cohort (NAKO): Current state and further follow-up data collection

Abstract The German National Cohort (NAKO) is a multidisciplinary, population-based cohort study that aims to investigate the development and aetiology of diseases, identify risk factors and enhance early detection and prevention of diseases. Between 2014 and 2019, a total of 205,415 subjects aged 20 -74 years were recruited and examined at 18 study centres across Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires, a wide range of biomedical examinations and the collection of various bio samples. Furthermore, whole-body magnetic resonance imaging (MRI) was performed on 30,861 participants at 5 of the18 study centres. The first re-examination of study participants started in October 2018, and will be completed end of July 2024 aiming for at least 135, 000 participants. Until April 2024 134,428 participants completed their second examination, including 18,707 participants with additional MRI examination. The second re-examination will start in May 2024 and will last until April 2028 aiming to examine at least 85,000 participants for a third time. Besides the examinations at the study centres, participants receive written health questionnaires (GEFUs) 2-3 years after their last examination to get additional information on incident diseases and changes in exposures. The first GEFU questionnaire (GEFU-1) was conducted between October 2017 and May 2023 and was filled in by 171,181 participants. Since the start of GEFU-2 in March 2023 65,624 participants have answered the GEFU-2 questionnaire. Due to the longitudinal design, the large sample size and the broad examination programme, NAKO provides information on determinants of population health and disease. Thus, it is a valuable resource for researchers from different disciplines.

Risk Factors for Unplanned Readmissions in Paediatric Neurosurgery: A Systematic Review

Abstract Background Unplanned hospital readmission (UHR) after paediatric neurosurgery is an important indicator of surgical outcomes. As this field deals with complex cases, there is an increased likelihood of potential complications and the subsequent need for readmission. Hence, the study aims to identify factors contributing to 30-day and 90-day UHR rates in children undergoing neurosurgical procedures. Methods A systematic review (Prospero CRD 42023455779) was conducted, which included studies from Embase, Medline, CINAHL, and Global Index Medicus databases that reported unplanned readmissions within 30-/90-days of an index neurosurgical procedure. Quality and risk of bias assessment was done using the Newcastle-Ottawa scale. Data extraction and narrative synthesis were performed to identify significant factors associated with UHR. Results 2593 titles were identified following the search strategy. 52 studies were included after screening and quality appraisal. Most studies were from the United States and are retrospective cohort in nature. Majority were cranial procedures (n = 30), with common ones being shunt procedures for hydrocephalus and cranial tumour resections. Aetiology-related, procedural complexities, and age emerged as the three most common significant risk factors. Age is a significant predictor (9/52), with younger children facing higher odds compared to their older counterparts across different procedures. While early readmissions can be due to disease progression, some are linked to preventable causes. The included studies also exhibited significant heterogeneity. Variations in definitions and examined variables, as well as the inclusion of studies from both national databases and single institutions, contributed to this heterogeneity. Conclusions Overall, findings from this study contribute to a collective understanding of factors affecting unplanned readmissions in paediatric neurosurgery. Key messages • Identified risk factors can help guide creating and refining surgical protocols for post-operative monitoring and follow-up. • UHRs reflect the interplay among surgical complexity, patient characteristics such as age, and disease aetiology.

Safety and efficacy of simultaneous liver transplantation and sleeve gastrectomy in morbid obese end-stage liver disease patients: The LT-SG study.

In obese patients, metabolic dysfunction-associated steatotic liver disease is becoming a leading aetiology of end-stage liver disease and hepatocellular carcinoma. Simultaneous liver transplantation and sleeve gastrectomy (LT-SG) has been proposed in the US, but the safety and efficacy of the procedure have not been widely explored in Europe. Between January 2016 and December 2022, morbidly obese patients listed for LT at Tor Vergata University were enrolled in the LT-SG study. Primary outcomes were: i) safety expressed as 30- and 90-days overall survival (OS) and ii) major postoperative complications (Clavien-Dindo > IIIa). The secondary outcome was efficacy expressed as a 3-year %excess BMI loss(%EBMIL). Eleven patients were enrolled in the study. The median BMI at transplantation was 42 (IQR 38-48). Indications to LT-SG were HCC (63.6%) and cirrhosis (36.4%). In 54% of cases, donors had high-risk characteristics (ET-DRI>1.6). The 30 and 90-day OS were 63.6% and 54.5%, respectively. All deaths occurred in patients with p-SOFT>15 or in patients who had at least three of the following characteristics: >60 years, BMI >45, metabolic syndrome, MELD>25 or ET-DRI >1.6. The six months, 1, 2 and 3 years %excess BMI loss was 73%, 60%, 50% and 43%, respectively. LT-SG is a complex procedure thatmay carry excess risk in an unselected population. It should be considered only in highly selected patients. Standard donors are recommended and prioritization of severely obese patients on the waiting list should be considered.

Gene-gene and gene-environment interaction in coronary artery disease risk

Abstract Coronary Artery Disease (CAD) is a lethal illness that kills millions of individuals each year worldwide. This disorder is multifactorial, resulting in the complex interplay of genetic, epigenetic, and environmental factors. Exploring gene-gene and gene-environment interactions is essential to understanding the aetiology of common complex diseases like CAD. Aim We proposed investigating the interaction between two genetic variants robustly associated with CAD by GWAS (MTHFR rs1801133 and APOE rs7412/rs429358) in cardiovascular susceptibility. After that, consider whether there was a new interaction between this genetic association and environment (hypertension, dyslipidemia and smoking). Methods A case-control study enrolled 3,157 individuals, 1,721 coronary patients (with at least 70% stenosis of one or more major coronary arteries or its primary branches on the coronary angiography) and 1,436 controls without CAD. Traditional risk factors were investigated, and the two polymorphisms were performed by TaqMan real-time PCR. Bivariate analysis was used to study genotypic proportions between CAD and non-CAD patients with respective odds ratios (OR). Logistic regression analysis displayed the interaction between the two genetic variants each other and with some important environmental risk factors. Results In bivariate analysis, the genetic models were studied for both genes, being the dominant model the one which showed significance for CAD. In MTHFR, 57.8% of the patients and 53.4% of the controls presented the CT+TT genotype (OR=1.20; p=0.013). In APOE, 26.5% of the patients and 22.3% of the controls had E2E4;E3E4+E4E4 (OR=1.26; p=0.006). The first multivariate logistic regression showed a synergistic interaction between the two genetic variants (OR=1.50; p=0.001). After adjusting for conventional risk factors, the logistic regression analysis entered the MTHFR rs1801133 and APOE rs7412/rs429358, showing a combined interaction effect between those genes and smoking status with an OR of 3.44 (p<0.0001), with hypertension (OR=1.55; p=0.002) and with dyslipidemia (OR=1.71; p<0.0001). Conclusion According to our results, the genetic interaction between APOE and MTHFR synergistically affected the susceptibility to CAD. This interaction, linked to conventional risk factors, consistently increased the risk of CAD in our population, particularly in the group of genetic carriers who did not quit smoking.

High prevalence of cardiotropic viruses in endomyocardial biopsies from patients with inflammatory cardiomyopathy demonstrated by a novel targeted NGS approach

Abstract Background Viral infection of the heart muscle is a common cause of myocarditis and viral persistence can lead to chronic inflammatory cardiomyopathies (DCMi). A number of viruses including parvovirus B19 (B19V), adenovirus (AdV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes virus 6 (HHV-6) and enteroviruses (EV) are known to infect the myocardium, but their prevalence and role in persisting DCMi are not well understood. Virological etiologies can only be determined via endomyocardial biopsy (EMB), but the low tissue amount limits the number of conventional viral nucleic acid tests (virus-specific PCR) that can be performed in parallel. This study aimed to detect known and novel cardiotropic viruses in EMB of DCMi patients using a targeted next generation sequencing (NGS) approach. Methods A cohort of 33 patients with inflammatory cardiomyopathy (DCMi) (LVEF=29±12%) were retrospectively analyzed and compared to previous results of virus-specific PCR. DNA and RNA extracted from EMB were used for sequencing library preparation, and viral nucleic acids were enriched via a custom myBaits hybridization capture approach. Enriched libraries were sequenced on an Illumina MiSeq-platform in paired-end mode (500.000 reads/sample), and reads were taxonomically classified via Kraken2 and mapped against viral reference genomes using BWA-MEM2 or HiSat2, and subsequently deduplicated. Viral reads detected via both Kraken2 and mapping were classified as valid. Results Targeted NGS confirmed 19 out of 22 (86%) of the previous PCR-based viral detections. However, NGS was able to detect B19V DNA and RNA in an additional 11 and 15 patient samples respectively; CMV DNA/RNA in additional 5 and 4 samples respectively; EBV DNA/RNA in additional 5 and 1 samples respectively; and HHV-6 DNA/RNA in additional 3 and 1 samples respectively. Furthermore, viral reads of adenovirus type 2, adenovirus-associated virus type 2 (AAV-2), herpes viruses 7 and 8, and human parvovirus 4 were also found among the cohort. Thus, targeted NGS was able to identify 82 viral infections in a cohort of 33 DCMi patients, while only 22 were found using routine PCR tests. For routinely tested B19V, the use of the new NGS diagnostic approach improved sensitivity by 42% and specificity by 72%. Conclusions The presented NGS method represents a powerful new tool for the diagnosis of viral and inflammatory heart disease. The sensitivity is significantly higher than with conventional PCR approaches and the taxonomic classification is more specific. This enables the detection of previously false-negative routine viruses as well as potentially new cardiotropic pathogens from limited bioptic patient material – thus significantly increasing the diagnostic yield of EMB. In addition, our study demonstrates a high prevalence of non-enteroviral cardiotropic viruses in DCMi patients, shedding new light on the etiology of this heterogenous diseases and paving the way for more specific future treatments.

Genome-wide association study of CMR image-based aortic stiffness in 45,789 individuals identifies loci linked with cardiovascular diseases

Abstract Background The use of artificial intelligence on large-scale cardiac magnetic resonance (CMR) imaging data has enabled detailed characterisation of cardiac shape and function for use in genome-wide association studies (GWAS), leading to improved understanding of genetic aetiology of cardiovascular diseases (CVDs). Aortic stiffness is associated with increased risk of cardiovascular events in observational studies. Here, we present a novel CMR-based pressure-independent measure of aortic stiffness, identify genetic associations and explore links with CVDs. Purpose Identify genetic contributions to pressure-independent aortic stiffness and links to CVDs using large-scale GWAS analysis on the UK Biobank cohort. Methods A pre-trained neural network was used to segment CMR images of participants in the UK Biobank to quantify ascending aorta diameter, which together with contemporaneous systolic and diastolic blood pressure measurements (SBP, DBP, respectively) were used to calculate a pressure-independent measure of aortic stiffness (β0). The measurement assumes an exponential relationship between pressure and aortic diameter. We then performed a GWAS on β0 in 45,789 participants of European ancestry without CVDs. A multi-trait-based conditional & joint analysis (mtCOJO) was performed to estimate genetic effects independent of SBP, DBP and aortic area. We mapped the independent lead variants associated with aortic stiffness at P < 5x10-8 to nearest gene, and characterised shared genetic association across CVDs using Open Targets Platform database. Results The GWAS identified 17 independent lead variants, including 6 that remained significant in the conditional analysis. Four of these lead variants, not previously reported in GWAS of other aortic traits, were located near CTD-2203A3.1, MCF2L, CFDP1 and CDH13 genes (red annotations in the Figure). MCF2L, CFDP1 and CDH13 have been associated with coronary artery disease, and CFDP1 with myocardial infarction and coronary atherosclerosis in previous studies. Conclusion A GWAS of CMR-derived aortic stiffness identified 4 loci distinct from other aortic traits that also associate with other CVDs, suggesting genetic links between aortic stiffness and CVDs. Further analyses are required to explore biological mechanisms underlying these genetic associations.Aortic Stiffness Manhattan Plot

Beyond 2D echocardiography: A novel multiparametric assessment of right ventricular dysfunction in transcatheter tricuspid valve repair

Abstract Background Patients with severe tricuspid regurgitation (TR) are heterogenous and complex in terms of etiology, comorbidities and state of disease. Right ventricular (RV) function measured by RV to pulmonary artery coupling (RVPAc) is prognostic in transcatheter tricuspid valve repair (T-TEER). However, traditional 2D echocardiographic measures have critical limitations and RVPAc fails to respect the degree of volume overload/dilation of the RV, which is a key clinical tracer for right ventricular dysfunction (RVD). Purpose We aimed to refine RVPAc by incorporating RV dilation, assessed by 3D echocardiography, to improve the assessment of RV dysfunction for an enhanced outcomeprediction in T-TEER patients. Methods We analyzed 262 patients undergoing T-TEER with complete 3D echocardiography. Results Despite similar RV function across groups, RV dilation (HR 1.85; 1.10, 3.12; p=0.020) and impaired RV free wall longitudinal strain (RVFWLS, HR 1.73, 1.02, 2.92, p=0.042) predicted increased 1-year mortality. A novel RVPAc parameter [RVFWLS/(3D-RVEDV*sPAPinvasive)] was developed, associating RVPA-Uncoupling with a tripled risk of death (HR 3.19, 1.7-6.0, p<0.001). NYHA Class IV and the new RVPAc were independent mortality predictors after T-TEER, with the modified RVPAc showing superior predictive value over traditional RVPAc (c-index 0.68 vs. 0.57, p=0.027). Conclusion The novel RVPAc parameter, integrating RV dilation and function, is a powerful predictor of survival post-T-TEER, underscoring the importance of timely intervention in severe TR and RVD. 3D echocardiography plays a critical role in assessing RV dimension and function, with implications for the management and prognosis of TR patients.Central Figure

Skeletal and respiratory muscle weakness contributes to decreased exercise capacity in hypertrophic cardiomyopathy

Abstract Background and Aims Although decreased exercise capacity (due to dyspnea or angina-like symptoms) constitutes the fundamental characteristics of hypertrophic cardiomyopathy (HCM), the pathophysiology of these symptoms remains only partly understood. We investigated clinical and functional determinants of decreased exercise capacity in a broad range of HCM patients irrespective of primary disease aetiology (either genetic disorder or e.g. infiltrative phenocopies in the course of cardiac amyloidosis), overt heart failure (HF) and the presence of haemodynamically significant left ventricular outflow tract obstruction (LVOTO). Further, we deterimined the contribution of skeletal and respiratory muscle weakness to decresed exercise capacity. Methods We analyzed clinical data and functional assessments (skeletal and respiratory muscle strength, physical fitness) in relation to symptomatology and sub-maximal exercise capacity in 82 clinically stable patients with HCM (females: 32 %; age: 62±16 years; left ventricular ejection fraction [LVEF] 59±7%; intraventricular septum wall thickness [IVS] 19±4 mm; median plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP]: 818 pg/mL [lower and upper quartile: 208-1917]; New York Heart Association [NYHA] class 0/I/II/III: 38/18/33/11 % [0 indicates no HF]; significant LVOTO: 29%). Results HCM patients with more severe symptomatology (NYHA class II-III vs 0-I) were older, had more frequently significant LVOTO and greater comorbidity burden, and had higher NT-proBNP and worse estimated renal function (all p≤0.03). Gender distribution, percentage of beta-blocker therapy and implanted device, body mass index, major echocardiography parameters (including LVEF, left ventricular end-diastolic diameter and IVS), high-sensitive (hs) cardiac troponin type I and hs-C-reactive protein were comparable in these 2 groups of subjects (all p>0.05). In multivariable linear regression models more advanced age, higher circulating natriuretic peptides (NT-proBNP) and previous coronary revascularization were independent predictors of more advanced NYHA class (standardized β-coefficient=0.30, p<0.01; β=0.27, p<0.01; and β=0.22, p<0.05; respectively). Similarly, more advanced age, female sex and higher NT-proBNP were independent correlates of shorter distance in 6-minute walking test (6MWT) (β=-0.46, p<0.001; β=-0.26, p<0.001; and β=-0.36, p<0.001; respectively). All analyzed muscle parameters (including respiratory muscle strength parameters) and objective measures of physical fitness (Functional Fitness Test for older adults) remained independently associated with 6MWT distance (all p<0.001) when adjusted for aforementioned clinical and laboratory correlates of 6MWT. Conclusions Muscle weakness and low physical fitness are related to decreased exercise capacity in HCM and may be potential therapeutic targets to alleviate disease symptoms also in non-obstructive HCM phenotype.

Assessment of right ventricular function in patients with severe secondary tricuspid regurgitation, following to the TVARC recommendations: association with outcome

Abstract Introduction Severe tricuspid regurgitation (TR) is associated with increased mortality if left untreated. Recently, the Tricuspid Valve Academic Research Consortium (TVARC) has published standardized definitions of disease aetiology and severity, as well as endpoints for future clinical trials. Right ventricular (RV) function assessment represents one of the cornerstones for risk stratification in these patients, but current guidelines do not propose specific cut-off values for the echocardiographic measures. Also, the thresholds proposed by the TVARC have been derived from normative value and not yet validated in large cohorts of TR patients. Purpose To test the prognostic value of the TVARC proposed echocardiographic cut-offs for grading RV-dysfunction (figure1) in a large real-world cohort of patients with severe secondary TR (STR). Methods Consecutive patients from a single centre with first diagnosis of severe secondary STR, and without a cardiac implantable electronic device, were included. Tricuspid annulus plane systolic excursion (TAPSE), RV global and free wall strain (RVGLS and RVFWLS) and fractional area change (FAC) were used to measure RV function. The study endpoint was all-cause mortality, censored for tricuspid valve intervention. Results A total of 1043 patients (mean age 69 ± 13 years, 43% male), were included. Approximately half of the population (45%) was in NYHA class III or IV and 52% was treated with loop diuretics. Overall patients showed mild RV-dilatation (RV end-diastolic area indexed 12.2 [10.1-15.2cm2/m2]) and moderate-to-severe right atrial dilatation (right atrial maximal area indexed: 13.9 [11.0-17.5cm2/m2]). Using the proposed cut-off values, strain analysis identified a higher number of patients with impaired RV function as compared to standard echocardiographic parameters (89% based on RVGLS; 80% based on RVFWS, 61% based on TAPSE and 54% based on RVFAC). During a median follow-up of 51 [IQR 6 - 98] months, 445 (43%) patients died. The Kaplan-Meier survival curves for each echocardiographic parameter of RV-function are shown in Figure 1. TAPSE, which is the most widely used RV-function parameter, was able to clearly identify patients at high and intermediate risk when mildly, moderately and severely impaired. However, patients with normal TAPSE were still at intermediate risk when RVFWLS was (even mildly) reduced (figure 2). We therefore propose a stepwise practical approach including the measure of RVFWLS when measuring normal TAPSE, in order to possibly re-stratify patients into a higher risk group (Figure 2). This novel grading approach remained independently associated with all-cause mortality after correcting for relevant clinical and echocardiographic variables on multivariable analysis. Conclusion Novel TAVRC cut-off values for RV function show prognostic value in patients with severe STR; particularly the combination of TAPSE and RVFWLS could be use in clinical practice for risk stratification.Figure 1Figure 2

Real-world evidence for patient phenotypes in heart failure with preserved ejection fraction

Abstract Background Heart failure (HF) with preserved ejection fraction (HFpEF) presents a high mortality risk due to its heterogeneous and multifactorial nature, coupled with limited treatment options. The incompletely understood pathophysiology is influenced by various comorbidities, resulting in different clinical phenotypes. Identifying these could be crucial for tailored HFpEF treatments. While previous studies focused on small, well-characterized patient populations, electronic health records (EHRs) offer the potential to unveil HFpEF phenotypes in larger real-world patient groups. Purpose We aimed to establish a sizable, unselected HFpEF patient population using real-world data. Employing cluster analysis, we intended to uncover distinct groups with varied disease aetiology and medical needs based on comorbidity profiles and prognoses. Methods From EHRs of n = 1,610,101 HF patients, we identified an HFpEF cohort of n = 32,009 patients, by applying thresholds for the LVEF and data availability, and by excluding confounding conditions. Clustering by the relative frequency of common comorbidities aimed to reveal patient populations with unique prognoses, comorbidity profiles, and clinical and demographic characteristics. Results Six clusters of different sizes, comorbidity prevalence, clinical presentation, and all-cause mortality were identified. About 50% of patients (n = 15,445) were predominantly hypertensive, with varying extents of coronary heart disease and diabetes mellitus (DM), and a 5-year mortality of about 30%. Around 22% (n = 7,089) exhibited a cardiometabolic comorbidity profile, with an increased prevalence of obesity and sleep apnea, but also DM and hypertension, and a 5-year mortality of 22.5%. Over 15% of patients (n = 5,298) had a 5-year mortality rate of 45.0%, marked by highest rates of anaemia and chronic kidney disease (CKD) but also DM, elevated N-terminal prohormone of brain natriuretic peptide levels, and a reduced estimated glomerular filtration rate. Conclusion Despite the favourable prognosis, a significant proportion of patients represent a cardiometabolic HFpEF phenotype with notable unmet medical needs regarding cohort size and multimorbidity. Patients simultaneously suffering from CKD, anaemia, and the highest mortality rates may represent a previously underrecognized phenotype. Our study demonstrates that distinct medical needs can be identified in a large, unselected real-world HFpEF cohort. In contrast to clinical trials, this approach enabled access to a broader patient population, revealing novel phenotypes to be targeted by precision medicine in the future.

Ultrasound-guided percutaneous microwave ablation for metabolic-associated fatty liver disease-related hepatocellular carcinoma (HCC) versus hepatitis virus B-related HCC: a propensity score matching study

Objectives To compare the long-term outcomes of microwave ablation (MWA) for primary hepatocellular carcinoma (HCC) in patients with metabolic-associated fatty liver disease (MAFLD) with those infected by hepatitis virus B (HBV). Methods The clinical data of HCC patients under the treatment of MWA were analyzed retrospectively between 2010 and 2021 at Chinese PLA General Hospital. Patients were divided into MAFLD-HCC and HBV-HCC group according to the chronic liver disease etiology. The propensity score matching (PSM) was performed to reduce the interference of confounders. The primary outcomes were overall survival (OS), recurrence-free survival (RFS), cancer-specific survival (CSS) and intrahepatic distant recurrence (IDR). Results A total of 648 patients (age range, 18–91 years) with 1019 lesions were enrolled including 601 with HBV-HCC and 47 with MAFLD-HCC. After a variable ratio of 1:n ≤ 4 PSM, 100 patients were included in the HBV-HCC and 41 in the MAFLD-HCC group. No statistical differences in OS and CSS (p = 0.880 and p = 0.980, respectively) were observed between the two groups in the matched cohort, while MAFLD-HCC exhibited better RFS and lower IDR rates compared to HBV-HCC (p = 0.043 and p = 0.041, respectively). Additionally, MAFLD-HCC generated lower ascending range in the liver function indexes like ΔALT (46.7 vs. 98.5, p < 0.001), ΔTBIL (1.9 vs. 7.5, p = 0.001) and ΔAST (38.1 vs. 148.6, p < 0.001) than HBV-HCC after MWA. Conclusions MWA is an effective treatment for HCC patients with MAFLD. The recurrence prognosis of MAFLD-HCC was better than HBV-HCC and the degree of liver injury after MWA was lower.

Hepatic steatosis estimated by VCTE-derived CAP scores was associated with lower risks of liver-related events and all-cause mortality in patients with chronic liver disease.

The Controlled Attenuated Parameter (CAP) score derived from vibration-controlled transient elastography (VCTE, i.e. Fibroscan®) is a well-validated marker of hepatic steatosis. It is unclear if CAP scores are associated with risks of liver-related outcomes or all-cause mortality. In this retrospective cohort study, we identified 7,587 U.S. Veterans (2,689 with cured hepatitis C [HCV], 1,523 with alcohol-associated liver disease [ALD], 3,375 with metabolic dysfunction-associated steatotic liver disease [MASLD]) who underwent VCTE between 5/2015-12/2021. We followed patients for new hepatic decompensation, hepatocellular carcinoma (HCC), and death from the VCTE date until 1/1/2022. Multivariable Cox-proportional hazards regression was used to assess for the associations between CAP measurements and clinical outcomes, adjusting for age, sex, race/ethnicity, body mass index, Charlson Comorbidity Index, diabetes, liver disease etiology, liver stiffness measurements, and FIB-4, and was reported separately by disease etiology and advanced fibrosis status. Over a median follow-up time of ∼1.9 years, hepatic steatosis (grades 1-3 vs. 0) was associated with a lower risk of death (aHR 0.70, 95% CI: 0.57-0.85). Among patients with MASLD, hepatic steatosis was associated with a lower risk of decompensation (aHR 0.54, 95% CI: 0.32-0.90) and death (aHR 0.52, 95% CI: 0.37-0.73). These associations persisted in subgroup analyses of patients with advanced fibrosis and without cirrhosis. Among patients who underwent VCTE in clinical practice, the presence of substantial hepatic steatosis estimated by the CAP score was associated with lower all-cause mortality among all patients and lower risk of decompensation and death among those with MASLD.

A mathematical model of glomerular fibrosis in diabetic kidney disease to predict therapeutic efficacy

BackgroundGlomerular fibrosis is a tissue damage that occurs within the kidneys of chronic and diabetic kidney disease patients. Effective treatments are lacking, and the mechanism of glomerular damage reversal is poorly understood.MethodsA mathematical model suitable for hypothesis-driven systems pharmacology of glomerular fibrosis in diabetes was developed from a previous model of interstitial fibrosis. The adapted model consists of a system of ordinary differential equations that models the complex disease etiology and progression of glomerular fibrosis in diabetes.ResultsWithin the scope of the mechanism incorporated, advanced glycation end products (AGE)—matrix proteins that are modified due to high blood glucose—were identified as major contributors to the delay in the recovery from glomerular fibrosis after glucose control. The model predicted that inhibition of AGE production is not an effective approach for accelerating the recovery from glomerular fibrosis. Further, the model predicted that treatment breaking down accumulated AGE is the most productive at reversing glomerular fibrosis. The use of the model led to the identification that glucose control and aminoguanidine are ineffective treatments for reversing advanced glomerular fibrosis because they do not remove accumulated AGE. Additionally, using the model, a potential explanation was generated for the lack of efficacy of alagebrium in treating advanced glomerular fibrosis, which is due to the inability of alagebrium to reduce TGF-β.ImpactUsing the mathematical model, a mechanistic understanding of disease etiology and complexity of glomerular fibrosis in diabetes was illuminated, and then hypothesis-driven explanations for the lack of efficacy of different pharmacological agents for treating glomerular fibrosis were provided. This understanding can enable the development of more efficacious therapeutics for treating kidney damage in diabetes.

Metagenome-based characterization of the gut bacteriome, mycobiome, and virome in patients with chronic hepatitis B-related liver fibrosis

IntroductionThe gut microbiota is believed to be directly involved in the etiology and development of chronic liver diseases. However, the holistic characterization of the gut bacteriome, mycobiome, and virome in patients with chronic hepatitis B-related liver fibrosis (CHB-LF) remains unclear.MethodsIn this study, we analyzed the multi-kingdom gut microbiome (i.e., bacteriome, mycobiome, and virome) of 25 CHB-LF patients and 28 healthy individuals through whole-metagenome shotgun sequencing of their stool samples.ResultsWe found that the gut bacteriome, mycobiome, and virome of CHB-LF patients were fundamentally altered, characterized by a panel of 110 differentially abundant bacterial species, 16 differential fungal species, and 90 differential viruses. The representative CHB-LF-enriched bacteria included members of Blautia_A (e.g., B. wexlerae, B. massiliensis, and B. obeum), Dorea (e.g., D. longicatena and D. formicigenerans), Streptococcus, Erysipelatoclostridium, while some species of Bacteroides (e.g., B. finegoldii and B. thetaiotaomicron), Faecalibacterium (mainly F. prausnitzii), and Bacteroides_A (e.g., B. plebeius_A and B. coprophilus) were depleted in patients. Fungi such as Malassezia spp. (e.g., M. japonica and M. sympodialis), Candida spp. (e.g., C. parapsilosis), and Mucor circinelloides were more abundant in CHB-LF patients, while Mucor irregularis, Phialophoraverrucosa, Hortaea werneckii, and Aspergillus fumigatus were decreases. The CHB-LF-enriched viruses contained 18 Siphoviridae, 12 Myoviridae, and 1 Podoviridae viruses, while the control-enriched viruses included 16 Siphoviridae, 9 Myoviridae, 2 Quimbyviridae, and 1 Podoviridae_crAss-like members. Moreover, we revealed that the CHB-LF-associated gut multi-kingdom signatures were tightly interconnected, suggesting that they may act together on the disease. Finally, we showed that the microbial signatures were effective in discriminating the patients from healthy controls, suggesting the potential of gut microbiota in the prediction of CHB-LF and related diseases.DiscussionIn conclusion, our findings delineated the fecal bacteriome, mycobiome, and virome landscapes of the CHB-LF microbiota and provided biomarkers that will aid in future mechanistic and clinical intervention studies.

Thyroid Metastases from Hepatocellular Carcinoma after Liver Transplantation

Hepatocellular carcinoma (HCC) patients with metastases to the thyroid are extremely rare. A patient who underwent liver transplantation for HCC recurrence had metastatic thyroid recurrence detected 4 years later. A literature review identi"ed six documented cases, analyzing relevant data on HCC with thyroid metastasis following liver transplantation. !ere is a prevalence of hepatitis B virus (HBV ) and hepatitis C virus (HCV ) as etiologies of liver disease (83.3%), with alpha-fetoprotein (AFP) levels elevated in "ve cases. Additionally, the time between the diagnosis of HCC and thyroid metastasis was within 3 years. !e patient remains clinically stable in outpatient follow-up, with an 8-month current survival after total thyroidectomy.

Spatially resolved metabolomics: From metabolite mapping to function visualising.

Mass spectrometry imaging (MSI)-based spatially resolved metabolomics addresses the limitations inherent in traditional liquid chromatography-tandem mass spectrometry (LC-MS)-based metabolomics, particularly the loss of spatial context within heterogeneous tissues. MSI not only enhances our understanding of disease aetiology but also aids in the identification of biomarkers and the assessment of drug toxicity and therapeutic efficacy by converting invisible metabolites and biological networks into visually rendered image data. In this comprehensive review, we illuminate the key advancements in MSI-driven spatially resolved metabolomics over the past few years. We first outline recent innovations in preprocessing methodologies and MSI instrumentation that improve the sensitivity and comprehensiveness of metabolite detection. We then delve into the progress made in functional visualization techniques, which enhance the precision of metabolite identification and annotation. Ultimately, we discuss the significant potential applications of spatially resolved metabolomics technology in translational medicine and drug development, offering new perspectives for future research and clinical translation. HIGHLIGHTS: MSI-driven spatial metabolomics preserves metabolite spatial information, enhancing disease analysis and biomarker discovery. Advances in MSI technology improve detection sensitivity and accuracy, expanding bioanalytical applications. Enhanced visualization techniques refine metabolite identification and spatial distribution analysis. Integration of MSI with AI promises to advance precision medicine and accelerate drug development.

Cirrhosis in primary practice: many patients remain potentially undiagnosed and are not receiving liver cancer surveillance.

Most patients with cirrhosis have compensated disease and are cared for in primary care; however, the exact epidemiology within Australia remains largely unknown. The aim of this study was to assess cirrhosis care in an Australian primary care setting by evaluating rates of cirrhosis diagnosis, appropriate hepatocellular carcinoma (HCC) surveillance and specialist communication. Electronic medical records in consenting general practices were reviewed using the "Liver Toolkit" to identify patients with an existing cirrhosis diagnosis. Individual cases were reviewed to identify outcomes of interest. One hundred seventy-one patients with confirmed cirrhosis across nine general practices were identified (74% male, mean age: 61.2years). There was significant variation in the rate of cirrhosis diagnosis between practices (range 31.7-637.9 per 100 000 patients, P<0.0001). Patients with cirrhosis had predominately compensated disease (75% Child-Pugh A) and common etiologies of cirrhosis were alcohol (49%), hepatitis C (47%), and metabolic dysfunction-associated steatotic liver disease (29%). Forty-two patients (25%) had received appropriate HCC surveillance. Predictors of inadequate HCC surveillance were time from last specialist correspondence (odds ratio [OR]=1.06 per month increase, 95% confidence interval [CI]: 1.02-1.10, P=0.002) and hepatitis B (OR=0.24, 95% CI: 0.06-0.98, P=0.047). Specialist correspondence with primary care was older than 2years or absent in 37% of cases. There was a 20-fold difference in the rate of cirrhosis diagnosis between general practices within Sydney, suggesting a large proportion of patients remain undiagnosed. Three quarters of patients with diagnosed cirrhosis are not receiving appropriate HCC surveillance.

Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation.

The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.

Long-term Outcomes and Risk Modifiers of MASLD Between Lean and Non-Lean Populations.

One-third of adults across the globe exhibit metabolic dysfunction-associated steatotic liver disease (MASLD) - formerly known as nonalcoholic fatty liver disease (NAFLD). To date, MASLD is the fastest-growing etiology of chronic liver disease and hepatocellular carcinoma (HCC). Besides the population with obesity, MASLD can also be found in lean populations, accounting for 13% of the global population, especially Asians. Notably, individuals with lean MASLD face equal or higher overall mortality rates compared to their non-lean counterparts. Risk modifiers encompass advanced age, hepatic fibrosis, and type 2 diabetes mellitus (T2DM). Moreover, the population with lean MASLD is associated with an increased risk of HCC, while their non-lean counterparts are more prone to cardiovascular outcomes and T2DM. Existing evidence indicates a similar risk of liver-related events and extrahepatic cancer between the two groups. However, MASLD-related genetic variants, such as PNPLA3 and TM6SF2, did not significantly affect mortality between the two populations. Still, underreporting alcohol consumption and regional representation limits the study's comprehensiveness. Longitudinal studies and mechanistic explorations are needed to understand differences in lean versus non-lean MASLD populations. This review highlights the need for awareness and tailored interventions in managing MASLD, considering lean individuals' unique risks.

Single-cell multiomics: a new frontier in drug research and development

Single-cell multiomics (sc-multiomics) is a burgeoning field that simultaneously integrates multiple layers of molecular information, enabling the characterization of dynamic cell states and activities in development and disease as well as treatment response. Studying drug actions and responses using sc-multiomics technologies has revolutionized our understanding of how small molecules intervene for specific cell types in cancer treatment and how they are linked with disease etiology and progression. Here, we summarize recent advances in sc-multiomics technologies that have been adapted and improved in drug research and development, with a focus on genome-wide examination of drug-chromatin engagement and the applications in drug response and the mechanisms of drug resistance. Furthermore, we discuss how state-of-the-art technologies can be taken forward to devise innovative personalized treatment modalities in biomedical research.