Utility of Radiological Follow Up of Main-Duct Intraductal Papillary Mucinous Neoplasms and Mixed-Type Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) have the potential to evolve into pancreatic adenocarcinoma (PDAC). While main-duct IPMNs (MD-IPMNs), involving the main pancreatic duct (MPD), are less common than side-branch IPMNs (SB-IPMNs) or mixed-type IPMNs (mixed-IPMNs), their malignant transformation potential is far greater. Controversy exists between different guidelines in terms of recommended management strategies. This study was aimed at assessing the utility of the radiological follow up of MD-IPMNs and mixed-type IPMNs, including prevalence of worrisome radiological findings as well as clinical and laboratory parameters, and their correlation with the development of progression or pancreatic adenocarcinoma. METHODS: Eighty-four patients with MD-IPMNs or mixed-type IPMNs who underwent at least one magnetic resonance cholangiopancreatography (MRCP) were included. Clinical and laboratory data were obtained retrospectively. A cross-sectional analysis was carried out to establish clinical and laboratory parameters associated with development of PDAC. A retrospective cohort analysis was performed on 44 patients who had at least six months of follow up, trying to identify factors correlating with worrisome radiological features. RESULTS: Nine cases (10.7%) of PDAC were recorded in this cohort. The laboratory and imaging factors associated with cyst size progression greater than 5 mm during follow up were elevated alanine transaminase (ALT) levels, the maximal cyst size, and the MPD diameter. Cross-sectional analysis indicated that PDAC was associated with nausea (p = 0.01), as well as increased levels of aspartate aminotransferase (AST) (p = 0.05), gamma glutamyl transpeptidase (GGT) (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01). CONCLUSIONS: Elevated levels of liver enzymes were associated with IPMN progression and, subsequently, the development of PDAC. ALT levels, maximal cyst size, and MPD diameter are associated with the progression of cyst size. These data may aid in risk-stratifying patients when determining the follow up approach for IPMNs.

[THE MULTIDISCIPLINARY APPROACH TO ACUTE NECROTIZING PANCREATITIS].

INTRODUCTION: Acute pancreatitis is among the most common gastrointestinal diseases, and a major cause of hospitalization and morbidity. Gallstones and alcohol abuse are the most common causes of acute pancreatitis. Other etiologies include hypertriglyceridemia, medications, post- endoscopic retrograde cholangiopancreatography (ERCP), trauma, hypercalcemia, infections and toxins, anatomic anomalies, etc. In most cases acute pancreatitis is a mild self-limiting disease. However, up to 20% of patients develop severe pancreatitis with pancreatic necrosis, which possess high rates of multi-organ failure and mortality. Conservative management of acute necrotizing pancreatitis includes fluid resuscitation, nutritional support, and broad spectrum antibiotics for infected necrotic peripancreatic fluid collection (PFC). Indications for further invasive interventions include infected necrotic PFC and/or persistent severe symptoms due to mass effect. Current clinical management algorithms favor endoscopic ultrasound (EUS)-guided drainage of PFCs. In case of a large collection or extension to the paracolic gutters, a percutaneous drainage is indicated. Dual modalities (percutaneous together with endoscopic drainage) possess lower rates of pancreatic-cutaneous fistulas, shorter length of hospitalization and less endoscopic interventions. Direct endoscopic necrosectomy should be considered when the patient fails to improve despite endoscopic and percutaneous drainage. A multidisciplinary approach, which involves advanced endoscopists, interventional radiologists, pancreaticobiliary surgeons as well as nutrition and infectious disease specialists, is needed for the optimal management of severe necrotizing pancreatitis.

Safety of Pneumatic Dilation in Older Adults with Achalasia: An International Multicenter Cross-Sectional Study.

BACKGROUND: Pneumatic dilation (PD) is an effective first line treatment option for many patients with achalasia. PD use may be limited in adults with achalasia who are older than 65 because of concern for adverse events (AE), and less efficacious therapies are often utilized. We explored the periprocedural safety profile of PD in older adults. METHODS: An international real world cross-sectional study of patients undergoing PD between 2006-2020 in two tertiary centers. Thirty-day AEs were compared between older adults (65 and older) with achalasia and younger patients. RESULTS: A total of 252 patients underwent 319 PDs. In 319 PDs, 18 (5.7%) complications occurred: 6 (1.9%) perforations and 12 (3.8%) emergency department referrals with benign (non-perforation) chest pain, of which 9 (2.8%) were hospitalized. No bleeding or death occurred within 30 days. Perforation rates were similar in both age groups and across achalasia subtypes. Advanced age was protective of benign chest pain complications in univariate analysis, and the limited number of AEs precluded multivariable analysis. CONCLUSIONS: The safety of PD in older adults is at least comparable to that of younger patients and should be offered as an option for definitive therapy for older patients with achalasia. Our results may affect informed consent discussions.

Dysglycemia in non-functioning pancreatic neuroendocrine tumors (NF-PNET): Further insights into an under recognized entity.

Objective: Pancreatic neuroendocrine tumors (PNETs) are rare, but their incidence has risen significantly in recent years. Whereas diabetes mellitus (DM) is recognized in association with chronic pancreatitis and pancreatic cancer, it has not been well-characterized concerning non-functioning (NF)-PNETs.Study aim: to determine whether NF-PNETs are associated with DM/ Pre-DM and characterize the features of this putative association. Methods: Retrospective study to evaluate rate of Pre-DM /DM in subjects with NF-PNETs. Results: Study cohort of 129 patients with histologically confirmed NF-PNETs, ∼60% were men (M/F: 77/52). Abnormal glucose metabolism that preceded any treatment was seen in 70% of this cohort: overt DM in 34% and Pre-DM in 36% of the subjects. However, during follow-up, the overall prevalence rose to 80.6%, owing exclusively to newly diagnosed DM in subjects who received treatment.Patients with DM/Pre-DM were older (65 ± 11; 54 ± 14; p < 0.0001), the tumor was more commonly localized in the pancreatic body and tail (76.5% vs. 23.5% p = 0.03), while BMI (27 ± 6 vs. 28 ± 5 kg/m2), and tumor size (2.4 ± 2 vs. 2.9 ± 3.2 cm) were similar. The relative prevalence of DM in our cohort of NF-PNETs was 1.6 higher than that in the age and gender-adjusted general Israeli population (95 %CI: 1.197-2.212p = 0.03). Conclusions: We found a high rate of impaired glucose metabolism, either DM or Pre-DM, in a large cohort of NF-PNETs. The high prevalence of diabetes/pre-diabetes was unrelated to obesity or tumor size. This observation should increase awareness of the presence of DM on presentation or during treatment of "NF"-PNETs.

Esophagogastroduodenal Findings in Patients with Intraductal Papillary Mucinous Neoplasms.

The association between intraductal papillary mucinous neoplasms (IPMNs) and extra-pancreatic malignancies is controversial. This cross-sectional study compared esophagogastroduodenal findings in 340 IPMN patients to those of age- and gender-matched controls without known IPMNs who underwent esophagogastroduodenoscopies (EGDs) for similar clinical reasons. The presence of gastric and esophageal cancer, Barrett's esophagus, neuroendocrine tumors (NETs), gastrointestinal stromal tumors (GISTs), gastric adenomas, and ampullary tumors was assessed. The results showed that 4/340 (1.2%) of the IPMN patients had gastric cancer and 1/340 (0.3%) had esophageal cancer. The matched control group had a similar incidence of gastric cancer (5/340) (1.5%), with no esophageal cancer cases (p > 0.999). The overall incidence of other esophagogastroduodenal conditions did not significantly differ between the IPMN patients and the controls. However, the incidence of gastric cancer in the IPMN patients was higher than expected based on national cancer registry data (standardized incidence ratio of 31.39; p < 0.001; CI 8.38-78.76). In conclusion, IPMN patients have a significantly higher incidence of gastric cancer compared to the general population. However, the incidence of esophagogastroduodenal findings, including gastric and esophageal cancer, is similar between IPMN patients and those who undergo an EGD for similar clinical indications. Further research is needed to determine optimal surveillance strategies for IPMN patients regarding their risk of developing gastric cancer.

Psychological Factors Associated With Adherence to Oral Treatment in Ulcerative Colitis.

INTRODUCTION: Medication nonadherence in patients with ulcerative colitis (UC) can result in frequent relapses, severe disease, and higher risk of colorectal cancer. Behavioral models relying on motivation and perceived competence, like the self-determination theory (SDT), have been implicated in nonadherence; however, the SDT has not been evaluated in the adult UC population. We sought to examine the association between adherence to oral medications in patients with UC and psychological distress, relationship with health care providers, motivation, and competence. METHODS: We performed a cross-sectional study within the Inflammatory Bowel Disease (IBD) Partners online registry in which participants completed a baseline survey including demographic information, IBD history, symptoms, medication adherence, and psychosocial factors. Members of the registry with a diagnosis of UC received an online follow-up survey that included baseline questionnaires and assessment of competence, motivation, and patient-physician relationship. Logistic regression models were performed to determine the relationship between psychosocial factors, adherence modifiers, and medication adherence. RESULTS: Of the 410 UC patients included, 29% had low adherence to their medications, 36% had medium adherence, and 34% had high adherence. In the multivariable analysis, younger patients, those with a lower perceived competence, and those with worse relationship with their providers were more likely to have lower adherence to their medications. CONCLUSIONS: Poor adherence to oral medications in UC was associated with lower perceived competence and worse relationship with providers. Further interventions based on the SDT can potentially improve adherence and optimize patient care.

In a cross-sectional study within the Inflammatory Bowel Disease Partners online registry, poor adherence to oral medications in adult patients with ulcerative colitis was associated with lower perceived competence and worse relationship with providers.

Barriers and Facilitators of Hepatitis C Care in Persons Coinfected with Human Immunodeficiency Virus.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are often co-transmitted. Viral coinfection results in worse outcomes. Persons who inject drugs (PWIDs) face barriers to medical treatment, but HCV treatment is indicated and effective even with ongoing active drug use. We aimed to assess access to HCV care and treatment results in patients coinfected with HIV-HCV. This is a real-world retrospective single-center study of patients followed in the HIV clinic between 2002 and 2018. Linkage to care was defined as achieving care cascade steps: (1) hepatology clinic visit, (2) receiving prescription of anti-HCV treatment, and (3) documentation of sustained virologic response (SVR). Of 1660 patients with HIV, 254 with HIV-HCV coinfection were included. Only 39% of them achieved SVR. The rate limiting step was the engagement into hepatology care. Being a PWID was associated with ~50% reduced odds of achieving study outcomes, active drug use was associated with ~90% reduced odds. Older age was found to facilitate treatment success. Once treated, the rate of SVR was high in all populations. HCV is undertreated in coinfected young PWIDs. Further efforts should be directed to improve access to care in this marginalized population.

Pancreatic cyst fluid glucose: a rapid on-site diagnostic test for mucinous cysts.

Background: Pancreatic cystic fluid (PCF) analysis is frequently used for cyst diagnosis with carcinoembryonic antigen (CEA) being the most accepted biomarker. Low glucose levels in PCF were previously suggested as a marker for mucinous cysts. A bed-side glucometer is a point-of care, immediate, simple, and cheap method which requires a small volume of PCF. Objectives: The aim of our study was to identify the optimal glucose cut-off level for identifying mucinous cysts, evaluate the diagnostic accuracy of glucose compared to CEA, and validate glucometry against reference laboratory biochemical analysis. Design: A single-center prospective cohort study. Methods: Consecutive patients aged 18 and older, who underwent pancreatic cyst evaluation, at the Tel Aviv Medical Center between 2016 and 2021 were analyzed. Cyst type was defined based on clinical, laboratory, and radiologic findings. Glucose was measured using laboratory biochemical analysis and two glucometers. Receiver operating characteristic analysis derived sensitivity, specificity, and accuracy were calculated and McNemar test was used to compare between methods. Results: One hundred and one PCF samples were evaluated. The areas under the receiver operating characteristics curve for identifying mucinous cysts using glucometer, glucose laboratory, and their combination were 0.88 (p < 0.001), 0.92 (p < 0.001), and 0.93 (p < 0.001), respectively. A glucose level of 87 mg/dL was identified as the optimal laboratory glucose threshold value to detect mucinous cyst with a sensitivity of 90.9%, specificity of 83.3%, and accuracy of 89.3, higher in comparison to cyst fluid CEA. Furthermore, PCF glucose levels had the strongest association with mucinous cysts. Conclusion: Our findings suggest that PCF glucose level is more accurate than CEA for the diagnosis of mucinous cysts. Glucometry glucose level assessment demonstrated an excellent correlation with laboratory glucose measurements and may become a useful diagnostic test.

The Cytotoxic Effect of Isolated Cannabinoid Extracts on Polypoid Colorectal Tissue.

Purified cannabinoids have been shown to prevent proliferation and induce apoptosis in colorectal carcinoma cell lines. To assess the cytotoxic effect of cannabinoid extracts and purified cannabinoids on both colorectal polyps and normal colonic cells, as well as their synergistic interaction. Various blends were tested to identify the optimal synergistic effect. Methods: Biopsies from polyps and healthy colonic tissue were obtained from 22 patients undergoing colonic polypectomies. The toxicity of a variety of cannabinoid extracts and purified cannabinoids at different concentrations was evaluated. The synergistic effect of cannabinoids was calculated based on the cells' survival. Isolated cannabinoids illustrated different toxic effects on the viability of cells derived from colorectal polyps. THC-d8 and THC-d9 were the most toxic and exhibited persistent toxicity in all the polyps tested. CBD was more toxic to polypoid cells in comparison to normal colonic cells at a concentration of 15 µM. The combinations of the cannabinoids CBDV, THCV, CBDVA, CBCA, and CBGA exhibited a synergistic inhibitory effect on the viability of cells derived from colon polyps of patients. Isolated cannabinoid compounds interacted synergistically against colonic polyps, and some also possessed a differential toxic effect on polyp and adjacent colonic tissue, suggesting possible future therapeutic value.

Endoscopic ultrasound-guided radiofrequency ablation of premalignant pancreatic-cystic neoplasms and neuroendocrine tumors: prospective study.

BACKGROUND: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a developing therapeutic approach for premalignant pancreatic-cystic neoplasms (PCNs) and small pancreatic neuroendocrine tumors (PNETs). The safety and efficacy of pancreatic EUS-RFA were previously reported in small series. Herein we report our initial experience with RFA of PCNs and small PNETs. METHODS: This is a prospective single-center study including 12 patients with a median follow-up of 7 months, with either PCN or PNET &lt;2 cm. Eligible PCNs were either intraductal papillary mucinous neoplasms (IPMN) with worrisome features or mucinous cystic neoplasms (MCN) that were not eligible or refused surgery. Ablation was performed using a 19-gauge dedicated needle. RESULTS: Twelve patients were treated, five had PCNs (four IPMNs, one MCN; median size of 36 mm, range 12-60) and seven had PNETs (median size 8.9 mm, range 6-18). Among patients with PCNs, the complete radiologic response was achieved in 3/5 (60%), partial response in 1/5 (20%) and failure in 1/5 (20%). Among six patients with nonfunctioning PNETs, the complete radiologic response was achieved in 4/6 (66.7%), partial radiologic response in 0/6 (0%) and failure in 2/6 (33.3%). Following a median follow-up of 7 months. One patient with insulinoma showed complete resolution of hypoglycemia-related symptoms. Three postprocedural adverse events occurred, including one case (1/12, 8.3%) of mild acute pancreatitis and two cases (2/12, 16.7%) of abdominal pain. CONCLUSION: EUS-guided RFA for premalignant PCNs and PNETs is feasible and well-tolerated. Efficacy would be further evaluated with continued follow-up of patients.

Increased prevalence of colorectal neoplasia in patients with intraductal papillary mucinous neoplasms.

Background: The association between intraductal papillary mucinous neoplasms (IPMNs) and colorectal cancer (CRC) and polyps is controversial. Objectives: To compare the prevalence of CRC and colorectal polyps among patients with IPMN and matched average risk individuals. Methods: A match cross-sectional historical study comparing colonoscopy findings of 310 patients with IPMN cysts who underwent at least one colonoscopy examination from 2004 through 2019, with 310 age- and gender-matched average risk participants who underwent a screening colonoscopy. CRC and polyps were assessed in both groups. The prevalence and odds ratio were calculated. Results: CRC was diagnosed in 16 of 310 patients with IPMN (5.2%), and at least one polyp was detected in 96 patients (31%). The prevalence of CRC was greater among patients with IPMN than in matched individuals [5.2% versus 1.3%, p = 0.012, prevalence odds ratio (POR) 4, confidence interval (CI) 1.29-16.44]. The overall prevalence of polyps was not higher among patients with IPMN than in matched individuals (31% versus 26.8%, p = 0.291, POR 1.22, CI 0.85-1.76). However, the prevalence of colorectal adenomas with high-grade dysplasia was higher in patients with IPMN than in matched individuals (4.2% versus 1%, p = 0.02, POR 4.33, CI, 1.19-23.7). The prevalence of large polyps (i.e. more than 20 mm in size) was also greater in patients with IPMN than in matched individuals (6.1% versus 1.9%, p = 0.011, POR 3.6, CI, 1.29-12.40). Conclusion: Patients with IPMN have a significantly higher prevalence of CRC and advanced polyps than the average risk population. In view of our findings, we suggest that once the diagnosis of IPMN is made, special consideration of CRC should be undertaken.

Adolescent Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Young Adulthood.

CONTEXT: The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. OBJECTIVE: To assess type 2 diabetes risk among adolescents with NAFLD. DESIGN AND SETTING: A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997-2011 and were followed until December 31, 2016. PARTICIPANTS: A total of 1 025 796 normoglycemic adolescents were included. INTERVENTIONS: Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. MAIN OUTCOME MEASURES: Type 2 diabetes incidence. RESULTS: During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47-4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). CONCLUSIONS: Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.

Serum MMP-9: a novel biomarker for prediction of clinical relapse in patients with quiescent Crohn's disease, a post hoc analysis.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is a novel marker of intestinal inflammation. The aim of this study was to assess if serum MMP-9 levels predict clinical flare in patients with quiescent Crohn's disease (CD). METHODS: This study was a post hoc analysis of a prospective observational study in which quiescent CD patients were included and followed until clinical relapse or the end of a 2-year follow-up period. Serial C-reactive protein (CRP) and fecal calprotectin (FC) levels were measured, and the patients underwent repeated capsule endoscopies (CEs) every 6 months. Small bowel inflammation was quantified by Lewis score (LS) for CE. A baseline magnetic resonance enterography was also performed, and MaRIA score was calculated. Serum MMP-9 levels in baseline blood samples were quantified by ELISA. RESULTS: Out of 58 eligible enrolled patients, 16 had a flare. Higher levels of baseline MMP-9 were found in patients who developed subsequent symptomatic flare compared with patients who did not [median 661 ng/ml, 25-75 interquartile range (IQR; 478.2-1441.3) versus 525.5 ng/ ml (339-662.7), respectively, p = 0.01]. Patients with serum MMP-9 levels of 945 ng/ ml or higher were at increased risk for relapse within 24 months [area under the curve (AUC) of 0.72 [95% confidence interval (CI): 0.56-0.88]; hazard ratio 8.1 (95% CI 3.0-21.9, p < 0.001)]. Serum MMP-9 concentrations showed weak and moderate correlation to baseline LS and FC, respectively (r = 0.31, p = 0.02; r = 0.46, p < 0.001). No correlation was found between serum MMP-9 to CRP and MaRIA score. CONCLUSIONS: Serum MMP-9 may be a promising biomarker for prediction of clinical flare in CD patients with quiescent disease.

Endoscopic ultrasound-guided liver biopsy using a 22-G fine needle biopsy needle: a prospective study.

BACKGROUND: Endoscopic ultrasound-guided liver biopsy (EUS-LB) using a 19-gauge (19-G) EUS needle is becoming increasingly popular. We evaluated the efficacy and safety of a 22-G EUS fine needle biopsy (FNB) needle for performing EUS-LB. METHODS: Patients referred for evaluation of elevated liver enzymes and without obstructive disease requiring endoscopic retrograde cholangiopancreatography (ERCP) were included. Using a 22-G FNB needle, two passes were made from the left lobe and one from the right. The main outcome measure was adequacy of the specimen for histology interpretation, and the secondary outcome was the safety of EUS-guided liver biopsy with a 22-G FNB needle. Patients were followed for post-procedure complications for 30 days. RESULTS: 40 patients (median age 61 years; 26 women) underwent EUS-LB. Analyzing by needle passes, the median longest core fragment was 12 mm (1st quartile - 3rd quartile 10 mm - 16.25 mm, interquartile range [IQR] 6.25 mm) from the left lobe and 11 mm (10 mm - 15.75 mm, IQR 5.75 mm) from the right lobe. The median cumulative core length per patient was 55 mm (44.5 mm - 68 mm, IQR 23.5 mm). The median cumulative number of complete portal triads (CPTs) per patient was 42 (28.5 - 53, IQR 24.5). The specimen was considered adequate in all 40 patients (100 %). Self-limiting abdominal pain was reported in 6 patients (15 %). CONCLUSIONS: EUS-LB using a 22-G FNB needle is a safe and viable alternative to the use of larger gauge needles, yielding adequate tissue for evaluation of parenchymal disease in 100 % of the patients.

Characteristics of Pericardial Biopsy: 100 Cases in a Single Center.

BACKGROUND: Pericardial biopsies are rarely performed during the diagnosis and management of pericardial diseases. The circumstances and clinical profile of patients undergoing pericardial biopsies are largely uncharacterized. OBJECTIVES: To examine the circumstances in which pericardial biopsies are obtained and to evaluate their diagnostic yield. METHODS: We studied a total of 100 cases (71% males, mean age 60.8 years, range 8.1-84.5 years) of surgically resected pericardium specimens obtained from 2000 to 2015 at Sheba Medical Center, the largest medical center in Israel. Patients were classified into groups according to four major histological etiologies: idiopathic pericarditis, constrictive pericarditis, malignant pericarditis, and post-cardiac injury syndrome (PCIS). The clinical history and course, laboratory, echocardiography, and histological results were reviewed retrospectively. RESULTS: Causes of pericarditis according to histological definitions included idiopathic pericarditis (29%), constrictive pericarditis (29%), PCIS (9%), and malignant pericarditis (26%). Overall sensitivity of the pericardial biopsy in patients with malignancy was 57.7%. During the study period, we found a trend toward an increased number of biopsies due to constrictive pericarditis and PCIS, along with a decrease in the number of biopsies performed in patients with malignant or idiopathic pericarditis. The diagnosis following biopsy did not change for any of the patients. CONCLUSIONS: Our findings suggest a low diagnostic yield from pericardial biopsies, especially in malignant pericarditis. This conclusion, along with novel therapies, resulted in the infrequent use of pericardial biopsy in recent years.

Immunomodulation of Murine Chronic DSS-Induced Colitis by Tuftsin-Phosphorylcholine.

Helminths or their products can immunomodulate the host immune system, and this phenomenon may be applied as the basis of new anti-inflammatory treatments. Previously, we have shown the efficacy of tuftsin-phosphorylcholine (TPC), based on a helminth product, in four animal models of autoimmune diseases: arthritis, colitis, systemic lupus erythematosus, and experimental autoimmune encephalomyelitis. We demonstrated that TPC reduced inflammatory process ex vivo in peripheral blood lymphocytes (PBLs) and in biopsies from giant-cell arteritis. In the present study, we assessed the therapeutic potential of TPC treatment on a chronic colitis murine model. C57BL/6 mice with chronic colitis were treated with TPC after the third cycle of 2% dextran sodium sulfate (DSS). Oral TPC treatment resulted in amelioration of the colitis clinical manifestations exemplified by reduced disease activity index (DAI) score, expansion of mesenteric lymph nodes (MLN) T regulatory cells (shown by Fluorescence Activated Cell Sorting (FACS)), significant reduction in the expression of pro-inflammatory cytokines (IL-1ß, IL17, IL-6, TNFα), and elevation in the expression of anti-inflammatory cytokine IL-10 (shown by RT-PCR). This study demonstrated the potential immunomodulatory effects of oral administration of TPC in a chronic colitis murine model. Further clinical trials are needed in order to evaluate this novel approach for the treatment of patients with inflammatory bowel disease.

Helminths-based bi-functional molecule, tuftsin-phosphorylcholine (TPC), ameliorates an established murine arthritis.

A novel small molecule named tuftsin-phosphorylcholine (TPC), which is linked to the biological activity of helminths, was constructed. The current study address the effect of TPC treatment in established collagen-induced arthritis (CIA) mice and propose TPC bi-functional activity. TPC treatment was initiated when clinical score was 2 to 4. Arthritis scores in TPC treated mice were lower compared to mice treated with vehicle (P < 0.001). Joint staining showed normal joint structure in TPC-treated mice compared to control groups treated with phosphate buffered saline (PBS), phosphorylcholine, or tuftsin, which exhibited severely inflamed joints. TPC enhanced anti-inflammatory response due to increased IL-10 secretion, and reduced pro-inflammatory cytokine secretion (IL-1-ß, IL-6, TNF-αP < 0.001). Furthermore, TPC therapy increased expansion of CD4+CD25+FOXP3+T regulatory cells and IL-10+CD5+CD1d+B regulatory cells. We propose that the immunomodulatory activity of TPC can be a result of a bi-specific activity of TPC: (a) The tuftsin part of the TPC shifts RAW macrophage cells from pro-inflammatory macrophages M1 to anti-inflammatory M2-secreting IL-10 (P < 0.001) through neuropilin-1 and (b) TPC significantly reduce mouse TLR4 expression via NFkB pathway by HEKTM cells (P < 0.02) via the phosphorylcholine site of the molecule. Our results indicate that TPC, significantly ameliorated established CIA by its immunomodulatory activity. These data could lead to a novel self bi-functional small molecule for treating patients with progressive RA.

Pericarditis among giant cell arteritis patients: From myth to reality.

BACKGROUND: Giant cell arteritis (GCA) is an inflammatory disease of unknown etiology affecting adults age > 50 years. GCA (also known as temporal arteritis) is a vasculitis of large and medium-size vessels that involves the extracranial branches of the carotid artery. Common manifestations include constitutional symptoms, headache, jaw claudication, scalp tenderness, and vision loss. Cardiac involvement in GCA is considered to be as low as 5%, and < 30 cases of pericarditis among GCA patients have been reported in the literature. The aim of this study was to evaluate the association between GCA and pericarditis by conducting a cross-sectional study utilizing the database of the largest healthcare provider in Israel. HYPOTHESIS: GCA is associated with pericarditis. METHODS: The proportion of past documentation of pericarditis among patients diagnosed with GCA was compared with that of their age- and sex-matched controls. Univariate analysis was performed using the χ2 and t tests; multivariate analysis was performed using logistic regression. RESULTS: The study included 4329 GCA patients and 21 611 controls. GCA patients had higher rates of cardiovascular risk factors. Pericarditis was observed in 53 GCA patients and 72 controls (1.22% vs 0.33%, respectively; P < 0.001), significantly higher among GCA patients in comparison with controls. A significant interaction was found between GCA, pericarditis, and young age (<70 years). CONCLUSIONS: The study showed an independent association between GCA and pericarditis, especially among young patients. Proper screening should be applied whenever a suspicion arises as to the existence of comorbidity in patients with either disease.

An infodemiological investigation of the so-called "Fluad effect" during the 2014/2015 influenza vaccination campaign in Italy: Ethical and historical implications.

Influenza vaccines represent a major tool to contain the clinical and epidemiological burden generated by influenza. However, in spite of their effectiveness, vaccines are victims of prejudices and false myths, which contribute to the increasing phenomenon of vaccine hesitancy and loss of confidence. Media and, mainly, new media, and information and communication technologies play a major role in disseminating health-related information. While, on the one hand, they can be extremely promising in promoting disease prevention, on the other hand, they can also have a negative impact on population's health attitudes and behaviors when delivering information not based on scientific evidences. The "Fluad-case" is an excellent example of the crucial role of an adequate information campaign. Following the cluster of deaths allegedly related to the administration of the adjuvanted influenza vaccine "Fluad" during the 2014-2015 influenza campaign, the Italian health authorities and regulatory bodies decided the withdrawal of two potentially contaminated Fluad batches. This fostered a huge media coverage, with resulted in negatively impacting on influenza vaccination coverage. Monitoring and tracking the Fluad-related web searches, we showed that Liguria resulted the Italian region with the highest number of Fluad-related website searches and that, interestingly, Fluad was searched also in Regions in which this vaccine was not distributed. A positive moderate correlation between accessing Fluad-related websites and overall influenza vaccination coverage was found (r = 0.66 ([95%CI 0.29-0.86], p = 0.0026). Considering subjects ≥65 years, who are the subjects for which the Fluad vaccination is recommended, the correlation resulted r = 0.49 ([95%CI 0.03-0.78], p = 0.0397). As such, health authorities and decision-makers should promote high-quality communication campaigns in order to raise awareness of vaccination practices.

Time to diagnosis of fibromyalgia and factors associated with delayed diagnosis in primary care.

Fibromyalgia is a complex disorder, and its diagnosis often comprises a challenge for physicians. We aimed to assess the time from the appearance of early symptoms to the definite diagnosis of fibromyalgia and to delineate patient and physician factors associated with this delay. The database of a large healthcare services provider was searched for all fibromyalgia patients (age 21 years or more) diagnosed during 2008-2011. Patients with a diagnosis confirmed by a physician with a relevant specialization were compared with age- and sex-matched nonfibromyalgia controls to retrospectively identify an initial complaint pattern characteristic of fibromyalgia. The time from initial complaints to fibromyalgia diagnosis, as well as the fraction of time while the patient was treated continuously by the same primary physician as at time of diagnosis, was assessed among all eligible fibromyalgia patients. An initial complaint pattern was identified in 67.9% of 2,055 patients with confirmed fibromyalgia vs. 27.6% of 9,172 controls. Among 2,369 (69.0%) of all 3,434 eligible patients with fibromyalgia, mean (SD) total time to diagnosis was 6.42 (3.57) years and mean (SD) time while treated by the same primary physician as at diagnosis was 3.75 (3.26) years. Comorbidity, younger patient, and older physician age were associated with longer time to diagnosis. By analysis of "real-world" data, fibromyalgia remains a complex and elusive diagnosis, taking years to be properly diagnosed. There is a need to increase the awareness of this syndrome among physicians, especially of older age.