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Background: The International Anorectal Physiology Working Group (IAPWG) suggests a standardized protocol to perform high-resolution anorectal manometry. The applicability and possible limitations of the IAPWG protocol in performing three-dimensional high-definition anorectal manometry (3D-ARM) have still to be extensively evaluated., Methods: The IAPWG protocol was applied in performing 3D-ARM. Anorectal manometry (ARM) and a balloon expulsion test (BET) were performed according to IAPGW protocol in 290 patients., Key Results: A total of 84 males and 206 females (mean age 57.1 ± 15.7 years) were enrolled in six Italian centers. The reasons for which the patients were sent to perform 3D-ARM were: constipation (53.1%), fecal incontinence (26.9%), anal pain (3.1%), postsurgical (3.8%) and presurgical evaluation (4.8%), prolapse (3.4%), anal fissure (2.8%), and other (2.1%). Due to organic and functional conditions (low rectal anterior resections, rectal prolapses, and J-pouch after colectomy), we were unable to perform a complete 3D-ARM on six patients. Overall, a complete 3D-ARM and BET following IAPWG protocol was carried out in 284 patients (97.9%). The following were recorded: rest pressure (81.9 ± 32.0 mmHg) and length of the anal sphincter (37.0 ± 6.2 cm), maximum anal squeeze pressure (201.6 ± 81.3 mmHg), squeeze duration (22.0 ± 8.8 s), maximum rectal (48.7 ± 41.0 mmHg) and minimum anal pressure (73.3 ± 36.5 mmHg) during push, presence/absence of a dyssynergic pattern, cough reflex and rectal sensations (first constant sensation 48.4 ± 29.5 mL, desire to defecate 83.7 ± 52.1 mL, and maximum tolerated volume 149.5 ± 72.6 mL), and presence/absence of rectoanal inhibitory reflex. Mean 3D-ARM registration time was 14 min 7 s ± 3 min 12 s., Conclusions: This is the first multicentric study that evaluates the applicability of the IAPWG protocol in 3D-ARM performed in different manometric laboratories (both gastroenterological and surgical). The IAPWG protocol was easy to perform and was not time consuming. A diagnosis according to the London Classification was easily obtained in most patients in which 3D-ARM was carried out. No clear limitations to the applicability of the IAPWG protocol were detected., (© 2024. Springer Nature Switzerland AG.)

In this paper, a critical review of results obtained using a reticulated vitreous carbon (RVC) three-dimensional cathode for the electrochemical depletion of various divalent ions, such as Cu +2 , Cd +2 , Pb +2 , Zn +2 , Ni +2 , and Co +2 , often present in wastewater, has been carried out. By analyzing the kinetics and fluid dynamics of the process found in literature, a general dimensionless equation, Sh = f ( Re ), has been determined, describing a general trend for all the analyzed systems regardless of the geometry, dimensions, and starting conditions. Thus, a map in the log ( Sh ) vs. log ( Re ) plane has been reported by characterizing the whole ion electrochemical depletion process and highlighting the existence of a good correlation among all the results. Moreover, because in recent years, the interest in using this three-dimensional cathode material seems to have slowed, the intent is to revive it as a useful tool for metal recovery, recycling processes, and water treatments.

Background & Aims: Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice for high-risk acute variceal bleeding (AVB; i.e., Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13). Nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation for secondary prophylaxis. We investigated prognostic factors for re-bleeding and mortality in 'non-high-risk' AVB to identify subgroups who may benefit from more potent treatments (i.e., TIPS) to prevent further decompensation and mortality., Methods: A total of 2,225 adults with cirrhosis and variceal bleeding were prospectively recruited at 34 centres between 2011-2015; for the purpose of this study, case definitions and information on prognostic indicators at index AVB and on day 5 were further refined in low-risk patients, of whom 581 (without failure to control bleeding or contraindications to TIPS) who were managed by non-selective beta-blockers/endoscopic variceal ligation, were finally included. Patients were followed for 1 year., Results: Overall, 90 patients (15%) re-bled and 70 (12%) patients died during follow-up. Using clinical routine data, no meaningful predictors of re-bleeding were identified. However, re-bleeding (included as a time-dependent co-variable) increased mortality, even after accounting for differences in patient characteristics (adjusted cause-specific hazard ratio: 2.57; 95% CI 1.43-4.62; p = 0.002). A nomogram including CTP, creatinine, and sodium measured at baseline accurately (concordance: 0.752) stratified the risk of death., Conclusion: The majority of 'non-high-risk' patients with AVB have an excellent prognosis, if treated according to current recommendations. However, about one-fifth of patients, i.e. those with CTP ≥8 and/or high creatinine levels or hyponatremia, have a considerable risk of death within 1 year of the index bleed. Future clinical trials should investigate whether elective TIPS placement reduces mortality in these patients., Impact and Implications: Pre-emptive transjugular intrahepatic portosystemic shunt placement improves outcomes in high-risk acute variceal bleeding; nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation. This is the first large-scale study investigating prognostic factors for re-bleeding and mortality in 'non-high-risk' acute variceal bleeding. While no clinically meaningful predictors were identified for re-bleeding, we developed a nomogram integrating baseline Child-Turcotte-Pugh score, creatinine, and sodium to stratify mortality risk. Our study paves the way for future clinical trials evaluating whether elective transjugular intrahepatic portosystemic shunt placement improves outcomes in presumably 'non-high-risk' patients who are identified as being at increased risk of death., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: Intestinal ultrasound (IUS) is widely used as the first exam in patients with suspected inflammatory bowel disease (IBD). This study investigated the accuracy of several IUS parameters, including increased bowel wall thickening (BWT), in detecting IBD in a paediatric population., Methods: The study included an unselected series of 113 patients aged 2-18 years (mean age 10.8 years, 65 male), referred for recurrent abdominal pain or altered bowel habits, without known organic diseases, to perform an IUS as first investigation of a diagnostic workup. Patients with full systematic IUS examination, clinical and biochemical exams, and ileocolonoscopy or an uneventful follow-up at least one year follow up were eligible., Results: 23 IBD patients (20.4%; 8 ulcerative colitis, 12 Crohn's disease and 3 indeterminate colitis) were diagnosed. We found that increased BWT > 3 mm (OR 5.4), altered IUS bowel pattern (IUS-BP, OR 9.8) and mesenteric hypertrophy (MH, OR 5.2) accurately identified IBD at the multivariate analysis. IUS-BP, MH and BWT > 3 mm had a sensitivity of 78.3%, 65.2% and 69.6% and a specificity of 93.3%, 92.2% and 96.7%, respectively. The combination of these three alterations increased the specificity up to 100%, whilst decreased sensitivity to 56.5%., Conclusion: Among several US parameters suggestive of IBD, the increased BWT, MH and altered echopattern are independent predictors of IBD. The ultrasonographic diagnosis of IBD could be more accurate if relied on combination of different sonographic parameters, than on the sole BWT evaluation., (© 2023. The Author(s).)

Amyloidosis includes a heterogeneous group of diseases caused by the extracellular deposition of insoluble fibrillar proteins, leading to multiple organ dysfunction and a poor life expectancy. In the early stages of amyloidosis, gastrointestinal (GI) symptoms are uncommon. We describe a rare case of hereditary transthyretin amyloidosis (ATTRv) with involvement of the heart, nervous system and GI tract. A man in his 60s was hospitalised due to chronic diarrhoea, orthostatic hypotension, malabsorption and weight loss. An organic origin for the diarrhoea was suspected, but the most common causes were ruled out. The review of GI biopsies and an abdominal fat aspirate confirmed the diagnosis of amyloidosis. The diagnosis of ATTRv amyloidosis with GI presentation is challenging, especially in the early stages, and misdiagnosis is common. The recent approval of therapies emphasises the importance of early diagnosis to prevent irreversible organ damage., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis., Methods: Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d-ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a-ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD., Results: The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty-two days transplant-free survival was worse among AH, but statistical differences were only observed between AH and d-ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one-year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a-ALD (0.48; 0.29-0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH., Conclusions: Contrary to expected, AH patients with AVB present no worse one-year survival than other patients with different alcohol-related phenotypes or viral cirrhosis. Abstinence influences long-term survival and could explain these counterintuitive results., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: To evaluate the ability of intestinal ultrasound (IUS) in discriminating symptomatic uncomplicated diverticular disease (SUDD) among patients with abdominal symptoms including irritable bowel syndrome (IBS)., Methods: This observational, prospective study included consecutive patients classified into the following categories: (i) SUDD; (ii) IBS; (iii) unclassifiable abdominal symptoms; and (iv) controls, including asymptomatic healthy subjects and diverticulosis. The IUS evaluation of the sigmoid: assessed the presence of diverticula, thickness of the muscularis propria, and IUS-evoked pain, namely the intensity of pain evoked by compression with the ultrasound probe on sigmoid colon compared with an area of the left lower abdominal quadrant without underlying sigmoid colon., Results: We enrolled 40 patients with SUDD, 20 patients with IBS, 28 patients with unclassifiable abdominal symptoms, 10 healthy controls, and 20 patients with diverticulosis. Patients with SUDD displayed significantly ( P < 0.001) greater muscle thickness (2.25 ± 0.73 mm) compared with patients with IBS (1.66 ± 0.32 mm), patients with unclassifiable abdominal pain, and healthy subjects, but comparable with that of patients with diverticulosis (2.35 ± 0.71 mm). Patients with SUDD showed a greater (not significant) differential pain score than other patients. There was a significant correlation between the thickness of the muscularis propria and the differential pain score only for patients with SUDD ( r = 0.460; P : 0.01). Sigmoid diverticula were detected by colonoscopy in 40 patients (42.4%) and by IUS with a sensitivity of 96.0% and a specificity of 98.5%., Discussion: IUS could represent a useful diagnostic tool for SUDD, potentially useful in characterizing the disease and appropriately address the therapeutic approach., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: A pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that <15% of patients eligible for pTIPS ultimately undergo transjugular intrahepatic portosystemic shunt (TIPS) due to concerns about hepatic encephalopathy (HE). The outcome of patients undergoing pTIPS with HE is unknown. We aimed to (1) assess the prevalence of HE in patients with AVB; (2) evaluate the outcome of patients presenting HE at admission after pTIPS; and (3) determine if HE at admission is a risk factor for death and post-TIPS HE., Patients and Methods: This is an observational study including 2138 patients from 34 centres between October 2011 and May 2015. Placement of pTIPS was based on individual centre policy. Patients were followed up to 1 year, death or liver transplantation., Results: 671 of 2138 patients were considered at high risk, 66 received pTIPS and 605 endoscopic+drug treatment. At admission, HE was significantly more frequent in high-risk than in low-risk patients (39.2% vs 10.6%, p<0.001). In high-risk patients with HE at admission, pTIPS was associated with a lower 1-year mortality than endoscopic+drug (HR 0.374, 95% CI 0.166 to 0.845, p=0.0181). The incidence of HE was not different between patients treated with pTIPS and endoscopic+drug (38.2% vs 38.7%, p=0.9721), even in patients with HE at admission (56.4% vs 58.7%, p=0.4594). Age >56, shock, Model for End-Stage Liver Disease score >15, endoscopic+drug treatment and HE at admission were independent factors of death in high-risk patients., Conclusion: pTIPS is associated with better survival than endoscopic treatment in high-risk patients with cirrhosis with variceal bleeding displaying HE at admission., Competing Interests: Competing interests: CB has received speaker fees from GORE and is a board member in Alfa Wassemran/Norgine. VH-G, AG, JB, AA, DT and FN have received speaker fees from GORE. J-CG-P has consultant fees from GORE, and Shionogi and Cook grants from GORE and Novartis. JT has speaking and/or consulting fees from GORE, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis and Martin Pharmaceuticals. RB has received speaker fees from GORE and Grifols, unrelated to the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The COVID-19 pandemic has severely affected people's health, daily routine, and behaviors. Its effects have been most pronounced for the youngest and oldest generations. Their daily lives have completely changed throughout the pandemic. Self-transcendence values and positive orientation could facilitate optimal adjustment to this situation by promoting prosociality. The present study aimed to discover if applying a new, web-based intervention could activate self-transcendence values in a group of Italian adolescents, fostering COVID-19 prosocial behaviors while also considering the role of positive orientation. The study adopted a longitudinal, web-based, and quasi-experimental design. One hundred and forty adolescents between 15 and 19 years of age were involved in the study two times (T1-T2). Participants were assigned to an intervention or control group. All participants completed the self-transcendence subscale extracted from the 21-item Portrait Values Questionnaire, the Positive Orientation Scale, and the COVID-19 Prosocial Experiences Scale. The results showed that adolescents' self-transcendence values and positive orientation were positively associated with COVID-19 prosociality. However, the relationship between self-transcendence values and COVID-19 prosocial behaviors was significantly more robust in the intervention group. Finally, a three-way interaction (self-transcendence*group*positive orientation) emerged as significant. For the intervention group, the effect of self-transcendence values on COVID-19 prosocial behaviors was significant only for adolescents who reported a strong positive orientation. Limitations of the study, future research developments, and practical implications are discussed.

Background & Aims: Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis., Methods: A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization., Results: A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9)., Conclusion: Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade., Lay Summary: Bacterial infections develop during hospitalization in close to 20% of patients with acute variceal bleeding despite antibiotic prophylaxis. Respiratory bacterial infections are the most frequent and occur early after admission. Respiratory infection is associated with advanced liver disease, severe hepatic encephalopathy and a need for a nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade., Competing Interests: Conflicts of interest Juan Carlos Garcia-Pagan has consultant fees for GORE, Shionogi and Cook grants from GORE and Novartis. Álvaro Giráldez has served as speaker for Gore. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: Esophageal dysmotility and disorders of the lower esophageal sphincter are well documented in morbidly obese patients. Esophageal achalasia has been reported in up to 1% of obese patients but the development of such esophageal motility disorder after laparoscopic sleeve gastrectomy (LSG) is extremely rare. The purpose of this video was to demonstrate the management of a type II esophageal achalasia diagnosed in a 46-year-old female patient 4-year after LSG., Materials and Methods: An intraoperative video has been anonymized and edited to demonstrate the feasibility of laparoscopic Heller myotomy and anterior Dor fundoplication on the mentioned patient., Results: The operation started with the section of the perigastric adhesions. Proceeding in a clockwise direction, the esophagogastric junction, the anterior esophageal wall, and the His angle were freed. A residual slightly dilated fundus was found and isolated. After mobilization of the distal esophagus and identification of the anterior vagus nerve, a "hockey stick" myotomy was carried out for 6 cm on the esophagus and for 2 cm on the gastric side. An anterior Dor fundoplication was fashioned using the residual gastric fundus., Conclusion: Esophageal achalasia in patients that previously underwent LSG is exceptional but should always be suspected in case of pathognomonic symptoms onset. In tertiary referral centers, laparoscopic Heller myotomy and, if technically feasible, an anterior Dor fundoplication seem safe and effective to relieve gastroesophageal outflow obstruction and prevent gastroesophageal reflux.

The aim of this work was to describe the physical principles behind the reverberation artifacts in ultrasound imaging and list the correct interpretation. This work focuses on the understanding of the principle of reverberation imaging artifacts.

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date., Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality., Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not., Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB., Lay Summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt., Competing Interests: Conflict of interest Christophe Bureau has received speaker fees from GORE and is a board member of Alfawassemran/Norgine. Virginia Hernández - Gea, Álvaro Giráldez, Jaume Bosch, Agustin Albillos, Dominique Thabut, Michael Praktiknjo and Frederik Nevens have received speaker fees from GORE. Juan Carlos Garcia – Pagan has received consultant fees from GORE, Shionogi and Cook grants from GORE and Novartis. Jonel Trebicka has received speaking and/or consulting fees from GORE, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical, and Rafael Bañares has received speaker fees from GORE and Grifols, unrelated to the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Wall shear stress (WSS) is considered as a key factor for atherosclerosis development. Previous WSS research based on pulsed wave Doppler (PWD) showed limitations in complex flows. To improve accuracy for nonlaminar flow, a commercial ultrasound vector flow imaging (UVFI)-based WSS calculation is proposed. Errors for PWD are presented theoretically when flow is not laminar. Based on this, simulations of WSS calculations between PWD and UVFI were set up for different turbulent flows. Our simulations show that UVFI has obviously better performance than PWD in WSS calculations. Wall shear stress results in different flow conditions at carotid bifurcations are described., (© 2020 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of the American Institute of Ultrasound in Medicine.)

Introduction: the aim of this study was to evaluate the correlation among dysphonic and vocal tract discomfort symptoms in patients who underwent empiric therapeutic trial with proton pump inhibitor (PPI) for a suspected laryngopharyngeal reflux (LPR)., Materials and Methods: A total of 34 patients with suspected LPR were enrolled in this study. All of them were evaluated using the reflux finding score, the reflux symptom Index (RSI), the vocal tract discomfort scale (VTDS), and the voice symptom scale (VoiSS) before and after the PPI treatment., Results: A significant difference was found between pretreatment and posttreatment reflux finding score, RSI, VTDS, and VoiSS scores. Significant correlations among RSI, VTDS, and VoiSS before the PPI treatment were found., Conclusion: PPI treatment determined a significant improvement of symptoms related to dysphonia and vocal tract discomfort in patients with suspected LPR, in addition, significant correlations among the RSI, VTDS, and VoiSS scores were demonstrated thus suggesting that LPR might influence the response of questionnaires not specifically developed in order to assess the complains in LPR patient., (Copyright © 2018. Published by Elsevier Inc.)

Background: Budesonide-MMX has an established role in the management of relapsing mild-to-moderate ulcerative colitis. Data regarding effectiveness and tolerability in real-life clinical practice are limited., Aim: The aim of this study was to assess the use of budesonide-MMX in ulcerative colitis, as well as short-term effectiveness and tolerability in real-life practice., Methods: We conducted a retrospective study of adult patients with mild-to-moderate ulcerative colitis treated with budesonide-MMX at four tertiary inflammatory bowel disease centres in Italy from June 2016 to February 2018. Demographic and clinical features of patients, the use of budesonide-MMX, disease course and concomitant therapy were recorded. The primary outcome assessed was clinical remission at 2 months., Results: A total of 82 patients with active mild-to-moderate ulcerative colitis were included in the study with a mean age of 45.9 years and a median partial Mayo Score of 4 (interquartile range 3-5). A total of 41 patients were male. Overall, 36 had extensive colitis, 38 left-sided colitis and eight proctitis. Treatments at the time of inclusion included 10 patients receiving biologic therapy, seven azathioprine and 54 mesalazine or salazopyrin. The main reasons for the addition of budesonide-MMX were clinical relapse (47.5%) or inadequate response to current therapy (39.0%). In total, 50% of patients achieved clinical remission, whereas 9.8% had clinical improvement. No response was noted in 40.2% of subjects. Using multivariate binary logistic regression, a moderate degree of activity was the main independent predictor of non-response. Eight significant adverse effects were reported in six patients with three discontinuing treatment., Conclusion: In real-life clinical practice, budesonide-MMX is commonly used in combination with other therapies, both for acute disease flares and for partial response to therapy., (© Author(s) 2019.)

Use of fiber Bragg gratings (FBGs) to monitor high temperature (HT) applications is of great interest to the research community. Standard commercial FBGs can operate up to 600 ∘ C. For applications beyond that value, specific processing of the FBGs must be adopted to allow the grating not to deteriorate. The most common technique used to process FBGs for HT applications is the regeneration procedure (RP), which typically extends their use up to 1000 ∘ C. RP involves a long-term annealing of the FBGs, to be done at a temperature ranging from 550 to 950 ∘ C. As at that temperature, the original coating of the FBGs would burn out, they shall stay uncoated, and their brittleness is a serious concern to deal with. Depositing a metal coating on the FBGs prior to process them for RP offers an effective solution to provide them with the necessary mechanical strengthening. In this paper, a procedure to provide the FBG with a bimetallic coating made by copper and nickel electrodeposition (ED) is proposed, discussing issues related to the coating morphology, adherence to the fiber, and effects on the grating spectral response. To define the processing parameters of the proposed procedure, production tests were performed on dummy samples which were used for destructive SEM-EDS analysis. As a critical step, the proposed procedure was shown to necessitate a heat treatment after the nickel ED, to remove the absorbed hydrogen. The spectral response of the FBG samples was monitored along the various steps of the proposed procedure and, as a final proof test for adherence stability of the bimetallic coating, along a heating/cooling cycle from room temperature to 1010 ∘ C. The results suggest that, given the emergence of Kirkendall voids at the copper-nickel interface, occurring at the highest temperatures (700-1010 ∘ C), the bimetallic layer could be employed as FBG coating up to 700 ∘ C.

Objective: To assess the accuracy of noninvasive parameters, fecal calprotectin (FC), increased bowel wall thickening (BWT) at intestinal ultrasound (IUS) and blood inflammatory indexes (BII), alone or in combination, as diagnostic tools for inflammatory bowel disease (IBD) in pediatric patients. Methods: Retrospective data were collected on consecutive children (age 2-18 years) referred to our pediatric gastroenterology clinic, for recurrent abdominal pain and/or altered bowel habit from 2007 to 2013. Subjects who had diagnostic workup: laboratory tests (FC, BII, white blood cell (WBC), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and IUS as initial assessment were eligible. Subjects with known gastrointestinal (GI) diseases, or signs or symptoms highly suggestive for organic diseases necessitating prompt endoscopy (e.g., perianal disease or rectal bleeding), or who had recently performed endoscopy were excluded. The accuracy of noninvasive tests for detecting IBD was assessed using endoscopic and/or radiological investigations, performed in subsequent clinical follow up, as reference gold standard. Results: Seventy-seven patients (mean age 11.3, 44 males) were included, 23 (29.9%) with a final diagnosis of IBD. As single tests, FC gave the highest sensitivity (96%) but lower specificity (72%) and IUS highest specificity (96%) with lower sensitivity (70%). The combination of FC + IUS showed excellent accuracy for detecting children with IBD with positive predictive value: 100%; negative predictive value: 88.5%. The probability of IBD in children with normal FC, BII and IUS was 0.09%. Conclusions: FC and increased BWT at IUS are accurate to guide reassurance or proceeding with further invasive procedures for detecting IBD in children with mild GI symptoms.

Patients admitted with acute variceal bleeding (AVB) and Child-Pugh C score (CP-C) or Child-Pugh B plus active bleeding at endoscopy (CP-B+AB) are at high risk for treatment failure, rebleeding, and mortality. A preemptive transjugular intrahepatic portosystemic shunt (p-TIPS) has been shown to improve survival in these patients, but its use in clinical practice has been challenged and not routinely incorporated. The present study aimed to further validate the role of preemptive TIPS in a large number of high-risk patients. This multicenter, international, observational study included 671 patients from 34 centers admitted for AVB and high risk of treatment failure. Patients were managed according to current guidelines, and use of drugs and endoscopic therapy (D+E) or p-TIPS was based on individual center policy. p-TIPS in the setting of AVB is associated with a lower mortality in CP-C patients compared with D+E (1 year mortality 22% vs. 47% in D+E group; P = 0.002). Mortality rate in CP-B+AB patients was low, and p-TIPS did not improve it. In CP-C and CP-B+AB patients, p-TIPS reduced treatment failure and rebleeding (1-year cumulative incidence function probability of remaining free of the composite endpoint: 92% vs. 74% in the D+E group; P = 0.017) and development of de novo or worsening of previous ascites without increasing rates of hepatic encephalopathy. Conclusion: p-TIPS must be the treatment of choice in CP-C patients with AVB. Because of the strong benefit in preventing further bleeding and ascites, p-TIPS could be a good treatment strategy for CP-B+AB patients., (© 2018 by the American Association for the Study of Liver Diseases.)

Background: Laparoscopic ileo-pouch-anal anastomosis (IPAA) has been reported as having low morbidity and several advantages., Aims: To evaluate safety, efficacy and long-term results of laparoscopic IPAA, performed in elective or emergency settings, in consecutive unselected IBD patients., Methods: All the patients received totally laparoscopic 2-stage (proctocolectomy and IPAA - stoma closure) or 3-stage (colectomy - proctectomy and IPAA - stoma closure) procedure according to their presentation., Results: From July 2007 to July 2016, 160 patients entered the study. 50.6% underwent a 3-stage procedure and 49.4% a 2-stage procedure. Mortality and morbidity were 0.6% and 24.6%. Conversion rate was 3.75%. 8.7% septic complications were associated with steroids and Infliximab treatment (p = 0.0001). 3-stage patients were younger (p = 0.0001), with shorter disease duration (p = 0.0001), minor ASA scores of 2 and 3 (p = 0.0007), lower inflammatory index and better nutritional status (p = 0.003 and 0.0001), fewer Clavien-Dindo's grade II complications (p = .0001), reduced rates of readmission and reoperation at 90 days (p = 0.03), and shorter hospitalization (p = .0001), but with similar pouch and IPAA leakage, compared to 2-stage patients. 8 years pouch failure and definitive ileostomy were 5.1% and 3.7%., Conclusion: A totally laparoscopic approach is safe and feasible, with very low mortality and morbidity rates and very low conversion rate, even in multi-stage procedures and high-risk patients., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Titanium biomaterials' response has been recognized to be affected by particles size, crystal structure, and surface properties. Chemical and structural properties of these nanoparticle materials are important, but their size is the key aspect. The aim of this study is the synthesis of TiO₂ nanoparticles by the sol-gel method, which is an ideal technique to prepare nanomaterials at low temperature. The heat treatment can affect the structure of the final product and consequently its biological properties. For this reason, the chemical structure of the TiO₂ nanoparticles synthesized was investigated after each heat treatment, in order to evaluate the presence of different phases formed among the nanoparticles. FTIR spectroscopy and XRD have been used to evaluate the different structures. The results of these analyses suggest that an increase of the calcination temperature induces the formation of mixed-crystalline-phases with different content of anatase and rutile phases. The results obtained by SEM measurements suggest that an increase in the particles size accompanied by a noticeable aggregation of TiO₂ nanoparticles is due to high temperatures achieved during the thermal treatments and confirmed the presence of different content of the two crystalline phases of titanium dioxide.

SiO₂-based organic-inorganic hybrids (OIHs) are versatile materials whose properties may change significantly because of their thermal treatment. In fact, after their preparation at low temperature by the sol-gel method, they still have reactive silanol groups due to incomplete condensation reactions that can be removed by accelerating these processes upon heating them in controlled experimental conditions. In this study, the thermal behavior of pure SiO₂ and four SiO₂-based OIHs containing increasing amount (6, 12, 24 and 50 wt %) of poly(ε-caprolactone) (PCL) has been studied by simultaneous thermogravimetry (TG) and differential scanning calorimetry (DSC). The FTIR analysis of the gas mixture evolved at defined temperatures from the samples submitted to the TG experiments identified the mechanisms of thermally activated processes occurring upon heating. In particular, all samples already release ethanol at low temperature. Moreover, thermal degradation of PCL takes place in the richest-PCL sample, leading to 5-hexenoic acid, H₂O, CO₂, CO and ε-caprolactone. After the samples' treatment at 450, 600 and 1000 °C, the X-ray diffraction (XRD) spectra revealed that they were still amorphous, while the presence of cristobalite is found in the richest-PCL material., Competing Interests: The authors declare no conflict of interest.

The synthesis of organic-inorganic hybrid compounds based on phenylphosphonate and their use as precursors to form LiMn x Fe (1-x) PO₄ composites containing carbonaceous substances with sub-micrometric morphology are presented. The experimental procedure includes the preliminary synthesis of Fe 2+ and/or Mn 2+ phenylphosphonates with the general formula Fe (1-x) Mn x [(C₆H₅PO₃)(H₂O)] (with 0 < x < 1), which are then mixed at different molar ratios with lithium carbonate. In this way the carbon, obtained from in situ partial oxidation of the precursor organic part, coats the LiMn x Fe (1-x) PO₄ particles. After a structural and morphological characterization, the electrochemical behavior of lithium iron manganese phosphates has been compared to the one of pristine LiFePO₄ and LiMnPO₄, in order to evaluate the doping influence on the material., Competing Interests: The authors declare no conflict of interest.

Background & Aims: Excessive intestinal gas and liver steatosis are frequent sonographic findings. Both of these appear to be caused by variations of the gut microflora. We assessed the relationship between ultrasonographic detection of intestinal gas and liver steatosis., Methods: This study included 204 consecutive patients (99 male; mean age 53.0 ± 15.6 years), who underwent ultrasonography for abdominal complaints or follow-up of benign lesions. Body mass index, biochemical liver markers, sonographic presence of liver steatosis and/or degree of intestinal gas interfering with the examination were collected. Both sonographic findings were assessed based on standardized criteria. The association between liver steatosis and intestinal gas was evaluated by means of univariate and multivariate analyses., Results: Eighty (39.2%) of patients showed moderate to large amounts of gas preventing an accurate evaluation of the liver or pancreas and 90 (44.1%) had liver steatosis. A significant correlation between the degree of intestinal gas and liver steatosis both in obese (r=.603; P<.001) and in nonobese patients (r=.555; P<.001) was found. Univariate analysis showed that intestinal gas, body mass index, aspartate transaminase, alanine transaminase, gamma-GT, age and sex were predictors of liver steatosis; only intestinal gas (OR 7.4; 95% CI 3.4-16.1) and body mass index (OR; 1.4, 95% CI 1.2-1.5), however, were independent predictors at multivariate analysis. The presence of excessive gas was also significantly correlated with liver steatosis coupled with elevated ALT (P = .001)., Conclusion: This study shows a significant correlation between excessive intestinal gas and liver steatosis. The reasons of this finding and its clinical implications remain to be defined., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Crohn's disease (CD) is characterized by inflammation and angiogenesis of affected bowel. We evaluated the correlation among vascularity of intestinal wall in CD, splanchnic hemodynamics, clinical activity and biochemical parameters of inflammation and angiogenesis. Sixteen patients with ileal CD and 10 healthy controls were investigated by means of Doppler ultrasound of the superior mesenteric artery and color Doppler and contrast-enhanced ultrasound of the ileal wall. In parallel, serum levels of vascular endothelial growth factor, tumor necrosis factor-α (TNF-α) and nitric oxide, before and 30 min after a standard meal, were evaluated. In CD patients, there was a significant post-prandial reduction in the resistance index and pulsatility index of the superior mesenteric artery, associated with increased levels of nitric oxide and decreased amounts of TNF-α. A correlation was observed between vascular endothelial growth factor and contrast-enhanced ultrasound parameters of intestinal wall vascularity (r = 0.63-0.71, p < 0.05) and between these parameters and superior mesenteric artery blood flow after fasting (resistance and pulsatility indexes: r = -0.64 and -0.72, p < 0.05). Our results revealed a post-prandial increase in nitric oxide and decrease in TNF-α in CD patients in vivo. They also confirm the role of vascular endothelial growth factor in angiogenesis and in pathologic vascular remodeling of CD and its effect on splanchnic blood flow., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Reutilization of single-use vials containing medical drugs is still under discussion. This practice has been adopted as a standard to avoid drug wastage, particularly in developing countries and in the aftermath of disasters. Some studies have assessed sterility of medications stored in single-use vials after utilization as multiple doses; however, most of these were limited to one single drug, included a low number of samples and did not consider an intermediate transfer step from the vial to a disposable syringe. The purpose of this study was to assess microbial contamination of samples withdrawn over three days from disposable syringes prepared from single-use vials., Methods: A prospective sterility study was conducted. A total of 600 initial samples were prepared from six-hundred 10 mL single-use vials of physiological solution into six-hundred 20 mL disposable syringes. Samples were prepared in three different standard operating rooms, on six different days and by the same operator, using basic sterile technique. All syringes were capped, placed together in a non-sterile steel container, covered with a clean drape and stored in the refrigerator at 4°C under non-sterile conditions. Using basic sterile technique, four samples were withdrawn daily and cultured from each syringe over the next 3 days. Microbial growth was examined on Sabouraud agar and chocolate agar culture media., Results: A total of 7200 samples were collected and 14,400 cultures were performed. No evidence of microbial growth in any of the culture media plates was found., Conclusion: This study demonstrated that contents initially stored in single-use vials and subsequently transferred into disposable syringes in an operating room using sterile technique, maintain sterility after 4 withdrawals per day for a total of 3 days., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Assessing the presence of clinically significant portal hypertension and esophageal varices is clinically important in cirrhosis. The reference standard techniques to assess the presence of portal hypertension and varices are the measurement of the hepatic vein pressure gradient and esophagogastroduodenoscopy, respectively. Some newer methods have shown a good performance, but none has been proven precise enough to replace hepatic vein pressure gradient measurement or esophagogastroduodenoscopy for the diagnosis of portal hypertension or the presence and grade of esophageal varices., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Influence of portal vein thrombosis on efficacy of endoscopic variceal banding in patients with cirrhosis or extrahepatic portal vein obstruction has never been evaluated. Aim of the study was to assess influence of thrombosis on rate and time to eradication in cirrhosis and extrahepatic portal vein obstruction undergoing banding, compared to cirrhotic patients without thrombosis., Methods: Retrospective analysis of 235 consecutive patients (192 with cirrhosis without thrombosis, 22 cirrhosis and thrombosis and 21 extrahepatic portal vein obstruction) who underwent banding. Banding was performed every 2-3 weeks until eradication; endoscopic follow-up was performed at 1, 3, 6 months, then annually., Results: Eradication was achieved in 233 patients. Median time to eradication in cirrhotic patients with portal vein thrombosis vs. cirrhotic patients without thrombosis was 50.9 days (12-440) vs. 43.4 days (13-489.4); log-rank: 0.04; patients with extrahepatic portal vein obstruction vs. cirrhotic patients without thrombosis 63.9 days (31-321.6) vs. 43.4 days (13.0-489.4); log-rank: 0.008. Thrombosis was shown to be the only risk factor for longer time to eradication., Conclusions: Portal vein thrombosis per se appears to be the cause of a longer time to achieve eradication of varices but, once eradication is achieved, it does not influence their recurrence., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: Budd-Chiari syndrome (BCS) is a rare, life-threatening disease caused by obstruction of hepatic venous outflow. The aim of the study was to assess long-term outcome and identify prognostic factors in BCS patients managed by a step-wise approach using anticoagulation, angioplasty/thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), and orthotopic liver transplantation (OLT). We reviewed long-term data on 157 patients previously included by the European Network for Vascular Disorders of the Liver, a multicenter prospective study of newly diagnosed BCS patients in nine European countries. Patients were followed for a median of 50 months (range, 0.1-74.0). During the study, 88 patients (56%) received at least one invasive intervention (22 patients angioplasty/thrombolysis, 62 TIPS, and 20 OLT) and 36 (22.9%) died. Most interventions and/or deaths occurred in the first 2 years after diagnosis. The Rotterdam score was excellent in predicting intervention-free survival, and no other variable could significantly improve its prognostic ability. Moreover, BCS-TIPS prognostic index (PI) score (based on international normalized ratio, bilirubin, and age) was strongly associated with survival and had a discriminative capacity, which was superior to the Rotterdam score., Conclusions: The current study confirms, in a large cohort of patients with BCS recruited over a short period, that a step-wise treatment approach provides good long-term survival. In addition, the study validates the Rotterdam score for predicting intervention-free survival and the BCS-TIPS PI score for predicting survival., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Cirrhosis is characterized by a complex coagulation defect leading to the prolongation of the prothrombin and activated partial thromboplastin times (PT and APTT). Arbitrary PT cut-off values are still used as a yardstick to guide treatment with fresh-frozen plasma (FFP) or other pro-coagulant agents in patients undergoing invasive procedures. No randomized studies on the FFP efficacy are available, and are unlikely to be carried out because of their complex organization. An interim solution could be to evaluate the in vitro thrombin generation in plasmas from patients with cirrhosis when mixed with appropriate amounts of pooled normal plasma (PNP). The PT, APTT and thrombin generations in the presence of thrombomodulin were examined in 58 patients with cirrhosis and 24 healthy subjects both before and after mixing their plasmas with PNP at a proportion of 4 + 1 (patient + PNP), chosen to mimic in vivo conditions when patients are treated with 10 ml/kg of FFP. The PT and APTT, which were abnormal in the majority of unmixed patient plasmas were shortened considerably, but did not normalize completely when mixed with PNP. Thrombin generation, which was already within normal limits in all unmixed patient plasmas, remained essentially unchanged after mixing with PNP. In conclusion, thrombin generation in patients with cirrhosis does not appreciably change after in vitro addition of PNP despite PT and APTT shortening would suggest otherwise. These results question the validity of the PT as a stand-alone test to guide transfusion of FFP in the setting of chronic liver disease.

Background and Methods: Portal vein thrombosis (PVT) has been reported as a complication of IBD in some case reports. We describe the presentation, diagnostic approaches, underlying risks factors and clinical outcome of 8 IBD patients with PVT. CASE-SERIES: The patients presented with partial PVT (4 patients) or portal cavernoma. Five patients had undergone surgery. In 2 patients portal biliopathy was diagnosed after detection of PVT. In 4 patients, the diagnosis of PVT was made while IBD was in remission. Five patients showed at least one risk factor for hypercoagulability: lupus anti-coagulant (one patient), increased von Willebrand factor (2 patients) or homocysteine levels (4 patients). Four patients received anticoagulant therapy for 6 months. None experienced other thrombotic events during a median of 5 years (range 2-8 years)., Conclusion: PVT is a potential complication of IBD, usually associated with acquired or inherited risks factors for hypercoagulability and with a benign outcome., (Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

The acoustic emission technique is proposed for assessing the irreversible phenomena occurring during hydrogen absorption/desorption cycling in LaNi 5 . In particular, we have studied, through a parametric analysis of in situ detected signals, the correlation between acoustic emission (AE) parameters and the processes occurring during the activation of an intermetallic compound. Decreases in the number and amplitude of AE signals suggest that pulverization due to hydrogen loading involves progressively smaller volumes of material as the number of cycles increases. This conclusion is confirmed by electron microscopy observations and particle size distribution measurements.

Background: Colorectal polyps of mesenchymal origin represent a small percentage of gastrointestinal (GI) lesions. Nevertheless, they are encountered with increasing frequency since the widespread adoption of colonoscopy screening., Case Presentation: We report a case of a small colonic polyp that presented as intramucosal diffuse spindle cell proliferation with a benign cytological appearance, strong and diffuse immunoreactivity for S-100 protein, and pure Schwann cell phenotype. Careful morphological, immunohistochemical and clinical evaluation emphasize the differences from other stromal colonic lesions and distinguish it from schwannoma, a circumscribed benign nerve sheath tumor that rarely arises in the GI tract., Conclusion: As recently proposed, this lesion was finally described as mucosal Schwann cell hamartoma.

Background: Gastrointestinal haemorrhage from ruptured esophageal varices (EV) is a significant cause of morbidity and mortality in patients with HCV-related cirrhosis. The risk of developing EV and bleeding is influenced by hepatitis severity, which can be attenuated by successful interferon (IFN) therapy. Our aim was to prospectively assess whether a successful IFN therapy modifies development and/or progression of EV in patients with HCV-related compensated cirrhosis., Methods: Child-Pugh A patients with either no or small (F1) EV underwent surveillance with repeated endoscopy during and after completion of IFN-based therapy., Results: A total of 127 patients (59 years, 79 males, 65 HCV-1/4 and 17 F1 EV) received weight-based ribavirin (RBV) combined with either IFN-α2b 3 MU three times per week (n=36), weekly pegylated (PEG)-IFN-α2b 1.5 μg/kg (n=68) or weekly PEG-IFN-α2a 180 μg (n=23). Patients were followed-up for 18-108 months after treatment completion with a median endoscopic follow-up of 68 months for the 62 patients with a sustained virological response (SVR) and 57 months for the 65 non-SVR patients (P=0.3). De novo EV developed in 10 (9.1%) patients including 2/57 SVR and 8/53 non-SVR (3.5% versus 15.1%; P=0.047), whereas EV progressed in size in 3 patients, including 1/5 SVR and 2/12 non-SVR (P=0.87). Two non-SVR patients bled from EV and one died., Conclusions: A successful IFN therapy prevents or delays the de novo onset of EV in patients with compensated cirrhosis due to HCV, but does not abrogate the need for continued endoscopic surveillance.

Unlabelled: Patients with cirrhosis possess an imbalance in procoagulant versus anticoagulant activity due to increased factor VIII and decreased protein C. This imbalance can be detected by thrombin-generation assays performed in the presence/absence of thrombomodulin (predicate assay) that are not readily available in clinical laboratories. We sought to assess this hypercoagulability with a simpler thrombin-generation assay performed in the presence/absence of Protac, a snake venom that activates protein C in a manner similar to thrombomodulin (new assay). We analyzed blood from 105 patients with cirrhosis and 105 healthy subjects (controls). Results for the predicate-assay or the new-assay were expressed as ratio (with:without thrombomodulin) or as Protac-induced coagulation inhibition (PICI%). By definition, high ratios or low PICI% translate into hypercoagulability. The median(range) PICI% was lower in patients (74% [31%-97%]) than controls (93% [72%-99%]; P < 0.001), indicating that patients with cirrhosis are resistant to the action of Protac. This resistance resulted in greater plasma hypercoagulability in patients who were Child class C than those who were A or B. The hypercoagulability of Child C cirrhosis (63% [31%-92%]) was similar to that observed for patients with factor V Leiden (69% [15%-80%]; P = 0.59). The PICI% values were correlated with the levels of protein C (rho = 0.728, P < 0.001) or factor VIII (rho = -0.517, P < 0.001). Finally, the PICI% values were correlated with the predicate assay (rho = -0.580, P < 0.001)., Conclusion: The hypercoagulability of plasma from patients with cirrhosis can be detected with the new assay, which compares favorably with the other markers of hypercoagulability (i.e., high factor VIII and low protein C) and with the predicate-assay based on thrombin-generation with/without thrombomodulin. Advantages of the new assay over the predicate assay are easy performance and standardized results. Prospective trials are needed to ascertain whether it is useful to predict thrombosis in patients with cirrhosis.

Background & Aims: Patients with cirrhosis have an increased tendency to develop thromboses despite the longer coagulation times of their plasma, compared with that of healthy individuals. We investigated whether plasma from cirrhotic patients has an imbalance of pro- vs anti-coagulation factors., Methods: We analyzed blood samples from 134 cirrhotic patients and 131 healthy subjects (controls) for levels of pro- and anti-coagulants and for thrombin generation in the presence or absence of thrombomodulin (the main physiologic activator of the protein C anticoagulant pathway)., Results: The median ratio of thrombin generation (with/without thrombomodulin) was higher in patients (0.80; range, 0.51-1.06) than controls (0.66; range, 0.17-0.95), indicating that cirrhotic patients are resistant to the action of thrombomodulin. This resistance resulted in greater hypercoagulability of plasma from patients of Child-Pugh class C than of class A or B. The hypercoagulability of plasma from patients of Child-Pugh class C (0.86; range, 0.70-1.06) was slightly greater than that observed under the same conditions in patients with congenital protein C deficiency (0.76; range, 0.60-0.93). Levels of factor VIII, a potent pro-coagulant involved in thrombin generation, increased progressively with Child-Pugh score (from Child-Pugh class A to C). Levels of protein C, one of the most potent naturally occurring anti-coagulants, showed the opposite trend., Conclusions: The hypercoagulability of plasma from patients with cirrhosis appears to result from increased levels of factor VIII and decreased levels of protein C-typical features of patients with cirrhosis. These findings might explain the risk for venous thromboembolism in patients with chronic liver disease.

Background/aims: The MELD defines a score used to prioritize patients awaiting liver transplantation and includes results for bilirubin, creatinine and PT expressed as INR. It is assumed that the MELD for individual patients is the same regardless of the laboratory method used for testing, thus ensuring parity of organ allocation. Previous studies showed that the INR calibrated for patients on vitamin K antagonists (INR(vka)) does not normalize results across thromboplastins, whereas an alternative calibration called INR(liver) does. However, implementation of INR(liver) calibration for thromboplastins is difficult in practice. This study aimed to assess whether easy-to-run whole-blood coagulation monitors (widely used for patients on VKA) can be calibrated to measure efficiently the INR(liver) and minimize the interlaboratory variability., Methods: PT values for 61 cirrhotic patients were measured on native-blood with 2 monitors calibrated in terms of INR(vka). PTs for these subjects were also measured with a WHO-standard for thromboplastin. Paired-PTs with the monitors and the standard were subsequently used to calibrate the monitors in terms of INR(liver). INR(vka) and INR(liver) were then compared to assess for statistical significance., Results: The mean INR(vka) obtained with the monitors and the standard were significantly different (p<0.001). Conversely, the corresponding INR(liver) were not., Conclusions: The INR(liver) calibration as previously described for thromboplastins works also for the easy-to-run whole-blood coagulation monitors. Once the monitors are calibrated by the manufacturer in terms of INR(liver) they could be used as near-patient-testing devices directly by the personnel of liver units making the determination of the INR for patients awaiting liver transplantation much easier and standardized.

Background: Thromboelastometry allows continuous registration of the blood viscoelastic changes upon activation by cephaline or tissue-factor plus calcium-chloride. The technique is used as a near-patient-testing device to guide transfusion in cardiac surgery or liver transplantation and less to investigate hemostasis in acquired or congenital coagulopathies., Aims: (i) Review of the coagulopathy associated with cirrhosis and (ii) report on its investigation by thromboelastometry in comparison with conventional coagulation parameters., Methods: We investigated citrated blood samples from 51 adult cirrhotics for the following thromboelastometry parameters: coagulation-time (CT), clot-formation-time (CFT), maximum-clot-firmness (MCF)., Results: Relatively few patients [14/51(27%)] were identified as abnormal by CT; in contrast, a greater proportion were identified by the CFT [41/51(80%)] or MCF [39/51(76%)]. CFT and MCF were correlated with the platelet-count, antithrombin and fibrinogen. Prothrombin time (PT) was correlated with CFT and MCF. None of the coagulation parameters were correlated with CT. The correlation of the Child-Pugh-score (taken as index of severity) versus MCF or PT was -0.457(p < 0.001) or 0.484(p < 0.001), suggesting MCF as a suitable prognostic index. CFT and MCF, but not CT obtained ROC curves that were useful to distinguish patients from healthy individuals., Conclusions: Thromboelastometry, currently used to assist liver transplantation is also suitable for investigating stable cirrhosis. CFT and MCF are the most interesting parameters to be considered for future clinical studies needed to assess their value as measures of bleeding-risk and prognosis in this category of patients.

Background/aims: High levels of coagulation factor VIII are a risk factor for lower-limb deep vein thrombosis (DVT). Their role in extra-hepatic portal vein obstruction (EHPVO) is not established., Methods: Factor VIII was measured in 85 patients with EHPVO (primary in 58 and complicating liver cirrhosis in 27), in 200 with lower-limb DVT, in 108 with liver cirrhosis without thrombosis and in 200 healthy controls., Results: Factor VIII levels were significantly higher in patients with primary EHPVO (138 IU/dL, range 86-366), EHPVO and cirrhosis (147 IU/dL, 95-242), lower-limb DVT (140 IU/dL, 64-400) and cirrhosis alone (160 IU/dL, 43-446) than in controls (112 IU/dL, 62-250, p<0.001). When factor VIII exceeded 129 IU/dL (66th percentile), the odds ratios were 10.5 (95%CI 3.3-33.4) for primary EHPVO, 6.0 (1.2-30.7) for EHPVO and cirrhosis, 5.0 (2.6-9.4) for lower-limb DVT. After exclusion of the effect of the acute phase reaction, the odds ratio for primary EHPVO was 4.2 (0.8-22.7), and was 8.7 (0.9-80.5) after exclusion also of patients with chronic myeloproliferative disorders., Conclusions: High factor VIII levels are independently associated with an increased risk for EHPVO. The risk of EHPVO increased with increasing factor VIII levels and was only partially dependent on the acute phase reaction.

Background: Current guidelines recommend beta-blockers for primary prevention of variceal haemorrhage in cirrhotic patients, and band ligation for patients with contraindications or intolerance to beta-blockers. However, it has been suggested that these patients may respond poorly to band ligation., Aim: We evaluated the usefulness of a strategy in which band ligation was used to treat patients with contraindications or intolerance and patients not responding to beta-blockers identified by hepatic vein pressure gradient measurement. Haemodynamic responders and patients refusing hepatic vein pressure gradient measurement were given long-term beta-blockers., Methods: One hundred and thirty-five consecutive patients with high-risk oesophageal varices and no prior bleeding were enrolled. Twenty-five patients with contraindications (group A), 26 with intolerance to beta-blockers (group B) and 25 showing a poor haemodynamic response (Group C) underwent band ligation. Twenty-two haemodynamic responders (Group D) and 37 refusing hepatic vein pressure gradient measurement (Group E) were treated with beta-blockers., Results: Median follow-up was 32 months. 12/135 patients (8.9%) bled: 3/25 (12%) in group A, 1/26 (3.8%) in group B, 0/25 (0%) in group C, 0/22 (0%) in group D and 8/37 (22.2%) in group E. Mortality was 8/135 (5.9%)., Conclusions: Patients with contraindications, intolerance or not responding to beta-blockers treated with band ligation achieve protection from variceal bleeding comparable to that of good responders to beta-blockers.

Background and Aim: Variceal bleeding carries a high-mortality rate in patients with liver cirrhosis. Since coagulation and fibrinolysis are abnormal in these patients we evaluated whether or not abnormalities of these haemostasis systems were independently related to mortality., Methods: Global coagulation, coagulation activation and fibrinolysis measurements were performed in 43 cirrhotics bleeding from esophageal varices at baseline and during follow-up and in 43 non-bleeding cirrhotic patients at baseline only., Results: Baseline measurements of coagulation activation and fibrinolysis were more impaired in bleeders. In bleeders, prothrombin time, tissue type plasminogen activator antigen and D-dimer plasma levels were persistently more abnormal in patients who died. High-D-dimer, infection, Child-Pugh C class and MELD score >or=17 were the significant predictors of death at univariate analysis. Two different multivariate analyses to assess the independent prognostic value of these variables, one including the Child-Pugh class, the other including MELD, were performed. Independent predictors of death were high-D-dimer and infection, but not Child-Pugh class, in the former; MELD and infection, but not D-dimer, in the latter., Conclusions: Beside infection, high-D-dimer is a stronger predictor of death as compared to Child-Pugh C class, but not to a MELD score >or=17.

Purpose of Review: Esophageal variceal bleeding is a life-threatening complication of liver cirrhosis. The aim of this review is to discuss the most important studies published in 2007 concerning diagnosis of esophageal varices, primary and secondary prophylaxis and treatment of variceal bleeding., Recent Findings: The specific areas reviewed are the noninvasive or minimally invasive diagnosis of oesophageal varices, prevention of the formation of varices and their progression from small to large, prevention of the first variceal hemorrhage, treatment of acute bleeding episodes and prevention of rebleeding, assessment of costs related to prophylaxis and treatment of variceal bleeding. Multidetector computed tomographic esophagography was found to identify the presence and grade the size of esophageal varices. Portal vein thrombosis was found to be an independent predictor of the aggravation of esophageal varices in patients with cirrhosis and hepatocellular carcinoma. The role of hepatic vein pressure gradient measurement in the prediction of decompensation of cirrhosis has been elucidated., Summary: Relevant studies are reviewed on the diagnosis and the natural history of esophageal varices, prevention of their formation and growth, prevention of the first variceal bleed, use of hepatic vein pressure gradient to predict the evolution of portal hypertension and to estimate the response to pharmacological treatment, prediction of bleeding, treatment of variceal bleeding and prevention of rebleeding, and cost strategies.

Currently, oesophago-gastroduodenoscopy is the standard method to diagnose the presence of oesophago-gastric varices and to estimate the risk of bleeding. It is recommended that all patients undergo endoscopic screening for varices at the time when cirrhosis is diagnosed. After screening endoscopy, patients with medium or large varices should be treated to prevent bleeding, while all other patients should undergo periodic surveillance endoscopy. However, at a given point in time a variable proportion of patients will not have varices, since the prevalence of varices is variable. Thus, screening all cirrhotic patients with endoscopy to detect the presence of varices implies a number of unnecessary endoscopies. In recent years a wealth of new methods have been proposed as alternatives to conventional oesophago-gastroduodenoscopy for the non-invasive or minimally invasive diagnosis of oesophageal varices. Three of these methods (the platelet count/spleen diameter ratio, Fibrotest and Fibroscan) are truly non-invasive. Of these, the former is promising and needs a proper validation, Fibrotest appears to be insufficiently precise, while Fibroscan needs further evaluation. Multidetector CT oesophagography and capsule endoscopy are not entirely "non-invasive", since the first requires air insufflation into the oesophagus via an orally passed tube, and the latter requires swallowing the capsule. Multidetector CT oesophagography is promising, but needs further evaluation; capsule endoscopy is safe and reliable and might be proposed as an alternative to oesophago-gastroduodenoscopy in patients unable or unwilling to undergo oesophago-gastroduodenoscopy.

Variceal bleeding is one of the most severe complications of portal hypertension related to liver cirrhosis. Primary prophylaxis is considered mandatory in patients with cirrhosis and high-risk oesophageal varices, and once varices have bled, every effort should be made to arrest the haemorrhage and prevent further bleeding episodes. In acute variceal bleeding, vasoactive drugs that lower portal pressure should be started even before endoscopy, and should be maintained for up to 5 days. The choice of vasoactive drug should be made according to local resources. Terlipressin, somatostatin and octreotide can be used; vasopressin plus transdermal nitroglycerin may be used if no other drug is available. In variceal bleeding, antibiotic therapy is also mandatory. In primary and secondary prophylaxis, beta-blockers are the mainstay of therapy. In secondary prophylaxis (but not in primary prophylaxis) these drugs can be combined with organic nitrates.

Unlabelled: The model for end-stage-liver-disease (MELD) is a mathematical score used to prioritize patients for liver transplantation and includes results for creatinine, bilirubin, and prothrombin time (PT) expressed as international normalized ratio (INR). The rationale of using the MELD rests on the assumption that the score would be the same across the country if the methods used to measure the variables yield the same numerical results regardless of the testing laboratory. Evidence was provided that specific methodologies may influence the MELD, and the PT-INR was identified as the most important. This study was designed to provide information on the between-thromboplastin variability and to explore alternatives to obviate such variability. Fifty-seven patients with cirrhosis were selected, and their PTs were measured with 7 thromboplastins. The thromboplastins were previously calibrated by testing plasmas from patients on vitamin K antagonists and healthy subjects to assign the international sensitivity index (ISI(vka)) needed to convert PT into INR. Each of the thromboplastins was also assigned an ISI(liver) by substituting in the calibration the plasmas from vitamin K antagonist patients with plasmas from patients with cirrhosis. INR and MELD values for individual patients were calculated by using the ISI(vka) or the ISI(liver). The mean INR(vka) obtained with the 7 thromboplastins were significantly different (P < 0.001). Conversely, the mean INR(liver) were not. Similarly, the mean MELD(vka) were significantly different (P < 0.001), but those differences were abrogated for the MELD(liver)., Conclusion: The alternative thromboplastin calibration using plasmas from patients with cirrhosis instead of from vitamin K antagonist patients is feasible and may resolve the variability of the MELD to prioritize patients for transplantation.