The Contribution of Genetic and Epigenetic Factors: An Emerging Concept in the Assessment and Prognosis of Inflammatory Bowel Diseases.

Inflammatory bowel disease (IBD) represents heterogeneous and relapsing intestinal conditions with a severe impact on the quality of life of individuals and a continuously increasing prevalence. In recent years, the development of sequencing technology has provided new means of exploring the complex pathogenesis of IBD. An ideal solution is represented by the approach of precision medicine that investigates multiple cellular and molecular interactions, which are tools that perform a holistic, systematic, and impartial analysis of the genomic, transcriptomic, proteomic, metabolomic, and microbiomics sets. Hence, it has led to the orientation of current research towards the identification of new biomarkers that could be successfully used in the management of IBD patients. Multi-omics explores the dimension of variation in the characteristics of these diseases, offering the advantage of understanding the cellular and molecular mechanisms that affect intestinal homeostasis for a much better prediction of disease development and choice of treatment. This review focuses on the progress made in the field of prognostic and predictive biomarkers, highlighting the limitations, challenges, and also the opportunities associated with the application of genomics and epigenomics technologies in clinical practice.

Real-World Utilization of Corticosteroids in Severe Alcoholic Hepatitis: Eligibility, Response, and Outcomes.

Background and Objectives: Alcoholic hepatitis (AH) poses a medical challenge, causing moderately severe to life-threatening episodes with high short- and long-term mortality. This study aimed to explore real-world corticosteroid utilization in severe AH, response predictors, and patient outcomes. Materials and Methods: We conducted a retrospective study on patients admitted for severe AH, defined as a Maddrey Discriminant Function score equal to or above 32, at a tertiary care center. We reviewed patients' medical observation charts to identify corticosteroid prescriptions, reasons for ineligibility, and response rates. Responders were defined based on the Lille score, and predictors of non-response were identified. Short-term (one-month) and long-term (one-year) mortality rates were calculated according to treatment and response. Results: Out of 310 patients enrolled with severe AH, 59% received corticosteroids, achieving a response rate of 75.4%. The reasons for not administering corticosteroids were as follows: uncontrolled infections (27.6%), renal dysfunction (20.4%), gastrointestinal bleeding (18.9%), acute pancreatitis (7.1%), uncontrolled diabetes (3.1%), and other or unknown causes (22.8%). The overall 1-month mortality rate was 12.2%, higher in non-responders (35.3%) and patients who did not receive corticosteroids (13.4%) compared to responders (3.6%). The overall 1-year mortality rate was 62.5%, similar between patients who did not receive corticosteroids (78.7%) and non-responders (77.7%) and higher compared to responders (42.8%). Predictive factors for non-response included older age (OR = 1.05, 95%CI: 1.01-1.08), concomitant cirrhosis (OR= 2.11, 95% CI: 1.064-4.20), MELD scores exceeding 30 (OR = 2.42, 95% CI: 1.21-4.80), severe hypoalbuminemia (OR = 2.46, 95%CI: 1.12-5.37), and increased serum creatinine (OR = 1.5, 95% CI: 1.1-2.03). Among the prognostic scores, MELD 3.0 score exhibited superior efficacy for short-term (AUC = 0.734, 95% CI 0.656-0.811) and long-term mortality (AUC = 0.777, 95% CI: 0.724-0.830) compared to alternative scoring systems. Conclusions: Low eligibility rate and poor prognosis underscore the need for effective therapies. Our findings contribute to refining risk stratification and early prediction of non-response, aiding clinicians in identifying more beneficial therapies.

Reclassification of Inflammatory Bowel Disease Type Unclassified by Small Bowel Capsule Endoscopy.

Background and Objectives: Ulcerative colitis (UC) and Crohn's disease (CD) are idiopathic inflammatory bowel diseases (IBDs) without a unique, gold standard diagnostic test. UC and Crohn's colitis are impossible to distinguish in approximately 10% of cases. The term IBD type unclassified (IBD-U) is recommended for cases of chronic colitis showing overlapping endoscopic, radiological, and biopsy histological features between UC and CD, while indetermined colitis is reserved for colectomy specimens. Our aim was to assess the role of small-bowel capsule endoscopy (SBCE) in the diagnostic work-up of IBD-U. Materials and Methods: We retrospectively studied the cases of IBD-U explored by SBCE in a tertiary referral gastroenterology center. Patients were investigated using SBCE after contraindications were excluded. Diagnostic criteria for small bowel CD consisted in more than three ulcerations, irregular ulcers, or stenosis, and the Lewis score was used for the quantification of inflammation. The immediate impact of reclassification and outcome data was recorded over a follow-up period of more than one year. Results: Twenty-eight patients with IBD-U were examined using SBCE. Nine patients had small bowel lesions that met the diagnostic criteria for CD, resulting in a reclassification rate of 32.1%. In five of these cases, the treatment was subsequently changed. In the remaining nineteen examinations, no significant findings were observed. There were no complications associated with SBCE. Median follow-up time was 32.5 months (range 12-60). During follow-up, twelve patients were classified as having UC, and seven remained as having an unclassified type; one case of colectomy, for medically refractory UC, was recorded. Conclusions: SBCE is a useful safe tool in the work-up of IBD-U, allowing reclassification in about one third of cases, with subsequent treatment modifications. SBCE may provide a definite diagnosis, enhance the comprehension of the disease's progression, and optimize the short- and long-term management strategy.

Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease-Oxidative Stress and Inflammation Relevance.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Its incidence is progressively rising and it is possibly becoming a worldwide epidemic. NAFLD encompasses a spectrum of diseases accounting for the chronic accumulation of fat within the hepatocytes due to various causes, excluding excessive alcohol consumption. In this study, we aimed to focus on finding evidence regarding the implications of oxidative stress and inflammatory processes that form the multifaceted pathophysiological tableau in relation to thrombotic events that co-occur in NAFLD and associated chronic liver diseases. Recent evidence on the pathophysiology of NAFLD suggests that a complex pattern of multidirectional components, such as prooxidative, proinflammatory, and prothrombotic components, better explains the multiple factors that promote the mechanisms underlying the fatty acid excess and subsequent processes. As there is extensive evidence on the multi-component nature of NAFLD pathophysiology, further studies could address the complex interactions that underlie the development and progression of the disease. Therefore, this study aimed to describe possible pathophysiological mechanisms connecting the molecular impairments with the various clinical manifestations, focusing especially on the interactions among oxidative stress, inflammation, and coagulation dysfunctions. Thus, we described the possible bidirectional modulation among coagulation homeostasis, oxidative stress, and inflammation that occurs in the various stages of NAFLD.

A Comprehensive Overview of the Past, Current, and Future Randomized Controlled Trials in Hepatic Encephalopathy.

Background: Hepatic encephalopathy (HE) caused by cirrhosis has severe consequences on an individual's lifespan, leading to long-term liver complications and potentially life-threatening outcomes. Despite recent interest in this condition, the effectiveness of secondary prophylaxis involving rixafimin, lactulose, or L-ornithine L-aspartate (LOLA) may be hindered by the unique microbial profiles each patient possesses. Methods: Thus, in this manuscript, we aimed to search, identify, and gather all randomized controlled trials (RCTs) published between 2000-2023 (November) in four major academic databases such as PubMed, ISI Web of Science, Scopus, and ScienceDirect by using a controlled terminology and web strings that reunite six main keywords. We complementarily retrieved data on the ongoing RCTs. Results: Regardless of the relatively high number of results displayed (n = 75), 46.66% (n = 35) were initially deemed eligible after the first evaluation phase after removing duplicates, n = 40 (53.34%). At the second assessment stage, we eliminated 11.42% (n = 4) studies, of which n = 22 finally met the eligibility criteria to be included in the main body of the manuscript. In terms of RCTs, otherwise found in distinct stages of development, n = 3 target FMT and n = 1 probiotics. Conclusions: Although we benefit from the necessary information and technology to design novel strategies for microbiota, only probiotics and synbiotics have been extensively studied in the last decade compared to FMT.

Predictive Factors for the Prognosis of Alcoholic Liver Cirrhosis.

Alcoholic liver cirrhosis (ALC) is a disease with multiple complications and is associated with poor prognosis and significant mortality. Identifying risk factors associated with a poor outcome is important to ensure effective treatment and increase life expectancy. We aimed to evaluate the predictive values of complications regarding mortality in ALC. We retrospectively analyzed 1429 patients with ALC hospitalized between January 2019 and April 2022 at the Institute of Gastroenterology and Hepatology Iasi. The electronic medical records were interrogated to obtain information about demographic data, complications, comorbidities, and prognostic scores: MELD-Na (model for end-stage liver disease-sodium) and CTP (Child−Turcotte−Pugh). Based on uni- and multivariate analysis, independent predictors of mortality were identified. The mean age at diagnosis was 56.15 ± 11.49 years with a ratio of 2:1 in favor of males. There were 296 deaths (20.8%), most of them during the first hospitalization (208/14.6%). It was observed during the univariate analysis that complications of the disease negatively affected the survival rate, significant values being related to infections (sepsis; OR = 21.98; p < 0.001; spontaneous bacterial peritonitis (SBP) (OR = 11.94; p < 0.001) and hepatorenal syndrome (HRS) (OR = 9.35; p < 0.001). The independent predictors, confirmed by multivariate analysis, were the association of variceal bleeding, infections, and hepatic encephalopathy or ascites, each combination being responsible for two out of 10 of the deaths during the first admission. The prognosis of the disease was negatively influenced by the worsening of liver dysfunction and the appearance of complications. The main predictors of mortality were infections, hepatic encephalopathy, variceal bleeding, and hepatorenal syndrome. Improving compliance and strict application of specific follow-up and treatment strategies could contribute to a better prognosis of patients with alcoholic liver cirrhosis.

Deep Remission at 1 Year Prevents Progression of Early Crohn's Disease.

BACKGROUND & AIMS: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD). METHODS: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period. RESULTS: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome. CONCLUSIONS: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy.

The Risk of Clostridioides difficile Infection in Cirrhotic Patients Receiving Norfloxacin for Secondary Prophylaxis of Spontaneous Bacterial Peritonitis-A Real Life Cohort.

Background and Objectives: Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis. Antibiotic prophylaxis is effective but can lead to an increased incidence of Clostridioides difficile infection (CDI). The aim of this study was to evaluate the incidence of CDI and the risk factors in cirrhotic patients with a previous episode of SBP receiving norfloxacin as secondary prophylaxis. Materials and Methods: We performed a prospective, cohort study including patients with liver cirrhosis and SBP, successfully treated over a 2-year period in a tertiary university hospital. All the patients received secondary prophylaxis for SBP with norfloxacin 400 mg/day. Results: There were 122 patients with liver cirrhosis and SBP included (mean age 57.5 ± 10.8 years, 65.5% males). Alcoholic cirrhosis was the major etiology accounting for 63.1% of cases. The mean MELD score was 19.7 ± 6.1. Twenty-three (18.8%) of all patients developed CDI during follow-up, corresponding to an incidence of 24.8 cases per 10,000 person-years. The multivariate Cox regression analysis demonstrated that alcoholic LC etiology (HR 1.40, 95% CI 1.104-2.441, p = 0.029) and Child-Pugh C class (HR 2.50, 95% CI 1.257-3.850, p = 0.034) were independent risk factors for CDI development during norfloxacin secondary prophylaxis. The development of CDI did not influence the mortality rates in cirrhotic patients with SBP receiving norfloxacin. Conclusions: Cirrhotic patients with SBP and Child-Pugh C class and alcoholic liver cirrhosis had a higher risk of developing Clostridioides difficile infection during norfloxacin secondary prophylaxis. In patients with alcoholic Child-Pugh C class liver cirrhosis, alternative prophylaxis should be evaluated as SBP secondary prophylaxis.

L3 Skeletal Muscle Index Dynamics in Patients with HCV-Related Compensated Cirrhosis Following Sustained Virological Response after Direct Acting Antiviral Treatment.

Background and Objectives: Sarcopenia is commonly associated with liver cirrhosis and predicts clinical outcome. Our aim was to identify the changes in skeletal muscle index (SMI) on computed tomography (CT) examination, as a quantitative marker of sarcopenia, in patients with HCV-related cirrhosis after direct acting antivirals (DAAs) treatment and to assess predictive factors for the evolution of SMI. Materials and Methods: This is a single center retrospective study in patients with HCV-related compensated cirrhosis who obtained sustained virological response (SVR) after DAAs. CT examinations were performed in 52 patients before and within 5-24 months after treatment. The total muscle area (TMA) of abdominal muscle at the level of third lumbar vertebra (L3) was measured at baseline and after SVR. The L3-SMI was calculated from TMA divided by body height squared (cm2/m2). We assessed changes in L3-SMI after SVR according to baseline body mass index (BMI) and laboratory data. Predictive factors were assessed by linear regression model. Results: Patients with L3-SMI above the gender-specific cut-off value at baseline had higher values of serum creatinine (median 0.73) compared to patients with low L3-SMI (median 0.68, p = 0.031). After SVR, 14 patients showed increase of L3-SMI, and 38 patients had a decrease of L3-SMI. BMI in the decreased L3-SMI group was significantly lower (median 26.17) than those without decreased L3-SMI (median 28.84, p = 0.021). ALT values in the decreased L3-SMI group (median 66.5) were significantly lower than those without a decrease in L3-SMI (median 88, p = 0.045). Conclusions: Low creatinine serum level correlates with sarcopenia. SMI was partially influenced by the viral clearance. Lower BMI and ALT serum levels at baseline were predictive for no benefit in terms of muscle mass dynamics. Understanding all the mechanisms involved in sarcopenia and identifying the most vulnerable patients could ensure optimal adapted care strategies.

Irritable Bowel Syndrome between Molecular Approach and Clinical Expertise-Searching for Gap Fillers in the Oxidative Stress Way of Thinking.

Irritable bowel syndrome (IBS) remains to date an intriguing functional gastrointestinal disorder. Recent studies described a multitude of exogenous factors that work together in IBS, gradually impairing intestinal lining cellular metabolism, including oxidative status balance, with or without a genetic background. Although the current biomarkers support the differentiation between IBS subtypes and other functional gastrointestinal disorder, they are mostly non-specific, referring to clinical, biochemical, and inflammatory imbalances. Since IBS could be also the result of deficient signaling pathways involving both gastrointestinal secretion and neuro-vegetative stimulation, IBS makes no exception from the oxidative hypothesis in the pathological mechanisms. Regarding the oxidative stress implication in IBS, the previous research efforts showed controversial results, with some animal models and patient studies reporting clear oxidative imbalance both on systemic and local levels, but still with no concrete evidence to point to a direct correlation between oxidative stress and IBS. Additionally, it seems that a major role could be also attributed to gut microbiota and their ability to shape our bodies and behaviors. Moreover, the genetic features study in IBS patients showed that several genetic similarities point to a possible correlation of IBS with affective spectrum disorders. Thus, we focus here the discussion on the assumption that IBS could in fact be more likely a stress-related disorder rather than a gastrointestinal one.

Clinical Impact of Small Bowel Capsule Endoscopy in Obscure Gastrointestinal Bleeding.

Background and objectives: The most frequent indications for small bowel capsule endoscopy (SBCE) are obscure gastrointestinal bleeding (OGIB) and iron deficiency anemia (IDA). The aim of this study was to evaluate the diagnostic yield (DY) of SBCE in overt and occult OGIB, as well as its impact on the clinical outcome. Materials and Methods: This study retrospectively included all cases of OGIB investigated by SBCE in a tertiary care referral center, between 1st January 2016 and 31st December 2018. OGIB was defined by overt or occult gastrointestinal bleeding, with negative upper and lower endoscopy. Occult gastrointestinal bleeding was either proved by a fecal test or presumptively incriminated as a cause for IDA. DY was defined as the detection rate for what were thought to be clinically significant findings. DYs for overt and occult bleeding were assessed and compared. Gender, age, hemoglobin levels, NSAID consumption and the use of anticoagulants were recorded. Following SBCE results, individual therapeutic decisions were made, and follow-up data were recorded. Results: 224 SBCE examinations were performed for OGIB, of which 148 were for overt OGIB, and 76 for unexplained IDA. Positive findings were found in 139 patients, resulting in an overall DY for OGIB of 62%, higher in overt OGIB (75%) compared to IDA (37%). The most frequent findings were small bowel angioectasias (62.2% in overt OGIB and 78.5% in IDA). On multivariate logistic regression analysis, only hemoglobin level <10 g/dL and anticoagulants were the variables independently associated with positive findings. All patients received medical, endoscopic or surgical treatment and had good clinical outcome during follow-up. Conclusion: SBCE has a high diagnostic yield and a positive impact on management of patients with OGIB.

Liver Remodeling on CT Examination in Patients with HCV Compensated Cirrhosis Who Achieved Sustained Virological Response after Direct-Acting Antivirals Treatment.

Aims: The purpose of this study was to assess the changes in hepatic morphology evaluated by computed tomography (CT) examination in patients with hepatitis C virus (HCV)-related compensated cirrhosis who achieved sustained virologic response (SVR) after direct-acting antivirals (DAAs) treatment. Methods: CT examination was performed in 56 patients with HCV-related compensated cirrhosis before and within 6-18 months after the treatment with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir. The liver CT changes were assessed by measuring liver volume, caudate-right lobe ratio (C/RL), hepatic vessels diameters, periportal widening space, and right posterior notch. Portal trunk, splenic and superior mesenteric vein diameters, as well as spleen volume were assessed as part of portal hypertension. Results: Right hepatic vein diameter was significantly wider after treatment (median: 8.12 mm; IQR: 4.20) than before treatment (median: 6.36 mm; IQR: 3.94) z = -3.894; p < 0.001. The liver volume was significantly higher prior to the treatment (median: 1786.77 mm3; IQR: 879.23) than after treatment (median: 1716.44 mm3; IQR: 840.50), z = -1.970; p = 0.049. Splenic volume was considerably higher before treatment (median: 564.79 mm3; IQR: 342.54) than after (median: 474.45 mm3; IQR: 330.00), z = -2.500; p = 0.012. The other parameters, such as C/RL, periportal space widening, and right hepatic notch showed no significant changes. Conclusions: SVR in patients with HCV-related compensated cirrhosis treated with DAAs is associated with some improvements of hepatic morphology detectable by CT, the most constant being the increase of right hepatic vein diameter.

Systemic Oxidative Stress Markers in Cirrhotic Patients with Hepatic Encephalopathy: Possible Connections with Systemic Ammoniemia.

Background and objectives: Oxidative stress shows evidence of dysregulation in cirrhotic patients with hepatic encephalopathy (HE), although there are still controversies regarding the connections between oxidative stress and ammonia in these patients. The aim of this study was to evaluate the oxidative stress implication in overt HE pathogenesis of cirrhotic patients. Materials and Methods: We performed a prospective case-control study, which included 40 patients divided into two groups: group A consisted of 20 cirrhotic patients with HE and increased systemic ammoniemia, and group B consisted of 20 cirrhotic patients with HE and normal systemic ammoniemia. The control group consisted of 21 healthy subjects matched by age and sex. The activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) levels (lipid peroxidation marker), and ammoniemia were evaluated. Results: We found a significant decrease in SOD and GPx activity and also a significant increase of MDA levels in cirrhotic patients with HE as compared to the healthy age-matched control group (1.35 ± 0.08 vs. 0.90 ± 0.08 U/mL, p = 0.002; 0.093 ± 0.06 vs. 0.006 ± 0.008 U/mL, p = 0.001; and 35.94 ± 1.37 vs. 68.90 ± 5.68 nmols/mL, p = 0.0001, respectively). Additionally, we found significant correlations between the main oxidative stress markers and the levels of systemic ammonia (r = 0.452, p = 0.005). Patients from group A had a significant increase of MDA as compared with those from group B (76.93 ± 5.48 vs. 50.06 ± 5.60 nmols/mL, p = 0.019). Also, there was a compensatory increase in the activity of both antioxidant enzymes (SOD and GPx) in patients with increased systemic ammoniemia (group A), as compared to HE patients from group B. Conclusions: Our results demonstrated a significant decrease in antioxidants enzymes activities (SOD and GPx), as well as a significant increase in MDA concentrations, adding new data regarding the influence of oxidative stress in HE pathogenesis in cirrhotic patients.

Laparoscopic Cholecystectomy in Cirrhotic Patients.

Laparoscopic cholecystectomy is the gold standard procedure in patients with cirrhosis and symptomatic gallbladder disease or acute cholecystitis. In this retrospective study we evaluated laparoscopic cholecystectomy in patients with cirrhosis based on Child-Pugh score as a predictor of morbidity. In the First Surgical Clinic of Iasi, from 01 jan 2010 to 31 jan 2020, we performed 111 laparoscopic cholecystectomies in Child-Pugh A, B, and C cirrhotic patients. Intraoperative difficulty (grade 3 Cuschieri) was experienced in 32 patients (28.8%). Highly vascular sub hepatic adherences have been reported in a quarter of all patients. Intraoperative incidents were more frequent 27 (24.3%) compared to laparoscopic cholecystectomy performed in other patient groups. The conversion rate to open cholecystectomy was 6.3% (7 cases). Mean operative time was 84 min. Mean duration of hospitalization stay was 4.7 days. The morbidity rate was 16.2% of patients and included bleeding, intraabdominal fluid collections and wound complications more common in patients with Child-Pugh Cirrhosis B and C. The results are dependent of the perioperative management of the liver function.

Duodenoscope-associated infections: a review.

Flexible digestive endoscopes are used for the management of various conditions with hundreds of thousands of therapeutic procedures performed worldwide each year. Duodenoscopes are indispensable tools for the delivery of minimally invasive vital care of numerous pancreaticobiliary disorders. Despite the fact that nosocomial infections after endoscopic retrograde cholangiopancreatography (ERCP) have always been among the most frequently cited postprocedural complications, recent emergence of duodenoscope-transmitted multiple drug-resistant bacterial infections has led to intense research and debate yet with no clearly delineated solution. Duodenoscope-transmitted nosocomial infections have become one of the most visible topics in the recent literature. Hundreds of high-impact articles have therefore been published in the last decade. This review article discusses how such infections were seen in the past and what is the current situation in both research and practice and thus tries to solve some of the unanswered questions for the future. With the persistence of nosocomial infections despite strict adherence to both manufacturer-issued reprocessing protocols and international guidelines and regulations, an urgent and proper microbiologically driven common action is needed for controlling such nosocomial worldwide threat.

A Descriptive Review on the Prevalence of Gastrointestinal Disturbances and Their Multiple Associations in Autism Spectrum Disorder.

Background and Objectives: Gastrointestinal disturbances have been frequently, but not unanimously, reported in autism spectrum disorder (ASD) individuals. Thus, digestive symptoms, such as constipation, diarrhea, abdominal bloating, and pain have been reported to correlate to the various maladaptive behaviors in ASD children, such as irritability, social withdrawal, stereotypy, hyperactivity, and even language regression. In this context, the present study provides an overview on the prevalence of the gastrointestinal (GI) disorders in ASD and the correlation between these and ASD symptoms and comorbidities and subsequently discusses the metabolic and microbiome factors underlying the effects of GI disorders in ASD. Materials and Methods: For our analysis of GI symptoms in children with ASD, we have searched peer-reviewed journals from 2005 to 2017 in PubMed databases that addressed the specificity of GI symptoms in ASD and included correlations of GI and ASD symptoms. The criteria for inclusion were clear quantitative mentioning of GI modifications, GI symptoms correlation with specific ASD symptoms or comorbidities, an appropriate methodology for defining ASD, and larger size samples. For this topic, only studies on human patients and original research were considered. A subsequent search in PubMed databases in journals from 2000 to 2017 we analyzed 13 articles on the mechanisms underlying the impact of GI dysfunctions in ASD, including gut microbial dysbiosis, immune reactivity, genetics, and altered neurotransmitters on the gut-brain axis. Results: In the 18 original research studies that we selected out of an initial 327 studies, despite the different methodology, a predominant 83% highlighted the increased prevalence of GI symptoms in ASD patients. Constipation was most frequently cited, appearing in 12 of the studies (80%), followed by diarrhea reports in eight studies (53%). The association between cognitive and behavioral deficits and GI disorders was suggested in certain groups of ASD individuals. Conclusion: The evidence presented so far by numerous studies seems to indicate that GI dysfunctions are of particular relevance in ASD, underlined by various abnormalities along the nervous connections between the central nervous system and the gut, such as impaired parasympathetic activity and increased endocrine stress response. Sufficiently large size samples and standardized methodology are required for future studies to clarify the complex interactions between GI disturbances and ASD symptoms.

Preliminary Biochemical Description of Brain Oxidative Stress Status in Irritable Bowel Syndrome Contention-Stress Rat Model.

Background and objectives: Oxidative stress and inflammation have been implicated in the etiology of irritable bowel syndrome (IBS), a common gastrointestinal functional disease. This study aimed to further characterize the contention-stress rat model by exploring a possible correlation between oxidative stress markers measured in brain tissues with behavioral components of the aforementioned model. Thus, it is hereby proposed a possible IBS animal model relevant to pharmacological and complementary medicine studies. Materials and Methods: Wild-type male Wistar rats (n = 5/group) were chronically exposed to 6-hour/day contention, consisting of isolating the animals in small, vital space-granting plastic devices, for seven consecutive days. Following contention exposure, temporal lobes were extracted and subjected to biochemical analyses to assess oxidative stress-status parameters. Results: Our results show increased brain oxidative stress in contention-stress rat model: decreased superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde production in the IBS group, as compared to the control group. Furthermore, the biochemical ratios which are used to evaluate the effectiveness of an antioxidant system on oxidative stress could be described in this model. Conclusions: The correlations between the behavioral patterns and biochemical oxidative stress features could suggest that this may be a complex model, which can successfully mimic IBS symptomatology further providing evidence of a strong connection between the digestive system, enteric nervous system, and the central nervous system.

Improved Bone Safety of Tenofovir Alafenamide Compared to Tenofovir Disoproxil Fumarate Over 2 Years in Patients With Chronic HBV Infection.

BACKGROUND & AIMS: Long-term use of tenofovir disoproxil fumarate (TDF) reduces bone mineral density (BMD). Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has shown non-inferior efficacy to TDF in patients with chronic hepatitis B virus (HBV) infection, with improved bone effects at 48 weeks. We performed a randomized trial to evaluate the bone safety of TAF compared with TDF over 2 years, assessing baseline risk factors for bone loss, were evaluated after 2 years of treatment. METHODS: In a double-blind study, hepatitis B e antigen (HBeAg)-positive patients (n = 873) and HBeAg-negative patients (n = 425) were randomly assigned (2:1) to groups given TAF (25 mg; n = 866) or TDF (300 mg; n = 432) once daily. We assessed bone safety, including hip and spine BMD, using dual-energy X-ray absorptiometry and measured changes in serum markers of bone turnover over 96 weeks. RESULTS: At baseline, treatment groups were well matched. At week 96, patients receiving TAF had significantly smaller decreases in hip BMD (mean reduction of 0.33%) than patients receiving TDF (mean reduction of 2.51%) (P < .001) and spine BMD (reduction of 0.75% in patients receiving patients receiving TAF vs reduction of 2.57% in patients receiving TDF) (P < .001). For hip BMD, the magnitude of difference in bone loss between the TAF and TDF groups increased at week 96 compared to week 48 (P < .001). The TAF group had minimal changes in markers of bone turnover by 12 weeks of treatment, but the TDF group had significant changes, compared to baseline. Risk factors for bone loss had fewer effects in patients receiving TAF than TDF at week 96. CONCLUSIONS: In double-blind randomized trials, we found that after 2 years of treatment, patients receiving TAF had continued improvements in bone safety compared with patients receiving TDF. Clinicaltrial.gov ID NCT01940471 and NCT01940341.

Efficacy of immunotherapy with TG4040, peg-interferon, and ribavirin in a Phase 2 study of patients with chronic HCV infection.

BACKGROUND & AIMS: TG4040 is a modified vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα/RBV) in patients with chronic HCV infection. METHODS: Treatment-naive patients with HCV genotype 1 infection were assigned randomly to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n = 31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n = 63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n = 59). The primary end point was complete early virologic response (cEVR), defined as HCV-RNA level less than 10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment. RESULTS: In group C, 64.2% of evaluable patients achieved cEVR, compared with 30.0% in group A and 45.9% in group B (P = .0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were observed predominantly in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα-associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04. CONCLUSIONS: A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared with patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821.

Bridging the gap: Unveiling the crisis of physical inactivity in inflammatory bowel diseases.

In this editorial we comment on the article titled "Inflammatory bowel diseases patients suffer from significant low levels and barriers to physical activity: The BE-FIT-IBD study" published in a recent issue of the World Journal of Gastroenterology 2023; 29 (41): 5668-5682. Inflammatory bowel diseases (IBD) are emerging as a significant global health concern as their incidence continues to rise on a global scale, with detrimental impacts on quality of life. While many advances have been made regarding the management of the disease, physical inactivity in these patients represents an underexplored issue that may hold the key for further and better understanding the ramifications of IBD. Chronic pain, fatigue, and fear of exacerbating symptoms promotes physical inactivity among IBD patients, while the lack of clear guidelines on safe exercise regimens contributes to a norm of physical inactivity. Physical activity (PA) is accepted to have a positive effect on disease outcomes and quality of life, while inactivity exacerbates comorbidities like cardiovascular disease and mental health disorders. The "BE-FIT-IBD" study, focusing on PA levels and barriers in IBD patients of Southern Italy, revealed that a significant proportion (42.9%) were physically inactive. This lack of PA is attributed to barriers such as fear of flare-ups and misconceptions about exercise exacerbating the disease. The study also highlighted the need for better communication between healthcare providers and patients regarding the benefits of PA and safe incorporation into lifestyles. Moreover, physical inactivity may also contribute to disability in IBD patients, having a great impact on employment status. Of note is the fact that IBD also comes with an important psychological burden with relevant evidence suggesting that regular PA can improve mood, reduce anxiety, and enhance mental health. The "BE-FIT-IBD" study advocated for the integration of PA into IBD management, emphasizing the bidirectional link between PA and IBD. Regular exercise can influence the course of IBD, potentially reducing symptom severity and prolonging remission periods. As such, it is mandatory that healthcare providers actively educate patients, dispel misconceptions, and tailor exercise recommendations to improve the quality of life and reduce IBD-related complications.