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  • 1. Agréus, Lars
    et al.
    Hellström, Per M.
    Talley, Nicholas J.
    Wallner, Bengt
    Forsberg, Anna
    Vieth, Michael
    Veits, Lothar
    Björkegren, Karin
    Engstrand, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Towards a healthy stomach? Helicobacter pylori prevalence has dramatically decreased over 23 years in adults in a Swedish community2016In: United European Gastroenterology journal, ISSN 2050-6406, E-ISSN 2050-6414, Vol. 4, no 5, p. 686-696Article in journal (Refereed)
    Abstract [en]

    Background In Western countries the prevalence of Helicobacter pylori (H. pylori) infection may be declining but there is a lack of recent longitudinal population studies. We evaluated the changing epidemiology over a 23-year period in Sweden. Materials and methods In 1989, the validated Abdominal Symptom Questionnaire (ASQ) was mailed to a random sample of inhabitants (ages 22-80 years) in a Swedish community, and 1097 (87%) responded. H. pylori serology was analysed in a representative subsample (n=145). Twenty-three years later, the ASQ was mailed again using similar selection criteria, and 388 out of 1036 responders had an upper endoscopy with assessment of H. pylori and corpus atrophy status. Results The prevalence of positive H. pylori serology decreased from 37.9% (1989) to 15.8% (2012), corresponding to a decrease in odds of 75% per decade (odds ratio (OR): 0.25; 95% confidence interval (CI): 0.11-0.59, p=0.001) independent of age, gender, body mass index (BMI) and level of education, with a pattern consistent with a birth cohort effect. The prevalence increased with increasing age (p=0.001). The prevalence of H. pylori on histology in 2012 was 11.4% (95% CI 8.6-15.0). The prevalence of corpus atrophy on serology and/or histology in 2012 was 3.2% (95% CI 1.8-5.5); all cases were 57 years old. Conclusion The stomach is healthier in 2012 compared with 1989. H. pylori prevalence in adults has decreased over the last two decades to a level where clinical management might be affected.

  • 2. Alexandersson, Bjarki
    et al.
    Hamad, Yousef
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska University Hospital, Sweden; Macquarie University, Australia.
    Rubio, Carlos A.
    Ando, Yugo
    Tanaka, Kyosuke
    Ichiya, Tamaki
    Rezaie, Reza
    Schmidt, Peter T.
    High-Definition Chromoendoscopy Superior to High-Definition White-Light Endoscopy in Surveillance of Inflammatory Bowel Diseases in a Randomized Trial2020In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 18, no 9, p. 2101-2107Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: There is debate over the optimal method for colonoscopic surveillance of patients with inflammatory bowel diseases. Guidelines recommend chromoendoscopy, but the value of chromoendoscopy in high-definition colonoscopy has not been proven. Furthermore, the value of random biopsies is controversial. METHODS: We performed a prospective study of 305 patients with ulcerative colitis or Crohn's colitis referred for surveillance colonoscopy at a university hospital in Sweden, from March 2011 through April 2016. Patients randomly assigned to a group that received high-definition chromoendoscopy with indigo carmine (HD-CE; n=152), collection of 32 random biopsies, and targeted biopsies or polypectomies or to a group that received high-definition white light endoscopy (HD-WLE; n=153), collection of 32 random biopsies, and targeted biopsies or polypectomies. The primary endpoint was number of patients with dysplastic lesions. RESULTS: Dysplastic lesions were detected in 17 patients with HD-CE and 7 patients with HD-WLE (P=.032). Dysplasias in random biopsies (n=9760) were detected in 9 patients: 6 (3.9%) in the HD-CE group and 3 (2.0%) in the HD-WLE group (P=.72). Of the 9 patients with dysplasia, 3 patients (33%) had primary sclerosing cholangitis-only 18% of patients (54/305) included in the study had primary sclerosing cholangitis. The number of dysplastic lesions per 10 min of withdrawal time was 0.066 with HD-CE and 0.027 with HD-WLE (P=.056). CONCLUSIONS: In a randomized trial, we found HD-CE with collection of random biopsies to be superior to HD-WLE with random biopsies for detection of dysplasia per colonoscopy. These results support the use of chromoendoscopy for surveillance of patients with inflammatory bowel diseases. ClinicalTrials.gov no: NCT01505842.

  • 3. Alexandersson, Bjarki T.
    et al.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, North Ryde, Australia.
    Hedin, Charlotte
    Broms, Gabriella
    Schmidt, Peter T.
    Forsberg, Anna
    Inflammatory Bowel Disease Is not Linked to a Higher Rate of Adverse Events in Colonoscopy: a Nationwide Population-based Study in Sweden2023In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 17, no 12, p. 1962-1967Article in journal (Refereed)
    Abstract [en]

    Background and Aims: Inflammatory bowel disease may cause long-standing inflammation and fibrosis and may increase the risk of adverse events in colonoscopy. We evaluated whether inflammatory bowel disease and other potential risk factors are associated with bleeding or perforation in a nationwide, population-based, Swedish study.

    Methods: Data from 969 532 colonoscopies, including 164 012 [17%] on inflammatory bowel disease patients, between 2003 and 2019, were retrieved from the National Patient Registers. ICD-10 codes for bleeding [T810] and perforation [T812] within 30 days of the colonoscopy were recorded. Multivariable logistic regression was used to test if inflammatory bowel disease status, inpatient setting, time period, general anaesthesia, age, sex, endoscopic procedures, and antithrombotic treatment were associated with higher odds for bleeding and perforation.

    Results: Bleeding and perforation were reported in 0.19% and 0.11% of all colonoscopies, respectively. Bleeding [odds ratio 0.66, p <0.001] and perforation [odds ratio 0.79, p <0.033] were less likely in colonoscopies in individuals with inflammatory bowel disease status. Bleeding and perforation were more common in inpatient than in outpatient inflammatory bowel disease colonoscopies. The odds for bleeding but not perforation increased between 2003 to 2019. General anaesthesia was associated with double the odds for perforation.

    Conclusions: Individuals with inflammatory bowel disease did not have more adverse events compared with individuals without inflammatory bowel disease status. However, the inpatient setting was associated with more adverse events, particularly in inflammatory bowel disease status. General anaesthesia was associated with a greater risk of perforation.

  • 4. Alexandersson, Bjarki T.
    et al.
    Hugerth, Luisa W.
    Hedin, Charlotte
    Forsberg, Anna
    Talley, Nicholas J.
    Agreus, Lars
    Järbrink-Sehgal, Ellionore
    Engstrand, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Schmidt, Peter T.
    Diverticulosis is not associated with altered gut microbiota nor is it predictive of future diverticulitis: a population-based colonoscopy study2023In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 58, no 10, p. 1131-1138Article in journal (Refereed)
    Abstract [en]

    Background: The etiopathogenesis of diverticular disease is unknown.

    Objective: To compare the fecal and mucosa-associated microbiota between participants with and without diverticulosis and participants who later developed diverticulitis versus those that did not from a population-based study.

    Methods: The PopCol study, conducted in Stockholm, Sweden, invited a random sample of 3556 adults to participate, of which 745 underwent colonoscopy. Overall, 130 participants (17.5%) had diverticulosis. 16S rRNA gene sequencing was conducted on available sigmoid biopsy samples from 529 and fecal samples from 251 individuals. We identified individuals who subsequently developed acute diverticulitis up to 13 years after sample collection. In a case-control design matching for gender, age (+/−5 years), smoking and antibiotic exposure, we compared taxonomic composition, richness and diversity of the microbiota between participants with or without diverticulosis, and between participants who later developed acute diverticulitis versus those who did not.

    Results: No differences in microbiota richness or diversity were observed between participants with or without diverticulosis, nor for those who developed diverticulitis compared with those who did not. No bacterial taxa were significantly different between participants with diverticulosis compared with those without diverticulosis. Individuals who later developed acute diverticulitis (2.8%) had a higher abundance of genus Comamonas than those who did not (p = .027).

    Conclusions: In a population-based cohort study the only significant difference was that those who later develop diverticulitis had more abundance of genus Comamonas. The significance of Comamonas is unclear, suggesting a limited role for the gut microbiota in the etiopathogenesis of diverticular disease.

  • 5.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden.
    Bosch, Jos A.
    Balter, Leonie J. T.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden.
    Poor sleep quality is associated with worse self-rated health in long sleep duration but not short sleep duration2021In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 88, p. 262-266Article in journal (Refereed)
    Abstract [en]

    Unhealthy sleep duration, either short or long, is associated with worse health and central subjective dimensions of sleep and health such as fatigue. It has been argued that the link between sleep duration and health may depend on the quality of the slept hours, and on its functional impact (ie, fatigue). The present study therefore assessed whether the relationship between last night's sleep duration and general self-rated health (SRH) differs as a function of sleep quality, and secondly, whether current fatigue and sleep quality are factors linking sleep duration and SRH. The present cross-sectional dataset involved 1304 individuals (57% female, M age = 28.8, range 18-79). Participants completed surveys for general SRH, previous night's sleep duration and sleep quality, and current fatigue. Results showed the expected inverted U-shaped (ie, quadratic) relation between last night's sleep duration and SRH and a linear relation between last night's sleep quality and SRH. However, long sleep duration was only associated with poorer SRH in individuals who also reported poor sleep quality. Further, the quadratic relationship between sleep duration and SRH was partially mediated by fatigue and sleep quality. The results of this multi-study analysis suggest that SRH is particularly poor in those who slept both long and with poor quality the night before, while good sleep quality may protect those with a long sleep duration from poor SRH. Thus, last night's long sleep does not seem to be associated with poor subjective health unless it is coupled with poor sleep quality. Furthermore, fatigue and sleep quality are potential pathways linking short and long sleep duration with SRH. Different dimensions of sleep interact in their association with health, and future research will benefit from an integrative approach. 

  • 6.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Carlsson, A. C.
    Wändell, P. E.
    High levels of leptin are associated with poor self-rated health in men and women with type 2 diabetes treated with metformin2013In: NMCD. Nutrition Metabolism and Cardiovascular Diseases, ISSN 0939-4753, E-ISSN 1590-3729, Vol. 23, no 2, p. E11-E12Article in journal (Other academic)
  • 7.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Carlsson, Axel C.
    Önnerhag, Kristina
    Hagström, Hannes
    Waist/Hip Ratio Better Predicts Development of Severe Liver Disease Within 20 Years Than Body Mass Index: A Population-based Cohort Study2017In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 15, no 8, p. 1294-+Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Obesity, commonly assessed based on body mass index (BMI), is associated with an increased risk for severe liver disease. It is not known if other measures of body composition are better determinants of risk for severe liver disease, and/or if these differ between women and men. We investigated the body composition measures that best predict the development of severe liver disease. METHODS: We collected data from the Malmo Diet and Cancer study in Sweden, comprising 16,784 women and 10,833 (mean age, 58.1 years at baseline), and followed patients for a median 19.8 years. We analyzed data on measures of body composition including BMI, waist/hip ratio, and others. We determined whether subjects were diagnosed with severe liver disease, or died from severe liver disease, until the end of 2014 using Swedish national registers. Associations between body composition measures and severe liver disease were assessed using Cox regression models, stratified by sex and adjusted for age, alcohol consumption, smoking, education, and physical activity. RESULTS: All studied measures of body composition were significantly associated with severe liver disease. Waist/hip ratio was the best predictor of severe liver disease in women (hazard ratio [HR] per standard deviation increment, 1.30; 95% confidence interval [CI], 1.16-1.46) and men (HR, 1.46; 95% CI, 1.31-1.63). BMI had the lowest HR in women (HR, 1.12; 95% CI, 1.00-1.27) and men (HR, 1.26; 95% CI, 1.12-1.42). The association between waist/hip ratio and development of liver disease was independent of BMI. CONCLUSIONS: In a Swedish population-based cohort study, we associated all measures of body composition with risk of severe liver disease. However, measures of abdominal obesity were best at predicting development of severe liver disease.

  • 8.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Hagström, Hannes
    Sköldberg, Filip
    Önnerhag, Kristina
    Carlsson, Axel C.
    Schmidt, Peter T.
    Forsberg, Anna M.
    The prediction of colorectal cancer using anthropometric measures: A Swedish population-based cohort study with 22 years of follow-up2019In: United European Gastroenterology journal, ISSN 2050-6406, E-ISSN 2050-6414, Vol. 7, no 9, p. 1250-1260Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is a risk factor for colorectal cancer (CRC).

    Objective: The objective of this article is to investigate whether anthropometric measures reflecting visceral obesity are better predictors of CRC than body mass index (BMI).

    Methods: Data were analysed from the Malmo Diet and Cancer study in Sweden, comprising 16,669 women and 10,805 men (median age 56.6 and 59.1 years) followed for a median 21.5 years. Diagnoses of CRC were identified using Swedish national registers. Cox regression was used to test the associations of BMI, waist circumference (WC), waist-hip ratio, waist-to-height ratio, waist-to-hip-to-height ratio, A Body Shape Index (ABSI) and percentage body fat with the development of CRC adjusted for age, alcohol consumption, smoking, education and physical activity in men and women.

    Results: None of the measures were significantly associated with an increased risk for CRC in women. WC was the strongest predictor of colon cancer (CC) in men and the only measure that was independent of BMI. ABSI was the only measure significantly associated with the risk of rectal cancer in men.

    Conclusions: Visceral obesity, best expressed as WC, is a risk factor for CC in men but a poor predictive marker for CRC in women.

  • 9.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lidberg, Lisa
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Ingvar, Martin
    Hoglund, Caroline Olgart
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 3, article id e0212313Article in journal (Refereed)
    Abstract [en]

    Background Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status. Methods Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD = 3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once (28.6 years; SD = 7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin-6, interleukin-8 and tumour necrosis factor-alpha, before and after injection. Results Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b = 1.88 for 0.8 ng/kg) and current health (Experiment 1 b = -3.00; and Experiment 2 b = -1.79) 1.5h after injection (p's<0.01), effects that remained after 4.5 to 5 hours (p's<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (beta = -0.28, p = 0.01). Conclusion Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity.

  • 10.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Macquarie University, Australia; Karolinska Institutet, Sweden.
    McNaughton, David
    Beath, Alissa
    Lodin, Karin
    Wicksell, Rikard K.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden.
    Jones, Michael P.
    Properties of the Sickness Questionnaire in an Australian sample with chronic medically unexplained symptoms2020In: Brain, Behavior, & Immunity - Health, ISSN 2666-3546, Vol. 3, article id 100059Article in journal (Refereed)
    Abstract [en]

    Sickness behavior including malaise, fatigue and increased pain sensitivity is thought to be adaptive and facilitate recovery from disease. However, it may also reduce functioning and health if symptoms persists, which is why validated instruments for its assessment are needed. We evaluated the English translation of the Sickness Questionnaire (SicknessQ) in an Australian population of 156 participants with high level of persistent musculoskeletal pain and/or gastrointestinal symptoms without an organic explanation. The SicknessQ total score had an adequate model fit and no other models were found to fit data better. The SicknessQ correlated most strongly with fatigue, stress, anxiety and depression, which explained 62% of the variance in SicknessQ, but not with physical functioning. The mean score (8.9; 95 %CI: 8.0–9.8) was in between those previously reported in a general population sample and in primary care patients. In conclusion, the evaluation of the English version of the SicknessQ in an Australian sample with significant, chronic unexplained medical symptoms supports the use of the English version of the total SicknessQ score as an overall measure of sickness behavior.

  • 11.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Jones, M. P.
    Walker, M. M.
    Talley, N. J.
    Nyhlin, H.
    Agréus, L.
    Prediction pathways for innate immune pathology, IBS, anxiety and depression in a general population (The POPCOL Study)2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, p. e46-e46Article in journal (Other academic)
    Abstract [en]

    The aim of this study was to ascertain whether low grade innate inflammation contributes to a pathway of depression and anxiety via irritable bowel syndrome (IBS). We evaluated innate immune cell counts in colonic mucosa in normal subjects and those with IBS (Rome III) from a population based study in which 745 randomly selected subjects had a colonoscopy (mean age 51 years;57% women). Intraepithelial lymphocytes (IELs) per 100 enterocytes and eosinophils (eos) per five non-overlapping high power fields (HPF) were counted in 90 controls and 100 cases; immunocytochemistry (CD117) was performed for mast cells per 5HPF in 80 controls and 81 cases. IELs, mast cells and eos were individually summed over 5 sites (terminal ileum, caecum, transverse colon, sigmoid colon and rectum). Anxiety and depression scores were calculated from HADS. A causal model path model which hypothesises immune cells being associated with IBS which, in turn, is associated with elevated anxiety and depression was tested using path analysis implemented in the MPlus software. All hypothesised paths reached statistical significance (p < .05) supporting the individual hypothesized pathways. The overall model fit was reasonable although imperfect. In conclusion, a significant contribution of innate immune inflammatory load leading to anxiety and depression via IBS was found. Whether therapy directed to decreasing this inflammatory load also lifts depression and anxiety should be further explored.

  • 12.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Schiller, Helena
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Contemplate your symptoms and re-evaluate your health2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e38-e39Article in journal (Refereed)
    Abstract [en]

    Bodily signals and how these are interpreted affect self-ratings of health. It is thus reasonable that appraisals of health are affected by imminent exposures and disease primes. We aimed to investigate whether self-ratings of health are affected by a symptom rating and if changes are substantiated in persons who report more symptoms. We used data from 813 persons who completed a questionnaire daily for 21 consecutive days. The questionnaire included a one-item self-rating of health (“pre-SRH”; 1 = excellent, 7 = very poor), a subsequent 26-item rating of physical and mental symptoms and thereafter a second (identical) self-rating of health (“post-SRH”). Paired t-tests were used to test for differences between pre-SRH and post-SRH. Mixed effect regression models were used to calculate the interaction effect of pre-SRH and symptom score on post-SRH adjusted for gender, age and if the person had been working that day (13545 observations). SRH worsened significantly (p  <<.0001) after the symptom rating, from 2.72 pre-SRH (95%CI:−2.70–2.74) to 2.77 post-SRH (95%CI:2.75–2.79). There was a significant interaction between pre-SRH and symptoms on post-SRH so that persons who reported more symptoms changed their post-SRH rating to a higher degree than those who reported fewer symptoms, irrespective of their subjective health status. The results support the notion that subjective health perception is affected by focus of attention, and that the effect depends on level of symptoms.

  • 13.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Wicksell, B.
    Karshikoff, B.
    Lodin, K.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Development and preliminary validation of the Sickness Questionnaire (SicknessQ)2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, article id e14Article in journal (Refereed)
    Abstract [en]

    The lack of questionnaires to measure subjective feelings of being sick made us develope the Sickness Questionnaire (SicknessQ) for assessment of sickness behavior in people. The objective of the present investigation was to test its internal consistency, criteria validity, and sensitivity to capture the sickness response in an experimental setting. An initial pool of items was developed based on previous research. The statistical properties of SicknessQ was assessed in 172 men and women primary care patients with acute complaints and involved three steps: (1) principal component analyses to reduce the number of items and to identify latent factor structures, (2) tests of internal consistencies of subscales, and (3) hierarchical regression analyses to test criteria validity of the subscales. Subsequently, sensitivity to change was tested in a placebo controlled experiment in which 31 blinded healthy men and women were injected with endotoxin (LPS) to provoke sickness behavior. Principal components analysis suggested a 3-factor solution with a total of 11 items measuring fatigue (5 items), pain (4 items) and emotion (2 items). The total scale as well as each of the three separate factors were significantly changed 90 min after endotoxin injection as compared to baseline (p’s < .01). In all, the new 11-item SicknessQ is highly sensitive to a mild systemic inflammation. Further studies are planned to test its usefulness and prognostic value in clinical settings.

  • 14.
    Andreasson, Anna Nixon
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet.
    Szulkin, Robert
    Undén, Anna-Lena
    von Essen, Jan
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet.
    Inflammation and positive affect are associated with subjective health in women of the general population2013In: Journal of Health Psychology, ISSN 1359-1053, E-ISSN 1461-7277, Vol. 18, no 3, p. 311-320Article in journal (Refereed)
    Abstract [en]

    Poor subjective health has been associated with higher levels of inflammatory cytokines. We investigated whether such an association would apply to women of the general population. Levels of cytokines, affect and subjective health were assessed in 347 women of the general population aged 45 to 90 years. Higher levels of interleukin-6 were associated with poor subjective health, especially in participants over 65 years of age. Positive affect was a more robust determinant of subjective health than negative affect. The presence of low-grade inflammation and absence of positive affect, rather than presence of negative affect, may be important determinants of subjective health.

  • 15.
    Andreasson, Anna Nixon
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Undén, Anna-Lena
    Elofsson, Stig
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Brismar, Kerstin
    Leptin and adiponectin: Distribution and associations with cardiovascular risk factors in men and women of the general population2012In: American Journal of Human Biology, ISSN 1042-0533, E-ISSN 1520-6300, Vol. 24, no 5, p. 595-601Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: In view of the increasing prevalence of obesity worldwide, understanding the role of the recently discovered adipokines leptin and adiponectin is of high clinical relevance. The aim of the present study was to assess the association between levels of leptin and adiponectin with age, known cardiovascular risk factors and to establish whether there are differences between men and women of the general population.

    METHODS: A total of 98 men and 107 women of the general population, aged between 20 and 74 years, underwent a medical examination at a clinical research center and fasting morning blood samples were also taken.

    RESULTS: Leptin (mean 7.5 μg l(-1) in men and 16.0 μg l(-1) in women) and adiponectin (mean 7.3 mg l(-1) in men and 11.9 mg l(-1) in women) levels were higher in women than men (Ps < 0.001). Both leptin and adiponectin levels increased with advancing age in both men and women (Ps < 0.05). Leptin was highly associated with factors for metabolic syndrome in men while in women, leptin was highly associated with inflammatory factors. Adiponectin was associated with blood lipids in both men and women, and glucose homeostasis more in women than in men.

    CONCLUSIONS: Leptin and adiponectin levels were ∼2 times and 1.5 times higher in women than in men, respectively. In addition, although leptin and adiponectin were associated to CVD risk factors in both men and women, we observed differences in specific CVD risk factor groups between men and women. These differences may be due to different regulatory mechanisms and effects of these adipokines in men and women.

  • 16.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Schiller, Helena
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Berntson, Erik
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Work and organizational psychology.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Brief report: Contemplate your symptoms and re-evaluate your health. A study on working adults2019In: Journal of Health Psychology, ISSN 1359-1053, E-ISSN 1461-7277, Vol. 24, no 11, p. 1562-1567Article in journal (Refereed)
    Abstract [en]

    We investigated whether self-ratings of health are affected by a symptom rating. A diary including a one-item self-rating of health ("pre-self-rated health"; 1 = excellent, 7 = very poor), a subsequent 26-item rating of symptoms, and thereafter a second (identical) health rating ("post-self-rated health") was completed by 820 persons 21 times. Self-rated health worsened significantly ( p < .0001) after the symptom rating, from 2.72 pre-self-rated health (95% confidence interval: 2.70-2.74) to 2.77 post-self-rated health (95% confidence interval: 2.75-2.79) and more so in persons who reported more symptoms ( b = .058, p < .05). The results support the notion that subjective health perception is influenced by attending to symptoms, especially so in persons with a high symptom burden.

  • 17.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Macquarie University, Australia; Karolinska Institutet, Sweden.
    Talley, Nicholas J.
    Walker, Marjorie M.
    Jones, Michael P.
    Platts, Loretta G.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute.
    Wallner, Bengt
    Kjellström, Lars
    Hellström, Per M.
    Forsberg, Anna
    Agréus, Lars
    An Increasing Incidence of Upper Gastrointestinal Disorders Over 23 Years: A Prospective Population-Based Study in Sweden2021In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 116, no 1, p. 210-213Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: We hypothesized that the prevalence of functional dyspepsia and gastroesophageal reflux disease in the community may be increasing.

    METHODS: Randomly selected adults were surveyed on 4 occasions: 1988 (n = 1,151, 21–79 years, response rate [rr] = 90%), 1989 (n = 1,097, 22–80 years, rr = 87%), 1995 (n = 1,139, 20–85 years, rr = 76%), and 2011 (n = 1,175, 20–93 years, rr = 63%).

    RESULTS: In functional dyspepsia, the odds of postprandial distress syndrome tripled over 23 years' follow-up (odds ratio [OR]: 3.55; 95% confidence interval [CI]: 2.60–4.84, mixed-effect regression analysis), whereas a small decrease in epigastric pain syndrome was observed (OR: 0.65, 95% CI: 0.42–1.00). The odds of reporting gastroesophageal reflux disease doubled (OR: 2.02; 95% CI: 1.50–2.73).

    DISCUSSION: The underlying mechanisms behind the increase in postprandial distress syndrome and gastroesophageal reflux disease remain to be determined.

  • 18.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Stockholm, Sweden; Macquarie University, North Ryde, Australia.
    Tognetti, Arnaud
    Jones, Mike
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Stockholm, Sweden.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Stockholm, Sweden.
    Assessing sickness behavior in the French: Validation of the French translation of the sickness questionnaire (SicknessQ) in a non-clinical French population2023In: Brain, Behavior, & Immunity - Health, ISSN 2666-3546, Vol. 34, article id 100708Article in journal (Refereed)
    Abstract [en]

    The Sickness Questionnaire (SicknessQ) is a questionnaire developed to assess symptoms of sickness behavior, including somatic, behavioral, and affective dimensions. To promote cross-cultural assessments of sickness behavior, we aim to expand the use of this questionnaire to other populations and languages. The aim of the present study was to evaluate the French translation of SicknessQ in a French-speaking general population during the COVID-19 pandemic. One hundred and thirty-nine individuals completed the SicknessQ online, along with the construct criteria measures of self-rated health, state anxiety (STAI-S), and depressive symptoms (PHQ-9). The principal component analyses revealed two components: the first component included seven items concerning mood, motivation and experiences of fatigue and pain; the second component included three items concerning somatic sickness symptoms. Higher scores on the total scale and the two component subscales were associated with poorer self-rated health and higher STAI-S and PHQ-9 scores. Since the associations with construct criteria variables were relatively similar between the single- and the two-dimensional solutions, both the total scale and the subscales of the two components of the French SicknessQ can be used in future studies to measure sickness behavior in French-speaking populations.

  • 19.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Wicksell, Rikard K.
    Lodin, Karin
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    A global measure of sickness behaviour: Development of the Sickness Questionnaire2018In: Journal of Health Psychology, ISSN 1359-1053, E-ISSN 1461-7277, Vol. 23, no 11, p. 1452-1463Article in journal (Refereed)
    Abstract [en]

    Symptoms after inflammatory activation, so-called sickness behaviour, overlap with trans-diagnostic complaints. As no self-report questionnaire to assess sickness behaviour exists, we aimed to develop such an instrument, the Sickness Questionnaire. Items responsive to experimentally induced inflammatory activation (randomized double-blind study endotoxin (0.6 ng/kg) versus placebo, n = 52) were selected and the statistical properties were examined in 172 primary care patients. A principal component analysis indicated a one-factor solution (Cronbach's alpha = .86). This 10-item scale correlated with depression ( β = .41, p < .001), anxiety ( β = .36, p < .001), self-rated health ( β = .28, p < .001) and a single item of feeling sick ( β = .55, p < .001). The results support the adequacy of Sickness Questionnaire as a brief assessment instrument of perceived sickness behaviour.

  • 20. Bonfiglio, Ferdinando
    et al.
    Liu, Xingrong
    Smillie, Christopher
    Pandit, Anita
    Kurilshikov, Alexander
    Bacigalupe, Rodrigo
    Zheng, Tenghao
    Nim, Hieu
    Garcia-Etxebarria, Koldo
    Bujanda, Luis
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Division of Clinical Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Agreus, Lars
    Walter, Susanna
    Abecasis, Gonçalo
    Eijsbouts, Chris
    Jostins, Luke
    Parkes, Miles
    Hughes, David A.
    Timpson, Nicholas
    Raes, Jeroen
    Franke, Andre
    Kennedy, Nicholas A.
    Regev, Aviv
    Zhernakova, Alexandra
    Simren, Magnus
    Camilleri, Michael
    D’Amato, Mauro
    GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome2021In: Cell Genomics, E-ISSN 2666-979X, Vol. 1, no 3, article id 100069Article in journal (Refereed)
    Abstract [en]

    Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10-8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.

  • 21. Bonfiglio, Ferdinando
    et al.
    Zheng, Tenghao
    Garcia-Etxebarria, Koldo
    Hadizadeh, Fatemeh
    Bujanda, Luis
    Bresso, Francesca
    Agreus, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Dlugosz, Aldona
    Lindberg, Greger
    Schmidt, Peter T.
    Karling, Pontus
    Ohlsson, Bodil
    Simren, Magnus
    Walter, Susanna
    Nardone, Gerardo
    Cuomo, Rosario
    Usai-Satta, Paolo
    Galeazzi, Francesca
    Neri, Matteo
    Portincasa, Piero
    Bellini, Massimo
    Barbara, Giovanni
    Latiano, Anna
    Hübenthal, Matthias
    Thijs, Vincent
    Netea, Mihai G.
    Jonkers, Daisy
    Chang, Lin
    Mayer, Emeran A.
    Wouters, Mira M.
    Boeckxstaens, Guy
    Camilleri, Michael
    Franke, Andre
    Zhernakova, Alexandra
    D'Amato, Mauro
    Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome2018In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 155, no 1, p. 168-179Article in journal (Refereed)
    Abstract [en]

    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 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also [GRAPHICS] 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 IKB-KAP), 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.

  • 22. Brew, Bronwyn K.
    et al.
    Almqvist, Catarina
    Lundholm, Cecilia
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute.
    Lehto, Kelli
    Talley, Nicholas J.
    Gong, Tong
    Comorbidity of atopic diseases and gastro-oesophageal reflux evidence of a shared cause2022In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 52, no 7, p. 868-877Article in journal (Refereed)
    Abstract [en]

    Introduction: Gastro-oesophageal reflux disease (GERD) is the most common non-allergic comorbidity in adults with asthma; however, comorbidity with other atopic diseases such as eczema and hay fever is unclear. The objective was to assess the comorbidity of GERD with asthma and atopic diseases and to investigate possible mechanisms, including genetic and/or affective factors.

    Methods: A co-twin control study harnessing 46 583 adult twins. Questionnaires on health status were linked to national patient and prescribed drug register data. Analyses tested associations of comorbidity between multiple definitions of atopic diseases (self-report and register-based) with GERD. Comparisons were made between unpaired, monozygotic (MZ) and dizygotic (DZ) twins to assess genetic liability. Affective traits (depression, anxiety and neuroticism) were added to models as possible explanatory factors.

    Results: The risk of GERD in those with asthma was OR (odds ratio) 1.52 (95% CI 1.38, 1.68), hay fever OR 1.22 (95%CI 1.12, 1.34) and eczema OR 1.23 (95%CI 1.10, 1.38). Adjusting for affective traits completely attenuated the comorbidity associations for hay fever and eczema with GERD, and partly for asthma with GERD. Co-twin control associations attenuated suggesting a shared cause for both GERD and atopic diseases. For example, all twins adjOR 1.32 (95%CI 1.00, 1.74), 0.97 (95% CI 0.76–1.23) and 1.11 (95%CI 0.85–1.45) for self-report asthma, hay fever and eczema with GERD respectively.

    Conclusions: GERD is a common comorbidity in adults with asthma, hay fever and/or eczema. We found evidence for shared mechanisms suggesting common underlying causes that may involve affective traits requiring further investigation.

  • 23. Carlsson, A C
    et al.
    Nixon Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Wändell, P E
    Poor self-rated health is not associated with a high total allostatic load in type 2 diabetic patients--but high blood pressure is2011In: Diabetes & Metabolism, ISSN 1262-3636, E-ISSN 1878-1780, Vol. 37, no 5, p. 446-51Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Allostatic load has been linked to self-rated health (SRH), cardiovascular disease and mortality in non-diabetic individuals. The aim of this study was to construct an allostatic load score and to find any correlations with SRH.

    METHODS: The subjects included in the study came from a randomized, controlled trial of type 2 diabetes. Blood samples were drawn, urine was collected for 24h, and questionnaires, including SRH, were filled out on three occasions: at baseline; after the 10-week intervention; and at a follow-up 3 months after the intervention. Allostatic load was estimated using a wide range of variables, including systolic and diastolic blood pressure, pulse pressure, cortisol, catecholamines, HbA(1c), insulin, plasma glucose and waist circumference.

    RESULTS: There was no association between SRH and allostatic load. However, three other components were significantly correlated with allostatic load at the baseline investigation and the two follow-up investigations - namely, systolic blood pressure, diastolic blood pressure and HbA(1c).

    CONCLUSION: The absence of an association between allostatic load and SRH in diabetic individuals contrasts with previous findings in non-diabetic women, and shows that it is hazardous to apply findings in one population to another, especially diabetic and non-diabetic populations.

  • 24. Carstens, A.
    et al.
    Fahlen, A.
    Lundin, D.
    Andreasson, Anna N.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Agréus, L.
    Engstrand, L.
    Halfvarson, J.
    The faecal flora does not reflect the colonic musicalflora. A 454, pyrosequencing study of a population-based cohort of healthy individuals2013Conference paper (Refereed)
  • 25. Carstens, Adam
    et al.
    Roos, Annika
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institute, Sweden.
    Magnuson, Anders
    Agreus, Lars
    Halfvarson, Jonas
    Engstrand, Lars
    Differential clustering of fecal and mucosa-associated microbiota in 'healthy' individuals2018In: Journal of Digestive Diseases, ISSN 1751-2972, E-ISSN 1751-2980, Vol. 19, no 12, p. 745-752Article in journal (Refereed)
    Abstract [en]

    Objective Fecal samples are often used to characterize gut microbiota. However, whether or not fecal microbiota differs from mucosa-associated microbiota remains largely unknown. This may be specifically relevant in conditions that are characterized by complex mucosal microbe-host interactions, such as Crohn's disease. We aimed to determine the degree of agreement between fecal and mucosal microbiota profiles in 'healthy' individuals, using two commonly used collection procedures. Methods The gut microbiota composition of fecal samples (sent at ambient temperature before storage at -70 degrees C) and of colonic biopsies (obtained at endoscopy and immediately stored at -70 degrees C) was determined by sequencing the 16S rRNA gene. Altogether 31 randomly selected 'healthy' individuals from the population-based colonoscopy (Popcol) study were included. Results The fecal samples were characterized by a reduced degree of richness (P < 0.0001) and diversity (P = 0.016), and also differences in several phyla, including a lower relative abundance of Proteobacteria (P < 0.0001) and Verrucomicrobia (P = 0.008) than in biopsies. Only three of 30 individuals had a similar fecal and mucosal microbiota profile, based on weighted UniFrac analysis. A difference in Crohn's disease dysbiosis-associated bacteria was observed, including a lower relative abundance of Faecalibacterium (P = 0.004) and a higher relative abundance of Ruminococcus (P = 0.001) in feces than in biopsies. Conclusions The observed differences between fecal samples, transported at ambient temperature, and the colonic mucosa-associated microbiota have implications for the interpretation of the previous literature, and may be specifically relevant to studies on Crohn's disease.

  • 26. Ek, Weronica E.
    et al.
    Reznichenko, Anna
    Ripke, Stephan
    Niesler, Beate
    Zucchelli, Marco
    Rivera, Natalia V.
    Schmidt, Peter T.
    Pedersen, Nancy L.
    Magnusson, Patrik
    Talley, Nicholas J.
    Holliday, Elizabeth G.
    Houghton, Lesley
    Gazouli, Maria
    Karamanolis, George
    Rappold, Gudrun
    Burwinkel, Barbara
    Surowy, Harald
    Rafter, Joseph
    Assadi, Ghazaleh
    Li, Ling
    Papadaki, Evangelia
    Gambaccini, Dario
    Marchi, Santino
    Colucci, Rocchina
    Blandizzi, Corrado
    Barbaro, Raffaella
    Karling, Pontus
    Walter, Susanna
    Ohlsson, Bodil
    Törnblom, Hans
    Bresso, Francesca
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Dlugosz, Aldona
    Simrén, Magnus
    Agréus, Lars
    Lindberg, Greger
    Boeckxstaens, Guy
    Bellini, Massimo
    Stanghellini, Vincenzo
    Barbara, Giovanni
    Daly, Mark J.
    Camilleri, Michael
    Wouters, Mira M.
    D'Amato, Mauro
    Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts2015In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 64, no 11, p. 1774-1782Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies.

    DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls.

    RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls.

    CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.

  • 27. Ethier, J-F.
    et al.
    Curcin, V.
    Barton, A.
    McGilchrist, M. M.
    Bastiaens, H.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Rossiter, J.
    Zhao, L.
    Arvanitis, T. N.
    Taweel, A.
    Delaney, B. C.
    Burgun, A.
    Clinical Data Integration Model: Core Interoperability Ontology for Research Using Primary Care Data2015In: Methods of Information in Medicine, ISSN 0026-1270, Vol. 54, no 1, p. 16-23Article in journal (Refereed)
    Abstract [en]

    Introduction: This article is part of the Focus Theme of Methods of Information in Medicine on "Managing Interoperability and Complexity in Health Systems". Background: Primary care data is the single richest source of routine health care data. However its use, both in research and clinical work, often requires data from multiple clinical sites, clinical trials databases and registries. Data integration and interoperability are therefore of utmost importance. Objectives: TRANSFoRm's general approach relies on a unified interoperability frame-work, described in a previous paper. We developed a core ontology for an interoperability framework based on data mediation. This article presents how such an ontology, the Clinical Data Integration Model (CDIM), can be designed to support, in conjunction with appropriate terminologies, biomedical data federation within TRANSFoRm, an EU FP7 project that aims to develop the digital infrastructure for a learning healthcare system in European Primary Care. Methods: TRANSFoRm utilizes a unified structural /terminological interoperability framework, based on the local-as-view mediation paradigm. Such an approach mandates the global information model to describe the domain of interest independently of the data sources to be explored. Following a requirement analysis process, no ontology focusing on primary care research was identified and, thus we designed a realist ontology based on Basic Formal Ontology to support our framework in collaboration with various terminologies used in primary care. Results: The resulting ontology has 549 classes and 82 object properties and is used to support data integration for TRANSFoRm's use cases. Concepts identified by researchers were successfully expressed in queries using CDIM and pertinent terminologies. As an example, we illustrate how, in TRANSFoRm, the Query Formulation Workbench can capture eligibility criteria in a computable representation, which is based on CDIM. Conclusion: A unified mediation approach to semantic interoperability provides a flexible and extensible framework for all types of interaction between health record systems and research systems. CDIM, as core ontology of such an approach, enables simplicity and consistency of design across the heterogeneous software landscape and can support the specific needs of EHR-driven phenotyping research using primary care data.

  • 28. Forsberg, Anna
    et al.
    Kjellström, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden .
    Jaramillo, Edgar
    Rubio, Carlos A.
    Björck, Erik
    Agréus, Lars
    Talley, Nicholas J.
    Lindblom, Annika
    Colonoscopy findings in high-risk individuals compared to an average-risk control population2015In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 50, no 7, p. 866-874Article in journal (Refereed)
    Abstract [en]

    Background and aims: There is clear evidence of reduced morbidity and mortality from regular colonoscopy programs in patients with Lynch syndrome (LS). Today, also individuals with empirically increased risks of colorectal cancer (CRC) are offered colonoscopic surveillance. The aim was to compare the findings at the first screening colonoscopy in LS carriers, and individuals with an increased risk of bowel cancer due to family history of CRC with a control population. Methods: Altogether 1397 individuals with an increased risk for CRC were divided in four risk groups: one with LS carriers and three groups with individuals with different family history of CRC. The findings were compared between the different risk groups and a control group consisting of 745 individuals from a control population who took part in a population-based colonoscopy study. Results: In LS, 30% of the individuals had adenomas and 10% advanced adenomas. The corresponding figures in the other risk groups were 14-24% and 4-7%, compared with 10% and 3% in the control group. The relative risk of having adenomas and advanced adenomas was, compared to controls, significantly higher for all risk groups except the group with the lowest risk. Age was a strong predictor for adenomas and advanced adenomas in both risk individuals and controls. Conclusions: Individuals with a family history of CRC have a high prevalence and cumulative risk of adenomas and advanced adenomas, and screening is motivated also in this risk group.

  • 29. Forsberg, Anna M.
    et al.
    Kjellström, Lars
    Agréus, Lars
    Nixon Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Nyhlin, Henry
    Talley, Nicholas J.
    Björck, Erik
    Prevalence of colonic neoplasia and advanced lesions in the normal population: a prospective population-based colonoscopy study2012In: Scandinavian journal of gastroenterology, ISSN 1502-7708, Vol. 47, no 2, p. 184-90Article in journal (Refereed)
    Abstract [en]

    Objective. There are few prospective studies of the prevalence of colonic neoplasia in the normal population. In order to properly evaluate screening-protocols for colorectal cancer in risk groups (e.g., older subjects or those with a family history), it is essential to know the prevalence of adenomas and cancer in the normal population. Methods. A prospective population-based colonoscopy study on 745 individuals born in Sweden aged 19-70 years was conducted (mean age 51.1 years). All polyps seen were retrieved and examined. Results. Out of the 745 individuals 27% had polyps, regardless of kind. Adenomas were found in 10% of the individuals and finding of adenomas was positively correlated to higher age. Men had adenomas in 15% and women in 6% of the cases. Women had a right-sided dominance of adenomas. Hyperplastic polyps were seen in 21% of the individuals. The presence of hyperplastic polyps was significantly positively correlated to the presence of adenomas. Advanced adenomas were seen in 2.8% of the study participants, but no cancers were detected. Conclusion. One in 10 healthy subjects had an adenoma but advanced adenomas were uncommon. Men and women have a different adenoma prevalence and localization. The results provide baseline European data for evaluating colonoscopy screening-protocols for colorectal cancer risk groups, and the findings may have implications for colon cancer screening in the normal, otherwise-healthy population.

  • 30. Hadizadeh, Fatemeh
    et al.
    Bonfiglio, Ferdinando
    Belheouane, Meriem
    Vallier, Marie
    Sauer, Sascha
    Bang, Corinna
    Bujanda, Luis
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Agreus, Lars
    Engstrand, Lars
    Talley, Nicholas J.
    Rafter, Joseph
    Baines, John F.
    Walter, Susanna
    Franke, Andre
    D'Amato, Mauro
    Faecal microbiota composition associates with abdominal pain in the general population2018In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 67, no 4, p. 778-779Article in journal (Other academic)
  • 31. Hagström, Hannes
    et al.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Carlsson, Axel C.
    Jerkeman, Mats
    Carlsten, Mattias
    Body composition measurements and risk of hematological malignancies: A population-based cohort study during 20 years of follow-up2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 8, article id e0202651Article in journal (Refereed)
    Abstract [en]

    High body mass index (BMI) is associated with development of hematological malignancies (HMs). However, although BMI is a well-established measurement of excess weight, it does not fully reflect body composition and can sometimes misclassify individuals. This study aimed at investigating what body composition measurements had highest association with development of HM. Body composition measurements on 27,557 individuals recorded by healthcare professionals as part of the Malmo Diet and Cancer study conducted in Sweden between 1991-1996 were matched with data from national registers on cancer incidence and causes of death. Cox regression models adjusted for age and sex were used to test the association between one standard deviation increments in body composition measurements and risk of HM. During a median follow-up of 20 years, 564 persons developed an HM. Several body composition measurements were associated with risk of developing an HM, but the strongest association was found for multiple myeloma (MM). Waist circumference (HR 1.31, p = 0.04) and waist-hip ratio (HR 1.61, p = 0.05) had higher risk estimates than BMI (HR 1.18, p = 0.07) for MM. In conclusion, our study shows that measurements of abdominal adiposity better predict the risk of developing HM, particularly MM, compared to BMI.

  • 32. Hagström, Hannes
    et al.
    Hemmingsson, Tomas
    Stockholm University, Faculty of Social Sciences, Centre for Social Research on Alcohol and Drugs (SoRAD). Karolinska Institutet, Sweden.
    Discacciati, Andrea
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Alcohol consumption in late adolescence is associated with an increased risk of severe liver disease later in life2018In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 68, no 3, p. 505-510Article in journal (Refereed)
    Abstract [en]

    Background & Aims: High alcohol consumption is associated with an increased risk of severe liver disease. Current recommendations suggest it is safe for men to consume 30 grams of alcohol per day. We investigated the association between alcohol consumption early in life and later development of severe liver disease.

    Methods: We used data on alcohol consumption at conscription to military service from 43,296 men (18-20 years) in Sweden between 1969 and 1970. Outcomes were defined as incident diagnoses of severe liver disease from systematic national registration of clinical events until the end of 2009. A Cox regression model adjusted for body mass index, smoking, use of narcotics, cognitive ability and cardiovascular capacity was applied.

    Results: During a mean follow-up of 37.8 years, 383 men developed severe liver disease. Alcohol consumption was associated with an increased risk of development of severe liver disease in a dose-response pattern (adjusted hazard ratio for every one gram/day increase 1.02; 95% CI 1.01-1.02). No evidence of a threshold effect was found. Importantly, a clear trend pointed towards an increased risk of severe liver disease in men who consumed less than 30 grams of alcohol per day.

    Conclusion: Alcohol consumption in young men is associated with an increased risk of severe liver disease, up to 39 years later in life. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised.

    Lay summary: We investigated more than 43,000 Swedish men in their late teens enlisted for conscription in 1969–1970. After almost 40 years of follow-up, we found that alcohol consumption was a significant risk factor for developing severe liver disease, independent of confounders. This risk was dose-dependent, and was most pronounced in men consuming two drinks per day or more.

  • 33. Hagström, Hannes
    et al.
    Hemmingsson, Tomas
    Stockholm University, Faculty of Social Sciences, Centre for Social Research on Alcohol and Drugs (SoRAD). Karolinska Institutet, Sweden.
    Discacciati, Andrea
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Reply to: "A measure of alcohol consumption in late adolescence associated with liver disease after 39 years of follow-up is insufficient to guide alcohol safe limits"2018In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 69, no 1, p. 252-253Article in journal (Other academic)
  • 34. Hagström, Hannes
    et al.
    Hemmingsson, Tomas
    Stockholm University, Faculty of Social Sciences, Department of Public Health Sciences. Karolinska Institutet, Sweden.
    Discacciati, Andrea
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Risk Behaviors Associated with Alcohol Consumption Predict Future Severe Liver Disease2019In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 64, no 7, p. 2014-2023Article in journal (Refereed)
    Abstract [en]

    Background

    Excess consumption of alcohol can lead to cirrhosis, but it is unclear whether the type of alcohol and pattern of consumption affects this risk.

    Aims

    We aimed to investigate whether type and pattern of alcohol consumption early in life could predict development of severe liver disease.

    Methods

    We examined 43,242 adolescent men conscribed to military service in Sweden in 1970. Self-reported data on total amount and type of alcohol (wine, beer, and spirits) and risk behaviors associated with heavy drinking were registered. Population-based registers were used to ascertain incident cases of severe liver disease (defined as cirrhosis, decompensated liver disease, liver failure, hepatocellular carcinoma, or liver-related mortality). Cox regression models were used to estimate hazard ratios for development of severe liver disease.

    Results

    During follow-up, 392 men developed severe liver disease. In multivariable analysis, after adjustment for BMI, smoking, use of narcotics, cardiovascular fitness, cognitive ability, and total amount of alcohol, an increased risk for severe liver disease was found in men who reported drinking alcohol to alleviate a hangover (“eye-opener”; aHR 1.47, 95% CI 1.02–2.11) and men who reported having been apprehended for being drunk (aHR 2.17, 95% CI 1.63–2.90), but not for any other risk behaviors. Wine consumption was not associated with a reduced risk for severe liver disease compared to beer and spirits.

    Conclusions

    Certain risk behaviors can identify young men with a high risk of developing severe liver disease. Wine consumption was not associated with a reduced risk for severe liver disease compared to beer and spirits.

  • 35. Hagström, Hannes
    et al.
    Höijer, Jonas
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Bottai, Matteo
    Johansson, Kari
    Ludvigsson, Jonas F.
    Stephansson, Olof
    Body mass index in early pregnancy and future risk of severe liver disease: a population-based cohort study2019In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 49, no 6, p. 789-796Article in journal (Refereed)
    Abstract [en]

    Background

    In young men, high body mass index (BMI) has been linked to liver disease later in life, but it is unclear if this also applies to women.

    Aim

    To study the association between BMI early in life and development of liver disease later in life in women.

    Methods

    We obtained data on early pregnancy BMI from 1 139 458 Swedish women between 1992 and 2015. National registers were used to ascertain incident severe liver disease, defined as cirrhosis, decompensated liver disease (hepatocellular carcinoma, oesophageal varices, hepatorenal syndrome or hepatic encephalopathy) or liver failure. A Cox regression model was used to investigate associations of BMI with incident severe liver disease adjusting for maternal age, calendar year, country of birth, smoking, civil status and education.

    Results

    During an average follow-up of 13.8 years, 774 women developed severe liver disease. Compared to women with a low normal BMI (18.5-22.4), an increased risk of severe liver disease was found in women with BMI between 22.5 and 24.9 kg/m(2) (adjusted hazard ratio [aHR] 1.25, 95% CI 1.04-1.50), 25.0 and 29.9 kg/m(2) (aHR 1.27, 95% CI 1.05-1.53) and BMI >= 30 kg/m(2) (aHR 1.77, 95% CI 1.40-2.24). When examining BMI as a continuous variable, the aHR increased by 4% per kg/m(2) (95% CI 1.02-1.05). A diagnosis of diabetes was associated with an increased risk of severe liver disease independent of baseline BMI.

    Conclusion

    A high BMI early in life in women is associated with a dose-dependent, increased risk for future severe liver disease.

  • 36. Hagström, Hannes
    et al.
    Stål, Per
    Hultcrantz, Rolf
    Hemmingsson, Tomas
    Stockholm University, Faculty of Social Sciences, Centre for Social Research on Alcohol and Drugs (SoRAD). Karolinska Institutet, Sweden .
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden .
    Overweight in late adolescence predicts development of severe liver disease later in life: A 39 years follow-up study2016In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 65, no 2, p. 363-368Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: The increased prevalence of overweight has been suggested to contribute to the worldwide increase in liver diseases. We investigated if body mass index (BMI) in late adolescence predicts development of severe liver disease later in life.

    METHODS: We performed a cohort study using data from 44,248 men (18-20years) conscribed to military service in Sweden between 1969 and 1970. Outcome data were collected from national registers to identify any diagnosis of severe liver disease (i.e., diagnosis of decompensated liver disease, cirrhosis or death in liver disease) until the end of 2009. A Cox regression model was applied using BMI as independent variable. The model was adjusted for use of alcohol, use of narcotics, smoking, high blood pressure and cognitive ability at time of conscription.

    RESULTS: During a follow-up period of a mean of 37.8years, 393 men were diagnosed with severe liver disease (mean time to diagnosis 24.7years). BMI (Hazard ratio [HR]=1.05 for each unit increase in BMI, 95% confidence interval [CI]: 1.01-1.09, p=0.008) and overweight (HR=1.64 for BMI 25-30 compared to BMI 18.5-22.5, 95% CI: 1.16-2.32, p=0.006) were associated with an increased risk of development of severe liver disease.

    CONCLUSIONS: Being overweight in late adolescence is a significant predictor of severe liver disease later in life in men.

    LAY SUMMARY: We investigated close to 45,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40years of follow-up, we found that being overweight was a risk factor for developing severe liver disease, independent of established risk factors such as alcohol consumption.

  • 37. Hagström, Hannes
    et al.
    Talbäck, Mats
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Walldius, Göran
    Hammar, Niklas
    Ability of Noninvasive Scoring Systems to Identify Individuals in the Population at Risk for Severe Liver Disease2020In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 158, no 1, p. 200-214Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Noninvasive scoring systems are used to identify persons with advanced liver fibrosis. We investigated the ability of scoring systems to identify individuals in the general population at risk for future liver-related events. METHODS: We collected data from the Swedish Apolipoprotein Mortality Risk cohort on persons 35 to 79 years old who had blood samples collected from 1985 through 1996. We collected APRI (n = 127,302), BARD (n = 75,303), FIB-4 (n = 126,941), Forns (n = 122,419), and the nonalcoholic fatty liver disease (NAFLD) fibrosis scores (NFS, n = 13,160). We ascertained incident cases of cirrhosis or complications by linking Swedish health data registers. Cox regression was used to estimate hazard ratios (HRs) for severe liver disease at 5, 10, and a maximum follow-up time of 27 years. The predictive ability of the scores was evaluated using area under the receiver operating characteristic (AUROC) curve and C-statistics analyses. Our specific aims were to investigate the predictive capabilities of scoring systems for fatal and nonfatal liver disease, determine which scoring system has the highest level of accuracy, and investigate the predictive abilities of the scoring systems in persons with a higher probability of NAFLD at baseline. RESULTS: A similar proportion of individuals evaluated by each scoring system developed cirrhosis or complications thereof (1.0%-1.4%). The incidence of any outcome was increased in intermediate- and high-risk groups compared with low-risk groups, with HRs at 10 years in the high-risk group ranging from 1.67 for the BARD score to 45.9 for the APRI score. The predictive abilities of all scoring systems decreased with time and were higher in men. All scoring systems were more accurate in persons with risk factors for NAFLD at baseline, with AUROCs reaching 0.83. CONCLUSIONS: Higher scores from noninvasive scoring systems to evaluate fibrosis are associated with an increased risk of cirrhosis in a general population, but their predictive ability is modest. Performance was better when patients were followed for shorter time periods and in persons with a higher risk of NAFLD, with AUROC values reaching 0.83. New scoring systems are needed to evaluate risk of fibrosis in the general population and in primary care.

  • 38. Hagström, Hannes
    et al.
    Talbäck, Mats
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Walldius, Göran
    Hammar, Niklas
    Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease2020In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 73, no 5, p. 1023-1029Article in journal (Refereed)
    Abstract [en]

    Background & Aims: It is unclear whether the identification of individuals at risk of cirrhosis using non-invasive tests can be improved by repeated measurements. Herein, we tested whether repeated measurements of fibrosis-4 index (FIB-4) could improve the identification of individuals at risk of severe liver disease.

    Methods: Data were derived from the population-based Swedish AMORIS cohort with baseline examinations from 1985-1996. FIB4 was calculated at 2 time points within 5 years. Thereafter, we associated changes in FIB-4 with outcomes. Incident severe liver disease data was ascertained through linkage to Swedish national registers until 2011. Hazard ratios (HRs) and CIs for outcomes were calculated using Cox regression.

    Results: Of 126,942 individuals with available FIB-4 data, 40,729 (32.1%) underwent a second test within 5 years (mean interval 2.4 years). During 613,376 person-years of follow-up, 581 severe liver disease events were documented (0.95/1,000 person-years). An increase of 1 unit in FIB-4 was associated with an elevated risk of severe liver disease (adjusted hazard ratio [aHR] 1.81; 95% CI 1.67-1.96). Transitioning from a low-or intermediate-to a high-risk group was associated with an increased risk of severe liver disease compared with those consistently in the low-risk group (aHR 7.99 and 8.64, respectively). A particularly increased risk of severe liver disease was found in individuals defined as high risk at both tests (aHR 17.04; 95% CI 11.67-24.88). However, almost half of all events occurred in those consistently in the low-risk group.

    Conclusions: Repeated testing of FIB-4 within 5 years improves the identification of individuals at an increased risk of severe liver disease in the general population. However, the sensitivity is comparatively low and improved tests are needed for screening in a general population or primary care setting.

    Lay summary: The fibrosis-4 scoring system is often used to estimate the risk of advanced fibrosis in liver diseases. Herein, we found that changes in this score over time are associated with the risk of future severe liver disease in a population-based cohort. However, even if the prediction is improved by repeated testing, the overall ability of the score to predict future events is relatively low.

  • 39. Hagström, Hannes
    et al.
    Yan, Jacinth
    Talbäck, Mats
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Walldius, Göran
    Bottai, Matteo
    Hammar, Niklas
    Improved prediction of 10-year risk of severe liver disease in the general population using commonly available biomarkers2023In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 57, no 4, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Background: Estimating the risk for cirrhosis in the general population is complex. Existing prediction tools are in general unsatisfactory.

    Aims: To explore if using commonly available biomarkers can improve the commonly used FIB-4 score in the identification of subgroups at risk of cirrhosis.

    Methods: We used laboratory and clinical data on 126,925 individuals aged 35–79 years in Stockholm, Sweden, undergoing health examinations from 1985 to 1996. We used Swedish nationwide registries to ascertain 10-year cumulative incidence of severe liver disease, a composite of diagnoses corresponding to cirrhosis and its complications. We considered combinations of biomarkers associated with severe liver disease to identify subgroups with different risk profiles.

    Results: During an average follow-up of 9.3 years, we ascertained 630 incident cases of severe liver disease (0.5%). Age, the FIB-4 score, diabetes or impaired glucose and gamma-glutamyl transferase (gGT) were the most relevant characteristics for classifying risk profiles. Using these factors, we identified 24 groups with a cumulative incidence of severe liver disease at 10 years ranging from 0.2% (age 35–65, low FIB-4, no diabetes or impaired glucose and normal gGT) to 32.1% (age 35–65, high FIB-4, diabetes or impaired glucose and high gGT).

    Conclusions: Identification of subjects at increased risk of severe liver disease in the general population using the FIB-4 score can be substantially improved by adding age and specific biomarkers commonly available in the primary care setting. These parameters should be considered for inclusion in the development of future risk prediction models.

  • 40. Hansdotter, Ida
    et al.
    Björ, Ove
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Agreus, Lars
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Hellström, Per
    Forsberg, Anna
    Talley, Nicholas J.
    Vieth, Michael
    Wallner, Bengt
    Hill classification is superior to the axial length of a hiatal hernia for assessment of the mechanical anti-reflux barrier at the gastroesophageal junction2016In: Endoscopy International Open, ISSN 2364-3722, Vol. 4, no 3, p. E311-E317Article in journal (Refereed)
    Abstract [en]

    Background and study aims: The pathogenesis of gastroesophageal reflux disease (GERD) is multifactorial, including the mechanical anti-reflux barrier of the gastroesophageal junction. This barrier can be evaluated endoscopically in two ways: by measuring the axial length of any hiatal hernia present or by assessing the gastroesophageal flap valve. The endoscopic measurement of axial length is troublesome because of the physiological dynamics in the area. Grading the gastroesophageal flap valve is easier and has proven reproducible. The aim of the present study was to compare the two endoscopic grading methods with regard to associations with GERD. Patients and methods: Population-based subjects underwent endoscopic examination assessing the axial length of hiatus hernia, the gastroesophageal flap valve using the Hill classification, esophagitis using the Los Angeles (LA) classification, and columnar metaplasia using the Z-line appearance (ZAP) classification. Biopsies were taken from the squamocolumnar junction to assess the presence of intestinal metaplasia. Symptoms were recorded with the validated Abdominal Symptom Questionnaire. GERD was defined according to the Montreal definition. Results: In total, 334 subjects were included in the study and underwent endoscopy; 86 subjects suffered from GERD and 211 presented no symptoms or signs of GERD. Based on logistic regression, the estimated area under the curve statistic (AUC) for Hill (0.65 [95 % CI 0.59-0.72]) was higher than the corresponding estimate for the axial length of a hiatal hernia (0.61 [95 % CI 0.54-0.68]), although the difference was not statistically significant (P=0.225). Conclusion: From our data, and in terms of association with GERD, the Hill classification was slightly stronger compared to the axial length of a hiatal hernia, but we could not verify that the Hill classification was superior as a predictor. The Hill classification may replace the axial length of a hiatal hernia in the endoscopic assessment of the mechanical anti-reflux barrier of the gastroesophageal junction.

  • 41. Hedman-Lagerlöf, Erik
    et al.
    Axelsson, Erland
    Andersson, Erik
    Ljotsson, Brjann
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    The impact of exposure-based cognitive behavior therapy for severe health anxiety on self-rated health: Results from a randomized trial2017In: Journal of Psychosomatic Research, ISSN 0022-3999, E-ISSN 1879-1360, Vol. 103, p. 9-14Article in journal (Refereed)
    Abstract [en]

    Objective: Self-rated health (SRH) has been shown to be a stable predictor of illness and mortality. Improvement in SRH, even in the absence of change in objective health, predicts better health and reduced mortality. Severe health anxiety (SHA) is characterized by fear of illness and distorted health perception. The objective of the present study was to investigate if exposure-based cognitive behavior therapy (CBT) for SHA can lead to improvement in SRH and whether this improvement is mediated by reduced health anxiety. Methods: Data were collected from a randomized controlled trial where participants with SHA were allocated to 12 weeks of exposure-based CBT (n = 99) for SHA or to a no treatment control condition (n = 33). The mediation analysis was based on SRH- and health anxiety data collected weekly during the treatment phase. Results: Linear mixed effects models analysis showed a significant interaction effect of group and time indicating superior improvements in SRH in exposure-based CBT compared to the control condition (Z = 2.69, p = 0.007). The controlled effect size was moderately large (d = 0.64) and improvements were stable at 1-year follow-up. Reduced health anxiety was a significant mediator of improvement in SRH. Conclusions: 12 weeks of exposure-based CBT for SHA can lead to significant improvements in SRH. Considering the previously established importance of SRH as a predictor for disease and mortality, exposure-based CBT for severe health anxiety may lead to improvements on several important health parameters, possibly even increasing the likelihood of longevity.

  • 42. Henström, Maria
    et al.
    Diekmann, Lena
    Bonfiglio, Ferdinando
    Hadizadeh, Fatemeh
    Kuech, Eva-Maria
    von Köckritz-Blickwede, Maren
    Thingholm, Louise B.
    Zheng, Tenghao
    Assadi, Ghazaleh
    Dierks, Claudia
    Heine, Martin
    Philipp, Ute
    Distl, Ottmar
    Money, Mary E.
    Belheouane, Meriem
    Heinsen, Femke-Anouska
    Rafter, Joseph
    Nardone, Gerardo
    Cuomo, Rosario
    Usai-Satta, Paolo
    Galeazzi, Francesca
    Neri, Matteo
    Walter, Susanna
    Simrén, Magnus
    Karling, Pontus
    Ohlsson, Bodil
    Schmidt, Peter T.
    Lindberg, Greger
    Dlugosz, Aldona
    Agreus, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Mayer, Emeran
    Baines, John F.
    Engstrand, Lars
    Portincasa, Piero
    Bellini, Massimo
    Stanghellini, Vincenzo
    Barbara, Giovanni
    Chang, Lin
    Camilleri, Michael
    Franke, Andre
    Naim, Hassan Y.
    D'Amato, Mauro
    Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome2018In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 67, no 2, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase 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.

  • 43. Henström, Maria
    et al.
    Hadizadeh, Fatemeh
    Beyder, Arthur
    Bonfiglio, Ferdinando
    Zheng, Tenghao
    Assadi, Ghazaleh
    Rafter, Joseph
    Bujanda, Luis
    Agreus, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska institutet, Sweden.
    Dlugosz, Aldona
    Lindberg, Greger
    Schmidt, Peter T.
    Karling, Pontus
    Ohlsson, Bodil
    Talley, Nicholas J.
    Simren, Magnus
    Walter, Susanna
    Wouters, Mira
    Farrugia, Gianrico
    D'Amato, Mauro
    TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M2017In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 66, no 9, p. 1725-1727Article in journal (Other academic)
  • 44. Holliday, Elizabeth G.
    et al.
    Attia, John
    Hancock, Stephen
    Koloski, Natasha
    McEvoy, Mark
    Peel, Roseanne
    D'Amato, Mauro
    Agréus, Lars
    Nyhlin, Henry
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Almazar, Ann E.
    Saito, Yuri A.
    Scott, Rodney J.
    Talley, Nicholas J.
    Genome-wide association study identifies two novel genomic regions in irritable bowel syndrome2014In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 109, no 5, p. 770-772Article in journal (Other academic)
  • 45. Hugerth, Luisa W.
    et al.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Macquarie University, Australia.
    Talley, Nicholas J.
    Forsberg, Anna M.
    Kjellström, Lars
    Thelin Schmidt, Peter
    Agreus, Lars
    Engstrand, Lars
    No distinct microbiome signature of irritable bowel syndrome found in a Swedish random population2020In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 69, no 6, p. 1076-1084Article in journal (Refereed)
    Abstract [en]

    Objective The ethiopathogenesis of irritable bowel syndrome (IBS) is unknown. While a link to the gut microbiome is postulated, the heterogeneity of the healthy gut makes it difficult to draw definitive conclusions. We aimed to describe the faecal and mucosa-associated microbiome (MAM) and health correlates on a community cohort of healthy and IBS individuals with no colonoscopic findings.

    Design The PopCol study recruited a random sample of 3556 adults; 745 underwent colonoscopy. IBS was defined by Rome IV criteria and organic disease excluded. 16S rRNA gene sequencing was conducted on sigmoid biopsy samples from 376 representative individuals (63 IBS cases) and faecal samples from 185 individuals (32 IBS cases).

    Results While sigmoid MAM was dominated by Lachnospiraceae, faeces presented a higher relative abundance of Ruminococcaceae. Microbial richness in MAM was linearly correlated to that in faeces from the same individual (R-2=0.255, p<3E-11) as was diversity (R-2=0.06, p=0.0022). MAM diversity decreased with increasing body mass index (BMI; Pearson's r=-0.1, p=0.08) and poorer self-rated health (r=-0.15, p=0.007), but no other health correlates. Faecal microbiome diversity was correlated to stool consistency (r=-0.16, p=0.043). Several taxonomic groups were correlated to age, BMI, depression and self-reported health, including Coprococcus catus associated with lower levels of depression (r=-0.003, p=0.00017). The degree of heterogeneity observed between IBS patients is higher than that observed between healthy individuals.

    Conclusions No distinct microbial signature was observed in IBS. Individuals presenting with low self-rated health or high BMI have lower gut microbiome richness.

  • 46. Irani, Mudar Zand
    et al.
    Talley, Nicholas J.
    Ronkainen, Jukka
    Aro, Pertti
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Macquarie University, Australia; Karolinska Institutet, Sweden.
    Agreus, Lars
    Vieth, Michael
    Jones, Mike P.
    Walker, Marjorie M.
    Neutrophils, eosinophils, and intraepithelial lymphocytes in the squamous esophagus in subjects with and without gastroesophageal reflux symptoms2021In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 115, p. 112-122Article in journal (Refereed)
    Abstract [en]

    Whilst intraepithelial lymphocytes (IELs) are considered normal within the distal esophageal mucosa, they have an increasingly recognised role in the pathogenesis of reflux esophagitis, and IEL quantification establishes the diagnosis of lymphocytic esophagitis. Knowledge regarding the upper limit of a normal IEL count in health is lacking. We studied 117 non-healthcare seeking adult volunteers from a random community sample (the Kalixanda study) with esophageal biopsies 2 cm above the gastroesophageal junction. Subjects were divided into four groups based on the presence or absence of gastro-esophageal reflux symptoms and/or esophagitis on endoscopy. Asymptomatic subjects with no endoscopic esophagitis were selected as controls, and the cell counts in this group were used to define the upper limit of normal of IELs, eosinophils and neutrophils. The entire sample was used to identify independent predictors of increased cellular counts by logistic regression analysis. None of the healthy controls had an IEL count of more than three per five high power fields (HPF), and therefore this was considered as the upper limit of normal; no controls had eosinophils or neutrophils in esophageal biopsies. Independent predictors of an elevated IEL count were spongiosis on histology (OR 11.17, 95% CI 3.32–37.58, P < 0.01) and current smoking (OR 4.84, 95% CI 1.13–2.71, P = 0.03). A receiver operating characteristics analysis concluded that a threshold of 3 IELs/5HPFs performs best in predicting reflux symptoms when a normal esophageal mucosa is visualized on endoscopy (sensitivity = 100.0%, specificity = 35.2%). The healthy esophageal mucosa does not contain more than three IELs per five HPF in the distal esophagus.

  • 47. Jankipersadsing, Soesma A.
    et al.
    Hadizadeh, Fatemeh
    Bonder, Marc Jan
    Tigchelaar, Ettje F.
    Deelen, Patrick
    Fu, Jingyuan
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Agreus, Lars
    Walter, Susanna
    Wijmenga, Cisca
    Hysi, Pirro
    D'Amato, Mauro
    Zhernakova, Alexandra
    A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency2017In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 66, no 4, p. 756-758Article in journal (Other academic)
  • 48. Jarbrink-Sehgal, Ellionore
    et al.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute. Karolinska Institutet, Sweden.
    The gut microbiota and mental health in adults2020In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 62, p. 102-114Article, review/survey (Refereed)
    Abstract [en]

    A growing body of evidence point toward the bidirectional gut microbiota-brain axis playing a role in mental health. Most of this research is conducted on animals why we in this review summarize and comment upon recent studies evaluating the gut microbiome in mental health in humans. Further support for the relevance of the bidirectional gut microbiota-brain communication in mood disorders has been presented, such as the effect of probiotics on brain connectivity and mental health outcomes and pregnancy related stress on gut microbiota in the newborn child. However, the heterogeneity between studies precludes conclusions regarding differences in microbiota composition in mental disease and health and many of the studies are limited by a cross-sectional design, small sample sizes and multiple comparisons. Thus, welldesigned longitudinal studies with larger sample size, accounting for confounders are needed.

  • 49. Jones, Michael P.
    et al.
    Walter, Susanna
    Faresjo, Ashild
    Grodzinsky, Ewa
    Kjellstrom, Lars
    Viktorsson, Lisa
    Talley, Nicholas J.
    Agreus, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Gastrointestinal recall questionnaires compare poorly with prospective patient diaries for gastrointestinal symptoms: data from population and primary health centre samples2019In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 31, no 2, p. 163-169Article in journal (Refereed)
    Abstract [en]

    Background: Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome.Patients and methods: Data are reported from a randomly selected general population sample (n=238) and also a primary healthcare centre (PHC) sample (n=503, 10 PHCs). All the patients completed the questionnaires, which included Rome III-qualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated.Results: Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample.Conclusion: Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments.

  • 50. Jones, Michael P.
    et al.
    Walter, Susanna
    Talley, Nicholas J.
    Walker, Marjorie M.
    Holtmann, Gerald J.
    Shah, Ayesha
    D'Amato, Mauro
    Agréus, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Stress Research Institute.
    Clusters of community-dwelling individuals empirically derived from stool diaries correspond with clinically meaningful outcomes2021In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 33, no 1S, p. e740-e745Article in journal (Refereed)
    Abstract [en]

    Background Functional gastrointestinal disorders (FGIDs) are diagnosed according to expert consensus criteria based on recall of symptoms over periods of 3 months or longer. Whether the expert opinion concords with underlying disease process and whether individual recall is accurate are both in doubt. This study aimed to identify naturally occurring clusters of individuals with respect to symptom pattern, evaluate their significance, compare cluster profiles with expert opinion and evaluate their temporal stability.

    Methods  As part of a random population study of FGID-related symptoms, we first explored the use of prospective stool and symptom diaries combined with empirical grouping of individuals into clusters using nonhierarchical cluster analysis.

    Results The analysis identified two clusters of individuals, one of which was characterized by elevated scores on all domains of symptoms (26% of the sample) and one that was low to average on all domains (74% of the sample). Cluster membership was found to be stable over a long interval. Clusters were found to differ on most domains of quality-of-life (d = 0.46–0.74), self-rated health (d = −0.42) and depression (d = −0.42) but not anxiety. Prevalence of clinically diagnosed irritable bowel syndrome (IBS) was higher in the more impacted cluster (33%) compared with the healthy cluster (13%; P < 0.0001).

    Conclusion A naturalistic classification of individuals challenges consensus criteria in showing that some IBS individuals have a symptom experience not unlike health. The proposed approach has demonstrated temporal stability over time, unlike consensus criteria. A naturalistic disease classification system may have practical advantages over consensus criteria when supported by a decision-analytic system.

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