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Adi Lahat,1 Yehudith Assouline-Dayan,1 Lior H Katz,1 Herma H Fidder2 1Chaim Sheba Medical Center, Tel Hashomer, Israel; 2Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands Background and aim: The sex of the physician performing the endoscopic procedure is one of the parameters influencing patient satisfaction. Our aim was to characterize patients’ preferences according to their sex, socioeconomic status, and religious beliefs and according to procedure-related variables. Methods: All patients undergoing an endoscopic procedure at Sheba Hospital between April 2012 and September 2012 were asked to complete a questionnaire regarding their sex, ethnic background, socioeconomic status, religious practice, and preference for an endoscopist of a specific sex. Questionnaires were included for analysis only when more than 95% of the items were addressed. Results: A total of 1,009 patients agreed to complete the questionnaires; of these 946 (94% [59% male]) were eligible for inclusion. Most patients (675 [70%]) expressed no preference for sex of the endoscopist, while 234 patients (25%) preferred a same-sex endoscopist, and only 55 (6%) preferred an other-sex endoscopist. Stepwise logistic regression analysis showed that in female patients, lower education (odds ratio [OR] = 1.28), non-Jewish religion (OR = 4.86), orthodox religious practice (OR = 2.28), African or Asian ethnic origin (OR = 2.44), scheduled for colonoscopy (OR = 1.90), and no previous endoscopy experience (OR = 1.88) were all associated with a preference for a same-sex endoscopist. Conclusion: One-quarter of patients preferred the physician performing their examination to be of particular sex. Most of these patients preferred a same-sex endoscopist. Education level, intensity of religious practice, ethnic origin, and type of endoscopic examination were associated with a preference for a same-sex endoscopist. Addressing patients’ preferences may improve the atmosphere in the clinical environment, reduce stress, and facilitate better treatment and adherence to endoscopic surveillance programs. Keywords: endoscopy, patients’ satisfaction, compliance, patient’s preference

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8 + T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8 + T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy., (© 2024. The Author(s).)

Background : Sarcopenia is underdiagnosed in patients with inflammatory bowel disease (IBD). Low alanine transaminase (ALT) is associated with sarcopenia. We evaluated the association between low ALT and the presence of IBD and disease activity. Methods : Data were collected from a national Israeli health insurer cohort comprising 976,615 patients. Patients with a diagnosis of IBD were compared to healthy controls. After exclusion of patients with liver disease, ALT > 40 IU/L and age < 18, a total of 233,451 patients were included in the analysis. Low ALT was defined as <10 IU/L. Results : Low ALT was more common amongst patients with IBD than in healthy controls (7.76% vs. 5.7% p < 0.001). Low ALT was found in 148 (7.9%) of the patients with CD and 69 (6.9%) of the patients with UC. For CD, low ALT was associated with increased fecal calprotectin (FC) and CRP (223.00 μg/mg [63.45-631.50] vs. 98.50 [31.98-324.00], p < 0.001, 9.10 mg/L [3.22-19.32] vs. 3.20 [1.30-8.30], p < 0.001) and decreased albumin and hemoglobin (3.90 g/dL [3.60-4.20] vs. 4.30 [4.00-4.50], p < 0.001,12.20 g/dL [11.47-13.00] vs. 13.60 [12.60-14.70], p < 0.001). For UC, low ALT was associated with higher FC and CRP (226.50 μg/mg [143.00-537.00] vs. 107.00 [40.85-499.50], p = 0.057, 4.50 mg/L [1.90-11.62] vs. 2.30 [1.00-6.20], p < 0.001) and with lower albumin and hemoglobin (4.00 g/dL [3.62-4.18] vs. 4.30 [4.10-4.40], p < 0.001, 12.40 g/dL [11.60-13.20] vs. 13.60 [12.60-14.60], p < 0.001). These findings remained consistent following multivariate regression and in a propensity score-matched cohort. Conclusions : Low ALT is more common in patients with IBD and is associated with biochemical disease activity indices.

Background: Studies on the effect of computer-aided detection (CAD) in a daily clinical screening and surveillance colonoscopy population practice are scarce. The aim of this study was to evaluate a novel CAD system in a screening and surveillance colonoscopy population., Methods: This multicentre, randomised, controlled trial was done in ten hospitals in Europe, the USA, and Israel by 31 endoscopists. Patients referred for non-immunochemical faecal occult blood test (iFOBT) screening or surveillance colonoscopy were included. Patients were randomomly assigned to CAD-assisted colonoscopy or conventional colonoscopy; a subset was further randomly assigned to undergo tandem colonoscopy: CAD followed by conventional colonoscopy or conventional colonoscopy followed by CAD. Primary objectives included adenoma per colonoscopy (APC) and adenoma per extraction (APE). Secondary objectives included adenoma miss rate (AMR) in the tandem colonoscopies. The study was registered at ClinicalTrials.gov, NCT04640792., Findings: A total of 916 patients were included in the modified intention-to-treat analysis: 449 in the CAD group and 467 in the conventional colonoscopy group. APC was higher with CAD compared with conventional colonoscopy (0·70 vs 0·51, p=0·015; 314 adenomas per 449 colonoscopies vs 238 adenomas per 467 colonoscopies; poisson effect ratio 1·372 [95% CI 1·068-1·769]), while showing non-inferiority of APE compared with conventional colonoscopy (0·59 vs 0·66; p<0·001 for non-inferiority; 314 of 536 extractions vs 238 of 360 extractions). AMR in the 127 (61 with CAD first, 66 with conventional colonoscopy first) patients completing tandem colonoscopy was 19% (11 of 59 detected during the second pass) in the CAD first group and 36% (16 of 45 detected during the second pass) in the conventional colonoscopy first group (p=0·024)., Interpretation: CAD increased adenoma detection in non-iFOBT screening and surveillance colonoscopies and reduced adenoma miss rates compared with conventional colonoscopy, without an increase in the resection of non-adenomatous lesions., Funding: Magentiq Eye., Competing Interests: Declaration of interests HN reports equipment from Magentiq Eye. AAB is a consultant for Boston Scientific Corp. SN is a consultant for Boston Scientific Corp, Olympus, and Neptune Medical. HJ reports consultancy fees from Magentiq Eye, and stock options from Magentiq Eye from activities before the clinical trial. PDS reports research support from Pentax, The eNose company, Lucid Diagnostics, Micro Tech, Motus GI, Magentiq Eye, Norgine, and Endo Tools Therapeutics, and consultancy fees from Motus GI and Magentiq Eye. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the APC I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the APC I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals., Competing Interests: Competing interests: BH is an employee and shareholder of Invitae Corp., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Frailty is a known risk factor for many diseases, including COVID-19. However, many frail patients are undiagnosed as the diagnosis can be cumbersome. Alanine transaminase (ALT) is found not only in the liver but also in the muscle tissue, and multiple studies show that frail sarcopenic patients have lower ALT. Frail patients are at increased risk for severe COVID-19. We evaluated the association between pre-infection low ALT and the risk for severe COVID-19., Methods: We collected data regarding all subjects tested for SARS-CoV-2 between 1 March 2020 and 31 December 2021 from a national state-mandatory HMO in Israel, serving more than 1.3 million patients. Clinical and laboratory data were collected, including ALT from the year prior to infection. Severe COVID-19 was defined either as death, ICU admission, or ≥10 hospitalization days. Patients with low ALT (ALT ≤ 10 IU/l) were compared with patients with normal ALT (11-40 IU/l). Patients younger than 18 years with a diagnosis of liver disease and with ALT > 40 IU/l were excluded., Results: During the study period, 58,961 patients tested positive for SARS-CoV-2. The patients in the low ALT group were younger (40.53 vs. 42.73, p < 0.001), less likely to be males (12.3 vs. 38.7%, p < 0.001), and had lower BMI (25.97 vs. 27.15, p < 0.001). The patients in the low ALT group had higher mortality (2.36 vs. 0.57%, p < 0.001), more ICU hospitalizations (0.49 vs. 0.41%, p = 0.47), and more prolonged hospitalizations [2.63% (95% CI 2-3.2%) vs. 0.98% (95% CI 0.86-1.1%) p < 0.001]. In multivariate logistic regression analyses, low ALT was associated with an increased risk of severe COVID-19, with increased mortality (OR 1.88, 95% CI 1.37-2.56) and prolonged hospitalization (OR 1.78, 95% CI 1.33-2.35)., Conclusion: Low ALT level prior to infection is a significant risk factor for morbidity and mortality from COVID-19 infection. Further studies are warranted to address treatment options for this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Genzel, Katz, Safadi, Rozenberg, Milgrom, Jacobs and Shafrir.)

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants ( path&#95;MMR ) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time., Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path&#95;MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender., Findings: Gynaecological cancers were more frequent than colorectal cancers in path&#95;MSH2, path&#95;MSH6 and path&#95;PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path&#95;MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path&#95;MMR carriers undergoing colonoscopy surveillance, particularly path&#95;MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers., Interpretation: In path&#95;MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome., Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017., Competing Interests: R.B. has received honoraria for lectures and advisory boards from AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Illumina, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc. R.B. is a Co-Founder and Scientific Advisor for Targos Mol. Pathology Inc. Kassel/Germany. T.T.S. is the CEO and co-owner of Healthfund Finland Oy and reports consultation fees from Boehringer Ingelheim Finland and Amgen. FB is supported by JANSSEN PHARMACEUTICALS (clinical trial for Familial Adenomatous polyposis). RH is supported by the 10.13039/501100002424Fujifilm Germany and Janssen-Pharmaceuticals. LK is consultant of Sandoz, Novartis and Abbott. GM reports consultancy fees from Johnson & Johnson., (© 2023 The Author(s).)

Inflammation has long been recognized to contribute to cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for bowel cancers, and it has been posited that a field of genetic changes may underlie this risk. Here, we define the clinical features, genomic landscape, and germline alterations in 174 patients with colitis-associated cancers and sequenced 29 synchronous or isolated dysplasia. TP53 alterations, an early and highly recurrent event in colitis-associated cancers, occur in half of dysplasia, largely as convergent evolution of independent events. Wnt pathway alterations are infrequent, and our data suggest transcriptional rewiring away from Wnt. Sequencing of multiple dysplasia/cancer lesions from mouse models and patients demonstrates rare shared alterations between lesions. These findings suggest neoplastic bowel lesions developing in a background of inflammation experience lineage plasticity away from Wnt activation early during tumorigenesis and largely occur as genetically independent events., (© 2023. The Author(s).)

Purpose: APC I1307K has a higher prevalence among Ashkenazi Jews (AJ), and a two-fold increased risk for colorectal cancer (CRC) compared to non-Jewish populations. We assessed CRC and extracolonic malignancies among I1307K carriers from AJ and non-AJ whites (NAW). Methods: We compared the rate of I1307K in cancer patients who underwent germline genetic testing via a multi-gene panel with healthy subjects retrieved from the gnomAD database. Cases undergoing testing were not selected and testing was undertaken through a commercial laboratory. Results: Overall, 586/7624 (7.6%) AJ with cancer carried I1307K compared to 342/4918 (6.9%) in the AJ control group (p = NS). In the NAW, 318/141,673 (0.2%) cancer patients and 73/58,918 (0.1%) controls carried the variant [OR = 1.8, (95% CI 1.41−2.35), p < 0.001]. I1307K in NAW was associated with an increased risk of CRC [OR = 1.95, (95% CI 1.39−2.73), p < 0.01], melanoma [OR = 2.54, (95% CI 1.57−3.98)], breast [females, OR = 1.73, (95% CI 1.18−2.65), p < 0.01], and prostate cancer [males, OR = 2.42, (95% CI 1.45−3.94), p < 0.01]. Among AJ, the variant increased the risk for CRC [OR = 1.67, (95% CI 1.36−2.05), p < 0.001] and renal cancer [OR = 1.64, (95% CI 1.04−2.47)]. AJ men had a higher risk for any cancer [OR = 1.32, (95% CI 1.05−1.66), p < 0.05] and melanoma [OR = 2.04, (95% CI 1.24−3.22); p < 0.05]. Conclusions: This is the most extensive study to date conducted on I1307K carriers, although it is amenable to selection bias. NAW carrying I1307K had a higher risk of any cancer and several specific cancer types, whereas AJ carrying the variant had a risk for only a few select cancers. Our data add to the research base on I1307 carriers concerning future risk management.

Background and Aims: There is conflicting evidence regarding the association between proton pump inhibitors (PPI) and the risk of acquisition and severity of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Aim: To evaluate the association between PPI exposure and infection and development of severe disease in patients infected with SARS-CoV2in a large population-based historical cohort. Methods: Data were extracted from a health maintenance organization database in Israel that insures over 1,200,000 individuals from across the country. All patients who underwent SARS-CoV-2 testing between March and November 2020 were included. Logistic regression and matched analyses were used to compare patients prescribed and exposed to PPIs to those not prescribed PPIs regarding SARS-CoV-2 positivity. In addition, among SARS-CoV-2 positive patients (n = 44,397) the likelihood of developing severe disease, defined by a composite endpoint of death, ICU admission and prolonged hospitalization, was compared in those exposed and not exposed to PPIs. Results: Among 255,355 adult patients who underwent SARS-CoV-2 testing by PCR, 44,397 (17.4%) were positive for SARS-CoV-2 and 12,066 (4.7%) patients were prescribed PPIs in the 3 months before testing. In a multivariable logistic regression model controlling for age, gender, smoking status, BMI, diabetes mellitus, hypertension, COPD, history of ischemic heart disease and fasting blood glucose (FBG) levels, no significant association was found between PPIs and SARS-CoV-2 positivity ( p = 0.09 aOR 0.94, 95% CI - 0.88-1.01). Among SARS-CoV-2 positive patients, 910 (2%) had a severe infection. Multivariate logistic regression controlling for the abovementioned confounders, showed no such association between PPIs and severe COVID-19 ( p = 0.28). Elevated FBG levels were significantly associated with both PPI exposure ( p < 0.001) and severe COVID-19 infection ( p < 0.001). These results were reinforced by a matched analysis (n = 655 pairs). Conclusion: PPIs are spuriously associated with severe COVID-19 due to the presence of elevated FBG as a confounder. Our study accounted for the FBG levels of patients and known risk factors for severe COVID-19 infection, which may be the reason for the discrepancy in prior studies. These results may aid in understanding potential confounders when evaluating potential associations of PPIs with other respiratory or viral diseases., Competing Interests: Authors AS and MB were employed by the company Meuhedet Health Medical Organization. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shafrir, Benson, Katz, Hershcovici, Bitan, Paltiel, Calderon-Margalit, Safadi and Shauly-Aharonov.)

Juvenile polyposis syndrome (JPS), has diverse phenotypes., Aim: To assess mutation rate, clinical features and genotype-phenotype correlation among Israeli JPS kindreds from different ethnicities., Methods: Patients' data were extracted retrospectively from 5 centers., Results: Thirty five kindreds (49 patients) were included. Thirty one (89%) Jewish [10 (32%) Ashkenazi; 9 (29%) Sephardi; 11 (35%) non-Russia former Soviet-Union countries (NRFSU), one (3%) unknown]. 40/49 individuals from 27 families underwent genetic testing. Among them 34, from 21 families (85, 78%, respectively) had a pathogenic mutation: BMPR1A n = 15 (71%), SMAD4 n = 6 families (29%). While no SMAD4 mutation was described among Jewish families from NRFSU, 7 NRFSU families carried a founder mutation comprising a large genomic deletion of BMPR1A. GI involvement was reported in 42 patients (86%): colonic polyps (n = 40, 95%, > 50 polyps n = 14, 35%) and 12 underwent colonic resection. Fourteen patients (34%) had gastric or small bowel involvement (n = 5) and 4\14 underwent gastrectomy due to polyp burden. Families from NRFSU had more gastric involvement (66.7% vs. 22.2%- Sephardic and 20%- Ashkenazi Jews; p = 0.038), with more gastric polyps (p = 0.017)., Conclusions: We demonstrated a high rate of mutation detection in the heterogeneous population of Israel. Patients from NRFSU with BMPR1A mutation had high rate of gastric involvement., (© 2022. The Author(s).)

Background: Gliomas manifest in a variety of histological phenotypes with varying aggressiveness. The etiology of glioma remains largely unknown. Taller stature in adulthood has been linked with glioma risk. The aim of this study was to discern whether this association can be detected in adolescence., Methods: The cohort included 2 223 168 adolescents between the ages of 16 and 19 years. Anthropometric measurements were collected at baseline. Incident cases of glioma were extracted from the Israel National Cancer Registry over a follow-up period spanning 47 635 745 person-years. Cox proportional hazard models were used to estimate the hazard ratio (HR) for glioma and glioma subtypes according to height, body mass index (BMI), and sex., Results: A total of 1195 patients were diagnosed with glioma during the study period. Mean (SD) age at diagnosis was 38.1 (11.7) years. Taller adolescent height (per 10-cm increase) was positively associated with the risk for glioma of any type (HR: 1.15; P = .002). The association was retained in subgroup analyses for low-grade glioma (HR: 1.17; P = .031), high-grade glioma (HR: 1.15; P = .025), oligodendroglioma (HR: 1.31; P = .015), astrocytoma (HR: 1.12; P = .049), and a category of presumed IDH-mutated glioma (HR: 1.17; P = .013). There was a trend toward a positive association between height and glioblastoma, however this had borderline statistical significance (HR: 1.15; P = .07). After stratification of the cohort by sex, height remained a risk factor for men but not for women., Conclusions: The previously established association between taller stature in adulthood and glioma risk can be traced back to adolescence. The magnitude of association differs by glioma subtype., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Recently, three updated guidelines for post-polypectomy colonoscopy surveillance (PPCS) have been published. These guidelines are based on a comprehensive summary of the literature, while some recommendations are similar, different surveillance intervals are recommended after detection of specific types of polyps., Aim: In this review, we aimed to compare and contrast these recommendations., Methods: The updated guidelines for PPCS were reviewed and the recommendations were compared., Results: For patients with 1-4 adenomas <10 mm with low-grade dysplasia, irrespective of villous components, or 1-4 serrated polyps <10 mm without dysplasia, the European Society of Gastrointestinal Endoscopy (ESGE) and British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE) (BSG/ACPGBI/PHE) guidelines do not recommend colonoscopic surveillance and instead recommend that the participate in routine CRC screening program (typically based on the fecal immunochemical test), while the USMSTF recommends surveillance colonoscopies 7-10 years after diagnosis of 1-2 tubular adenomas <10 mm and 3-5 years for 3-4 tubular adenomas of the same size. The USMSTF define adenomas with tubulovillous or villous histology as high-risk adenomas; thus, surveillance colonoscopy is recommended after 3 years. However, the ESGE and BSG do not consider such histology as a criterion for repeating colonoscopy at this short interval. For patients with 1-2 sessile serrated polyps (SSPs) <10 mm and those with 3-4 SSPs <10 mm, the USMSTF recommends surveillance colonosocopy after 5-10 and 3-5 years, respectively., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Caloric restriction (CR) can prolong aged skeletal muscle function, yet the molecular mechanisms are not completely understood. We performed phosphoproteomic analysis on muscle from young and old mice fed an ad libitum diet, and old mice fed a CR diet. CR promoted a youthful phosphoproteomic signature, suppressing several known "pro-aging" pathways including Protein kinase A (PKA). This study validates global signaling changes in skeletal muscle during CR., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis impacting primarily joints and cardiac and skeletal muscle. RA's distinct impact on cardiac and skeletal muscle tissue is suggested by studies showing that new RA pharmacologic agents strongly improve joint inflammation, but have little impact on RA-associated mortality, cardiovascular disease, and sarcopenia. Thus, the objective is to understand the distinct effects of RA on cardiac and skeletal muscle, and to therapeutically target these tissues through endurance-based exercise as a way to improve RA mortality and morbidity. We utilize the well-characterized RA mouse model, the K/BxN mouse, to investigate cardiac and skeletal muscle pathologies, including the use of wheel-running exercise to mitigate these pathologies. Strikingly, we found that K/BxN mice, like patients with RA, also exhibit both cardiac and skeletal muscle myopathies that were correlated with circulating IL-6 levels. Three months of wheel-running exercise significantly improved K/BxN joint swelling and reduced systemic IL-6 concentrations. Importantly, there were morphological, gene expression, and functional improvements in both the skeletal muscle and cardiac myopathies with exercise. The K/BxN mouse model of RA recapitulated important RA clinical comorbidities, including altered joint, cardiac and skeletal muscle function. These morphological, molecular, and functional alterations were mitigated with regular exercise, thus suggesting exercise as a potential therapeutic intervention to lessen disease activity in the joint and the peripheral tissues, including the heart and skeletal muscle. NEW & NOTEWORTHY RA, even when controlled, is associated with skeletal muscle weakness and greater risk of cardiovascular disease (CVD). Using exercise as a therapeutic against, the progression of RA is often avoided due to fear of worsening RA pathology. We introduce the K/BxN mouse as an RA model to study both myocardial and skeletal muscle dysfunction. We show that endurance exercise can improve joint, cardiac, and skeletal muscle function in K/BxN mice, suggesting exercise may be beneficial for patients with RA.

Background: The success of Helicobacter pylori ( H. pylori ) eradication depends on several host and treatment factors. Serum vitamin D levels may be associated with H. pylori infection and eradication rates. We investigated the association between vitamin D and H. pylori infection and eradication, using a large electronic database based on medical records from a population-based health maintenance organization., Methods: Data regarding adults who underwent H. pylori testing and had vitamin D measurements within one month of H. pylori testing were collected. H. pylori infection was ascertained using urea breath or stool antigen tests. A negative H. pylori test following a positive result implied eradication. Multivariate regression models were constructed to assess associations between H. pylori infection, eradication, and vitamin D., Results: Among 150,483 members who underwent H. pylori testing from 2009 to 2018, 27,077 (18%) had vitamin D measurements. Vitamin D levels were inversely associated with H. pylori infection, p < 0.001. The odds of a positive H. pylori test were 31% higher among patients with vitamin D levels <20 ng/mL, compared with those with levels ≥20 ng/mL (OR 1.31, 99% CI 1.22-1.4, p < 0.001). Purchase of vitamin D supplements was associated with a negative subsequent H. pylori test ( p < 0.001). Mean vitamin D levels were moderately higher in those with successful vs. failed H. pylori eradication (19.34 ± 9.55 vs. 18.64 ± 9.61, p < 0.001)., Conclusions: Vitamin D levels are associated with H. pylori infection. Increased vitamin D levels are associated with successful H. pylori eradication. Vitamin D may have a role in H. pylori eradication.

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.

Background: Although the association of attention deficit hyperactivity disorder (ADHD) with psychiatric disorders is well known, its association with somatic diseases is unclear. Only few studies have investigated the gastrointestinal (GI) morbidity in adult patients with ADHD., Aim: To measure gastrointestinal comorbidity and its burden on healthcare in young adults with ADHD., Methods: The cohort included subjects aged 17-35 years recruited to the Israel Defense Forces in 2007-2013, 33380 with ADHD and 355652 without (controls). The groups were compared for functional and inflammatory conditions of the gastrointestinal tract and clinic and specialist visits for gastrointestinal symptoms/disease during service (to 2016). Findings were analyzed by generalized linear models adjusted for background variables ., Results: Compared to controls, the ADHD group had more diagnoses of functional gastrointestinal disorders (referred to as FGID), namely, dyspepsia [odds ratio (OR): 1.48, 95% confidence interval (CI): 1.40-1.57, P < 0.001], chronic constipation (OR: 1.64, 95%CI: 1.48-1.81, P < 0.001), and irritable bowel syndrome (OR: 1.67, 95%CI: 1.56-1.80, P < 0.001) but not of organic disorders (inflammatory bowel disease, celiac disease). They had more frequent primary care visits for gastrointestinal symptoms [rate ratio (RR): 1.25, 95%CI: 1.24-1.26, P < 0.001] and referrals to gastrointestinal specialists (RR: 1.96, 95%CI: 1.88-2.03, P < 0.001) and more episodes of recurrent gastrointestinal symptoms (RR: 1.29, 95%CI: 1.21-1.38, P < 0.001). Methylphenidate use increased the risk of dyspepsia (OR: 1.49, 95%CI: 1.28-1.73, P < 0.001) and constipation (OR: 1.42, 95%CI: 1.09-1.84, P = 0.009)., Conclusion: ADHD in young adults is associated with an excess of FGID and increased use of related health services. Research is needed to determine if an integrative approach treating both conditions will benefit these patients and cut costs., Competing Interests: Conflict-of-interest statement: All the authors have no conflicts of interest related to the manuscript., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults., Methods: The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease., Results: A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4-62.6). On univariate analysis, female sex (p < 0.01) and height (p < 0.01) were associated with risk of meningioma. When the data were stratified by sex, height remained a significant factor only in men. Spline analysis of the male subjects showed that a height of 1.62 m was associated with a minimum disease risk and a height of 1.85+ meters, with a significant risk., Conclusions: This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.

Background: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear., Methods: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018., Results: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals., Conclusions: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

Background: Inflammatory bowel diseases are associated with various immune- and non-immune-mediated conditions. We aimed to assess the association of inflammatory bowel diseases with comorbidities at late adolescence., Methods: Jewish Israeli adolescents who underwent a general health evaluation prior to enlistment to the Israeli Defense Forces from 2002 to 2016 were included., Results: Overall, 891 subjects (595 Crohn's disease, 296 ulcerative colitis, median age 17.1 years) and 1,141,841 controls were analyzed. Crohn's disease was associated with arthritis (odds ratio (OR) 4.7, 95% confidence interval (CI) 2.4-9.1), thyroid disease (OR 2.6, 95% CI 1.2-5.5), atopic dermatitis (OR 2, 95% CI 1.1-3.6), autoimmune hepatitis (OR 4.4, 95% CI 2.3-8.6), nephrolithiasis (OR 3.6, 95% CI 1.2-11.4), and pancreatitis (OR 41.8, 95% CI 17.2-101.9). Ulcerative colitis was associated with arthritis (OR 3.6, 95% CI 1.0-9.8), thyroid disease (OR 4.8, 95% CI 1.2-19.4), autoimmune hepatitis (OR 8, 95% CI 4-16.2), and pancreatitis (OR 51, 95% CI 16.1-158.9). Primary sclerosing cholangitis was associated with both diseases. Asthma, celiac, type 1 diabetes, psoriasis, and bone fractures were not more common in both diseases. Male predominance was noted for most associations., Conclusions: At adolescence, both Crohn's disease and ulcerative colitis are associated with multiple comorbidities, not limited to autoimmune disorders.

Agenesis of the permanent dentition is rare. This report describes a 20-year-old woman with 19 deciduous teeth, a single permanent mandibular premolar, and other physical traits associated with ectodermal dysplasia. The patient demonstrated esthetic parameters associated with maxillomandibular alveolar insufficiency, and her chief complaints were directed toward esthetics and the potential impact of restorative choices on function. Three typical options for restoration include overdentures, removable partial dentures, or implant-supported prostheses replacing her natural dentition. This report illustrates a fully integrated digital approach to treatment planning, the fabrication of a computer-aided design/computer-assisted manufacture surgical guide and provisional restoration, guided implant placement, and definitive restoration using monolithic zirconia implant-supported fixed dental prostheses. The lifelong management of this rehabilitation is an acknowledged challenge.

Background: cranial X radiation therapy was the standard of care for treating dermatological conditions until the 1960s, when its association to cancer and particularly high rates of brain tumors was discovered. This study examines associations found between incidence of brain tumor and ethnicity., Methods: This study analyzed two cohorts who underwent examination at age 17 and were followed by linkage to the national cancer registry. The first cohort included 376,336 participants born in 1948-1959 (when treatment with cranial X radiation was standard care for treating tinea capitis), and the second 474,923 participants born in 1960-1971., Results: In the first cohort, ethnicity was strongly associated with the incidence of brain tumor (BT), with higher incidence observed among patients with origins in North Africa or the Middle East. This effect was ablated in the second cohort, and a significant decrease in the rate of meningiomas was noted., Conclusion: The association of brain tumor with ethnicity was present only during the period when treatment with cranial X radiation was the standard of care for TC in Israel, therefore it is most likely that radiation exposure was a confounding factor, and that ethnic susceptibility for brain cancer was not causative in these cohorts., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer., Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years., Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer., Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Background: Lynch syndrome carries an increased risk of colorectal neoplasia, hence annual surveillance colonoscopy is recommended. This study aimed to compare the diagnostic yields of image enhancement modalities for colorectal neoplasia in patients with Lynch syndrome., Methods: Meta-analysis of pooled ratios of lesion detection rates (RRs) and odds ratios (ORs) with 95% confidence intervals (CIS), comparing white light endoscopy (WLE) and chromoendoscopy (ChE)., Results: Four studies comparing WLE to ChE were analyzed. ChE fared better than WLE in overall lesion detection (RR 1.97, 95% CI 1.63-2.38) and detection of adenomas (RR 1.53, 95% CI 1.07-2.17), flat lesions (RR 3.4, 95% CI 2.47-4.67) and proximally-located lesions (RR 2.93, 95% CI 1.91-4.5). The odds of a patient having any lesion found were higher in ChE compared to WLE (OR 2.42, 95% CI 1.56-3.75). The odds of a patient having adenoma(s) found on endoscopy were not significantly higher in chromoendoscopy compared to white light endoscopy (OR 1.81, 95% CI 0.65-5.01)., Conclusion: Using standard definition technology, ChE allows detection of more lesions, especially adenomas, flat lesions and proximal lesions in Lynch syndrome patients, compared to WLE. The results show that surveillance colonoscopy of Lynch syndrome patients should be performed using ChE., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited., Methods: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis., Results: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS., Discussion: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

Background: Growth impairment is common in pediatric inflammatory bowel disease (IBD) patients. Nevertheless, a controversy exists regarding disease impact on anthropometric measures in the long term. Thus, we aimed to investigate the impact of IBD on anthropometric measures, including weight, height, and body mass index (BMI), during late adolescence in a cross-sectional, population-based study., Methods: A total of 1,144,213 Jewish Israeli adolescents who underwent a general health examination from 2002 to 2016 at a median age (interquartile range) of 17.1 (16.9-17.3) years were included. Inflammatory bowel disease cases were stratified into Crohn's disease (CD) and ulcerative colitis (UC). Patients were also subgrouped based on age at IBD diagnosis., Results: Overall, 2372 cases of IBD were identified out of 1,144,213 persons examined (0.2%). Crohn's disease accounted for 68% of IBD cases. Males and females with CD (but not with UC) had significantly lower weight and BMI compared with controls. Differences in height at late adolescence were not statistically significant for either disease compared with controls (females: 162 cm vs 161.7 cm vs 161.5 cm; males: 174 cm vs 173.7 cm vs 173.6 cm for controls, UC, and CD, respectively). In a subgroup analysis, patients with CD diagnosed at age <14 years were significantly shorter than controls (males: 172.7 cm vs 174 cm; P = 0.001; females: 160.6 cm vs 162; P = 0.008). This pattern was not noted in UC patients., Conclusions: Adolescents with CD were leaner compared with the general population. No overall difference was noted in height at late adolescence. Younger age at diagnosis was associated with reduced height in CD patients., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dental implants continue to grow in popularity because they are a predictable treatment to replace missing teeth. They have a high success rate; however, they are still associated with some clinical complications. This article discusses a diverse range of complications related to the restorative and mechanical aspects of dental implants and the management of such complications, as well as potential factors contributing to them., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The incidence and prevalence trends of inflammatory bowel disease (IBD) vary between developed and developing countries., Aim: To investigate the prevalence and associated sociodemographic factors of IBD in Israeli Jewish adolescents METHODS: The files of the army medical corps were reviewed for adolescents recruited in 2002-2016 with confirmed IBD. Covariate data included birth date, patient and parental country of birth, number of children in the household, age at diagnosis, and socioeconomic status. Findings were compared with the remaining recruits without IBD., Results: Of the 1,144,213 adolescents recruited, 2372 (0.2%) had IBD (Crohn's disease, 68%). Median age of the cohort was 17.1 years (interquartile range, 16.9-17.3). Over the study period, the annual point prevalence per 100,000 examinees significantly increased: total IBD, 58 to 373; Crohn's disease, 42 to 425; ulcerative colitis, 16 to 128. Mean age at IBD diagnosis decreased from 15.0 ± 2.8 years in 2002-2008 to 14.3 ± 3.1 years in 2009-2016 (P < 0.0001). Significance was maintained on separate analyses of Crohn's disease and ulcerative colitis. Both diseases were significantly less prevalent in subjects from families with at least one parent born in a developing country and ≥3 children. There was a significant association of lower socioeconomic status with lower prevalence of Crohn's disease (odds ratio 0.41, 95% confidence interval, 0.31-0.54) and ulcerative colitis (odds ratio 0.25, 95% confidence interval, 0.15-0.42)., Conclusions: The point prevalence of Crohn's disease and ulcerative colitis in Israeli Jewish adolescents increased six-fold and eight-fold, respectively, over 15 years along with a decrease in age at diagnosis., (© 2019 John Wiley & Sons Ltd.)

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair ( path&#95;MMR ) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path&#95;MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal., Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path&#95;MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers., Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path&#95;MLH1 , 45 path &#95; MSH2 , 10 path&#95;MSH6 and 1 path&#95;PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively ( p  = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier ( p  = 0.14)., Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path&#95;MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path&#95;MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path&#95;MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path&#95;MMR carriers., Competing Interests: All reporting centers obtained informed consent for genetic testing and surveillance procedures. De-identified data was exported for the current study. No named registry needing approval was established for the current study.Not applicable.Toni Seppälä: a co-owner (20%) of Healthfund Finland Oy (educational and health care services in Finland, not related to patients or scope of this manuscript). Travel costs to a scientific meeting by Medtronic Finland. John Burn: a patent for high speed low cost tumor profiling pending to John Burn and QuantuMDx. All others: None declared.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

We investigated whether obesity and sociodemographic factors at adolescence are associated with incident gastroenteropancreatic neuroendocrine tumors (GEP-NET).Our cohort included 2.3 million Israeli adolescents examined at ages 16 to 19 years between 1967 and 2010. The baseline database included sex, country of birth, residential socioeconomic status (SES), body-mass index (BMI) and height. Participants were followed through linkage with the National Cancer Registry up to 2012. We identified 221 cases of GEP-NET (66 pancreatic, 52 gastric, 39 rectal, 27 appendiceal, 23 small bowel and 14 colonic). Immigration from the Former Soviet Union (FSU) was associated with the risk of small bowel and rectal NET's, [Hazard Ratio (HR) 4.79, 95% Confidence Interval (CI) 1.37-16.76 and 3.43, 95% CI 1.20-9.83, respectively].Height >75th percentile and BMI ≥ 85th percentile were associated with increased risk of gastric NET (HR 2.25 95% CI 1.14-4.42 and HR 2.38, 95% CI 1.19-4.75, respectively). Female sex was associated with appendiceal NET (HR 2.30, 95% CI 1.06-4.96) while male gender was associated with an increased risk for NET of the small bowel [HR 4.72 (95% CI 1.10-20.41)].In conclusion, our findings suggest different risk factor associations with the various GEP-NETS: immigrants from the FSU were at increased risk for small bowel and rectal NET; increased height and weight were associated with the risk of gastric NET and females were at increased risk for appendiceal NET. Further focus on the FSU population is indicated in addition to studies verifying the association of BMI and height with gastric NET., (© 2018 UICC.)

Background: Small bowel involvement in Crohn's disease (CD) is frequently proximal to the ileocecal valve and inaccessible by conventional ileocolonoscopy (IC). Small bowel capsule endoscopy (SBCE) is among the prime modalities for assessment of small bowel disease in these patients. Intestinal ultrasound (IUS) is an accurate bedside fast and low-cost diagnostic modality utilized in CD for both diagnosis and monitoring. The aim of this study was to examine the accuracy of IUS in patients with suspected CD after a negative IC, and to evaluate the correlation of IUS with SBCE, inflammatory biomarkers and other cross-sectional imaging techniques., Methods: Prospective single center study in which patients with suspected CD underwent IUS and SBCE examinations within 3 days. IUS results were blindly compared with SBCE that served as the gold standard. A post hoc comparison was performed of IUS and SBCE results and available cross-sectional imaging results (computed tomography or magnetic resonance enterography) as well as inflammatory biomarkers if measured. The study cohort was followed for 1 year. In case of discordance between the IUS and SBCE results, the diagnosis at 1 year was reported., Results: Fifty patients were included in the study. The diagnostic yield of both IUS and SBCE for the diagnosis of small bowel CD was 38%. The IUS findings significantly correlated to small bowel inflammation detected by SBCE ( r = 0.532, p < 0.001), with fair sensitivity and specificity (72% and 84%). Cross-sectional imaging results significantly correlated to IUS as well ( r = 0.46, p = 0.018). Follow up was available in 8 of the 10 cases of discordance between IUS and SBCE. In all of these cases, diagnosis of CD was not fully established at the end of the follow up., Conclusions: The diagnostic yield of CE and IUS for detection of CD in patients with negative ileocolonoscopy was similar. IUS can be a useful diagnostic tool in suspected CD when IC is negative., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: This study examined the association between the body mass index (BMI) in late adolescence and the risk of colon and rectal cancer., Methods: This study analyzed a cohort of 1,087,358 Jewish men and 707,212 Jewish women who underwent health examinations at the ages of 16 to 19 years between 1967 and 2002 and were followed by linkage to the national cancer registry up to 2012. Cox regression was used to estimate hazard ratios (HRs) for cancer according to age- and sex-adjusted BMI percentiles from the US Centers for Disease Control and Prevention (overweight, 85th percentile to <95th percentile; obesity, ≥95th percentile)., Results: Over a median follow-up of 23 years, 2967 incidence cases of colorectal cancer, including 1977 among men (1403 in the colon and 574 in the rectum) and 990 among women (764 in the colon and 226 in the rectum), were identified. Overweight and obesity were associated with the risk for colon cancer among both men (HR for overweight, 1.53; 95% confidence interval [CI], 1.28-1.84; HR for obesity, 1.54; 95% CI, 1.15-2.06; statistically significant from a BMI of 23.4 kg/m 2 [spline analysis]) and women (HR for overweight, 1.54; 95% CI, 1.22-1.93; HR for obesity, 1.51; 95% CI, 0.89-2.57; significant from a BMI of 23.6 kg/m 2 ). Obesity, but not overweight, was associated with a risk for rectal cancer among men (HR, 1.71; 95% CI, 1.11-2.65; significant from a BMI of 29.6 kg/m 2 ) and women (HR, 2.03; 95% CI, 0.90-4.58; significant from a BMI of 30.6 kg/m 2 )., Conclusions: Being overweight or obese in adolescence was associated with an increased risk of subsequent colon cancers in men and women, whereas obesity was associated with rectal cancer. Cancer 2017;123:4022-30. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background Gastric cancer occurs mainly in older patients, with a peak incidence over 60 years of age. It is relatively rare among younger individuals. However, the frequency of gastric cancer in young patients appears to be on the rise worldwide. Case presentation We report the case of a 19-year-old female soldier who, after a considerable diagnostic delay, was diagnosed with gastric adenocarcinoma. She is one of the youngest gastric adenocarcinoma patients ever reported in Israel. Conclusion This case should serve as a reminder that gastric carcinoma is a possible diagnosis even in young patients. It also highlights the critical importance of obtaining a thorough medical history in the process of clinical decision making.

Background & Aims: The risk of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and associated risk factors among patients with AIH., Methods: We searched PubMed, Embase, and reference lists from relevant articles through June 2016 to identify cohort studies that examined the incidence of HCC in patients with AIH. We used random effects models to estimate pooled incidence rates overall and in subgroup of patients with cirrhosis. The between-study heterogeneity was assessed using I 2 statistic., Results: A total of 25 studies (20 papers and 5 abstracts), including 6528 patients, met the eligibility criteria. The median cohort size was 170 patients with AIH (range, 25-1721 patients), followed for a median of 8.0 years (range, 3.3-16.0 years). The pooled incidence rate for HCC in patients with AIH was 3.06 per 1000 patient-years (95% confidence interval, 2.22-4.23; I 2  = 51.5%; P = .002). The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 10.07 per 1000 patient-years (95% confidence interval, 6.89-14.70; I 2  = 48.8%; P = .015). In addition, 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their HCC diagnosis. The risk of HCC seems to be lower in patients with AIH and cirrhosis than that reported for patients with cirrhosis from hepatitis B, hepatitis C, or primary biliary cholangitis., Conclusions: Based on the increased risked of HCC shown in this meta-analysis, there may be a role for HCC surveillance in patients with AIH and cirrhosis., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Recent data have shown that adults with celiac disease (CD) may have a higher prevalence of risk factors for cardiovascular disease (CVD) compared with the general population. Thus, we aimed to investigate the association of CD with CVD risk factors at late adolescence in a cross-sectional population-based study., Methods: A total of 2,001,353 Jewish Israeli adolescents who underwent a general health examination at median age of 17.1 years from 1988 to 2015 were included. Covariate data included demographic measures, blood pressure (BP), resting heart rate, and risk factors associated with CVD., Results: Overall, 10,566 cases of CD were identified (0.53%). Multivariate analysis showed that mean diastolic BP was significantly lower in subjects with CD (men: 72.0±8.7 vs 70.4 ± 8.5, P < 0.0001; women: 70.0 ± 8.3 vs 69.0 ± 8.2, P < 0.0001), whereas systolic BP did not differ between groups. Resting heart rate was higher in CD cases (an absolute difference of 0.4 beats per minute, P < 0.0001). The proportions of overweight and obese subjects were significantly lower in CD cases. Noninsulin-dependent diabetes mellitus (relative risk [RR], 4.1; 95% confidence interval [CI] 2.8-5.7), hypercoagulability (RR, 2.6; 95% CI 1.5-4.5), and hyperlipidemia (RR, 1.9; 95% CI 1.2-3) were significantly more common in subjects with CD., Conclusions: At the age of 17 years, the prevalence of risk factors for CVD is higher in subjects with CD compared with the general population. There is, however, neither increase in BP nor increase in overweight and obesity rates.

Background: Biallelic BLM gene mutation carriers are at an increased risk for cancer, including colorectal cancer (CRC). Whether heterozygous BLM gene mutations confer an increased cancer risk remains controversial., Objectives: To evaluate CRC and endometrial cancer risk in BLM heterozygous mutation carriers., Methods: Jewish Ashkenazim at high risk for colon or endometrial cancer and endometrial cancer cases unselected for family history were genotyped for the BLMAsh predominant mutation., Results: Overall, 243 high-risk individuals were included: 97 men CRC patients (55.12 ± 12.3 years at diagnosis), 109 women with CRC (56.5 ± 13.7 years), 32 women with endometrial cancer (58.25 ± 13.4 years) and 5 women with both CRC and endometrial cancer. In addition, 120 unselected Ashkenazi women with endometrial cancer (64.2 ± 11.58 years) were genotyped. The BLMAsh mutation was present in 4/243 (1.65%) high-risk patients; 2 CRC (0.97%) 2 endometrial cancer (5.4%), and 1/120 unselected endometrial cancer patients (0.84%). Notably, in high-risk cases, BLMAsh mutation carriers were diagnosed at a younger age (for CRC 47.5 ± 7.8 years; P = 0.32 ; endometrial cancer 49.5 ± 7.7 years; P = 0.36) compared with non-carriers., Conclusions: Ashkenazi high risk CRC/endometrial cancer, and women with endometrial cancer have a higher rate of BLMAsh heterozygous mutation compared with the general population. BLMAsh heterozygous mutation carriers are diagnosed with CRC and endometrial cancer at a younger age compared with non-carriers. These observations should be validated and the possible clinical implications assessed.

Aim: Celiac disease (CD) is a systemic disorder that is associated with various autoimmune disorders and a higher prevalence of other diagnoses and complications. This large, cross-sectional, population-based study investigated the associations between CD and various medical conditions during late adolescence., Methods: We included 2 001 353 Jewish Israeli adolescents who underwent a general health examination at a median age of 17.1 (16.9-17.4) years from 1988 to 2015. Comprehensive data regarding medical status were available for 1 588 041 (79%) subjects. A definite diagnosis of CD was based on accepted criteria. Covariate data included demographic measures and data on associated medical conditions., Results: Overall, data on 7145 subjects with CD and 1 580 896 controls were analysed. Multivariate analyses showed that autoimmune diseases were significantly more common in subjects with CD, including insulin dependent diabetes, with an odds ratio (OR) of 5.5, inflammatory bowel diseases (OR = 3.8), arthritis (OR = 2.4), thyroid diseases (OR = 1.8) and psoriatic skin disorders (OR = 1.6). Further associations included asthma (OR = 1.5), bile stones (OR = 3.6), migraine (OR = 2.3), anaemia (OR = 1.7) and menstrual abnormalities (OR = 1.5). Long bone fractures and axial fractures were no more common in adolescents with CD than controls., Conclusion: CD was already associated with multiple comorbidities by adolescence, and these were not limited to autoimmune disorders., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Communication gaps in families with unexplained mismatch repair (MMR) deficiency (UMMRD) could negatively impact the screening behaviors of relatives of individual with UMMRD. We evaluated cancer risk perception, screening behaviors, and family communication among relatives of colorectal cancer (CRC) patients with UMMRD. Fifty-one family members of 17 probands with UMMRD completed a questionnaire about cancer risk perception, adherence to Lynch syndrome (LS) screening recommendations, and communication with relatives. Clinical data about the probands were obtained from medical records. Thirty-eight participants (78%) were worried from having cancer and twenty-one participants (42%) had undergone colonoscopy in the past 2 years, as recommended for LS families. In terms of screening for extracolonic cancers, only two eligible participants (3.9%) were screened for gastric, endometrial (10.0%), and ovarian (9.5%) cancers. Additionally, 5 participants (10%) underwent genetic counseling. Most participants were not told by anyone to be screened for extracolonic cancers (84, 85, and 95% for gastric, ovarian, and endometrial cancers, respectively). A minority of family members of CRC patients with UMMRD follow cancer screening as recommended for LS families. Health care providers should encourage patients with UMMRD to share information on LS-related cancers screening, especially extracolonic cancers, with their relatives.

Objectives: To investigate the impact of coeliac disease (CD) diagnosis on anthropometric measures at late adolescence and to assess trends in the prevalence of diagnosed CD over time., Design: A population based study., Patients: Prior to enlistment, at the age of 17 years, most of the Israeli Jewish population undergoes a general health examination. Subjects' medical diagnoses are entered into a structured database., Interventions: The enlistment database was thoroughly searched for CD cases between the years 1988 and 2015. Medical records of 2 001 353 subjects were reviewed., Main Outcome Measures: Anthropometric measures at the age of 17 years., Results: Overall, 10 566 CD cases (0.53%) were identified and analysed. Median age at data ascertainment was 17.1 years (IQR, 16.9-17.4). Multivariable analysis demonstrated that boys with CD were leaner (Body Mass Index 21.2±3.7 vs 21.7±3.8, p=0.02) while girls with CD were shorter (161.5±6 cm vs 162.1±6 cm, p=0.017) than the general population. The prevalence of diagnosed CD increased from 0.5% to 1.1% in the last 20 years with a female predominance (0.64% vs 0.46%). CD prevalence was significantly lower in subjects of lower socioeconomic status and those of African, Asian and former Soviet Union origin., Conclusions: Adolescent boys with CD were leaner and girls with CD were shorter compared with the general population. However, the clinical relevance of the small differences suggests that when CD is diagnosed during childhood, final weight and height are not severely impaired. Our cohort reinforces the observed increase in diagnosed CD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor β/mothers against decapentaplegic homolog 3 adaptor β2-Spectrin (β2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. β2SP supports DNA repair through β2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of β2SP leads to decreased Fancd2 levels and sensitizes β2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor β stimulation is regulated by the β2SP/mothers against decapentaplegic homolog 3 complex., Conclusion: Dysfunctional transforming growth factor β/β2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693)., (© 2016 by the American Association for the Study of Liver Diseases.)

Transforming Growth Factor-β (TGF-β) plays crucial and complex roles in liver and gastrointestinal cancers. These include a multitude of distinct functions, such as maintaining stem cell homeostasis, promoting fibrosis, immune modulating, as a tumor suppressor and paradoxically, as a tumor progressor. However, key mechanisms for the switches responsible for these distinct actions are poorly understood, and remain a challenge. The Cancer Genome Atlas (TCGA) analyses and genetically engineered mouse models now provide an integrated approach to dissect these multifaceted and context-dependent driving roles of the TGF-β pathway. In this review, we will discuss the molecular mechanisms of TGF-β signaling, focusing on colorectal, gastric, pancreatic, and liver cancers. Novel drugs targeting the TGF-β pathway have been developed over the last decade, and some have been proven effective in clinical trials. A better understanding of the TGF-β pathway may improve our ability to target it, thus providing more tools to the armamentarium against these deadly cancers., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-β pathway member expression levels and β-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-β member expression with lower β-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-β pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and β-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.

Background: Fatigue is a common and disabling symptom in people with a primary brain tumour (PBT). The effectiveness of interventions for treating clinically significant levels of fatigue in this population is unclear., Objectives: To assess the effectiveness and safety of pharmacological and non-pharmacological interventions for adults with PBT and high levels of fatigue., Search Methods: In March 2016, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO and CINAHL and checked the reference lists of included studies. We also searched relevant conference proceedings, searched for ongoing trials via ClinicalTrials.gov and contacted major co-operative groups with trials in this area., Selection Criteria: We included randomised controlled trials (RCTs) that investigated any pharmacological or non-pharmacological intervention in adults with PBT and fatigue, where fatigue was the primary outcome measure. We restricted inclusion specifically to studies that enrolled only participants with clinically significant levels of fatigue., Data Collection and Analysis: Three review authors (JD, SYK, DC) independently evaluated search results, extracted data from selected studies and carried out a bias risk assessment. We extracted data on fatigue, cognition, mood, quality of life and adverse events outcomes., Main Results: We identified nine studies. We excluded eight of these as they did not restrict participation to people with high fatigue. The single eligible trial investigated the use of modafinil compared to placebo. Although this study found a significant improvement over time in the primary outcome of fatigue, the improvement occurred after both modafinil and placebo with no significant difference in response between the two groups. The included trial did not reach its planned recruitment target and therefore may not, in practice, have been adequately powered to detect a difference. The trial was at a low risk of bias across most areas. There was an unclear risk of bias related to the use of mean imputation because the investigators did not analyse the impact of imputation on the results., Authors' Conclusions: There was insufficient evidence to draw reliable and generalisable conclusions regarding potential effectiveness or harm of any pharmacological or non-pharmacological treatments for fatigue in people with PBT. More research is needed on how best to treat people with brain tumours with high fatigue.

Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one-third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Alcoholic Liver Disease Has Various Manifestations: asymptomatic steatosis, alcoholic hepatitis and alcoholic cirrhosis, which substantially increase the risk for developing hepatocellular carcinoma. Transforming growth factor (TGF-β) signaling pathway is a major regulator in chronic liver diseases contributing to all liver disease progression from liver injury, inflammation and fibrosis to HCC. With the aim of generating a mouse model of alcoholic liver disease that would rapidly develop steatosis, inflammation as well as fibrosis, we formulated a regimen that combined chronic injections of low dose (2mg/kg) lipopolysaccharide (LPS) with Lieber DeCarli-based diet containing 6.7% ethanol feeding to mice with impaired TGF-β signaling through constitutive disruption of β2-spectrin and/or Smad3. Unexpectedly, the mice treated with chronic low dose LPS and fed the alcohol-containing diet developed very aggressive T-cell lymphomas to which the TGF-β mutant mice succumbed more rapidly than the wild type mice. In contrast, their liver phenotype was mild as they only developed steatosis but not hepatitis or significant fibrosis. To our knowledge, this is the first report of a mouse model of aggressive T- cell lymphoma based on chronic challenge with low dose LPS and TGF-β disruption.