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

Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function

Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD

Transitioning from having no metabolic abnormality nor obesity to metabolic impairment in a cohort of apparently healthy adults

Abstract Introduction The global prevalence of metabolic syndrome and its association with increased morbidity and mortality has been rigorously studied. However, the true prevalence of “metabolic health”, i.e. individuals without any metabolic abnormalities is not clear. Here, we sought to determine the prevalence of “metabolically healthy” individuals and characterize the “transition phase” from metabolic health to development of dysfunction over a follow-up period of 5 years. Methods We included 20,507 individuals from the Tel Aviv Sourasky Medical Center Inflammation Survey (TAMCIS) which comprises apparently healthy individuals attending their annual health survey. A second follow-up visit was documented after 4.8 (± 0.6) years. We defined a group of metabolically healthy participants without metabolic abnormalities nor obesity and compared their characteristics and change in biomarkers over time to participants who developed metabolic impairment on their follow-up visit. The intersections of all metabolic syndrome components and elevated high sensitivity C-reactive protein (hs-CRP) were also analyzed. Results A quarter of the cohort (5379 individuals, (26.2%) did not fulfill any metabolic syndrome criteria during their baseline visit. A total of 985 individuals (12.7% of returning participants) developed metabolic criteria over time with hypertension being the most prevalent component to develop among these participants. Individuals that became metabolically impaired over time demonstrated increased overlap between metabolic syndrome criteria and elevated hs-CRP levels. The group that became metabolically impaired over time also presented higher delta values of WBC, RBC, liver biomarkers, and uric acid compared with participants who were consistently metabolically impaired. LDL-C (low-density lipoprotein cholesterol) delta levels were similar. Conclusions Roughly one-quarter of apparently healthy adults are defined as “metabolically healthy” according to current definitions. The transition from health to metabolic dysfunction is accompanied with active inflammation and several non-metabolic syndrome biomarkers. Aggressive screening for these biomarkers, blood pressure and hs-CRP might help identify apparently healthy individuals at increased risk of developing metabolic syndrome over time

Sepsis Related Mortality Associated with an Inflammatory Burst in Patients Admitting to the Department of Internal Medicine with Apparently Normal C-Reactive Protein Concentration

Background: Patients who are admitted to the Department of Internal Medicine with apparently normal C-reactive protein (CRP) concentration impose a special challenge due the assumption that they might not harbor a severe and potentially lethal medical condition. Methods: A retrospective cohort of all patients who were admitted to the Department of Internal Medicine with a CRP concentration of ≤31.9 mg/L and had a second CRP test obtained within the next 24 h. Seven day mortality data were analyzed. Results: Overall, 3504 patients were analyzed with a mean first and second CRP of 8.8 (8.5) and 14.6 (21.6) mg/L, respectively. The seven day mortality increased from 1.8% in the first quartile of the first CRP to 7.5% in the fourth quartile of the first CRP (p < 0.0001) and from 0.6% in the first quartile of the second CRP to 9.5% in the fourth quartile of the second CRP test (p < 0.0001), suggesting a clear relation between the admission CRP and in hospital seven day mortality. Conclusions: An association exists between the quartiles of CRP and 7-day mortality as well as sepsis related cause of death. Furthermore, the CRP values 24 h after hospital admission improved the discrimination

COMMD10 is critical for Kupffer cell survival and controls Ly6C(hi) monocyte differentiation and inflammation in the injured liver

Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6C(hi) monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6C(hi) monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6C(hi) monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6C(hi) monocyte fate decisions and reparative behavior in the diseased liver

Long term metabolic and renal outcomes of kidney donors compared to controls with excellent kidney function

Abstract Background Only few studies of living kidney donors have included controls that were similarly healthy, including excellent kidney function. Methods In this study, we aimed to estimate long term metabolic and renal outcome in a cohort of 211 living donors compared to two control groups: paired-matched controls, and another control group of 2534 healthy individuals with excellent kidney function. Results Donors presented with higher estimated Glomerular Filtration Rate (eGFR): (97.6 ± 15.2 vs 96.1 ± 12.2 vs 94.5 ± 12.4 ml/min/1.73m2) and lower urine albumin to creatinine ratio (UACR) (4.3 ± 5.9 vs 5.9 ± 6.1 vs 6.1 ± 6.9 mg/g) for donors, matched controls and healthy controls, respectively (p <  0.001). In a mean follow up period of 5.5 for donors, donors presented with positive eGFR slopes during the first 3 years post donation, followed by negative slopes, compared to constantly negative slopes presented in the control group (p <  0.05). The variables related to the slope were being a donor, baseline eGFR, Body Mass Index (BMI) and age but not eGFR on the last day of follow-up or increased delta UACR. There was a significant increase in UACR in donors, as well as a higher rate of albuminuria, associated with a longer time since donation, higher pre-donation UACR and higher pre-donation BMI. Healthy controls had a lower BMI at baseline and gained less weight during the follow up period. Donors and controls had similar incidence of new onset diabetes mellitus and hypertension, as well as similar delta systolic and diastolic blood pressure. Donors were more likely to develop new onset metabolic syndrome, even after adjustment for age, gender and BMI. The higher incidence of metabolic syndrome resulted mainly from increased triglycerides and impaired fasting glucose criteria. However, prevalence of major cardiovascular events was not higher in this group. Conclusions Donors are at increased risk to develop features of the metabolic syndrome in addition to the expected mild reduction of GFR and increased urine albumin excretion. Future studies are needed to explore whether addressing those issues will impact post donation morbidity and mortality

Copper Metabolism Domain-Containing 1 Represses Genes That Promote Inflammation and Protects Mice From Colitis and Colitis-Associated Cancer

BACKGROUND & AIMS: Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-kappa B activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings. METHODS: We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-kappa B. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. RESULTS: In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. CONCLUSIONS: Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD