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Objectives: Gastrointestinal symptoms are common in endometriosis, but the mechanisms behind these symptoms are yet poorly understood. Associations between endometriosis and irritable bowel syndrome (IBS), celiac disease, and various autoimmune diseases have been reported. These diseases express characteristic autoantibodies. The aim of the current study was to investigate autoantibodies against gonadotropin-releasing hormone 1 (GnRH1) and luteinizing hormone (LH) and their receptors, tenascin-C, matrix metalloproteinase-9, deamidated gliadin peptide, and tissue transglutaminase in a cohort of women with endometriosis, compared to controls and women with IBS or enteric dysmotility., Study Design: One hundred seventy-two women with laparoscopy-verified endometriosis completed questionnaires regarding socio-demographics, lifestyle habits, medical history, and gastrointestinal symptoms, and sera were analyzed with ELISA for the abovementioned antibodies. Healthy female blood donors (N = 100) served as controls, and women with IBS or enteric dysmotility (N = 29) were used for comparison., Results: A non-significantly higher prevalence of IgM antibodies directed at tenascin-C (7.6% vs. 2.0%; p = 0.06) was the only observed difference in autoantibody levels in endometriosis compared to controls. Antibody presence was not associated with any clinical parameters. Patients with IBS or enteric dysmotility expressed higher levels of IgM antibodies against GnRH1 compared to both patients with endometriosis (p = 0.004) and healthy controls (p = 0.002), and higher levels of tenascin-C antibodies compared to healthy controls (17.2% vs. 2.0%; p = 0.006)., Conclusions: Women with endometriosis do not express higher prevalence of autoantibodies found to be characteristic in other patient groups with gastrointestinal symptoms., (Copyright © 2019. Published by Elsevier B.V.)

Patients with irritable bowel syndrome (IBS) exhibit low-grade inflammation and increased gut permeability. Dietary sugar has been shown to contribute to low-grade inflammation and increased gut permeability, and to correlate with gastrointestinal (GI) symptoms. The aim of the present study was to examine the effect of a starch- and sucrose-reduced diet (SSRD) on gastrointestinal (GI) and extra-intestinal symptoms in IBS. One hundred and five IBS patients (82 women, 46.06 ± 13.11 years), with irritable bowel syndrome-symptom severity scale (IBS-SSS) > 175, were randomized to SSRD for 4 weeks or continued ordinary eating habits. The visual analog scale for irritable bowel syndrome (VAS-IBS), IBS-SSS, and 4-day food diaries were collected at baseline and after 2 and 4 weeks. After the intervention, one-third of the patients did not fulfill the criteria for IBS/functional gastrointestinal disorder. Half of the participants changed from moderate/severe disease to no/mild disease according to IBS-SSS. Comparisons between the groups showed decreased weight and sweet cravings, and parallel decreases in total IBS-SSS and extra-intestinal IBS-SSS scores, in the intervention group compared to controls ( p < 0.001 for all). When calculating separate extra-intestinal symptoms, belching ( p = 0.001), muscle/joint pain ( p = 0.029), urinary urgency ( p = 0.017), and tiredness ( p = 0.011) were decreased after introduction of SSRD compared to controls. In conclusion, SSRD improves both GI and extra-intestinal symptoms in IBS.

Aim: Parkinson's disease is often accompanied by gastrointestinal symptoms, especially constipation. Microscopic studies of the enteric nervous system and enteric neuropathy have often been performed by immunostaining in the myenteric plexa. The aim of the present study was to examine whether pathologic changes could be identified by conventional hematoxylin and eosin (H&E) staining and could also be seen in the submucosal plexa., Materials and Methods: In 20 deceased cases (11 male/9 female) of Parkinson's disease, the intestinal tract was investigated for potential neuroganglionic disease. Ten cases (7 male/3 female) of non-Parkinson, intestinally asymptomatic individuals were used as controls. Specimens from the jejunum and colon were sampled. The material was treated with standard histopathological procedures, i.e., fixed in formaldehyde solution, dehydrated and embedded in paraffin, sectioned at 5  μ m thickness, and stained with H&E and immunostaining for α -synuclein., Results: In 15 cases (7 male/8 female) of Parkinson's disease, atrophic/pycnotic nerve plexus cells were present, i.e., signs of ganglionic degeneration in the submucosal and/or myenteric plexa, mostly identified in both loci, by H&E staining. In some cases, the degenerative signs were mild, however, corroborated by findings of α -synuclein deposits in the ganglion cells. The remaining 5 cases showed no signs of degeneration in the H&E staining, but immunostaining revealed minimal α -synuclein deposits in 3 cases. None of the controls showed any ganglionic degeneration/α-synuclein deposits., Conclusion: It seems possible to identify a morphologic intestinal disease substrate in Parkinson's disease by H&E staining, showing ganglion cell pycnosis and degeneration in both plexa. This finding may indicate a potential to diagnose enteric neuropathy in highly accessible sites.

Dietary advice constitutes one of the first choices of treatment for irritable bowel syndrome (IBS). We have recognized an increased prevalence of sucrase-isomaltase (SI) gene variants in IBS patients, possibly rendering starch- and sucrose-intolerance. The aims were to examine participants' dietary habits at baseline, to correlate habits with gastrointestinal (GI) symptoms and blood levels of minerals and vitamins, and to examine the effect of a starch- and sucrose-reduced diet (SSRD) on GI symptoms. In the study 105 IBS patients (82 women, 46.06 ± 13.11 years), irritable bowel syndrome-symptom severity scale (IBS-SSS)>175, were randomized to SSRD for 2 weeks or continued ordinary eating habits. Blood samples, visual analog scale for irritable bowel syndrome (VAS-IBS), IBS-SSS, and 4-day food diaries were collected at baseline and after 2 weeks. Patients with irregular dietary habits exhibited higher IBS-SSS than patients with regular habits ( p = 0.029). Women already on a diet had lower ferritin levels than others ( p = 0.029). The intervention led to 66.3% of patients being responders, with differences in the change of IBS-SSS ( p < 0.001), abdominal pain ( p = 0.001), diarrhea ( p = 0.002), bloating and flatulence ( p = 0.005), psychological well-being ( p = 0.048), and intestinal symptoms' influence on daily life ( p < 0.001), compared to controls. Decreased intake of cereals and sweets/soft drinks correlated with decreased scores.

In this work, we present a method to synthesize arrays of hexagonal InGaN submicrometer platelets with a top c-plane area having an extension of a few hundred nanometers by selective area metal-organic vapor-phase epitaxy. The InGaN platelets were made by in situ annealing of InGaN pyramids, whereby InGaN from the pyramid apex was thermally etched away, leaving a c-plane surface, while the inclined {101̅1} planes of the pyramids were intact. The as-formed c-planes, which are rough with islands of a few tens of nanometers, can be flattened with InGaN regrowth, showing single bilayer steps and high-quality optical properties (full width at half-maximum of photoluminescence at room temperature: 107 meV for In 0.09 Ga 0.91 N and 151 meV for In 0.18 Ga 0.82 N). Such platelets offer surfaces having relaxed lattice constants, thus enabling shifting the quantum well emission from blue (as when grown on GaN) to green and red. For single InGaN quantum wells grown on the c-plane of such InGaN platelets, a sharp interface between the quantum well and the barriers was observed. The emission energy from the quantum well, grown under the same conditions, was shifted from 2.17 eV on In 0.09 Ga 0.91 N platelets to 1.95 eV on In 0.18 Ga 0.82 N platelets as a result of a thicker quantum well and a reduced indium pulling effect on In 0.18 Ga 0.82 N platelets. On the basis of this method, prototype light-emitting diodes were demonstrated with green emission on In 0.09 Ga 0.91 N platelets and red emission on In 0.18 Ga 0.82 N platelets.

National virtual multidisciplinary team meetings have been established in Swedish cancer care in response to centralized treatment of rare cancers. Though national meetings grant access to a large multidisciplinary network, we hypothesized that video-based meetings may challenge participants' contributions to the case discussions. We investigated participants' views and used observational tools to assess contributions from various health professionals during the multidisciplinary team meetings. Data on participants' views were collected using an electronic survey distributed to participants in six national multidisciplinary team meetings for rare cancers. Data from observations were obtained from the multidisciplinary team meetings for penile cancer, anal cancer, and vulvar cancer using the standardized observational tools Meeting Observational Tool and Metric of Decision-Making that assess multidisciplinary team meeting functionality and participants' contributions to the case discussions. Participants overall rated the multidisciplinary team meetings favorably with high scores for development of individual competence and team competence. Lower scores applied to multidisciplinary team meeting technology, principles for communicating treatment recommendations, and guidelines for evaluating the meetings. Observational assessment resulted in high scores for case histories, leadership, and teamwork, whereas patient-centered care and involvement of care professionals received low scores. National virtual multidisciplinary team meetings are feasible and receive positive ratings by the participants. Case discussions cover medical perspectives well, whereas patient-centered aspects achieve less attention. Based on these findings, we discuss factors to consider to further improve treatment recommendations from national multidisciplinary team meetings., Competing Interests: Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background & Aims: To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. We examined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC)., Methods: We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBCs), and 164 non-gallbladder extrahepatic bile duct cancers (NGBCs) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity and performed mediation analysis and secondary analyses to assess robustness to confounding (e.g. due to hepatitis virus infection)., Results: In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% CI 0.38-0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (95% CI 0.33-0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC., Conclusions: These findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity., Lay Summary: In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts., Design: Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability)., Results: The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC., Conclusion: Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained., Competing Interests: Competing interests: TS received a studentship from the Medical Research Council (MR/M501712/1). DCM is supported by a Cancer Research UK Population Research Fellowship (C57955/A24390). KJA received a research grant from the German Research Foundation (DFG) (AL 1784/3-1), KEB received research grants from Cancer Research UK (C570/A16491) and the Medical Research Council (MR/M012190/1); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; KGMM is director of Research of a large (around 500 employees) research and teaching institute within his University Medical Center. They perform both investigator-driven and industry-driven research projects with a number of pharmaceutical and diagnostic companies. In addition, some of the members of staff receive unrestricted grants for research projects from a number of companies. It is their explicit policy to work with several companies and not to focus on one or two industrial partners. He receives no personal payment from any industrial partner., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The Okinawan-based Nordic diet has been developed to improve glucose metabolism. The aim of the present study was to summarize all anthropometric, subjective, and biochemical findings obtained following two different studies investigating this diet. The diet was administered i) as a single breakfast to healthy volunteers and ii) as a 12-week dietary intervention to patients with type 2 diabetes. The degree of satiety, sweet cravings, gastrointestinal symptoms, and health-related quality of life were estimated. Weight and blood pressures of participants were measured, and analyses including circulating levels of inflammatory and metabolic biomarkers, hormones, and short-chain fatty acids (SCFA), and microbial diversity and amount of Enterobacteriaceae in feces, were performed. A single breakfast of the diet increased satiety (P<0.001), improved glucose homeostasis (P<0.001), and lowered levels of glucose-dependent insulinotropic polypeptide (GIP) (P=0.002), compared with a standard breakfast. A 12-week intervention in type 2 diabetes increased satiety and decreased sweet cravings, at the same time as health-related quality of life and gastrointestinal symptoms were improved. There were reductions in body mass index (P<0.001), waist circumference (P<0.001), and levels of glucose (P<0.001), cholesterol (P<0.001), and triglycerides (P=0.009), in alignment with the endocrine profile. These improvements were maintained at follow-up 16 weeks later, along with lower levels of ghrelin (P=0.012), polypeptide YY (P=0.002), and visfatin (P=0.021), compared with the parameters recorded at the study start. Levels of haptoglobin, interleukin-18 and thrombocytes were lowered, whereas some other inflammatory biomarkers were unaffected and zonulin levels elevated. Gut microbiota and SCFAs levels were mainly unaffected. The mechanisms governing the anthropometric and metabolic improvements appear to be mediated through alterations in the endocrine profile, yet not in the gut microbiota.

Although endometriosis is considered an inflammatory disease, no reliable diagnostic biomarkers exist for use in clinical practice. The aim was to investigate the inflammatory profile in endometriosis using an exploratory approach of inflammation-related proteins. Patients with laparoscopy-verified endometriosis ( N = 172), women with microscopic colitis ( N = 50), healthy controls ( N = 31), and age-matched controls from the general population ( N = 100) were enrolled and questionnaires regarding socioeconomic factors, lifestyle habits, and medical history were completed. Sera from patients and healthy controls were analyzed for 92 inflammatory biomarkers using Proximity Extension Assay technology (PEA). Plasma AXIN1 levels were analyzed in patients with endometriosis and controls from the general population by ELISA. General linear model adjusted for age, Mann⁻Whitney U -test, and principal component analysis (PCA) were used for statistical calculations. Serum levels of AXIN1 and ST1A1 were increased in endometriosis compared with MC ( p < 0.001) and healthy controls ( p = 0.001), whereas CXCL9 levels were decreased. Plasma levels of AXIN1 were elevated in endometriosis compared with age-matched controls from the general population (30.0 (17.0⁻38.0) pg/mL vs. 19.5 (15.0⁻28.0) pg/mL, p < 0.001). PCA analysis identified four clusters of proteins, where one cluster differed between endometriosis and controls, with strong correlations for AXIN1 and ST1A1. Plasma/serum AXIN1 is an interesting biomarker to be further evaluated in endometriosis.

Background and Aim: An abnormal immune response to intestinal bacteria has been observed in Crohn's disease (CD). Clostridium difficile infection incidence and severity are increased in CD, but reports on the humoral response have provided conflicting results. We aimed to shed light on the possible role of C. difficile in CD pathogenesis by paying attention to the influence of immunomodulatory treatment on the humoral response., Methods: A total of 71 consecutive outpatients with CD, 67 with ulcerative colitis (UC), and 121 healthy controls were analyzed for serum IgA and IgG to C. difficile toxins A and B., Results: IgA levels were similar in all study groups. IgG to toxin A was increased similarly in CD and UC ( P = 0.02 for both). In contrast, IgG to toxin B was elevated only in CD patients not receiving disease-modifying anti-inflammatory bowel disease drugs (DMAID) ( n  = 16) ( P = 0.0001), while the CD medication subgroup ( n  = 47) had a level similar to healthy controls. The UC results were not influenced by DMAID treatment., Conclusion: Our findings add support to the idea of a disturbed interaction between intestinal cells and the microbiota being part of the CD disease mechanism. An abnormal immune response to C. difficile toxin B may be a critical component of this interaction.

Food may induce inflammation and favor development of metabolic diseases, which have been associated with increased inflammation and potential risk of cognitive impairment. It is customary to know whether food or disease promote inflammation. Our hypothesis was that Okinawan-based Nordic (O-BN) diet leads to decreased circulating concentrations of inflammatory and neural biomarkers. The objectives of this study were to examine the effects of the O-BN diet on inflammatory and neural responses. First, 2 different breakfasts; one standard and another O-BN-based, were given in random order to 19 healthy volunteers. Second, a 12-week O-BN-dietary intervention was performed in type 2 diabetes mellitus (T2DM), where the participants were followed for another 16-weeks, with registration of anthropometry and metabolic parameters. Non-diabetic subjects served as controls at baseline. Plasma was analyzed for cytokines by a 10-plex Luminex assay and neurofilament light (NfL) by an ultrasensitive Single molecule assay. Cytokine levels decreased after a single breakfast intake, independent of diet composition. Cytokine levels were higher in T2DM than in controls. Anthropometric and metabolic parameters were improved by the dietary intervention. In parallel, cytokine levels were lowered, although only significantly for IL-18 (P = .001), with a tendency of significance for IL-12p70 (P = .07). Levels of IL-18 correlated with glucose, HbA1c and lipids, but not with body mass index, insulin or blood pressure. NfL levels increased during the intervention (P = .049). O-BN-based diet does not affect postprandial cytokine levels in health, whereas it renders decreased circulating IL-18 levels along with metabolic biomarkers in T2DM, with no beneficial effect on NfL., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Endometriosis has been associated with a wide range of factors. The disease share immunological features with autoimmune diseases, and the prevalence of both hypo- and hyperthyroidism has been reported to be increased. However, the associations have to be confirmed and the mechanisms explored. The aim of this observational study was to investigate socioeconomic factors, lifestyle habits, and somatic and mental comorbidities in endometriosis compared to the general population., Study Design: In all, 172 women with endometriosis completed a study questionnaire and were interviewed regarding socioeconomic factors, lifestyle habits, psychological well-being, and medical history. Bowel symptoms were measured by the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS). Serum was analyzed for IgG levels of TSH receptor antibodies (TRAb) and anti-thyroid peroxidase (TPO) antibodies. Women from the general population served as controls. Differences were calculated by logistic regression, adjusted for confounders., Results: Alcohol intake, leisure time physical activity, body mass index and asthma were inversely, whereas IBS was positively associated with endometriosis. Hypothyroidism and anti-TPO antibodies did not associate, but elevated TRAb antibody titers were associated with endometriosis (odds ratio (OR): 539.26; 95% confidence interval (CI): 114.29-2544.32 for highest versus lowest tertile; p for trend < 0.001). Impaired psychological well-being (p for trend = 0.003) and current intake of antidepressant medication (OR: 3.54; 95% CI: 1.22-10.28; p = 0.020) associated with endometriosis, and impaired psychological well-being correlated with all gastrointestinal symptoms measured (all p < 0.001)., Conclusions: Lifestyle habits and asthma are inversely associated, and IBS and impaired psychological well-being are positively associated with endometriosis. TRAb titers are associated with endometriosis, supporting a link between endometriosis, autoimmunity and thyroid pathophysiology, although overt thyroid diseases do not associate., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14 years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HR log2  = 1.06, 95% CI 0.99-1.14) or in men (HR log2  = 0.97, 95% CI 0.90-1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HR log2  = 0.91, 95% CI 0.85-0.97) and positively associated with rectal cancer in women (HR log2  = 1.10, 95% CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.

Background: Gastrointestinal symptoms and changes in colonic transit time (CTT) are common in the population., Purpose: To evaluate consecutive patients who had been examined for CTT, along with completion of a diary about laxative and drug use, lifestyle factors, and gastrointestinal symptoms, to identify possible associations with longer or prolonged CTT., Material and Methods: A total of 610 consecutive patients had undergone the radiopaque marker method with an abdominal X-ray for clinical purposes. The patients had completed a diary regarding medical treatment, lifestyle factors, stool habits, and their perceived constipation and abdominal pain during the examination period. The associations between CTT and laxative use, lifestyle factors, stool habits, and symptoms were calculated by logistic regression., Results: Women had longer CTT (2.5 [1.6-3.9] vs. 1.7 [1.1-3.0] days, P  < 0.001), lower weekly stool frequency (6 [3-10] vs. 8 [5-12], P  = 0.001), and perceived more constipation ( P  = 0.025) and abdominal pain ( P  = 0.001) than men. High coffee consumption ( P  = 0.045), bulk-forming ( P  = 0.007) and osmotic ( P  = 0.001) laxatives, and lower stool frequency, shaped stool, and perceived constipation ( P for trend < 0.001) were associated with longer CTT. In total, 382 patients (63%) were treated with drugs affecting motility. In the 228 patients without drug treatment, longer CTT was associated with female sex and smoking, and lower frequency of symptoms and prolonged CTT were observed compared to patients using drugs. Tea, alcohol, and abdominal pain did not associate with CTT., Conclusions: Female sex, coffee, smoking, drug use, infrequent stools, shaped stool, and perception of constipation are associated with longer or prolonged CTT.

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch) 1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms. 2 Hence, in a previous study, 3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls. 1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC)., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The Okinawan-based Nordic (O-BN) diet improves anthropometry and metabolism in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to study mechanisms behind improvements by examining Enterobacteriaceae abundance, microbial diversity, and concentrations of short-chain fatty acids (SCFAs). A secondary aim was exploring if metformin treatment affects microbiota or SCFAs. Thirty T2DM patients received the O-BN diet for 12 weeks. Faecal and blood samples were collected at baseline, 12 and 28 weeks. Although patients experienced weight loss and improved metabolic parameters, there were no significant changes in Enterobacteriaceae abundance or microbial diversity. Patients on metformin displayed higher Enterobacteriaceae abundance throughout the study (p = .008, p = .038, and p = .001, respectively). Isovaleric acid was decreased after 12 weeks (p = .018). Butyric acid was decreased at follow-up (p = .007). Improved anthropometry and metabolism in T2DM after introduction of the O-BN diet is not associated with changes in Enterobacteriaceae abundance, microbial diversity or SCFA concentrations.

[This corrects the article DOI: 10.1159/000486390.].

Background & Aims: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants., Methods: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations., Results: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10 -8 ) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10 -6 ). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10 -10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia., Conclusions: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Multidisciplinary team meetings (MDTMs) have developed into standard of care to provide expert opinion and to grant evidence-based recommendations on diagnostics and treatment of cancer. Though MDTMs are associated with a range of benefits, a growing number of cases, complex case discussion and an increasing number of participants raise questions on cost versus benefit. We aimed to determine cost of MDTMs and to define determinants hereof based on observations in Swedish cancer care., Methods: Data were collected through observations of 50 MDTMs and from questionnaire data from 206 health professionals that participated in these meetings., Results: The MDTMs lasted mean 0.88 h and managed mean 12.6 cases with mean 4.2 min per case. Participants were mean 8.2 physicians and 2.9 nurses/other health professionals. Besides the number of cases discussed, meeting duration was also influenced by cancer diagnosis, hospital type and use of video facilities. When preparatory work, participation and post-MDTM work were considered, physicians spent mean 4.1 h per meeting. The cost per case discussion was mean 212 (range 91-595) EUR and the cost per MDTM was mean 2675 (range 1439-4070) EUR., Conclusions: We identify considerable variability in resource use for MDTMs in cancer care and demonstrate that 84% of the total cost is derived from physician time. The variability demonstrated underscores the need for regular and structured evaluations to ensure cost effective MDTM services.

Background: Chronic inflammation plays a critical role in the pathogenesis of the 2 major types of gastric cancer. Several foods, nutrients, and nonnutrient food components seem to be involved in the regulation of chronic inflammation., Objective: We assessed the association between the inflammatory potential of the diet and the risk of gastric carcinoma, overall and for the 2 major subsites: cardia cancers and noncardia cancers., Design: A total of 476,160 subjects (30% men, 70% women) from the European Investigation into Cancer and Nutrition (EPIC) study were followed for 14 y, during which 913 incident cases of gastric carcinoma were identified, including 236 located in the cardia, 341 in the distal part of the stomach (noncardia), and 336 with overlapping or unknown tumor site. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated with the use of 28 dietary components and their corresponding inflammatory scores. The association between the ISD and gastric cancer risk was estimated by HRs and 95% CIs calculated by multivariate Cox regression models adjusted for confounders., Results: The inflammatory potential of the diet was associated with an increased risk of gastric cancer. The HR (95% CI) for each increase in 1 SD of the ISD were 1.25 (1.12, 1.39) for all gastric cancers, 1.30 (1.06, 1.59) for cardia cancers, and 1.07 (0.89, 1.28) for noncardia cancers. The corresponding values for the highest compared with the lowest quartiles of the ISD were 1.66 (1.26, 2.20), 1.94 (1.14, 3.30), and 1.07 (0.70, 1.70), respectively., Conclusions: Our results suggest that low-grade chronic inflammation induced by the diet may be associated with gastric cancer risk. This pattern seems to be more consistent for gastric carcinomas located in the cardia than for those located in the distal stomach. This study is listed on the ISRCTN registry as ISRCTN12136108.

Background: An Okinawa-based Nordic diet with moderately low carbohydrate content and high fat and protein content has been shown to improve anthropometry and metabolism in type 2 diabetes., Objective: The objectives of this study were to measure plasma or serum levels of hormones regulating energy metabolism and metabolic control, that is, cholecystokinin (CCK), Cortisol, C-peptide, ghrelin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, leptin, plasminogen activator inhibitor-1 (PAI-1), polypeptide YY (PYY), resistin, and visfatin after this diet intervention, and to determine partial correlations between hormonal levels and anthropometric and metabolic responses., Design: A total of 30 patients (17 women) with type 2 diabetes, mean age 57.5 ± 8.2 years, and body mass index (BMI) 29.9 ± 4.1 kg/m 2 were served the diet for 12 weeks. Fasting hormones were measured by Luminex and enzyme-linked immunosorbent assay (ELISA) before study start and after 12 and 28 weeks, along with anthropometric and metabolic parameters., Result: The levels of CCK ( P = 0.005), cortisol ( P = 0.015), C-peptide ( P = 0.022), glucagon ( P = 0.003), GLP-1 ( P = 0.013), GIP ( P < 0.001), insulin ( P = 0.004), leptin ( P < 0.001), and PYY ( P < 0.001) were lowered after dietary intervention. These reduced levels only remained for PYY at week 28 ( P = 0.002), when also ghrelin ( P = 0.012) and visfatin ( P = 0.021) levels were reduced. Changes of glucose values correlated with changed levels of C-peptide and PYY ( P < 0.001), insulin ( P = 0.002), and PAI-1 ( P = 0.009); changes of triglyceride values with changed levels of C-peptide, insulin, and PYY ( P < 0.001) and PAI-1 ( P = 0.005); changes of insulin resistance with changes of leptin levels ( P = 0.003); and changes of BMI values with changed levels of C-peptide, insulin, and leptin ( P < 0.001)., Conclusions: Okinawa-based Nordic diet in type 2 diabetes has significant impact on the endocrine profile, which correlates with anthropometric and metabolic improvements., Competing Interests: The authors have not received any funding or benefits from industry or elsewhere to conduct this study.

Aim: To compare gut bacterial diversity and amount of Enterobacteriaceae in colonic mucosa between patients with and without diverticular disease (DD)., Methods: Patients in a stable clinical condition with planned elective colonoscopy were included. Blood samples and colon mucosa biopsies were collected at the colonoscopy. Study questionnaires including questions about gastrointestinal symptoms were completed by the patients and physicians. DNA from mucosa samples was isolated and the amount of Enterobacteriaceae was estimated using PCR assay. Terminal restriction fragment length polymorphism was applied to assess microbial diversity. Diversity was estimated by calculations of richness (number of terminal restriction fragments) and Shannon-Wiener and Simpson's indices., Results: A total of 51 patients were included, 16 patients with DD [68 (62-76) years] and 35 controls [62 (40-74) years] without any diverticula. Patients with DD had significantly higher levels of Enterobacteriaceae than those without DD ( P = 0.043), and there was an inverse relationship between the amount of Enterobacteriaceae and the Simpson's index (rs = -0.361, P = 0.033) and the Shannon-Wiener index (rs = -0.299, P = 0.081). The Simpson's index ( P = 0.383), Shannon-Wiener index ( P = 0.401) or number of restrictions fragments ( P = 0.776) did not differ between DD and controls. The majority of patients experienced gastrointestinal symptoms, and 22 patients (43.1%) fulfilled the criteria for irritable bowel syndrome, with no difference between the groups ( P = 0.212). Demography, socioeconomic status, lifestyle habits, inflammatory biomarkers, or symptoms were not related to the amount of Enterobacteriaceae or bacterial diversity., Conclusion: Patients with DD had higher amount of Enterobacteriaceae in the colon mucosa compared to patients without diverticula., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interests to declare.

Objective: IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase ( SI ) gene variants for their potential relevance in IBS., Design: We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population., Results: CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05)., Conclusions: SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients., Competing Interests: Competing interests: The work was partially financed by an unrestricted grant from Medical Need Europe AB to MDA. MDA and HYN have received unrestricted research grants and lecturing honoraria from QOL Medical, and LC has served on a scientific advisory board for QOL Medical., (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/.)

Background: High levels of blood glucose are thought to be associated with colorectal cancer (CRC) and hyperinsulinemia, an interstage in the development of CRC. The purpose of this study was to examine associations between incident CRC and blood glucose; plasma insulin; and the homeostasis model assessment for insulin resistance (HOMA2-IR), respectively, and to determine whether these associations were dependent on sex and cancer site., Methods: The Malmö Diet and Cancer cardiovascular cohort comprises 6103 individuals. During 81,781 person-years of follow-up, 145 cases of CRC were identified. The hazard ratio of measured blood glucose and plasma insulin and calculated HOMA2-IR were estimated with Cox proportional hazard regression., Results: An association was found between high levels of blood glucose and risk of CRC (HR: 1.72 for the highest compared with the lowest quartile; 95% CI: 1.05, 2.84; p trend  = 0.044), and colon cancer (HR: 1.70 for the highest compared with the lowest quartile; 95% CI: 0.87, 3.33; p trend  = 0.032). In men, an association was found between blood glucose and CRC (HR: 2.80 for the highest compared with the lowest quartile; 95% CI: 1.37, 5.70; p trend  = 0.001), and colon cancer (HR: 4.48 for the highest compared with the lowest quartile; 95% CI: 1.27, 15.84; p trend  = 0.007), but this was not found in women. No associations between plasma insulin, or HOMA2-IR, and CRC, were found., Conclusion: High levels of blood glucose in men are associated with risk of colon cancer. The findings contribute to facilitating to identify those most in need of prevention and screening.

Objectives: The pathophysiology behind functional gastrointestinal disease (FGID) has not been defined, but an intestinal accumulation of fermentable short-chain carbohydrates (FODMAPs) is thought to be involved. A restricted coffee intake is recommended. The aim was to investigate if symptoms of FGID were associated with intake of certain foods (including FODMAPs), as well as beverages (including coffee and tea)., Method and Materials: Data were used from participants, age range 45-75 years, who had answered the EpiHealth questionnaire about their background factors, health status and intake of food and beverages. After exclusion of organic bowel diseases, 16,840 participants remained. The impact of food and beverages on functional abdominal pain, functional bloating, functional constipation and functional diarrhea were examined by adjusted binary logistic regression., Results: Wholemeal bread (Swedish cracker) (OR: 1.361; 95% CI: 1.001-1.851) and white bread (low fiber content) (OR: 1.527; 95% CI: 1.075-2.169) were associated with constipation, whereas soft wholemeal bread (high fiber content) was associated with diarrhea (OR: 1.601; 95% CI: 1.040-2.463). Cheese was associated with bloating (OR: 1.460; 95% CI: 1.004-2.123). A high tea intake was associated with abdominal pain (p for trend =.003), bloating (p for trend = .039) and diarrhea (p for trend <.001), whereas coffee intake was associated with a decreased risk of abdominal pain (p for trend = .002) and bloating (p for trend = .007). High soda intake associated with abdominal pain and bloating and juice with diarrhea., Conclusion: There are weak associations between intake of grain and dairy products and FGID symptoms. Tea is associated with increased risks, whereas coffee is associated with lower risks, of FGID symptoms.

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT 4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT 4 R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT 4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3'UTR binding sites. The novel isoform HTR4b&#95;2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.

Background: Altered microbial composition of the intestine, commonly referred to as dysbiosis, has been associated with several autoimmune diseases including primary Sjögren's syndrome (pSS). The aims of the current study were to study the intestinal microbial balance in pSS and to identify clinical features associated with dysbiosis., Methods: Forty-two consecutive pSS patients and 35 age-matched and sex-matched control subjects were included in the study in an open clinic setting. Stool samples were analyzed for intestinal dysbiosis using a validated 16S rRNA-based microbiota test (GA-map™ Dysbiosis Test; Genetic Analysis, Oslo, Norway). Dysbiosis and severe dysbiosis were defined in accordance with the manufacturer's instructions. Patients were evaluated with regard to disease activity (European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and Clinical ESSDAI (ClinESSDAI)). In addition, patients were examined for laboratory and serological features of pSS as well as fecal calprotectin levels. Furthermore, patients were investigated regarding patient-reported outcomes for pSS (EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI)) and irritable bowel syndrome (IBS)-like symptoms according to the Rome III criteria., Results: Severe dysbiosis was more prevalent in pSS patients in comparison to controls (21 vs 3%; p = 0.018). Subjects with pSS and severe dysbiosis had higher disease activity as evaluated by the ESSDAI total score (13 vs 5; p = 0.049) and the ClinESSDAI total score (12 vs 5; p = 0.049), lower levels of complement component 4 (0.11 vs 0.17 g/L; p = 0.004), as well as higher levels of fecal calprotectin (110 vs 33 μg/g; p = 0.001) compared to the other pSS patients. In contrast, severe dysbiosis among pSS patients was not associated with disease duration, IBS-like symptoms, or the ESSPRI total score., Conclusions: Severe intestinal dysbiosis is a prevalent finding in pSS and is associated both with clinical and laboratory markers of systemic disease activity as well as gastrointestinal inflammation. Further studies are warranted to elucidate a potential causative link between dysbiosis and pSS.

Functional gastrointestinal disorders (FGIDs) are common disorders in the population. Lifestyle habits have been suspected to influence the presence and degree of symptoms, and many studies have examined the role of food components and physical activity on the disease development. The role of smoking and alcohol intake on FGID has been less thoroughly examined. This systematic literature review, of a large amount of studies from different countries around the world with different design and application of FGID criteria, shows that smoking seems to be associated with a significant 50% increased risk of FD for current compared with never smokers. The associations between smoking and other FGIDs are weak, if present at all. A moderate alcohol intake is not associated with FGIDs. On the other hand, a high alcohol intake may lead to development and aggravation of FGID symptoms, especially functional dyspepsia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Chronic rhinosinusitis with and without nasal polyps (CRSw/sNP) are common conditions decreasing health-related quality of life (HRQOL). Individual symptoms capable of predicting outcome after endoscopic sinus surgery (ESS) are poorly defined, and the indirect costs of CRS is rarely reported in Europe., Methodology: Patients with CRSw/sNP admitted for ESS were prospectively enrolled. Patients completed the 22 Sinonasal Outcome Test (SNOT-22), the short-form 36-item questionnaire (SF-36), a Visual Analogue Scale (VAS) and reported CRS-related absenteeism pre- and post-operatively., Results: 181 patients were included. The SNOT-22 score diminished from 51.8 (48.7-55.0) pre-operatively to 33.0 (29.2-36.8) at 6 months. 64% achieved a clinically important improvement in the SNOT-22. SF-36 scores improved statistically significantly in all domains except Role Emotional. The VAS score halved from 68 (65-71) to 34 (29-39) at 6 months post-operatively. A pre-operative SNOT-22 score over 20 implied a greater chance of score improvement after 6 months. A multivariate model identified individual items associated with SNOT-22. Further, patients that had lees than 12 months of sinus disease derived greatest benefit. CRS-related absenteeism dropped from 8-14 days to 1-7 days 12 months after ESS., Conclusions: This prospective study showed that ESS significantly improved the HRQOL and decreased absenteeism of patients with CRSw/sNP. Shorter duration of disease and Need to blow nose and Blockage/congestion of nose of SNOT-22 were identified as predictive factors for good surgical outcome.

Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case-control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured serum levels of hepcidin-25, iron, ferritin, transferrin and C-reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin-gastric cancer pathway was also evaluated. After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5 ng/l = 0.96, 95% CI = 0.93-0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a nonsignificant 38% (95% CI: -69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis., (© 2017 UICC.)

Background : Colorectal cancer (CRC) is considered one of the most common forms of cancer in the Western world. High intake of red and processed meat is considered to increase CRC development. Objective : This study examined associations between intake of red meats, poultry, and fish and incident CRC, and if weight status modifies the associations. Design : In the Malmö Diet and Cancer Study, dietary data was collected through a modified diet history method. Via the Swedish Cancer Registry, 728 cases of CRC were identified during 428 924 person-years of follow-up of 16 944 women and 10 987 men. Results : Beef intake was inversely associated with colon cancer. However, in men high intake of beef was associated with increased risk of rectal cancer. High intake of pork was associated with increased incidence of CRC, and colon cancer. Processed meat was associated with increased risk of CRC in men. Fish intake was inversely associated with risk of rectal cancer. No significant interactions were found between different types of meat and weight status. Conclusions : Findings suggest that associations between meat intake and CRC differ depending on meat type, sex, and tumor location in the bowel. Weight status did not modify observed associations.

Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone, and luteinizing hormone orchestrate the reproduction cycle and regulate the sex steroid secretion from the gonads. In mammals, GnRH1 is secreted as a hormone from the hypothalamus, whereas both GnRH1 and GnRH2 are present as neurotransmitters/peptides in various tissues, where the peptides exert many different effects. mRNA coding for GnRH1 and GnRH2 have been described in the human gastrointestinal tract, and GnRH has been found in both submucosal and myenteric neurons. mRNA coding for GnRH and the fully expressed peptide have been found in rat enteric neurons by some researchers but not by others. mRNA coding for GnRH receptors, but not the fully expressed receptor, has been found in one rat study. GnRH influences gastrointestinal motility and secretion. GnRH analogs are clinically used in the treatment of sex hormone-dependent diseases, i.e., endometriosis and malignancies, and as pretreatment for in vitro fertilization. Reduced numbers of enteric neurons and IgM antibodies against GnRH and progonadoliberin-2 (precursor of GnRH2) have been observed after such treatment, with the clinical picture of gastrointestinal dysmotility. Similarly, a rat model of enteric neurodegeneration has been developed after administration of the GnRH analog buserelin. Serum IgM antibodies against GnRH1, progonadoliberin-2, and GnRH receptors have been described in patients with signs and symptoms of gastrointestinal dysmotility and/or autonomic dysfunction, such as irritable bowel syndrome, enteric dysmotility, diabetes mellitus, and primary Sjögren's syndrome. Thus, apart from regulation of reproduction and sex hormone secretion, GnRH also constitutes a part of enteric nervous system (ENS) and its functions during physiological and pathological conditions. This review aimed to describe the role of GnRH in the ENS.

Background: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking., Methods: We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression., Results: Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70-81.40; P trend  = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses., Conclusions: These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.

Calprotectin is a marker of inflammation and zonulin is a marker of intestinal permeability. Diets with lower carbohydrate content and higher contents of fat, fiber and protein, e.g., Okinawan-based diet, are considered to reduce inflammation and intestinal permeability. The aim of the present study was to evaluate calprotectin and zonulin levels in serum and feces after intervention with an Okinawan-based Nordic diet. Thirty patients (17 women) with type 2 diabetes, mean age 57.5±8.2 years, BMI 29.9±4.1 kg/m 2 , were served the diet during 12 weeks, and were followed for another 16 weeks. Anthropometric and metabolic parameters were registered. Fasting levels of calprotectin and zonulin in serum and feces, and hormones in plasma, were measured by Luminex or ELISA before study start and after 12 and 28 weeks. Calprotectin in serum tended to be increased (P=0.074) after 12 weeks. Zonulin in serum and feces were elevated after 12 weeks (P=0.019 vs. P<0.001), and remained elevated in serum after 28 weeks (P=0.014). In contrast to baseline, there was a correlation between calprotectin and zonulin in serum and feces after dietary intervention (P=0.025 vs. P=0.079). Energy percentage of protein in breakfast correlated with serum calprotectin (P=0.008) and tended to correlate with serum zonulin (P=0.059). Calprotectin in serum tended to be elevated, and zonulin in serum and feces are elevated after introduction of an Okinawan-based Nordic diet. These biomarkers correlate with energy percentage of protein.

Background: The Mediterranean diet (MD) has been proposed as a means for cancer prevention, but little evidence has been accrued regarding its potential to prevent pancreatic cancer. We investigated the association between the adherence to the MD and pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort., Methods: Over half a million participants from 10 European countries were followed up for over 11 years, after which 865 newly diagnosed exocrine pancreatic cancer cases were identified. Adherence to the MD was estimated through an adapted score without the alcohol component (arMED) to discount alcohol-related harmful effects. Cox proportional hazards regression models, stratified by age, sex and centre, and adjusted for energy intake, body mass index, smoking status, alcohol intake and diabetes status at recruitment, were used to estimate hazard ratios (HRs) associated with pancreatic cancer and their corresponding 95% confidence intervals (CIs)., Results: Adherence to the arMED score was not associated with risk of pancreatic cancer (HR high vs low adherence=0.99; 95% CI: 0.77-1.26, and HR per increments of two units in adherence to arMED=1.00; 95% CI: 0.94-1.06). There was no convincing evidence for heterogeneity by smoking status, body mass index, diabetes or European region. There was also no evidence of significant associations in analyses involving microscopically confirmed cases, plausible reporters of energy intake or other definitions of the MD pattern., Conclusions: A high adherence to the MD is not associated with pancreatic cancer risk in the EPIC study.

Zonulin is considered a biomarker of increased intestinal permeability, and elevated levels have been found in celiac disease. The primary aim of this study was to examine the association between serum zonulin levels and gastrointestinal (GI) symptoms, and secondarily, between zonulin levels and anthropometric and metabolic factors. The offspring ( n = 363) of the participants of the Malmö Diet and Cancer cardiovascular cohort (MDC-CV) were invited to an anthropometric and clinical examination, where fasting plasma glucose levels were measured. Questionnaires about lifestyle factors and medical history were completed along with the Visual Analog Scale for Irritable Bowel Syndrome (VAS-IBS). Zonulin levels were measured in serum by ELISA. Neither GI symptoms nor GI diseases had any influence on zonulin levels. Higher zonulin levels were associated with higher waist circumference ( p = 0.003), diastolic blood pressure ( p = 0.003), and glucose levels ( p = 0.036). Higher zonulin levels were associated with increased risk of overweight ( p < 0.001), obesity ( p = 0.047), and hyperlipidemia ( p = 0.048). We cannot detect altered zonulin levels among individuals reporting GI symptoms or GI diseases, but higher zonulin levels are associated with higher waist circumference, diastolic blood pressure, fasting glucose, and increased risk of metabolic diseases.

Objective: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role., Design: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin., Results: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10 -10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10 -11 ; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis)., Conclusions: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis., (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/.)

Background: Copper and zinc are essential micronutrients and cofactors of many enzymatic reactions that may be involved in liver-cancer development. We aimed to assess pre-diagnostic circulating levels of copper, zinc and their ratio (Cu/Zn) in relation to hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBD) and gall bladder and biliary tract (GBTC) cancers., Methods: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. Serum zinc and copper levels were measured in baseline blood samples by total reflection X-ray fluorescence in cancer cases (HCC n=106, IHDB n=34, GBTC n=96) and their matched controls (1:1). The Cu/Zn ratio, an indicator of the balance between the micronutrients, was computed. Multivariable adjusted odds ratios and 95% confidence intervals (OR; 95% CI) were used to estimate cancer risk., Results: For HCC, the highest vs lowest tertile showed a strong inverse association for zinc (OR=0.36; 95% CI: 0.13-0.98, P trend =0.0123), but no association for copper (OR=1.06; 95% CI: 0.45-2.46, P trend =0.8878) in multivariable models. The calculated Cu/Zn ratio showed a positive association for HCC (OR=4.63; 95% CI: 1.41-15.27, P trend =0.0135). For IHBC and GBTC, no significant associations were observed., Conclusions: Zinc may have a role in preventing liver-cancer development, but this finding requires further investigation in other settings.

Background/aim: The role of the microbiome has been widely discussed in the etiology of appendicitis. The primary aim was to evaluate the microbiome in the normal appendix and in appendicitis specifically divided into the three clinically and histopathologically defined grades of inflammation. Secondary aims were to examine whether there were any microbiome differences between proximal and distal appendices, and relate the microbiome with histopathological findings., Methods: A prospective pilot study was conducted of children undergoing appendectomy for appendicitis. The diagnosis was based on histopathological analysis. Children with incidental appendectomy were used as controls. The proximal and distal mucosa from the appendices were analyzed with 16S rRNA gene sequencing., Results: A total of 22 children, 3 controls and 19 appendicitis patients; 11 phlegmonous, 4 gangrenous, and 4 perforated appendices, were prospectively included. The amount of Fusobacterium increased and Bacteroides decreased in phlegmonous and perforated appendicitis compared to controls, but statistical significance was not reached, and this pattern was not seen in gangrenous appendicitis. No relation could be seen between different bacteria and the grade of inflammation, and there was a wide variation of abundances at phylum, genus, and species level within every specific group of patients. Further, no significant differences could be detected when comparing the microbiome in proximal and distal mucosa, which may be because the study was underpowered. A trend with more abundance of Fusobacteria in the distal mucosa was seen in appendicitis patients with obstruction (25 and 13 %, respectively, p = 0.06)., Conclusion: The pattern of microbiome differed not only between groups, but also within groups. However, no statistically significant differences could be found in the microbiome between groups or clinical conditions. No correlation between a specific bacteria and grade of inflammation was found. In the vast majority of cases of appendicitis, changes in microbiome do not seem to be the primary event. Since there seem to be differences in microbiome patterns depending on the sample site, the exact localization of biopsy sampling must be described in future studies., Competing Interests: Compliance with ethical standardsFunding sourceMag-TarmFonden, Swedish Gastroenterology Society, and Development Foundation, Region Skåne, Sweden.Financial disclosureAll authors have no financial relationships relevant to this article to disclose.Conflict of interestThe authors have no conflicts of interest to disclose.

Background/objectives: The incidence of microscopic colitis (MC) has increased over the previous decades. In addition to smoking and drugs, currently unidentified environmental factors may have a role. The aim of this study was to determine whether specific dietary or other lifestyle factors were associated with the development of MC., Subject/methods: The population-based cohort Malmö Diet and Cancer Study of 28 095 individuals was examined. Information about dietary habits was collected by a modified diet history method. Data on anthropometry were measured, and socio-economic and lifestyle factors were collected by questionnaires. Cases of MC were identified in medical registers. Associations were estimated using Cox regression analysis., Results: During a 22-year period, 135 patients were diagnosed with MC. Intakes of protein, carbohydrates, sucrose, saturated fat, monounsaturated fat, polyunsaturated fat, omega-3 or omega-6 fatty acids, fibre and zinc were not associated with MC. We could verify the previously reported association between MC and smoking (hazard ratio (HR): 2.29; 95% confidence interval (CI): 1.66-3.84) and the female gender (HR: 3.57; 95% CI: 2.22-5.74). High alcohol consumption was associated with an increased risk for MC (HR: 1.89 for the highest quartile; 95% CI: 0.82-4.33, P for trend=0.032). In a post hoc analysis, alcohol intake including all patients independently of consumption seemed to reduce the smoking-related risk., Conclusions: Despite a large cohort and a long follow-up period, we could not detect any dietary risk factors for MC. The aetiological mechanisms behind the positive impact of smoking and alcohol on MC risk should be investigated.

The aim was to compare postprandial plasma levels of calprotectin, cortisol, triglycerides and zonulin between a control breakfast and a moderately low-carbohydrate test breakfast, given randomly after 10-h fast. Blood samples were collected before and repeatedly after the meal. Plasma calprotectin, cortisol, triglycerides and zonulin were analyzed. The total area under the curve (tAUC) and change in AUC from baseline (dAUC) were calculated. Ratios between the test and control values were calculated to investigate equivalence. Healthy volunteers (8 men and 12 women; 46.0 ± 14.5 years) were included. tAUCs of cortisol and triglycerides did not differ between the breakfasts (p = 0.158 versus p = 0.579). Cortisol dAUCs were decreased and triglyceride dAUCs were increased after both breakfasts, with no differences between the breakfasts (p = 0.933 versus p = 0.277). Calprotectin and zonulin levels were unaffected. The meals were bioequivalent for cortisol, triglycerides and zonulin, but not for calprotectin.

Objectives: Few studies have examined how lifestyle factors affect functional gastrointestinal disorders. The aim of this study was to see if leisure time physical inactivity, dietary habits or body mass index (BMI) were associated with increased risk of functional abdominal pain, functional bloating, functional constipation or functional diarrhea., Methods and Materials: This study was based on a questionnaire as part of the Swedish EpiHealth study. The cohort included 16,840 subjects between 45 and 75 years of age. Subjects with organic gastrointestinal diseases were excluded. Gastrointestinal symptoms were defined as functional abdominal pain, functional bloating, functional constipation and functional diarrhea. A meal (breakfast, lunch and dinner) was considered irregular if not taken every day. The impact of leisure time physical activity, dietary habits and BMI on functional symptoms were examined by logistic regression, adjusted for age, gender, socio-economy, smoking and alcohol habits., Results: Higher the degree of physical activity, lower the risk for all kind of gastrointestinal complaints (p ≤ 0.001). Intakes of lunch more seldom or never versus every day were associated with diarrhea (OR: 1.592; 95% CI: 1.046-2.422). Irregular breakfast habits tended to associate with bloating (OR: 1.366; 95% CI 0.995-1.874). BMI was not significantly associated with gastrointestinal complaints, but BMI ≥25 kg/m(2) tended to reduce risk of constipation compared with BMI <25 kg/m(2)., Conclusion: Physical inactivity during leisure time shows independent associations with all functional gastrointestinal symptoms, whereas irregular dietary habits mainly associates with functional diarrhea. Higher degree of physical activity is associated with corresponding risk reductions of symptoms.

Background: Our hypothesis was that a modified diet would improve blood glucose control with beneficial impact on weight management and overall health in established diabetes., Objective: This prospective interventional study investigated the clinical effect of an Okinawan-based Nordic diet on anthropometry, metabolic control, and health-related quality of life (HRQoL) in Scandinavian type 2 diabetes patients., Design: Food was prepared and delivered to 30 type 2 diabetes patients. Clinical information along with data on HRQoL, blood samples, and urine samples were collected during 12 weeks of diet interventions, with follow-up 16 weeks after diet completion., Results: After 12 weeks of dietary intervention, a reduction in body weight (7%) (p<0.001), body mass index (p<0.001), and waist circumference (7.0 cm) (p<0.001) was seen. Improved levels of proinsulin (p=0.005), insulin (p=0.011), and fasting plasma glucose (p<0.001) were found already after 2 weeks; these improved levels remained after 12 weeks when lowered levels of C-peptide (p=0.015), triglycerides (p=0.009), total cholesterol (p=0.001), and low-density lipoprotein-cholesterol (p=0.041) were also observed. Insulin resistance homeostasis model assessment for insulin resistance was lowered throughout the study, with a 20% reduction in hemoglobin A1c levels (p<0.001) at week 12, despite reduced anti-diabetes treatment. Lowered systolic blood pressure (9.6 mmHg) (p<0.001), diastolic blood pressure (2.7 mmHg) (p<0.001), and heart and respiratory rates (p<0.001) were accompanied by decreased cortisol levels (p=0.015) and improvement in HRQoL. At follow-up, increased levels of high-density lipoprotein-cholesterol were found (p=0.003)., Conclusion: This interventional study demonstrates a considerable improvement of anthropometric and metabolic parameters and HRQoL in Scandinavian type 2 diabetes patients when introducing a modified Okinawan-based Nordic diet, independently of exercise or other interventions. Through these dietary changes, anti-diabetes treatment could be decreased or cancelled., Competing Interests: Conflict of interest and fundingSS is the founder of Igelösa Life Science AB. The other authors have no conflicts of interest.

We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758-65. ©2016 AACR., Competing Interests: Conflicts of Interest: None declared., (©2016 American Association for Cancer Research.)

Background: The aim of the study was to describe the technique of two-trocar laparoscopic appendectomy and compare the outcome between two- and three-trocar techniques in children., Methods: All children who underwent laparoscopic surgery for suspected appendicitis from 2006 to 2014 in a center for pediatric surgery were included in the study. Converted surgeries and patients with appendiceal abscess or concomitant intestinal obstruction were excluded. A total of 259 children underwent appendectomy with either two (35 %) or three (65 %) laparoscopic trocars according to the surgeons' preference and intraoperative judgment. Patient demographics, clinical symptoms, surgery characteristics, and complications were reviewed., Results: The mean age of the children was 10.4 years (range, 1-14 years). The mean follow-up time was 41.2 months (SD ± 29.2). No significant differences in age, gender, weight, or signs and symptoms were found between the two- and three-trocar groups. The mean surgery time was significantly shorter in the two-trocar group (47 min) than in the three-trocar group (66 min; p < 0.001). The rates of surgical complications were 2 % vs. 4 %, (p = 0.501), and the rates of postoperative complications were 0 % vs. 5 % (p = 0.054), in the two- and three-trocar groups. The overall incidence of postoperative wound infection was low (<1 %) and did not differ between groups., Conclusions: Two-trocar laparoscopic appendectomy seems to be a safe and feasible technique with a low rate of postoperative wound infections. The present findings demonstrate that when the two-trocar technique could be applied, it is a good complement to the conventional three-trocar technique.