Analyzing Non-Alcoholic Fatty Liver Disease Risk Using Time-Series Model

Non-alcoholic fatty liver disease (NAFLD) is the most global frequent liver disease, with a prevalence of almost 20% in the overall population. NAFLD may progress to fibrosis and later into cirrhosis in addition to other diseases. Our objective is to stratify patients\u27 risks for NAFLD and advanced fibrosis over time and suggest preventive medical decisions. We used a cohort of individuals from the Tel-Aviv medical center. Time-series clustering machine learning model (Hidden Markov Models (HMM)) was used to profile fibrosis risk by modeling patients’ latent medical status and trajectories over time. The best-fitting model had three latent HMM states. Initial results show that tracking individuals over time and their relative risk for fibrosis at each point of time provides significant clinical insights regarding each state (and its group of individuals). Thus, longitudinal risk stratification can enable the early identification of specific individual groups following distinct medical trajectories based on their routine visits

Total serum cholinesterase activity predicts hemodynamic changes during exercise and associates with cardiac troponin detection in a sex-dependent manner.

BACKGROUND: Imbalanced autonomic nervous system (ANS) activity is associated with poor cardiovascular outcome. However, clinically validated biomarkers to assess parasympathetic function are not yet available. We sought to evaluate parasympathetic dysfunction by measuring serum cholinesterase activity and to determine its relationship to high sensitive cardiac troponin T (hs-cTnT) as well as traditional non-invasive parameters of ANS function during exercise in apparently healthy individuals. METHODS: We enrolled 1526 individuals (mean age 49 ± 11 yr., 75% men) from the Tel Aviv Medical Center Inflammation Survey (TAMCIS). We used the acetylcholine (ACh) analog acetylthiocholine (ATCh) as a substrate that is hydrolyzed by both ACh degrading enzymes and reflects the total serum capacity for acetylcholine hydrolysis, referred to as cholinergic status (CS). All subjects performed a cardiac stress test reviewed on the spot by a cardiologist and multiple physiological and metabolic parameters including hs-cTnT were measured. RESULTS: CS values at rest predicted multiple exercise-hemodynamic changes. Heart rate recovery after exercise was inversely correlated to CS values (p  5 ng/L) presented with elevated CS levels compared to women with undetectable levels; 1423 ± 272.5 vs 1347 ± 297.9 (p = 0.02). An opposite trend was observed in men. Metabolic dysfunction parameters were also associated with CS elevation in both men and women. CONCLUSIONS: Parasympathetic dysfunction assessed by total serum cholinesterase activity predicts hemodynamic changes during exercise. CS is also associated with hs-cTnT detection in women and inversely so in men. Future studies to assess the potential clinical use of this new sex-specific biomarker in cardiovascular disease risk stratification are warranted

Deletion of Cdk5 in macrophages ameliorates anti-inflammatory response during endotoxemia through induction of C-Maf and Il-10

Immune response control is critical as excessive cytokine production can be detrimental and damage the host. Interleukin-10 (Il-10), an anti-inflammatory cytokine produced primarily by macrophages, is a key regulator that counteracts and controls excessive inflammatory response. Il-10 expression is regulated through the transcription factor c-Maf. Another regulator of Il-10 production is p35, an activator of the cyclin-dependent kinase 5 (Cdk5), which decreases Il-10 production in macrophages, thus increasing inflammation. However, Cdk5 regulation of c-Maf and the involvement of Il-10 production in macrophages has not yet been investigated. We used in vitro primary bone marrow-derived macrophages (BMDMs) lacking Cdk5, stimulated them with lipopolysaccharid (LPS) and observed increased levels of c-Maf and Il-10. In an in vivo mouse model of LPS-induced endotoxemia, mice lacking Cdk5 in macrophages showed increased levels of c-Maf and elevated levels of Il-10 in lungs as well as in plasma, resulting in ameliorated survival. Taken together, we identified Cdk5 as a potential novel regulator of Il-10 production through c-Maf in macrophages under inflammatory conditions. Our results suggest that inhibition of Cdk5 enhances the c-Maf-Il-10 axis and thus potentiates improvement of anti-inflammatory therapy

Age-Dependent Biomarkers for Prediction of In-Hospital Mortality in COVID-19 Patients

Background: Several biomarkers and models have been proposed to predict in-hospital mortality among COVID-19 patients. However, these studies have not examined the association in sub-populations. The present study aimed to identify the association between the two most common inflammatory biomarkers in the emergency department and in-hospital mortality in subgroups of patients. Methods: A historical cohort study of adult patients who were admitted to acute-care hospital between March and December 2020 and had a diagnosis of COVID-19 infection. Data on age, sex, Charlson comorbidity index, white blood cell (WBC) count, C-reactive protein (CRP), and in-hospital mortality were collected. Discrimination ability of each biomarker was observed and the CHAID method was used to identify the association in subgroups of patients. Results: Overall, 762 patients (median age 70.9 years, 59.7% males) were included in the study. Of them, 25.1% died during hospitalization. In-hospital mortality was associated with higher CRP (median 138 mg/L vs. 85 mg/L, p < 0.001), higher WBC count (median 8.5 vs. 6.6 K/µL, p < 0.001), and higher neutrophil-to-lymphocyte ratio (NLR) (median 9.2 vs. 5.4, p < 0.001). The area under the ROC curve was similar among all biomarkers (WBC 0.643, NLR 0.677, CRP 0.646, p > 0.1 for all comparisons). The CHAID method revealed that WBC count was associated with in-hospital mortality in patients aged 43.1–66.0 years (<11 K/µL: 10.1% vs. 11+ K/µL: 27.9%), NLR in patients aged 66.1–80 years (≤8: 15.7%, >8: 43.3%), and CRP in patients aged 80.1+ years (≤47 mg/L: 18.8%, 47.1–149 mg/L: 43.1%, and 149.1+: 71.7% mortality). Conclusions: WBC, NLR, and CRP present similar discrimination abilities. However, each biomarker should be considered as a predictor for in-hospital mortality in different age groups

Leukoaraiosis Is a Chronic Atherosclerotic Disease

Background and Purpose. White matter changes (WMCs), or leukoaraiosis (LA), are associated with increased age, hypertension, diabetes mellitus, and history of stroke. Although several lines of evidence suggest a role of atherosclerosis in atherothrombotic vascular events, their involvement in LA remains to be determined. Our study examines this association in ischemic stroke patients. Methods. One hundred and seventy consecutive ischemic stroke or transient ischemic attack (TIA) patients were included. All patients underwent brain computed tomography (CT) with assessment of the extension and severity of WMCs, carotid arteries duplex scan with measurements of intima-media thickness (IMT) and plaques. Results. Seventy-two patients (42.4%) were found to have white matter lesions, of whom 28.8% had advanced LA. Mean IMT was significantly higher in patients with LA and with advanced LA (P=0.002, P=0.003, resp.). In addition, LA and LA severity were associated with existence of carotid plaque (P=0.007, P=0.004, resp.). In multivariate logistic regression analysis, including all vascular risk factors, LA was found to be associated with age and IMT. Conclusion. This study reinforces the tight association between LA and carotid atherosclerosis in ischemic stroke patients. We conclude that a chronic atherosclerotic disease underlies the pathophysiology of leukoaraiosis and its progression