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Objectives: The objective of the study was to test attitudes, knowledge and competence of Swedish general practitioners and geriatricians concerning B12-associated problems in 1998.Methods: Postal questionnaires were sent to a random sample of 485 GPs and a total sample of 613 geriatricians. The response rates were 70% in the GP group and 69% in the geriatrician group. The questionnaire contained 24 statements to be evaluated by a visuo-analogue scale.Results: There were small numerical differences between the two physician groups. The geriatricians were more aware of risk groups for B12 deficiency. GPs were less categorical concerning low hit rate in the laboratory testing of clinical conclusions. There were statistical differences in both directions for statements on pitfalls in laboratory diagnostics. GPs were somewhat less prone to give risk groups prophylactic B12 therapy.Conclusions: GPs and geriatricians appeared to be familiar with the current debate on B12-associated problems, suggesting that health care quality will be unaffected by patient transfer from hospital care to primary health care. [ABSTRACT FROM AUTHOR]

AIMS: The diagnosis and management of vitamin B12 deficiency varies between countries and within countries. The aim of the study was to map current attitudes and values behind clinical decision-making in Swedish primary health care, which has a unique B12 tradition: two patients out of three are treated with oral high-dose cyanocobalamin. Most patients with B12-associated problems are managed in primary health care by general practitioners (GPs). METHODS: The study was designed to elucidate possible opinion shifts among GPs during the period 1996-1998. GPs (n=499), stratified and randomized, received a questionnaire with 24 statements on B12-associated clinical and laboratory problems, to be evaluated by a visuo-analogue scale. RESULTS: The majority of GPs in primary health care in Sweden accepted homocysteine and methylmalonic acid (MMA) as markers for functional deficiency of vitamin B12. The evaluation of classical markers of B12 deficiency was wary and balanced. There was a consensus of the need for B12 therapy to risk groups such as patients with atrophic gastritis or previous gastric surgery. The answers also appeared to reflect an improvement of professional knowledge and competence concerning B12-associated problems among Swedish GPs between 1996 and 1998. CONCLUSIONS: The overriding conclusion was that B12-associated opinions of Swedish GPs were stable within the period studied, with marginal improvements of knowledge and competence. [ABSTRACT FROM AUTHOR]

Background: The ABO blood group system has previously been associated with cardiovascular disease (CVD), where non-O blood group individuals have shown an increased risk. Studies assessing early atherosclerotic disease while also including RhD are few. We aimed to determine whether the ABO and RhD blood groups are associated with subclinical atherosclerosis in a healthy population. Methods: We included 3532 participants from the VIPVIZA trial with available carotid ultrasonography results to assess subclinical disease. Information about blood groups was obtained from the SCANDAT-3 database, where 85% of VIPVIZA participants were registered. Results: RhD- individuals aged 40 years showed increased carotid intima-media thickness (B 1.09 CI 95% 1.03; 1.14) compared to RhD+ individuals. For ABO, there were no differences in ultrasonography results when assessing the whole study population. However, 60-year-old individuals with heredity for CVD and a non-O blood group had decreased odds for carotid plaques (OR 0.54 CI 95% 0.33; 0.88). Conclusions: RhD blood group is associated with subclinical atherosclerosis in younger individuals, indicating a role as a mediator in the atherosclerotic process. In addition, a non-O blood group was associated with decreased subclinical atherosclerosis in individuals aged 60 and with heredity (corresponding to the group with the highest atherosclerotic burden).

Background: Nutri-score is now widely available in food packages in Europe., Aim: To study the overall nutritional quality of the diet in relation to risks of Crohn's disease (CD) and ulcerative colitis (UC), in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort METHODS: We collected dietary data at baseline from validated food frequency questionnaires. We used a dietary index based on the UK Food Standards Agency modified nutrient profiling system (FSAm-NPS-DI) underlying the Nutri-Score label, to measure the nutritional quality of the diet. We estimated the association between FSAm-NPS-DI score, and CD and UC risks using Cox models stratified by centre, sex and age; and adjusted for smoking status, BMI, physical activity, energy intake, educational level and alcohol intake., Results: We included 394,255 participants (68.1% women; mean age at recruitment 52.1 years). After a mean follow-up of 13.6 years, there were 184 incident cases of CD and 459 incident cases of UC. Risk of CD was higher in those with a lower nutritional quality, that is higher FSAm-NPS-DI Score (fourth vs. first quartile: aHR: 2.04, 95% CI: 1.24-3.36; p-trend: <0.01). Among items of the FSAm-NPS-DI Score, low intakes of dietary fibre and fruits/vegetables/legumes/nuts were associated with higher risk of CD. Nutritional quality was not associated with risk of UC (fourth vs. first quartile of the FSAm-NPS-DI Score: aHR: 0.91, 95% CI: 0.69-1.21; p-trend: 0.76)., Conclusions: A diet with low nutritional quality as measured by the FSAm-NPS-DI Score is associated with a higher risk of CD but not UC., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: Dietary intake of (poly)phenols has been linked to reduced adiposity and body weight (BW) in several epidemiological studies. However, epidemiological evidence on (poly)phenol biomarkers, particularly plasma concentrations, is scarce. We aimed to investigate the associations between plasma (poly)phenols and prospective BW change in participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort., Methods: This study included 761 participants with data on BW at baseline and after 5 years of follow-up. Plasma concentrations of 36 (poly)phenols were measured at baseline using liquid chromatography-tandem mass spectrometry. Associations were assessed through general linear mixed models and multinomial logistic regression models, using change in BW as a continuous or as a categorical variable (BW loss, maintenance, gain), respectively. Plasma (poly)phenols were assessed as log2-transformed continuous variables. The false discovery rate (FDR) was used to control for multiple comparisons., Results: Doubling plasma (poly)phenol concentrations showed a borderline trend towards a positive association with BW loss. Plasma vanillic acid showed the strongest association (-0.53 kg/5 years; 95% confidence interval [CI]: -0.99, -0.07). Similar results were observed for plasma naringenin comparing BW loss versus BW maintenance (odds ratio: 1.1; 95% CI: 1.0, 1.2). These results did not remain significant after FDR correction., Conclusion: Higher concentrations of plasma (poly)phenols suggested a tendency towards 5-year BW maintenance or loss. While certain associations seemed promising, they did not withstand FDR correction, indicating the need for caution in interpreting these results. Further studies using (poly)phenol biomarkers are needed to confirm these suggestive protective trends., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objectives: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR)., Design: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents., Results: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92-1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08-1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82-1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64-0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI)., Conclusions: The adipokine leptin may promote the development of AS.

Objective: The prevalence of chronic kidney disease (CKD) is increasing globally, and CKD is closely related to cardiovascular disease (CVD). CKD and CVD share several risk factors (RF), such as diabetes, hypertension, obesity and smoking, and the prevalence of these RF has changed during the last decades, and we aimed to study the effect on renal function over time., Design: Repeated cross-sectional population-based studies., Setting: The two Northern counties (Norr- and Västerbotten) in Sweden., Participants: Within the MONitoring Trends and Determinants of CArdiovascular Disease (MONICA) study, seven surveys were performed between 1986 and 2014, including participants aged 25-64 years (n=10 185)., Interventions: None., Measures: Information on anthropometry, blood pressure and cardiovascular risk factors was collected. Creatinine and cystatin C were analysed in stored blood samples and the estimated glomerular filtration rate (eGFR) calculated using the creatinine-based Lund-Malmö revised and Chronic Kidney Disease Epidemiology Collaboration (eGFR crea ) equations as well as the cystatin C-based Caucasian, Asian, Paediatric and Adult cohort (CAPA) equation (eGFR cysC ). Renal function over time was analysed using univariable and multivariable linear regression models., Results: Renal function, both eGFR crea and eGFR cysC , decreased over time (both p<0.001) and differed between counties and sexes. In a multivariable analysis, study year remained inversely associated with both eGFR crea and eGFR cysC (both p<0.001) after adjustment for classical cardiovascular RF., Conclusion: Renal function has deteriorated in Northern Sweden between 1986 and 2014., Competing Interests: Competing interests: MKS reports no conflict of interest or competing interests to declare related to this project. Provided expertise in ad boards and given lectures for Amgen, AstraZeneca, Boehringer Ingelheim and GSK. Been a clinical trialist and scientific collaborations with Bayer, MSD, Novo Nordisk, AstraZeneca and Vifor Pharma. SS reports speaker honoraria from Actelion Ltd. All others declare no disclosures., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of this study was to evaluate the associations among the intake of total polyphenols, polyphenol classes, and polyphenol subclasses and body weight change over 5 years., Methods: A total of 349,165 men and women aged 25 to 70 years were recruited in the Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home and Obesity (PANACEA) project of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from nine European countries. Body weight was measured at baseline and at follow-up after a median time of 5 years. Polyphenol intake, including four main polyphenol classes and eighteen subclasses, was estimated using validated dietary questionnaires and Phenol-Explorer. Multilevel mixed linear regression models were used to estimate the associations., Results: Participants gained, on average, 2.6 kg (±5.0 kg) over 5 years. Total flavonoids intake was inversely associated with body weight change (-0.195 kg/5 years, 95% CI: -0.262 to -0.128). However, the intake of total polyphenols (0.205 kg/5 years, 95% CI: 0.138 to 0.272) and intake of hydroxycinnamic acids (0.324 kg/5 years, 95% CI: 0.267 to 0.381) were positively associated with body weight gain. In analyses stratified by coffee consumption, hydroxycinnamic acid intake was positively associated with body weight gain in coffee consumers (0.379 kg/5 years, 95% CI: 0.319 to 0.440), but not in coffee nonconsumers (-0.179 kg/5 years, 95% CI: -0.490 to 0.133)., Conclusions: Higher intakes of flavonoids and their subclasses are inversely associated with a modest body weight change. Results regarding hydroxycinnamic acids in coffee consumers require further investigation., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: −0.071 (95% CI: −0.085; −0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.

Background: C-reactive protein (CRP) is a marker of systemic inflammation. Increased levels of CRP in young persons have been suggested to decrease the risk of multiple sclerosis (MS)., Objectives: To assess CRP as a risk factor for MS., Methods: Levels of CRP were measured with a high-sensitive immunoassay in biobank samples from 837 individuals who later developed MS and 984 matched controls. The risk of developing MS was analysed by conditional logistic regression on z -scored CRP values., Results: Levels of CRP were not associated with MS risk., Conclusions: We found no association between CRP levels and risk of MS development., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: MB has received a speaker fee from Biogen. JS has received material research support from Synapsys and Interacoustics, and institutional consultancy fees from Mabion S.A. VG, PSt, AL, LAM, OA, DJ, MG, MV, JH and PSu report no disclosures., (© The Author(s), 2022.)

Objectives: Cystathionine-gamma-lyase (CSE) in the transsulfuration pathway generates hydrogen sulfide (H 2 S), suggested regulating cardiovascular function. The G1208T polymorphism in the CTH gene, rs1021737, has, in addition to  MTHFR , been found to increase homocysteine, related to myocardial infarction (MI) risk. This study aimed, for the first time, to investigate the associations of the polymorphisms CTH G1208T, MTHFR C677T, and A1298C with the prospective risk of developing a fatal or non-fatal first MI., Methods: This case-referent study included 545 cases later developing a first-ever MI and 1,054 referents from the Northern Sweden Health and Disease Study. Fatal MI was defined as death within 28 days after MI symptoms., Results: Women, but not men, had a positive association between fatal MI and the CTH G1208T, odds ratio [95% confidence interval] 3.14 [1.16-8.54] for heterozygotes, and the dominant model 3.22 [1.22-8.51], and for the MTHFR A1298C heterozygotes 3.24 [1.26-8.34] and the dominant model 2.63 [1.06-6.50]. The MTHFR C677T polymorphism was not related to MI., Conclusions: This study indicates that the minor alleles of CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk for a fatal MI among women but not for non-fatal MI. No association was found in men., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Background and Purpose: High levels of 25-hydroxyvitamin D 3 (25[OH]D 3 ) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D 3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D 3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D 3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D 3 and DBP as risk factors for MS., Methods: A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D 3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D 3 was approximated as free vitamin D 3 index: (25[OH]D 3 /DBP) × 10 3 . MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs)., Results: Serum samples from 660 pairs of matched cases and controls were included. At <20 years of age, high levels of free vitamin D 3 index were associated with a lower risk of MS (highest vs. lowest quintile: OR = 0.37, 95% CI = 0.15-0.91, p for trend across quintiles = 0.04). At age 30-39 years, high levels of DBP were associated with a lower MS risk (highest vs. lowest quintile: OR = 0.36, 95% CI = 0.15-0.85, p for trend = 0.02)., Conclusions: These findings support the hypothesis that high levels of free 25(OH)D 3 at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background & Aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed., Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed., Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels., Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention., Competing Interests: Conflict of interest All authors have declared no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Many factors influence the clinical course of patients with renal cell carcinoma (RCC). The most commonly used prognostic indicators are TNM stage, tumor size and RCC type. In this study we evaluated the prognostic relevance of albumin and C-reactive protein (CRP), and Glasgow Prognostic scores (GPS), in patients with primary RCC., Methods: We retrospectively reviewed all patients surgically treated for primary RCC between 1982 and 2018 at Umeå University Hospital. There were 872 patients, 527 males and 345 females. Data on albumin, CRP and GPS points before surgery were extracted, as well as TNM stage, RCC type, tumor grade, tumor size, and primary treatment. The patients were followed for recurrence and death for up to 37.2 years. We used Kaplan-Meier estimators, Cox-proportional hazards models, to assess the relation between potentially prognostic indicators and RCC-specific death, and all-cause mortality., Results: Of 872 patients, 708 had clear-cell RCC, 114 papillary RCC, 36 chromophobe RCC and 9 undefined RCC type while 5 patients had missing RCC type data. Except that, women had a significantly ( p  = 0.002) lower proportion of pRCC, no difference in RCC types and levels of albumin and CRP was observed between genders. Albumin, CRP, and GPSs were all univariately associated to RCC survival ( p  < 0.001). CRP demonstrated the strongest prognostic association (HR 1.67 95% Ci (1.53-1.83, overriding both albumin and GPS in multivariable models. The AUC for CRP was 0.77 (95% CI: 0.74-0.80)., Conclusion: Elevated CRP, low albumin levels, and elevated GPSs were all associated to poor survival in patients with RCC, Only CRP remained independent in multivariate analysis.

Aims: Chronic kidney disease (CKD) has a complicated relationship with the heart, leading to many adverse outcomes. The aim of this study was to evaluate the relationship between CKD and the incidence of atrial fibrillation (AF) and heart failure (HF) along with mortality as a competing risk in general population cohorts. We also included an assessment of baseline biomarkers of inflammation, myocardial injury, and left ventricular dysfunction with risk of AF and HF, respectively, to shed light on the potential underlying pathophysiology., Methods and Results: This study was conducted within the BiomarCaRE project using harmonized data from 12 European population-based cohorts (n = 48 518 participants). Renal function was assessed by glomerular filtration rate estimated using the combined Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation with standardized serum creatinine (Cr) and non-standardized serum cystatin C (CysC). Incidence of AF and HF respectively, during a median follow-up of 8 years was recorded. Cox proportional hazards models were used to determine hazard ratios (HRs) for the incidence of AF and HF in CKD and the competing risk of mortality after adjustment for covariates. The mean age at baseline was 51.4 (standard deviation 12.1) years, 49% were men. Overall, 4.3% of subjects had CKD at baseline. The rate for AF was 3.8 per 1000 person-years during follow-up. The HR for AF in patients with CKD compared with patients without CKD was 1.28 (95% confidence interval 1.07-1.54) after adjustment for covariates. The rate for incident HF was 4.1 per 1000 person-years and the HR of CKD for HF was 1.71 (95% confidence interval 1.45-2.01. In subjects with CKD, N-terminal-pro-brain natriuretic peptide (NT-proBNP) showed an association with AF, whereas NT-proBNP and C-reactive protein were associated with HF., Conclusions: Chronic kidney disease is an independent risk factor for subsequent AF and is even more closely associated with HF. In these relatively young participants with CKD, NT-proBNP was strongly associated with subsequent risk of AF. For HF, in addition, elevated levels of hs-C-reactive protein at baseline were related to incident events., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Tobacco consumption is a renal risk factor, but the effects on the estimated glomerular filtration rate (eGFR) remain unclear. We aimed to evaluate the possible impact of using tobacco products (smoking and snus) on eGFR based on creatinine or cystatin C. We used a first cohort with 949 participants and a second cohort with 995 participants; none had pre-existing renal disease. All subjects donated a blood sample and completed a questionnaire, including questions about tobacco use. To assess the effect on eGFR, hierarchical multiple linear regression models were used. Active smoking associated independently with a higher eGFR creatinine in all subjects ( p  < 0.001; β = 0.11). Further analyses stratified for sex, showed similar findings for men ( p  < 0.001; β = 0.14) and for women ( p  = 0.026; β = 0.10). eGFR cystatin C was significantly associated with active smoking in all subjects ( p  = 0.040; β = -0.05), but no association was seen after stratification for sex. Snus did not associate with eGFR. In conclusion, smoking associated significantly with a higher eGFR creatinine . The mechanism may be renal hyperfiltration of smaller molecules such as creatinine. This is probably caused by substances from smoked tobacco other than nicotine, as no effect was seen for snus.

Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins., Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored., Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis., Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Plasma total homocysteine (tHcy) is a risk marker, and smoking is an established risk factor for cardiovascular disease. It is unclear if the effect of smoked tobacco on homocysteine is mediated by nicotine or other combustion products in smoked tobacco. Snus (moist smokeless tobacco) is high nicotine-containing tobacco, and little is known about the effect of snus on plasma homocysteine. Therefore, we studied, in a cross-section of subjects (n = 1375) from the Northern Sweden Health and Disease Study, with strictly defined current smokers (n = 194) and snus users (n = 47), the impact of tobacco exposure on tHcy, assessed by self-reported tobacco habits and plasma cotinine concentrations. The snus users had higher cotinine concentrations than the smokers. Cotinine, creatinine, methylmalonic acid, and the methylenetetrahydrofolate reductase genotype ( MTHFR ) T allele were positively associated with tHcy among the smokers, but not among the snus users. No association was observed between tHcy and the number of cigarettes/day. There was a positive association between cotinine and tHcy in the smokers, but not among the snus users. This indicates that substances other than nicotine in tobacco smoke could be responsible for the differential effects on homocysteine status. Self-reported smoking should be complemented by a cotinine assay whenever possible.

Background: Our objective was to determine if patients who later develop inflammatory bowel disease (IBD) show signs of increased inflammatory activity in plasma measured with high sensitivity C-reactive protein (CRP), calprotectin, and albumin before the clinical onset of IBD., Methods: We identified 96 subjects who later developed IBD (70 ulcerative colitis [UC] and 26 Crohn's disease [CD]). High sensitivity CRP, calprotectin, and albumin were analyzed in frozen plasma, donated from cases and sex-age matched controls 1-15 years before diagnosis., Results: We found that subjects who later developed UC had lower albumin levels, and subjects who later developed CD had higher CRP levels than controls. Multivariable conditional logistic regression with albumin, calprotectin, and CRP showed a lower risk for developing IBD and UC with higher albumin levels (odds ratio [OR] 0.79, confidence interval [CI] 0.69-0.90; respective OR 0.77, CI 0.66-0.91). Higher CRP levels were associated with an increased risk of developing CD (OR 1.314, CI 1.060-1.630). When adjusting for body mass index or smoking in the logistic regression model, similar results were found. Plasma calprotectin levels in the preclinical period among patients with IBD did not differ from controls., Conclusions: In this nested case-control study, subjects who later developed IBD had signs of low-grade systemic inflammation, indicated by significantly higher CRP plasma levels in CD and lower albumin plasma levels in UC, before the onset of clinical disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of Crohn\'s & Colitis Foundation.)

Impaired renal function is associated both with the development of cardiovascular disease and its prognosis. A new syndrome called 'Shrunken Pore Syndrome' has been suggested, as the estimated glomerular filtration rate for cystatin C (eGFR cystatin C ) is affected earlier due to differences in molecular size compared to eGFR creatinine . The aim was to investigate if a lower eGFR cystatin C /eGFR creatinine ratio in a prospective setting increases the risk of later developing a first-ever myocardial infarction (MI) independently of other cardiovascular risk factors. We used a nested case-referent study design within the Northern Sweden Health and Disease Study, and 545 subjects (29.0% women) were identified who prospectively developed a first-ever MI, and their 1054 matched referents. For women, but not for men, one standard deviation (SD) increase of ln z -scores of eGFR cystatin C /eGFR creatinine ratio was associated with a lower risk of a future MI: odds ratio [95% confidence interval] 0.58 [0.34-0.99], adjusted for apolipoprotein B/A1 ratio, CRP, homocysteine, systolic blood pressure, body mass index, and diabetes. Furthermore, a high eGFR creatinine associated independently with an increased risk of future MI in men only: OR 1.25 [1.05-1.48]. Thus, for women, a lower eGFR cystatin C /eGFR creatinine ratio is associated with a higher risk of having a future first-ever MI, and it may be a valuable, easily implemented biomarker for risk of cardiovascular disease.

Objective: Non-adherence to guidelines and preventive measures is a major challenge, particularly so to obtain long-term adherence to lifestyle changes and recommended medication. The objective was to investigate if pictorial information regarding subclinical carotid atherosclerosis provided to individuals and physicians gave sustained effects on cardiovascular risk beyond the previously reported effect after 1 year and up to 3 years., Methods: A Prospective Randomized Open Blinded End-point (PROBE) trial. Within a CVD prevention program in Västerbotten County, Sweden, 3532 healthy individuals aged 40, 50 or 60 years were enrolled and 1:1 randomized to intervention ( n  = 1749; pictorial information with additional prevention materials to participants and physicians) or control group ( n  = 1783; no pictorial information to participants and physicians). Preventive measures were managed within primary care. Participants were investigated at baseline during 2013-2016 and at follow-up after 1 and 3 years., Results: A beneficial effect on cardiovascular risk was observed at 3-year follow-up; Framingham Risk Score (FRS) was 13.38 for the intervention group and 14.08 for the control group ( p  = 0.047) and SCORE was 1.69 vs. 1.82 ( p  = 0.022). The effect observed at 1-year was sustained over 3 years after adjustment for sex and education and more pronounced among participants with a severe atherosclerotic picture at baseline., Conclusions: This study provides evidence of sustained beneficial effects on the adherence to prevention guidelines over 3 years of pictorial information about subclinical carotid atherosclerosis, resulting in lower cardiovascular risk regardless of sex and educational level. Direct visualization of the underlying still subclinical atherosclerotic disease, rather than just indirect information about risk factors and statistical risk of future myocardial infarction, stroke and death, is one way to tackle the problem of non-adherence to prevention of cardiovascular diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection., Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS)., Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z -scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs)., Results: A 1-unit leptin z -score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels., Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.

Background: Chronic kidney disease has emerged as a strong cardiovascular risk factor, and in many current guidelines, it is already considered as a coronary heart disease (CHD) equivalent. Routinely, creatinine has been used as the main marker of renal function, but recently, cystatin C emerged as a more promising marker. The aim of this study was to assess the comparative cardiovascular and mortality risk of chronic kidney disease (CKD) using cystatin C-based and creatinine-based equations of the estimated glomerular filtration rate (eGFR) in participants of population-based and disease cohorts., Methods: The present study has been conducted within the BiomarCaRE project, with harmonized data from 20 population-based cohorts (n = 76,954) from 6 European countries and 3 cardiovascular disease (CVD) cohorts (n = 4982) from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for the Systematic COronary Risk Evaluation (SCORE) variables and study center. Main outcome measures were cardiovascular diseases, cardiovascular death, and all-cause mortality., Results: The overall prevalence of CKD stage 3-5 by creatinine- and cystatin C-based eGFR, respectively, was 3.3% and 7.4% in the population-based cohorts and 13.9% and 14.4% in the disease cohorts. CKD was an important independent risk factor for subsequent CVD events and mortality. For example, in the population-based cohorts, the HR for CVD mortality was 1.72 (95% CI 1.53 to 1.92) with creatinine-based CKD and it was 2.14 (95% CI 1.90 to 2.40) based on cystatin-based CKD compared to participants without CKD. In general, the HRs were higher for cystatin C-based CKD compared to creatinine-based CKD, for all three outcomes and risk increased clearly below the conventional threshold for CKD, also in older adults. Net reclassification indices were larger for a cystatin-C based CKD definition. Differences in HRs (between the two CKD measures) in the disease cohorts were less pronounced than in the population-based cohorts., Conclusion: CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of creatinine- and cystatin C-based CKD differed considerably between low- and high-risk populations. Especially in low-risk settings, the use of cystatin C-based CKD may result in more accurate risk estimates and have better prognostic value.

Aims: High-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS., Methods: In total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery., Results: Median age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06-1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90-1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (p<0.001), and with increased myocardial mass (p=0.002). Hs-CRP did not associate with time to surgery or with myocardial mass., Conclusions: Hs-TnT-but not hs-CRP-was associated with increased risk of-and shorter time to-future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that hs-TnT could be a potential biomarker for determining intervention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Puumala orthohantavirus (PUUV) causes hemorrhagic fever with renal syndrome (HFRS). Patients with HFRS have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine whether circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients., Methods: Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n = 27) and those who did not (n = 61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and platelets., Results: Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity were significantly associated with plasma tPA and PAI-1, suggesting that endothelial cells could be a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared with those who did not, even after adjustment for sex and age. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with area under the curve = 0.63 (95% confidence interval, 0.51-0.76) and P = .046., Conclusions: Plasma EVTF activity during HFRS is associated with intravascular coagulation., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex., Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10 -8 ) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study., Results: The associations between circulating UCB levels and CRC risk differed by sex (P heterogeneity  = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity  ≥ 0.2)., Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

Background: Iron deficiency is common among inflammatory bowel disease (IBD) patients, generally reported without comparisons with controls. The aim of this study was to analyse if iron deficiency was more common among those later developing IBD compared to matched controls in a prospective setting., Methods: We included 96 healthy subjects later developing IBD and 191 matched controls from the Northern Sweden Health and Disease Study. We analysed iron, ferritin, transferrin, and calculated transferrin saturation in plasma sampled at least 1 year prior to IBD diagnosis. Iron deficiency was defined as plasma ferritin <30 µg/L if C-reactive protein (CRP) was <3 mg/L. When CRP was >3 mg/L, iron deficiency could not be excluded if ferritin was <100 µg/L., Results: Iron deficiency could not be excluded among more male cases vs controls (25.0% vs 2.2%; P < 0.001), whereas with no differences for women (39.6% vs 35.3%; P = 0.538). Ferritin was lower among male IBD cases (P = 0.001) and for ulcerative colitis (P = 0.016 for males and 0.017 for females), but not for Crohn's disease. Ferritin was associated with a lower risk for IBD and in the ulcerative colitis subgroup when using sex-based z-scores. Ferritin quartiles 2-4 had a 65% lower odds ratio for all IBD, ulcerative colitis, and Crohn's disease in multivariable analysis., Conclusions: Lower ferritin was associated with higher risk for developing IBD in a prospective setting. Iron deficiency was more common among healthy males years later developing IBD compared to matched controls, but not among women.

Objective: Smoking has previously been associated with inflammatory bowel disease (IBD), but no study has reported on cotinine, an objective, biochemical measure of tobacco use. We aimed at testing the hypothesis that cotinine levels among healthy subjects are associated with an increased risk of developing IBD in later life., Design: We analysed plasma cotinine and evaluated corresponding lifestyle questionnaires that included tobacco habits in subjects (n = 96) who later developed late-onset IBD (70 ulcerative colitis (UC) and 26 Crohn's disease (CD)) and in sex and age-matched controls (n = 191)., Results: Patients who later developed IBD had significantly higher plasma cotinine levels compared to controls. In multivariable analysis, higher log-cotinine was associated with a higher risk of developing IBD (OR 1.34 (95% CI 1.01-1.63)). After stratifying for time to diagnosis, the association was only significant in subjects with shorter time (< 5.1 years) to diagnosis (OR 1.45 (1.09-1.92)). The findings were similar for UC- and CD-cases, but did not reach statistical significance in CD-cases. Although plasma cotinine concentrations were higher in snuff users compared to combusted tobacco users, no increase in the risk of IBD and lower risk of developing IBD among subjects with shorter time (< 5.1 years) to diagnosis was seen among snuff users., Conclusions: Cotinine, a biomarker of tobacco use, is associated with increased risk of developing late-onset IBD in general, and UC in particular. No increased risk among snuff users indicates that other components in combusted tobacco than nicotine may be involved in the pathogenesis of IBD among smokers., Competing Interests: Author ØM was employed by Bevital AS, this does not alter our adherence to PLOS ONE policies on sharing data and materials. No other competing interests declared.

Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0·66, 95 % CI 0·46, 0·96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0·58, 95 % CI 0·39, 0·86), 3,4-dihydroxyphenylpropionic acid (OR 0·63, 95 % CI 0·46, 0·87), ferulic acid (OR 0·65, 95 % CI 0·44, 0·96) and caffeic acid (OR 0·69, 95 % CI 0·51, 0·93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0·67, 95 % CI 0·48, 0·93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.

Background: High 25-hydroxyvitamin D concentrations have been associated with a reduced risk of multiple sclerosis, with indications of a stronger effect among young individuals., Objective: Investigate the 25-hydroxyvitamin D association with multiple sclerosis and test if this association is age dependent., Methods: Prospectively drawn blood samples from individuals later developing relapsing-remitting multiple sclerosis and controls matched for biobank, sex, age and date of sampling, were analysed with liquid chromatography tandem mass spectrometry., Results: High levels of 25-hydroxyvitamin D (top quintile) were associated with a reduced multiple sclerosis risk (odds ratio 0.68, 95% confidence interval 0.50-0.93)., Conclusion: These findings further support a role for vitamin D in MS aetiology., (© The Author(s) 2019.)

Biomarkers reliably predicting progression to multiple myeloma (MM) are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor-alpha (TGF-α). In this study, we aimed to replicate these findings and study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases and 65 matched cancer-free controls each with two donated blood samples within the Northern Sweden Health and Disease Study. The first and repeated samples from myeloma cases were donated at a median 13 and 4 years, respectively, before the myeloma was diagnosed. Known risk factors for progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of MCP-3, VEGF, FGF-2, and TGF-α in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were noted for TGF-α ( P =2.5 × 10 -4 ) indicating progression to MM. Investigating this, we found that low levels of TGF-α assessed at the time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P =0.003). TGF-α can potentially improve early detection of MM., (Copyright© 2019 Ferrata Storti Foundation.)

Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFR cystatin C and eGFR creatinine and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFR cystatin C and eGFR creatinine . A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFR cystatin C and eGFR creatinine was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

Background: Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC- rs4588*A (Thr436Lys) variant encoding the vitamin D-binding protein-2 (DBP2) isoform, which may affect vitamin D status and bioavailability., Methods: We analyzed data from 1710 incident CRC cases and 1649 incidence-density-matched controls nested within three prospective cohorts of mostly Caucasians. Study-specific incidence rate ratios (RRs) for associations of prediagnostic, season-standardized 25(OH)D concentrations according to DBP2 isoform with CRC were estimated using multivariable unconditional logistic regression and were pooled using fixed-effects models. All statistical significance tests were two-sided., Results: The odds of having 25(OH)D concentrations less than 50 nmol/L (considered insufficient by the Institute of Medicine) were 43% higher for each DBP2-encoding variant (rs4588*A) inherited (per DBP2 odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.27 to 1.62, P trend = 1.2 × 10 -8 ). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (≥ 50 nmol/L), relative to deficient (< 30 nmol/L), were associated with a 53% lower CRC risk among individuals with the DBP2 isoform (RR = 0.47, 95% CI = 0.33 to 0.67), but with a non-statistically significant 12% lower risk among individuals without it (RR = 0.88, 95% CI = 0.61 to 1.27) ( P heterogeneity = .01)., Conclusions: Our results suggest that the 25(OH)D-CRC association may differ by DBP isoform, and those with a DBP2-encoding genotype linked to vitamin D insufficiency may particularly benefit from adequate 25(OH)D for CRC prevention., (© The Author(s) 2020. Published by Oxford University Press.)

Faecal calprotectin (FC) tests and faecal immunological tests (FIT) for haemoglobin have been used to monitor disease activity in patients with ulcerative colitis (UC) but used alone they have some limitation concerning the predictive ability. We aimed to test if an FC test used in combination with FIT could improve the predictive ability. Consecutive out-patients with UC ( n  = 93) who were admitted for colonoscopy completed a single faecal sample before the start of bowel preparation. A quantitative CALPRO ® calprotectin ELISA test and a qualitative FIT (cut-off < 40 ng/mL) were analyzed. An estimated Mayo score and a score of histological inflammation was performed blinded to the result of the faecal tests. The sensitivity, specificity, negative predictive value and positive predictive value for endoscopic inflammation (Mayo score > 1) was for FIT 85%, 83%, 96%, 57% and for FC > 186 µg/g 73%, 87%, 87%, 54%. Corresponding results for FIT*FC > 186 µg/g (at least one test positive) were 92%, 69%, 97%, 43%. For detecting moderate/severe histological inflammation the results were for FIT 69%, 79%, 92%, 43%, for FC > 75 µg/g 95%, 62%, 98%, 41%, and for FIT*FC > 75 µg/g 100%, 60%, 100%, 36%. None of the markers alone or in combination were useful to predict deep remission (Mayo score = 0 and no histological inflammation). We conclude that using the combination of an FC test and FIT shows minor improvement in predictive ability for inflammatory activity and remission in patients with UC.

Objectives: Faecal Calprotectin (FC) is a sensitive marker for gut inflammation. However, slightly elevated FC levels are also common in subjects without inflammation. We investigated the association between FC and clinical factors including concomitant use of medical therapy in patients with a normal colonoscopy., Material and Methods: Out-patients (n = 1263) referred for colonoscopy, performed FC test (CALPRO) the day before the start of bowel preparation. All subjects answered questionnaires that included questions on the present and past health history, concomitant medical treatment and gastrointestinal symptoms (GSRS). A medical record chart review was performed to check for concomitant disease, cause of referral and the result of the colonoscopy including biopsies. Inclusion criteria were a normal colonoscopy. Exclusion criteria were inflammatory bowel disease, colon cancer and high-grade dysplasia., Results: Five hundred ninety subjects fulfilled the inclusion criteria and completed the study. Thirty-six per cent of the subjects had a FC >50 µg/g. In a logistic regression analysis, age (adjusted OR: 1.051; CI: 1.032-1.071), and the use of proton pump inhibitors (adjusted OR: 3.843; CI: 2.338-6.316), non-steroid anti-inflammatory drugs (adjusted OR: 2.411; CI: 1.162-5.002) and acetylsalicylic acid (adjusted OR: 2.934; CI: 1.085-3.448) were significantly associated with an elevated FC (>50 µg/g)., Conclusions: More than one-third of the patients with a normal colonoscopy performed in clinical routine had a slightly elevated FC level. Our results emphasise the need for attention to age, the use of proton pump inhibitors, non-steroid anti-inflammatory drugs and acetylsalicylic acid in the interpretation of FC tests in clinical practice.

Background: Vitamin D has been implicated as being involved in the aetio-pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA). Previous studies present contradictory results. Vitamin D binding protein (DBP), the major transport protein, is also involved in various inflammatory processes. The aim of this study was to investigate the relationship between circulating levels of 25-hydroxyvitamin D [25(OH) D], DBP and polymorphisms in group-specific component (GC) in pre-symptomatic individuals and matched controls within prospective cohorts of the Northern Sweden., Methods: Blood samples donated to the Medical Biobank prior to the onset of symptoms of RA ( n  = 515, mean [SD] time before the onset of symptoms 6.2 [9.3] years) and from matched (2:1) population-based controls ( n  = 267) were used. Plasma 25(OH) vitamin D levels were analyzed using liquid chromatography tandem-mass spectrometry and DBP levels were analyzed using enzyme-linked immunosorbent assay. GC polymorphisms (rs4588 and rs7041) were analyzed with TaqMan assays (Applied Biosystems)., Results: Levels of 25(OH) D or DBP were not statistically different between pre-symptomatic individuals and controls in a crude, or a multiple-adjusted logistic regression model. However, an increased risk for future RA was found in females of DBP (OR 1.014 [95%CI 1.001-1.028]) per 10 mg/L adjusted for carriage of the minor allele of rs4588, in a multiple-adjusted model ( p  < 0.05)., Conclusions: This study indicated that vitamin D is not associated with the future risk of RA although increasing levels of DBP were however, associated with an increased risk of disease in females carrying the minor allele of a DBP encoding SNP., Competing Interests: The participants gave their written informed consent and the Regional Ethics Committee at Umeå University approved the study (reference number 2013/347–31).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights., Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study., Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease., Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR 4th vs. 1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status., (© 2017 UICC.)

Objectives: Life style factors have been associated with inflammatory bowel disease (IBD) but there is a lack of data on the exposure of life styles factors before the onset of IBD. Our aim was to study the association between lifestyle factors and the development of IBD in a prospective setting., Materials and Methods: We performed a case control study of 72 patients who later developed ulcerative colitis (UC), 26 patients who developed Crohn's disease (CD) and 427 healthy controls from the Västerbotten intervention project matched for gender, age, year of health survey and area of residence. At recruitment, participants completed validated lifestyle questionnaires including data on alcohol intake. Information from this was used to assess the connection between lifestyle factors and later developing IBD., Results: For CD and UC, the median age at diagnosis was 53 and 52 years and median time of survey was 4 and 6 years before diagnosis, respectively. Multivariate odds ratio (OR) showed an association between never smoking and not developing IBD, including both UC and CD, OR (95% CI) 0.341 (0.136-0.853) and 0.473 (0.259-0.864), respectively. Marital status, educational level, alcohol consumption, reported physical activity and use of moist smokeless tobacco (snus) did not differ between patients and controls., Conclusions: Smoking proves to be a risk factor for both CD and UC in this prospective case-control study. No association was seen for snus users, implying a non-nicotine pathogenic mechanism from combusted tobacco.

Background and Aims: Population-based prospective cohort studies investigating fibre intake and development of inflammatory bowel disease are lacking. Our aim was to investigate the association between fibre intake and the development of Crohn's disease [CD] and ulcerative colitis [UC] in a large European population., Methods: In total, 401326 participants, aged 20-80 years, were recruited in eight countries in Europe between 1991 and 1998. At baseline, fibre intake [total fibres, fibres from fruit, vegetables and cereals] was recorded using food frequency questionnaires. The cohort was monitored for the development of inflammatory bowel disease. Each case was matched with four controls and odds ratios [ORs] for the exposures were calculated using conditional logistic regression. Sensitivity analyses according to smoking status were computed., Results: In total, 104 and 221 participants developed incident CD and UC, respectively. For both CD and UC, there were no statistically significant associations with either quartiles, or trends across quartiles, for total fibre or any of the individual sources. The associations were not affected by adjusting for smoking and energy intake. Stratification according to smoking status showed null findings apart from an inverse association with cereal fibre and CD in non-smokers [Quartile 4 vs 1 OR = 0.12, 95% confidence interval = 0.02-0.75, p = 0.023, OR trend across quartiles = 0.50, 95% confidence interval = 0.29-0.86, p = 0.017]., Conclusion: The results do not support the hypothesis that dietary fibre is involved in the aetiology of UC, although future work should investigate whether there may be a protective effect of specific types of fibre according to smoking status in CD., (© European Crohn’s and Colitis Organisation 2017.)

Background: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS., Methods and Results: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83-1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10])., Conclusions: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies. Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions. Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory. Results: Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all- trans retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users. Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.

Background: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate., Methods: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort., Results: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06)., Conclusions: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk.See Video Abstract at http://links.lww.com/EDE/B83.

Low vitamin D levels during pregnancy may have negative consequences for the health of both the mother and child. Cross-sectional studies in childbearing women suggest that vitamin D levels are low during pregnancy, but few studies have followed the same women during pregnancy and postpartum. The aims of this study were to longitudinally assess vitamin D status during pregnancy and postpartum and identify the factors associated with vitamin D status in pregnant women in northern Sweden. Between September 2006 and March 2009, 184 women were consecutively recruited at five antenatal primary care clinics. Blood was sampled, and dietary intake was estimated using a food frequency questionnaire with 66 food items/food aggregates and questions on the intake of vitamin supplements at gestational weeks 12, 21, and 35, as well as at 12 and 29 weeks after birth. Plasma 25(OH) vitamin D levels were analyzed using liquid chromatography tandem-mass spectrometry. At least one-third of the women had 25(OH) vitamin D levels <50 nmol/L on at least one sampling occasion. Plasma levels increased slightly over the gestation period and peaked in late pregnancy. The levels reverted to the baseline levels after birth. Multivariate analysis showed that gestational and postpartum week, season, dietary intake of vitamin D, and vitamin supplementation were significantly related to plasma levels. There was also an influence of season on the longitudinal concentration patterns. In conclusion, more than one-third of the women studied had low 25(OH) vitamin D levels, and gestational and postpartum week was related to 25(OH) vitamin D levels after adjustment for season and vitamin D intake.

Background: Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation., Methods: Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications., Results: The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels., Conclusions: HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)