Clinical, Pathological Characteristics and Progression of Urothelial Bladder Cancer in Young Adult Patients. Our Experience and Literature Review.

BACKGROUND: Bladder cancer is highly prevalent even though its incidence is considerably lower in patients younger than 40 years, thus raising the issue of the influence of age at diagnosis on the natural history of this disease. This study aimed to evaluate the characteristics and progression of young patients with urothelial bladder carcinoma with at least 10 years of follow-up and to compare the results with those of previously reported studies. MATERIAL AND METHODS: A retrospective study between 1990 and 2007 was conducted. The medical records and tissue samples of patients with urothelial bladder tumours were reviewed, and patients with a first diagnosis of urothelial carcinoma of the bladder at age 40 years or younger were selected. Their clinical and pathological data and disease-free survival were analysed. RESULTS: This study included 43 patients, with a median follow-up of 152 months (interquartile range (IQR): 96-222) and a mean age at diagnosis of 34 years (SD: 4.6). Thirty-five patients (81.4%) had non-muscle invasive tumours at diagnosis, and 53.5%, 27.9% and 18.6% had tumour grades of G1, G2 and G3, respectively. Fifteen patients (34.9%) experienced recurrence, and eight (18.6%) progressed. At 24 and 60 months, the recurrence-free survival rates were 84.8% (95% confidence interval (CI): 69.2%-92.9%) and 68.9% (95% CI: 51.7%-81%), respectively, and the progression-free survival rates were 94.9% (95% CI: 81%-98.7%) and 92.2% (95% CI: 77.8%-97.4%), respectively. CONCLUSIONS: Bladder cancer is an uncommon disease in young patients. In most cases, it consists of non-muscle-invasive tumours, with a low rate of recurrence and progression. The prognosis is based on the tumour's characteristics and not on the patient's age.

Executive Summary of the Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR) Spanish Society of Emergency and Emergency Medicine (SEMES) and Spanish Society of Otolaryngology, Head and Neck Surgery (SEORL-CCC) Guideline for difficult airway management.

The Airway section of the Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR), Spanish Society of Emergency and Emergency Medicine (SEMES) and Spanish Society of Otolaryngology, Head and Neck Surgery (SEORL-CCC) present the Guidelines for the integral management of difficult airway in adult patients. This document provides recommendations based on current scientific evidence, theoretical-educational tools and implementation tools, mainly cognitive aids, applicable to the treatment of the airway in the field of anesthesiology, critical care, emergencies and prehospital medicine. Its principles are focused on the human factors, cognitive processes for decision-making in critical situations and optimization in the progression of the application of strategies to preserve adequate alveolar oxygenation in order to improve safety and quality of care.

Dynamic versus standard bougies for tracheal intubation with direct or indirect laryngoscopy in simulated or real scenarios: a systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to compare the efficacy of dynamic versus standard bougies to achieve tracheal intubation. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, Scopus and Google Scholar on 10 October 2023. We included clinical trials comparing both devices. The primary outcome was the first-attempt intubation success rate. The secondary outcome was the time required for tracheal intubation. RESULTS: Eighteen studies were included. Dynamic bougies do not increase first-attempt success rate (RR 1.11; p = 0.06) or shorten tracheal intubation time (MD -0.30 sec; p = 0.84) in clinical trials in humans. In difficult airways, first-attempt success intubation rate was greater for dynamic bougies (RR 1.17; p = 0.002); Additionally, they reduced the time required for intubation (MD -4.80 sec; p = 0.001). First-attempt intubation success rate was higher (RR 1.15; p = 0.01) and time to achieve intubation was shorter when using Macintosh blades combined with dynamic bougies (MD -5.38 sec; p < 0.00001). Heterogeneity was high. CONCLUSION: Dynamic bougies do not increase the overall first-pass success rate or shorten tracheal intubation time. However, dynamic bougies seem to improve first-attempt tracheal intubation rate in patients with difficult airways and in those intubated with a Macintosh blade. Further research is needed for definitive conclusions. REGISTRATION OF PROSPERO: CRD42023472122.

The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis.

BACKGROUND: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. OBJECTIVE: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. METHODS: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2-5; (c) cholestatic pattern(C), < 2. OUTCOMES: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. RESULTS: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69-0.79) vs. 0.83 (95% CI 0.80-0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69-0.85) vs. 0.84 (95% CI 0.80-0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12-5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. CONCLUSIONS: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.

Telomerase Reverse Transcriptase-Promoter Mutation in Young Patients with Bladder Tumors.

The TERT (Telomerase Reverse Transcriptase) gene promoter mutation is one of the most prevalent mutations in urothelial bladder tumors and this mutation is related to bladder tumor progression. Our purpose was to evaluate the presence of this mutation in a population of patients who were first diagnosed at age ≤ 40 years and to examine its relationship with tumor characteristics and progression. A molecular study was performed to detect the two most prevalent mutations in the TERT promoter (C228T and C250T). The study included 29 patients, with a mean follow-up of 152 months. There were no statistically significant differences in the clinical or tumor characteristics according to the presence or absence of the mutation. Although the mutation group showed poorer recurrence-free survival (RFS), there was no statistically significant difference and there was no difference in progression-free survival by group (p > 0.05). The pTERT mutations in bladder tumor cells occurred less frequently in younger patients than in older patients, a finding that could indicate different mechanisms of carcinogenesis. The trend towards lower RFS in patients with mutated pTERT needs to be confirmed by further studies, given the small number of patients included in these studies due to the low incidence of bladder tumors in this age group.

Cirrhosis-downregulated LSECtin can be retrieved by cytokines, shifts the TLR-induced LSECs secretome and correlates with the hepatic Th response.

BACKGROUND AND AIMS: We evaluated tolerogenic C-type lectin LSECtin loss in cirrhosis and its potential regulation by cytokines. METHODS: Liver tissue from patients with cirrhosis and healthy controls, immortalised and generated LSECtin-CRISPR immortalised LSECs, and murine primary LSECs from the CCl4 model were handled. RESULTS: LSECtin expression was reduced in liver tissue from cirrhotic patients, and it decreased from compensated to decompensated disease. Increased phosphorylation of MAPK, Akt and NFkB was observed upon LSECtin stimulation in LSEC murine cell line, showing a pattern of inflammatory and chemotactic cytokines either restrained (IL-10, CCL4) or unrestrained (TNF-α, IL-1ß, IL-6, CCL2). CD44 attenuated whereas LAG-3 increased all substrates phosphorylation in combination with TLR4 and TLR2 ligands except for NFkB. TNF-α, IL-1 ß, IL-6 and CCL2 were restrained by LSECtin crosslinking on TLRs studied. Conversely, IL-10 and CCL4 were upregulated, suggesting a LSECtin-TLRs synergistic effect. Also, LSECtin was significantly induced after IL-13 stimulation or combined with anti-inflammatory cytokines in cirrhotic and immortalised LSECs. Th17 and regulatory T cells were progressively increased in the hepatic tissue from compensated to decompensated patients. A significant inverse correlation was present between gene expression levels of CLEC4G/LSECtin and RORγT and FOXP3 in liver tissues. CONCLUSION: LSECtin restrains TLR proinflammatory secretome induced on LSECs by interfering immune response control, survival and MAPKs signalling pathways. The cytokine-dependent induction of LSECtin and the association between LSECtin loss and Th17 cell subset expansion in the liver, provides a solid background for exploring LSECtin retrieval as a mechanism to reprogram LSEC homeostatic function hampered during cirrhosis.

An altered expression of miR-376a-3p and miR-20a-5p in peripheral blood exosomes regulates the autophagy and inflammatory systemic substrates, and relates to the smoking habit and age in Crohn's disease.

miRNAs are short single-stranded noncoding RNAs that participate as epigenetic regulators in inflammatory bowel disease. Most miRNAs detectable in serum are concentrated in exosomes, with relevant cargo for immunobiological processes. We set to evaluate the exosomes miRNAs content in the serum of patients with Crohn's disease (CD) and run a prospective observational study on CD patients on biological monotherapy and healthy controls. miRNA cargo was evaluated in peripheral blood-derived exosomes. Serum autophagy and inflammatory substrates were measured. Patients were followed for 6 months. Patients (n = 28) showed an overexpression of miR-376a-3p and a downregulation of miR-20a-5p compared to controls (n = 10), without significant differences between patients according to biologics. Serum autophagy substrates ATG4C (r = .57; p = .001) and ACRV1C (r = .66; p = .001) inversely correlated with miR-376a-3p expression, whereas IGF1R correlated with miR-20a-5p expression (r = .42; p = .02). Th1-related cytokines correlated with miR-376a-3p expression, whereas the Th17-associated cytokines inversely correlated with miR-20a-5p expression. Smoking (ß = -2.301 CI 95% -3.790/-0.811, p = .004) remained as independent factor related to the overexpression of miR-376a-3p, whereas diagnosis before 16 years of age (ß = 2.044 CI 95% 0.934/3.154, p = .001) and a younger age of patients (ß = -.720 CI 95% -0.108/-0.035, p = .001) were related to decreased miR-20a-5p expression. Seven patients (25%) had a flare in the 6-month follow-up. Patients with overexpression of miR-376a-3p at the baseline showed an increased risk of flare during this period (OR 0.475 [0.237-0.950], p = .035). Finally, a comparative miRNA signature between biologic monotherapies was also explored. Targeting miR-376a-3p and miR-20a-5p epigenetic regulators may yield homeostatic effects on relevant biological processes related to disease progression in CD patients.

Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.

Immune changes over time and survival in patients with cirrhosis treated with non-selective beta-blockers: A prospective longitudinal study.

BACKGROUND: Treatment with non-selective beta-blockers (NSBB) has been associated with anti-inflammatory and anti-cancer effects in patients with cirrhosis. This study aims to analyze the impact of chronic NSBB treatment on immune activation and disease progression in stable outpatients with cirrhosis. METHODS: In this prospective follow-up of 150 patients with cirrhosis, 39 received treatment with NSBB. Blood samples were taken every 6-9 months, and immune and adrenergic variables were measured. Mixed linear models were used to assess the effect of NSBB on these variables over time. Multivariate Cox regression was used to study associations with adverse clinical events (hepatocellular carcinoma, death, or liver transplant). RESULTS: Median follow-up was 1635 days. NSBB treatment was associated with significantly lower levels of IL-6 (ß - 4.7; 95% confidence interval [CI] -6.9, -2.6) throughout the study. During follow-up, 11 patients developed hepatocellular carcinoma, 32 died, and 4 underwent liver transplant. Patients with higher concentrations of IL-10, IL-6 and IFN-γ developed more clinical events. Event-free survival was significantly better in patients treated with NSBB (hazard ratio 0.36, 95% CI 0.18, 0.71) in a multivariate Cox regression adjusted for Child-Pugh-Score, esophageal varices, and platelets. CONCLUSION: Chronic treatment with NSBB in patients with stable cirrhosis gives rise to a different state of immune activation, characterized by lower concentrations of IL-6 over time, and it is associated with a reduced risk of adverse event (death, hepatocellular carcinoma, or transplant), after controlling for disease severity.

Bacterial translocation occurs early in cirrhosis and triggers a selective inflammatory response.

BACKGROUND: Experimental data suggest that bacterial translocation (BT) promotes systemic inflammation, portal hypertension, and circulatory dysfunction in advanced chronic liver disease (ACLD). METHODS: Patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement and absence of acute decompensation or infections were included (n = 249). Serum biomarkers of BT (lipopolysaccharide [LPS], lipoteichoic acid [LTA], bacterial DNA [bactDNA]), systemic inflammation and markers of circulatory dysfunction were assessed. T-cell subsets in intestinal biopsies (n = 7 ACLD, n = 4 controls) were analyzed by flow cytometry. RESULTS: Patients had a median HVPG of 18 (12-21) mmHg and 56% had decompensated ACLD. LPS (0.04 [0.02-0.06] vs. 0.64 [0.30-1.06] EU/mL), LTA (4.53 [3.58-5.97] vs. 43.2 [23.2-109] pg/mL), and detection of bactDNA (≥ 5 pg/mL; 5% vs. 41%) were markedly higher in patients with ACLD than healthy controls (n = 40; p < 0.001) but were similar between different clinical stages of compensated and decompensated ACLD and displayed no meaningful correlation with HVPG and systemic hemodynamics. TNF-α and IL-10 correlated with LPS (Spearman's rs = 0.523, p < 0.001/rs = 0.143, p = 0.024) but not with LTA. Presence of bactDNA was associated with higher LPS (0.54 [0.28-0.95] vs. 0.88 [0.32-1.31] EU/mL, p = 0.001) and TNF-α (15.3 [6.31-28.1] vs. 20.9 [13.8-32.9] pg/mL). Patients with ACLD exhibited a decreased CD4:CD8-ratio and increased TH1-cells in the intestinal mucosa as compared to controls. During a median FU of 14.7 (8.20-26.5) months, bacterial antigens did not predict decompensation or liver-related death (in contrast to HVPG, IL-6, and MAP) as well as infections at 24 months. CONCLUSION: BT occurs already in early ACLD stages and triggers a systemic inflammatory response via TNF-α and IL-10. Interestingly, BT markers showed no clear correlation with portal hypertension and circulatory dysfunction in patients with stable ACLD. CLINICAL TRIAL NUMBER: NCT03267615.

Implementation of an ERAS program in patients undergoing thoracic surgery at a third-level university hospital: an ambispective cohort study

Abstract Objective To analyze the effects of an ERAS program on complication rates, readmission, and length of stay in patients undergoing pulmonary resection in a tertiary university hospital. Methods Ambispective cohort study with a prospective arm of 50 patients undergoing thoracic surgery within an ERAS program (ERAS group) versus a retrospective arm of 50 patients undergoing surgery before the protocol was implemented (Standard group). The primary outcome was the number of patients with 30-day surgical complications. Secondary outcomes included ERAS adherence, non-surgical complications, mortality, readmission, reintervention rate, pain, and hospital length of stay. We performed a multivariate logistic analysis to study the correlation between outcomes and ERAS adherence. Results In the univariate analysis, we found no difference between the two groups in terms of surgical complications (Standard 18 [36%] vs. ERAS 12 [24%], p = 0.19). In the ERAS group, only the readmission rate was significantly lower (Standard 15 [30%] vs. ERAS 6 [12%], p = 0.03). In the multivariate analysis, ERAS adherence was the only factor associated with a reduction in surgical complications (OR [95% CI] = 0.02 [0.00, 0.59], p = 0.03) and length of stay (HR [95% CI] = 18.5 [4.39, 78.4], p < 0.001). Conclusions The ERAS program significantly reduced the readmission rate at our hospital. Adherence to the ERAS protocol reduced surgical complications and length of stay.

Metabolic-associated fatty liver disease: From simple steatosis toward liver cirrhosis and potential complications. Proceedings of the Third Translational Hepatology Meeting, organized by the Spanish Association for the Study of the Liver (AEEH).

This is a meeting report of the 3rd Translational Hepatology Meeting held in Alicante, Spain, in October 2021. The meeting, which was organized by the Spanish Association for the Study of the Liver (AEEH), provided an update on the recent advances in the field of basic and translational hepatology, with a particular focus on the molecular and cellular mechanisms and therapeutic targets involved in metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), cirrhosis and end-stage hepatocellular carcinoma (HCC).

Absent in Melanoma 2 (AIM2) Regulates the Stability of Regulatory T Cells.

Absent in melanoma 2 (AIM2) is a cytosolic dsDNA sensor that has been broadly studied for its role in inflammasome assembly. However, little is known about the function of AIM2 in adaptive immune cells. The purpose of this study was to investigate whether AIM2 has a cell-intrinsic role in CD4+ T cell differentiation or function. We found that AIM2 is expressed in both human and mouse CD4+ T cells and that its expression is affected by T cell receptor (TCR) activation. Naïve CD4+ T cells from AIM2-deficient (Aim2-/-) mice showed higher ability to maintain forkhead box P3 (FOXP3) expression in vitro, while their capacity to differentiate into T helper (Th)1, Th2 or Th17 cells remained unaltered. Transcriptional profiling by RNA sequencing showed that AIM2 might affect regulatory T cell (Treg) stability not by controlling the expression of Treg signature genes, but through the regulation of the cell's metabolism. In addition, in a T cell transfer model of colitis, Aim2-/--naïve T cells induced less severe body weight loss and displayed a higher ability to differentiate into FOXP3+ cells in vivo. In conclusion, we show that AIM2 function is not confined to innate immune cells but is also important in CD4+ T cells. Our data identify AIM2 as a regulator of FOXP3+ Treg cell differentiation and as a potential intervention target for restoring T cell homeostasis.

Wound Infusion of 0.35% Levobupivacaine Reduces Mechanical Secondary Hyperalgesia and Opioid Consumption After Cesarean Delivery: A Prospective, Randomized, Triple-Blind, Placebo-Controlled Trial.

BACKGROUND: Some patients still report moderate-to-severe postoperative pain after cesarean delivery. Local anesthetic wound infusion improves acute pain and might act on peripheral and central sensitization mechanisms; however, no studies have proved this hypothesis. We evaluated the potential benefits of continuous wound infusion of levobupivacaine after cesarean delivery on secondary hyperalgesia (primary end point) and primary hyperalgesia, pain relief, persistent pain, and inflammatory and metabolic stress response. METHODS: Healthy women scheduled for elective cesarean delivery participated in this prospective, randomized, triple-blind, placebo-controlled trial (NCT01458431). All patients received spinal anesthesia with 0.5% hyperbaric bupivacaine with fentanyl and a multiholed wound catheter placed under the fascia. Women were randomized to receive continuous wound infusion (0.35% levobupivacaine 7 mL/h for 48 hours; group L) or an equal volume of saline (group S). Secondary hyperalgesia to punctate mechanical stimuli was evaluated using dynamic tests, and primary hyperalgesia was evaluated using an electronic von Frey anesthesiometer; both were assessed at 24, 48, and 72 hours. The following variables were collected: intensity of postoperative parietal and visceral pain at rest and on movement rated on a visual analog scale >72 hours, time to first bolus of patient-controlled analgesia (PCA), cumulative dose of rescue morphine (PCA) and acetaminophen, ability to sleep and sleep quality, and patient satisfaction. Persistent postoperative pain was evaluated during a telephone interview at 1, 3, 6, and 12 months after surgery. C-reactive protein, acid glycoprotein, preprandial glucose, insulin, cortisol, prolactin, growth hormone, and interleukin-6 were measured before cesarean delivery and at 8, 24, and 48 hours. Adverse events and patient outcomes were recorded. RESULTS: Seventy women were included. In group L, the area of secondary hyperalgesia was significantly reduced (43.4 [18.5-80] vs 68.4 [39.0-136] cm2 and 45.1 [0.9-89.8] vs 67.3 [31.3-175] cm2 at 24 and 48 hours, respectively; group:time interaction P value < .001), the mechanical pain threshold was significantly higher at 24 hours (633 [441-802] vs 417 [300-572] g.mm-2; P = .001), and morphine consumption was significantly lower at 24 hours (4 [2-11] vs 11[6-23]; P = .003) compared with group S. Levobupivacaine had no effect on persistent postoperative pain at 1, 3, 6, and 12 months. Plasma insulin levels in the immediate postoperative period and at 8, 24, and 48 hours were significantly lower in group L (P < .001). There were no significant differences in other biochemical parameters of inflammatory and endocrine-metabolic response. CONCLUSIONS: Levobupivacaine wound infusion provides adequate analgesia and might be an effective antihyperalgesic adjunct.

Transcriptional regulation of chemokine network by biologic monotherapy in ileum of patients with Crohn's disease.

BACKGROUND: Crohn's disease (CD) exacerbation is marked by an intense cellular trafficking. We set out to determine the specific impact of biologic therapies on regulating chemokine network gene expression in healthy, mildly and severely inflamed tissue of CD patients. METHODS: Twenty CD patients on biologics (adalimumab, ustekinumab, vedolizumab) or untreated undergoing colonoscopy due to clinical symptoms of flare. Healthy, mildly and severely inflamed ileum biopsies from each patient were collected. Chemokines and receptors gene expression was analyzed and a STRING analysis for functional enrichment was performed. RESULTS: The chemokine network exhibited wide transcriptional differences among tissues in active untreated patients, whereas all biologic treatments reduced these differences and homogenized their transcriptional activity. In mildly inflamed tissue, all treatments showed gene upregulation while ustekinumab additionally maintained the downregulation of genes such as CCL2, CCL3, CCL17 or CCL23, involved in T cell chemotaxis, inflammatory monocyte and NK trafficking. In severely inflamed tissue, all treatments shared a downregulatory effect on chemokines controlling T cell response (i.e. CXCL16, CXCR3). Adalimumab and vedolizumab significantly reduced the expression of genes promoting antigen presentation by DCs and the initiation of leukocyte extravasation (i.e. CXCL12, CCL25, CCR7). Ustekinumab significantly reduced genes positively regulating Th1 cytokine production and IL-8 mediated signaling (i.e. IL1B, XCL1, CXCR1, CXCR2). CONCLUSION: Biologic therapies differentially target the chemokine network gene expression profile in the ileal tissue of active CD patients. These results may contribute to better understanding cell homing and to defining future personalized therapeutic strategies for CD patients.

Dysbiotic microbiota interactions in Crohn's disease.

Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. The purpose of this review is to delve into the modification of the gut microbiota cluster network during CD progression and to discuss how this shift compromises the gut barrier integrity, granting the translocation of microbes and their products. We then complete the scope of the review by retracing gut microbiota dysbiosis interactions with the main pathophysiologic factors of CD, starting from the host's genetic background to the immune inflammatory and fibrotic processes, providing a standpoint on the lifestyle/exogenous factors and the potential benefits of targeting a specific gut microbiota.

Endocrine disruption in Crohn's disease: Bisphenol A enhances systemic inflammatory response in patients with gut barrier translocation of dysbiotic microbiota products.

The relevance of environmental triggers in Crohn's disease remains poorly explored, despite the well-known association between industrialization and disease onset/progression. We have aimed at evaluating the influence of endocrine disrupting chemicals in CD patients. We performed a prospective observational study on consecutive patients diagnosed of CD. Serum levels of endocrine disruptors, short-chain fatty acids, tryptophan and cytokines were measured. Bacterial-DNA and serum endotoxin levels were also evaluated. Gene expression of ER-α, ER-ß and GPER was measured in PBMCs. All patients were genotyped for NOD2 and ATG16L1 polymorphisms. A series of 200 CD patients (140 in remission, 60 with active disease) was included in the study. Bisphenol A was significantly higher in patients with active disease versus remission and in colonic versus ileal disease. GPER was significantly increased in active patients and correlated with BPA levels. BPA was significantly increased in patients with bacterial-DNA and correlated with serum endotoxin levels, (r = 0.417; P = .003). Serum butyrate and tryptophan levels were significantly lower in patients with bacterial-DNA and an inverse relationship was present between them and BPA levels (r = -0.491; P = .001) (r = -0.611; P = .001). Serum BPA levels correlated with IL-23 (r = 0.807; P = .001) and IL-17A (r = 0.743; P = .001). The multivariate analysis revealed an independent significant contribution of BPA and bacterial-DNA to serum levels of IL-23 and IL-17A. In conclusion, bisphenol A significantly affects systemic inflammatory response in CD patients with gut barrier disruption and dysbiotic microbiota secretory products in blood. These results provide evidence of an endocrine disruptor playing an actual pathogenic role on CD.

Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors.

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of chronic liver disease in the Western world, probably due to the growing prevalence of obesity, metabolic diseases, and exposure to some environmental agents. In certain patients, simple hepatic steatosis can progress to non-alcoholic steatohepatitis (NASH), which can sometimes lead to liver cirrhosis and its complications including hepatocellular carcinoma. Understanding the mechanisms that cause the progression of NAFLD to NASH is crucial to be able to control the advancement of the disease. The main hypothesis considers that it is due to multiple factors that act together on genetically predisposed subjects to suffer from NAFLD including insulin resistance, nutritional factors, gut microbiota, and genetic and epigenetic factors. In this article, we will discuss the epidemiology of NAFLD, and we overview several topics that influence the development of the disease from simple steatosis to liver cirrhosis and its possible complications.

Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.

BACKGROUND AND AIM: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD). METHODS: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years). RESULTS: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. CONCLUSIONS: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.

Non-alcoholic fatty liver disease is associated with bacterial translocation and a higher inflammation response in psoriatic patients.

Psoriasis and non-alcoholic fatty liver disease (NAFLD) are both inflammatory diseases. The study objective was to estimate the risk of NAFLD, non-alcoholic steatohepatitis, and liver fibrosis (by liver stiffness and liver biopsy) in patients with psoriasis and to determine the epidemiological, clinical, immunological (TNF-α, IL-2, IL-6, IL-12, IL-17, IL-23, and TGF-ß) characteristics, and bacterial translocation. Of the 215 psoriatic patients included, 91 presented NAFLD (prevalence: 42.3%). Compared to patients with psoriasis alone, those with NAFLD were significantly more likely to have metabolic syndrome, diabetes, dyslipidemia, body mass index ≥ 30 kg/m2, homeostatic model assessment of insulin resistance ≥ 2.15, and greater psoriasis area severity index. NAFLD patients also had significantly higher levels of TNF-α (p = 0.002) and TGF-ß (p = 0.007) and a higher prevalence of bacterial translocation (29.7% vs. 13.7%; p = 0.004). Liver stiffness measurement was over 7.8 kPa in 17.2% (15/87) of NAFLD patients; 13 of these underwent liver biopsy, and 5.7% (5/87) had liver fibrosis, while 1.1% (1/87) had advanced fibrosis or non-alcoholic steatohepatitis. In conclusion the prevalence of NAFLD in patients with psoriasis is high and associated with a higher prevalence of metabolic syndrome features, bacterial translocation and a higher pro-inflammatory state. It is worth mentioning that liver fibrosis and non-alcoholic steatohepatitis are not frequent in this population of patients.