Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound\u2010detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross\u2010sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, 120.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40\u2010ligand (P = 0.0238), soluble Nox2\u2010derived peptide (sNox2\u2010dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD40L (Spearman\u2019s rank correlation coefficient [rs], 120.33; P < 0.001), sNox2\u2010dp (rs, 120.57; P < 0.0001), and urinary excretion of isoprostanes (rs, 120.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2\u2010dp, and urinary 8\u2010iso prostaglandin F2\u3b1\u2010III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2\u2010dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Carotid plaque detection improves the predictive value of CHA2DS2-VASc score in patients with non-valvular atrial fibrillation::The ARAPACIS Study

BACKGROUND AND AIMS: Vascular disease (VD), as assessed by history of myocardial infarction or peripheral artery disease or aortic plaque, increases stroke risk in atrial fibrillation (AF), and is a component of risk assessment using the CHA2DS2-VASc score. We investigated if systemic atherosclerosis as detected by ultrasound carotid plaque (CP) could improve the predictive value of the CHA2DS2-VASc score. METHODS: We analysed data from the ARAPACIS study, an observational study including 2027 Italian patients with non-valvular AF, in whom CP was detected using Doppler Ultrasonography. RESULTS: VD was reported in 351 (17.3%) patients while CP was detected in 16.6% patients. Adding CP to the VD definition leaded to higher VD prevalence (30.9%). During a median [IQR] follow-up time of 36months, 56 (2.8%) stroke/TIA events were recorded. Survival analysis showed that conventional VD alone did not increase the risk of stroke (Log-Rank: 0.009, p=0.924), while addition of CP to conventional VD was significantly associated to an increased risk of stroke (LR: 5.730, p=0.017). Cox regression analysis showed that VD+CP was independently associated with stroke (HR: 1.78, 95% CI: 1.05-3.01, p=0.0318). Reclassification analysis showed that VD+CP allowed a significant risk reclassification when compared to VD alone in predicting stroke at 36months (NRI: 0.192, 95% CI: 0.028-0.323, p=0.032). CONCLUSIONS: In non-valvular AF patients the addition of ultrasound detection of carotid plaque to conventional VD significantly increases the predictive value of CHA2DS2-VASc score for stroke

Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease

OBJECTIVE: The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals. DESIGN: TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed. RESULTS: Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies. CONCLUSIONS: Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD

Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease

BACKGROUND & AIMS: Many patients with inflammatory bowel disease (IBD) fail to respond to anti–tumor necrosis factor (TNF) agents such as infliximab and adalimumab, and etanercept is not effective for treatment of Crohn’s disease. Activated matrix metalloproteinase 3 (MMP3) and MMP12, which are increased in inflamed mucosa of patients with IBD, have a wide range of substrates, including IgG1. TNFneutralizing agents act in inflamed tissues; we investigated the effects of MMP3, MMP12, and mucosal proteins from IBD patients on these drugs. METHODS: Biopsy specimens from inflamed colon of 8 patients with Crohn’s disease and 8 patients with ulcerative colitis, and from normal colon of 8 healthy individuals (controls), were analyzed histologically, or homogenized and proteins were extracted. We also analyzed sera from 29 patients with active Crohn’s disease and 33 patients with active ulcerative colitis who were candidates to receive infliximab treatment. Infliximab, adalimumab, and etanercept were incubated with mucosal homogenates from patients with IBD or activated recombinant human MMP3 or MMP12 and analyzed on immunoblots or in luciferase reporter assays designed to measure TNF activity. IgG cleaved by MMP3 or MMP12 and antihinge autoantibodies against neo-epitopes on cleaved IgG were measured in sera from IBD patients who subsequently responded (clinical remission and complete mucosal healing) or did not respond to infliximab. RESULTS: MMP3 and MMP12 cleaved infliximab, adalimumab, and etanercept, releasing a 32-kilodalton Fc monomer. After MMP degradation, infliximab and adalimumab functioned as F(ab’)2 fragments, whereas cleaved etanercept lost its ability to neutralize TNF. Proteins from the mucosa of patients with IBD reduced the integrity and function of infliximab, adalimumab, and etanercept. TNF-neutralizing function was restored after incubation of the drugs with MMP inhibitors. Serum levels of endogenous IgG cleaved by MMP3 and MMP12, and antihinge autoantibodies against neo-epitopes of cleaved IgG, were higher in patients who did not respond to treatment vs responders. CONCLUSIONS: Proteolytic degradation may contribute to the nonresponsiveness of patients with IBD to anti-TNF agents

Relationship between low Ankle-Brachial Index and rapid renal function decline in patients with atrial fibrillation: A prospective multicentre cohort study

OBJECTIVE: To investigate the relationship between Ankle-Brachial Index (ABI) and renal function progression in patients with atrial fibrillation (AF). DESIGN: Observational prospective multicentre cohort study. SETTING:Atherothrombosis Center of I Clinica Medica of 'Sapienza' University of Rome; Department of Medical and Surgical Sciences of University Magna Græcia of Catanzaro; Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study. PARTICIPANTS: 897 AF patients on treatment with vitamin K antagonists. MAIN OUTCOME MEASURES: The relationship between basal ABI and renal function progression, assessed by the estimated Glomerular Filtration Rate (eGFR) calculated with the CKD-EPI formula at baseline and after 2 years of follow-up. The rapid decline in eGFR, defined as a decline in eGFR >5 mL/min/1.73 m(2)/year, and incident eGFR<60 mL/min/1.73 m(2) were primary and secondary end points, respectively. RESULTS: Mean age was 71.8±9.0 years and 41.8% were women. Low ABI (ie, ≤0.90) was present in 194 (21.6%) patients. Baseline median eGFR was 72.7 mL/min/1.73 m(2), and 28.7% patients had an eGFR60 mL/min/1.73 m(2), 153 (23.9%) had a reduction of the eGFR <60 mL/min/1.73 m(2). ABI ≤0.90 was also an independent predictor for incident eGFR<60 mL/min/1.73 m(2) (HR 1.851, 95% CI 1.205 to 2.845, p=0.005). CONCLUSIONS: In patients with AF, an ABI ≤0.90 is independently associated with a rapid decline in renal function and incident eGFR<60 mL/min/1.73 m(2). ABI measurement may help identify patients with AF at risk of renal function deterioration

Pain and Frailty in Hospitalized Older Adults

Introduction: Pain and frailty are prevalent conditions in the older population. Many chronic diseases are likely involved in their origin, and both have a negative impact on quality of life. However, few studies have analysed their association. Methods: In light of this knowledge gap, 3577 acutely hospitalized patients 65&nbsp;years or older enrolled in the REPOSI register, an Italian network of internal medicine and geriatric hospital wards, were assessed to calculate the frailty index (FI). The impact of pain and some of its characteristics on the degree of frailty was evaluated using an ordinal logistic regression model after adjusting for age and gender. Results: The prevalence of pain was 24.7%, and among patients with pain, 42.9% was regarded as chronic pain. Chronic pain was associated with severe frailty (OR = 1.69, 95% CI 1.38–2.07). Somatic pain (OR = 1.59, 95% CI 1.23–2.07) and widespread pain (OR = 1.60, 95% CI 0.93–2.78) were associated with frailty. Osteoarthritis was the most common cause of chronic pain, diagnosed in 157 patients (33.5%). Polymyalgia, rheumatoid arthritis and other musculoskeletal diseases causing chronic pain were associated with a lower degree of frailty than osteoarthritis (OR = 0.49, 95%CI 0.28–0.85). Conclusions: Chronic and somatic pain negatively affect the degree of frailty. The duration and type of pain, as well as the underlying diseases associated with chronic pain, should be evaluated to improve the hospital management of frail older people

The multifaceted spectrum of liver cirrhosis in older hospitalised patients: Analysis of the REPOSI registry

Background: Knowledge on the main clinical and prognostic characteristics of older multimorbid subjects with liver cirrhosis (LC) admitted to acute medical wards is scarce. Objectives: To estimate the prevalence of LC among older patients admitted to acute medical wards and to assess the main clinical characteristics of LC along with its association with major clinical outcomes and to explore the possibility that well-distinguished phenotypic profiles of LC have classificatory and prognostic properties. Methods: A cohort of 6,193 older subjects hospitalised between 2010 and 2018 and included in the REPOSI registry was analysed. Results: LC was diagnosed in 315 patients (5%). LC was associated with rehospitalisation (age-sex adjusted hazard ratio, [aHR] 1.44; 95% CI, 1.10-1.88) and with mortality after discharge, independently of all confounders (multiple aHR, 2.1; 95% CI, 1.37-3.22), but not with in-hospital mortality and incident disability. Three main clinical phenotypes of LC patients were recognised: relatively fit subjects (FIT, N = 150), subjects characterised by poor social support (PSS, N = 89) and, finally, subjects with disability and multimorbidity (D&amp;M, N = 76). PSS subjects had an increased incident disability (35% vs 13%, P &lt; 0.05) compared to FIT. D&amp;M patients had a higher mortality (in-hospital: 12% vs 3%/1%, P &lt; 0.01; post-discharge: 41% vs 12%/15%, P &lt; 0.01) and less rehospitalisation (10% vs 32%/34%, P &lt; 0.01) compared to PSS and FIT. Conclusions: LC has a relatively low prevalence in older hospitalised subjects but, when present, accounts for worse post-discharge outcomes. Phenotypic analysis unravelled the heterogeneity of LC older population and the association of selected phenotypes with different clinical and prognostic features

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P &lt; 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P &lt; 0.001), sNox2-dp (r(s), -0.57; P &lt; 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P &lt; 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation