[TEN-HOUR INTERMITTENT FASTING PLUS MEDITERRANEAN DIET VERSUS MEDITERRANEAN DIET ALONE FOR TREATMENT OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)].

INTRODUCTION: Nonalcoholic Fatty Liver Disease (NAFLD) has become the leading cause of liver morbidity. The Mediterranean diet can improve NAFLD and may be offered as treatment. Intermittent fasting has been shown to improve aspects of the metabolic syndrome, but its effect on NAFLD is inconclusive. OBJECTIVES: A randomized - controlled study assessed the outcomes of the effect of the Mediterranean diet alone versus the Mediterranean diet in combination with intermittent fasting for 16 weeks in patients with NAFLD (1:2 ratio) and subsequent long term follow-up. Outcomes parameters included the response to treatment as measured by body mass index (height and weight), waist-hip ratio, and levels of steatosis and fibrosis as measured by transient elastography. In addition, satisfaction and compliance were assessed via questionnaires (ten-point Likert scale). RESULTS: Sixteen out of 40 recruited patients completed the study (69% men, mean age 45.8 ± 12.1 years, mean baseline BMI 33 ± 4.5), of which nine patients were included in the arm of diet in combination with intermittent fasting. The two groups were similar at baseline with regard to age, gender, height, weight, BMI, waist to hip ratio, and levels of steatosis and fibrosis. At the study end, a significant decrease was observed (p-value = 0.01) in the degree of steatosis from 316.4 ± 50.4 to 279 ± 35.7 DB/m. The improvement in steatosis was significant (p-value = 0.01) in the intermittent fasting group (an improvement of 13.8 ± 20.9%) as compared to the group without intermittent fasting (4.2 ± 20.9%, no statistical significance). The other physical outcome measures did not show a statistically significant change between values at the beginning of the study and study end (16 weeks). Participant questionnaires were completed at a mean follow-up of 1.6 ± 0.2 years and showed a high level (8.3 ± 1.69) of compliance at the beginning of the study in both groups. In addition, both study groups expressed a similar degree of difficulty in adhering to the assigned diet. By study end, participant adherence was significantly higher (p-value = 0.04) among the Mediterranean diet group alone (7 ± 2) as compared to the group in combination with intermittent fasting (4.9 ± 2). Furthermore, those in the Mediterranean diet alone group were more willing (9.7 ± 0.8) to continue the dietary treatment after completing the study as compared to the intermittent fasting group (6.4 ± 0.7) (p-value = 0.03). Study participants in both groups reported that their dietary treatment was overall beneficial (7.9 ± 2.2). CONCLUSIONS: This study, given the limitations of a small sample size, suggests that a Mediterranean diet in combination with intermittent fasting improves steatosis in NAFLD patients over the long term as compared to Mediterranean diet without time restricted eating.

Gastrointestinal manifestations of synthetic cannabinoids: a retrospective cohort study.

BACKGROUND: Synthetic cannabinoids (SC) are chemical substances which activate cannabinoid receptors similarly to tetrahydrocannabinol, but with a higher efficacy. These substances are used as illicit recreational drugs, often smoked as herbal mixtures. The continuing availability and rapid evolution of SC is an ongoing health risk. The adverse effects of SC are wide ranging, and span from mild behavioral changes to death. Knowledge regarding gastrointestinal (GI) manifestations of SC use is sparse. METHODS: Single tertiary-care referral medical center retrospective study. RESULTS: The medical records of patients presented to hospital emergency care due to SC use between January 2014 and February 2018 were retrieved from Hadassah Mount Scopus Hospital's computerized database. The records were reviewed for clinical outcomes and laboratory tests. Fifty-five (55) patients were identified with a hospital presentation due to SC use. Twenty-one (21) out of 55 patients (38%) reported gastrointestinal complaints. The most common complaints were abdominal pain and vomiting. Of those, 28% had recurrent emergency department presentations due to abdominal pain and 66% presented with leukocytosis. Serum lactate was elevated in 66% of patients with GI manifestations. One patient had an abnormal computerized tomography (CT) abdominal angiography scan, which was compatible with intestinal ischemia. CONCLUSIONS: The clinical spectrum of gastrointestinal manifestations in SC intoxication ranges from mild symptoms, such as abdominal pain and vomiting, to even more severe symptoms suggestive of intestinal ischemia. Clinicians should be aware that abdominal pain and other gastrointestinal complaints can be associated with SC use.

State of the art review with literature summary on gastric peroral endoscopic pyloromyotomy for gastroparesis.

Gastroparesis is a debilitating progressive disease that significantly impacts a patient's life with limited and challenging treatments available. Although the pathogenesis is multifactorial, pylorospasm is believed to have a major underlying role. Several therapeutic interventions directed to the pylorus have been developed over the last decade, including intra-pyloric injections of botulinum toxin, transpyloric stenting, and surgical pyloroplasty. All of these treatment options had limited and disappointing results. More recently, gastric peroral endoscopic myotomy (G-POEM) has been reported as a treatment for refractory gastroparesis. In this review article, we provide an overview on gastroparesis with a focus on the therapeutic interventions. In addition, we provide a literature summary and pool analysis of the clinical efficacy, scintigraphic efficacy, and safety profile of all studies that evaluated G-POEM in gastroparesis. Overall, seven studies have reported on the use of G-POEM in gastroparesis, and the pooled analysis of these studies showed a technical success of 100%, with clinical efficacy as assessed by the Gastroparesis Cardinal Symptoms Index of 81.5%, gastric emptying scintigraphy normalization in approximately 55.5% of the cases, perioperative complications in 7.6%, and intraoperative complications in 6.6%. This suggests that G-POEM is a new promising therapeutic intervention for the treatment of gastroparesis with durable effect and limited potential adverse events.

SARS-CoV-2 vaccine alleviates disease burden and severity in liver transplant recipients even with low antibody titers.

BACKGROUND AND AIMS: We retrospectively assessed the clinical Pfizer's mRNA SARS-CoV-2 BNT162b2 vaccination outcomes and the serologic impact on liver transplant (LT) recipients. PATIENTS AND METHODS: One hundred and sixty-seven LT cases followed between March 1, 2020 and September 25, 2021, and were stratified into two groups: (1) 37 LT recipients after SARS-CoV-2 infection before vaccine era and (2) 130 LT recipients vaccinated with 2 doses without earlier SARS-CoV-2 exposure. Serum SARS-CoV-2 spike immunoglobulins (anti-S) were assessed 7 days following vaccination (Liaison assay). RESULTS: In addition to the 37 nonvaccinated cases (22.2% of total group) who experienced SARS-CoV-2 infection (34 symptomatic and 3 asymptomatic), another 8 vaccinated symptomatic recipients (4.8%) were infected (5 from the third and three from the fourth waves). Three of the 45 infected cases died (6.7%) before the vaccine program. Vaccinated group: of the 130 LT vaccinated recipients, 8 (6.2%) got infected postvaccination (added to the infected group) and were defined as clinical vaccine failure; 38 (29.2%) were serological vaccine failure (total failure 35.4%), and 64.6% cases were serological vaccine responders (anti-S≥19 AU/mL). Longer post-LT interval and lower consumption of immunosuppressants (steroids, FK506, and mycophenolate mofetil) correlated with favorable SARS-CoV-2 vaccine response. Mammalian target of rapamycin inhibitors improved vaccine outcomes associated with lower FK506 dosages and serum levels. Patients with anti-S levels <100 AU/mL risked losing serologic response or being infected with SARS-CoV-2. A booster dose achieved an effective serologic response in a third of failures and most responders, securing better and possibly longer protection. CONCLUSION: Pfizer's BNT162b2 vaccine seems to lessen SARS-CoV-2 morbidity and mortality of LT recipients even with weak serological immunogenicity. Switching mycophenolate mofetil to mammalian target of rapamycin inhibitors might be effective before boosters in vaccine failure cases. A booster vaccine should be considered for nonresponders and low-responders after the second dose.

Advanced Liver Fibrosis Correlates With Impaired Efficacy of Pfizer-BioNTech COVID-19 Vaccine in Medical Employees.

The Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine has been offered to nonallergic ≥16-year-old Israeli adults since December 19, 2020. Data regarding factors associated with vaccine ineffectiveness are limited. The aim of this study is to assess the impact of hepatic fibrosis on the efficacy of the BioNTech vaccine. Serum severe acute respiratory syndrome coronavirus 2 spike immunoglobulins (S IgG) obtained at least 7 days following vaccination completion was correlated with the prevaccine calculated Fibrosis-4 (FIB-4) score among 719 employees in the Hadassah Medical Center, Jerusalem. Positive vaccine response (S IgG levels ≥ 19 AU/mL) was found in 708 of 719 individuals (98.5%). Vaccine failure (S IgG levels < 19) was found in 11 (1.5%); of these, 7 were immunosuppressed. Mean FIB-4 available in 501 of 708 vaccine responders was 1.13 ± 0.66, mean age 51.4 ± 12.4 years (29.3% males), and mean S IgG titers 239.7 ± 86.1 AU/mL. Similar to the general population, 70.5% had normal FIB-4 (<1.3), 26.8% undetermined FIB-4 (1.3-2.67), and 2.7% advanced FIB-4 (>2.67). When divided into response subgroups, 158 of 501 individuals (30.1%) with IgG titers 19-100 AU/mL had a mean FIB-4 of 1.48 ± 0.82; 198 (39.5%) with IgG titers 101-200 AU/mL had mean FIB-4 of 1.22 ± 0.76; 83 (16.6%) with titers 201-300 AU/mL had mean FIB-4 of 1.04 ± 0.48; 38 (7.6%) individuals with IgG titers 301-400 AU/ml had a mean FIB-4 of 1.08 ± 0.63; and 121 (24.2%) with IgG titers >400 AU/mL had mean FIB-4 of 1.18 ± 0.87. Increased FIB-4, age, and male gender significantly correlated with lower postvaccine IgG titers (P < 0.001). FIB-4 results were confirmed using FibroScan data displaying advanced fibrosis impact on weakened COVID-19 vaccine response. Conclusion: Immune suppression, older age, male gender, and advanced chronic liver disease are risk factors for lower vaccine response. The FIB-4 provides a simple tool to prioritize candidates for third-dose vaccine booster.

Neurotransmitters and Neuropeptides decrease PD-1 in T cells of healthy subjects and patients with hepatocellular carcinoma (HCC), and increase their proliferation and eradication of HCC cells.

T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4+ T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1+ T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1+ T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.

Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis.

BACKGROUND: Namodenoson, an A3 adenosine receptor (A3AR) agonist, improved liver function/pathology in non-alcoholic steatohepatitis (NASH) preclinical models. AIM: To evaluate the efficacy and safety of namodenoson for the treatment of non-alcoholic fatty liver disease (NAFLD) with or without NASH METHODS: This phase 2 study included 60 patients with NAFLD (ALT ≥60 IU/L) who were randomised (1:1:1) to oral namodenoson 12.5 mg b.d. (n = 21), 25 mg b.d. (n = 19), or placebo (n = 20) for 12 weeks (total follow-up: 16 weeks). The main efficacy endpoint involved serum ALT after 12 weeks of treatment. RESULTS: Serum ALT decreased over time with namodenoson in a dose-dependent manner. The difference between change from baseline (CFB) for ALT in the namodenoson 25 mg b.d. arm vs placebo trended towards significance at 12 weeks (P = 0.066). Serum AST levels also decreased with namodenoson in a dose-dependent manner; at 12 weeks, the CFB for 25 mg b.d. vs placebo was significant (P = 0.03). At Week 12, 31.6% in the namodenoson 25 mg b.d. arm and 20.0% in the placebo arm achieved ALT normalisation (P = 0.405). At week 16, the respective rates were 36.8% and 10.0% (P = 0.038). A3AR expression levels were stable over time across study arms. Both doses of namodenoson were well tolerated with no drug-emergent severe adverse events, drug-drug interactions, hepatotoxicity, or deaths. Three adverse events were considered possibly related to study treatment: myalgia (12.5 mg b.d. arm), muscular weakness (25 mg b.d. arm), and headache (25 mg b.d. arm). CONCLUSION: A3AR is a valid target; namodenoson 25 mg b.d. was safe and demonstrated efficacy signals (ClinicalTrials.gov #NCT02927314).

Acute Portal Vein Thrombosis Predicts Concomitant Diagnosis of Hepatocellular Carcinoma in Cirrhotic Patients.

PURPOSE: Portal vein thrombosis (PVT) is a common condition in cirrhotic patients and mostly attributed to portal hypertension. The objective of our study was to examine the association of PVT with hepatocellular carcinoma (HCC) in cirrhotic patients. METHODS: A retrospective study was performed to identify cirrhotic patients with thrombosis of the portal system. Clinical and laboratory characteristics were collected and analyzed. RESULTS: Thirty-nine patients were identified. Twenty-four out of 39 patients with PVT did not develop HCC (group A) after follow-up time of 38.5 months from the diagnosis of PVT. Eight patients (20.5%) were diagnosed with HCC within two weeks following diagnosis of PVT (group B). Seven patients (17.9%) were diagnosed with tumor thrombus (group C) at time of PVT diagnosis. The average age was 53.5, 66.5, and 69 years for groups A, B, and C respectively. Most patients (75 and 87.5% for groups B and C respectively) diagnosed with PVT and HCC were males. The most common cause of cirrhosis in groups B and C was chronic hepatitis B virus infection (HBV) in 62.5% and 50% respectively. The most common clinical presentation of PVT in group A was abdominal pain in 55.5% compared to new/worsening ascites in 43% and 37.5% for groups B and C respectively. The platelet count in groups B and C was higher as compared to that in group A (126 and 125 vs. 107 thousand, P = NS). CONCLUSION: In 38.4% of cases, new diagnosis of PVT was associated with concomitant diagnosis of HCC. Identifiable risk factors were chronic HBV infection and higher platelet count.

Endoscopic Ultrasound-Guided Angiotherapy for Gastric Varices: A Single Center Experience.

There are limited efficacious therapeutic options for management of gastric variceal bleeding. Treatment modalities include transjugular intrahepatic portosystemic shunt, surgical shunts, and endoscopic interventions, including the recent advancement of endoscopic ultrasound (EUS)-guided coiling. We present a case series of 10 patients with portal hypertension (7 with liver cirrhosis and 3 without cirrhosis), complicated by gastric varices (GV) with bleeding. All cases were treated successfully with EUS-guided coiling leading to variceal eradication. There were 10 occurrences of minimal self-limited bleeding at the puncture site during the procedure, and only one occurrence of major bleeding that necessitated cyanoacrylate glue injection for homeostasis. There were no other adverse events within a mean follow-up time of 9.7 months (range, 1-28 months). Conclusion: In our series, EUS-guided angiotherapy was effective for GV eradication with a high safety profile.

Pesticide distribution and depletion kinetic determination in honey and beeswax: Model for pesticide occurrence and distribution in beehive products.

Beehive products such as honey, beeswax and recently pollen have been regarded for many years as appropriate sentinels for environmental pesticide pollutions. However, despite yearly application of hundreds of approved pesticides in agricultural fields, only a minor fraction of these organic compounds were actually detected in honey and beeswax samples. This observation has led us to question the general suitability of beehive products as a sentinel for synthetic organic pesticides applied in the field. The aim of the present study was to experimentally determine the distribution (logarithmic ratio of beeswax to honey pesticide concentration, LogD) and depletion kinetics (half-life) of selected pesticides in honey and beeswax as a measure of the latter matrixes to serve as a pesticide sentinel. The obtained parameters were used to extrapolate to pesticide burden in honey and beeswax samples collected from German and Israeli apiaries. In addition, we aimed to establish a mathematical model, enabling us to predict distribution of selected pesticides between honey to beeswax, by utilizing simple substance descriptors, namely, octanol/water partitioning coefficient, molar weight and Henry coefficient. Based on the present results, it appears that pesticides with LogD values > 1 and half-life in beeswax > 1 day, were likely to accumulate and detected in beeswax samples, and less likely to be found in honey. On the other hand, pesticides with negative LogD values were highly likely to be found in honey and less so in beeswax samples. Finally, pesticides with LogD values between 0-1 were expected to be found in both matrixes. The developed model was successfully applied to predict LogD values, thereby identifying octanol/water partitioning and molar weight as the most prominent substance descriptors, which affect pesticide distribution between honey and beeswax.

A Validated Score Assessing the Risk of an Intra-Abdominal Abscess in Patients with Crohn's Disease Presenting at the Emergency Department.

BACKGROUND AND AIMS: A majority of acutely ill Crohn's disease [CD] patients who present to Emergency Department [ED] will undergo an abdominal CT to rule out disease complications. We aimed to generate a simple non-invasive scoring model to predict the presence of an intra-abdominal abscess in CD patients in the ED. METHODS: We performed a retrospective case-control study at four Israeli hospitals from January 1, 2010 to May 30, 2018. Inclusion criteria included patients with an established diagnosis of CD that had cross-sectional abdominal imaging performed. A total of 322 patients were included, and 81 [25%] were diagnosed with an intra-abdominal abscess. RESULTS: In univariate analysis, ileo-colonic location (odds ratio [OR] 1.88, p = 0.0148), perianal CD [OR 7.01, p = 0.0004], fever [OR 1.88, p = 0.0247], neutrophil-to-lymphocyte ratio [OR 1.12, p < 0.0001], and C-reactive protein [OR 1.10, p < 0.0001] were significantly associated with abscess formation, whereas current use of corticosteroids was negatively associated with abscess formation [OR 0.46, 95% CI, 0.2-0.88, p = 0.0192]. We developed a diagnostic score that included five parameters that were significant on multivariate regression analysis, with assignment of weights for each variable according to the coefficient estimate. A low cut-off score of ≤7 was associated with a negative predictive value [NPV] of 93% for abscess formation, whereas a high cut-off score of >9 was associated with a positive predictive value of 65%. We validated this score with an independent cohort [area under the curve of 0.881 and NPV of 98.5%]. CONCLUSION: We recommend incorporating this score as an aid for stratifying acutely ill CD patients in the ED with low or high probability of the presence of an intra-abdominal abscess.

Current and Future Treatment of Hepatocellular Carcinoma: An Updated Comprehensive Review.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality. The principal treatment is surgical resection or liver transplantation, depending on whether the patient is a suitable transplant candidate. However, in most patients with HCC the diagnosis is often late, thereby excluding the patients from definitive surgical resection. Medical treatment includes sorafenib, which is the most commonly used systemic therapy; although, it has been shown to only minimally impact patient survival by several months. Chemotherapy and radiotherapy are generally ineffective. Due to the poor prognosis of patients with HCC, newer treatments are needed with several being in development, either in pre-clinical or clinical studies. In this review article, we provide an update on the current and future medical and surgical management of HCC.

Portal lymphadenopathy predicts non-alcoholic steatohepatitis and advanced fibrosis in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: The progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is believed to be the driver for future development of fibrosis and cirrhosis. Nevertheless, there remains a clear deficit in non-invasive methods for the diagnosis of NASH. The aim of the present study was to evaluate the prevalence of portal lymphadenopathy (PL) in biopsy- proven NAFLD patients and to determine whether PL correlates with NAFLD stage and severity. METHODS: A retrospective study included biopsy-proven NAFLD patients with up to date (within one year) abdominal imaging by computed tomography (CT) and/or magnetic resonance imaging (MRI). Patients were clustered into three groups based on their NAFLD Activity Score (NAS): NAS1-2 (mild), NAS3-4 (moderate) and NAS≥5 (advanced). We Assessed for association between PL and other clinical and laboratory findings with NAS, NAS components and fibrosis. RESULTS: Seventy-five patients with NAFLD and no other competing etiologies for liver diseases or PL were included. The mean age was 50.7±14.84 years with male predominance (N = 47, 62.7%). Twenty-five (33.3%), 37 (49.3%) and 13 (17.3%) patients had mild, moderate and advanced NAS, respectively. PL significantly correlated with advanced NAS ≥ 5 (Fisher's (F) 9.5, P = 0.009). Correlation was driven mainly by a link to hepatocytes ballooning (F of 5.9, P = 0.043). In addition, PL significantly correlated with portal inflammation (F 4.29, P = 0.038). As for hepatic fibrosis, the F test wasn't significant, though spearman's coefficient (SC) was significant (0.277, P = 0.012). On multivariate analysis, PL was identified as a sole predictor of advanced NAS score (Odds ratio of 2.68, P = 0.002). Incorporation of PL into noninvasive fibrosis scores improved their diagnostic yield. CONCLUSION: PL predicts severity of NAFLD. Its presence may serve as a novel radiological marker for NAFLD/NASH differentiation and disease progression.