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The study examined results from previous studies of early life vitamin D exposure and risk of MS in adulthood, including studies on season or month of birth and of migration. A systematic review was conducted using PubMed and Web of Science databases as well as checking references cited in articles. The quality of studies was assessed using the Newcastle-Ottawa scale and the AMSTAR score. Twenty-eight studies were selected for analysis. Of these, six population studies investigated early life vitamin D exposure and risk of MS, and three found inverse while the remaining found no associations. A consistent seasonal tendency for MS seemed evident from 11/15 studies, finding a reduced occurrence of MS for Northern hemisphere children who were born late autumn, and late fall for children born in the Southern hemisphere. This was also confirmed by pooled analysis of 6/15 studies. Results of the migration studies showed an increased risk of MS if migration from high to low-MS-risk areas had occurred after age 15 years, while risk of MS was reduced for those migrating earlier in life (<15years). A similar, but inverse risk pattern was observed among migrants from low to high-MS-risk areas. One study found an increased risk of MS in the second generation of migrants when migrating from low to high-MS-risk areas. An association between early life vitamin D and later risk of MS seems possible, however evidence is still insufficient to conclude that low vitamin D exposure in early life increases the risk of MS in adulthood. PROSPERO register number: CRD 42016043229.

Understanding how inflammatory cytokines influence profibrogenic wound healing responses in fibroblasts is important for understanding the pathogenesis of fibrosis. TNF-α and IL-13 are key cytokines in Th1 and Th2 immune responses, respectively, while TGF-β1 is the principal pro-fibrotic mediator. We show that 12-day fibroblast culture with TNF-α or IL-13 induces fibrogenesis, marked by progressively increasing type III and VI collagen formation, and that TGF-β1 co-stimulation amplifies these effects. Tofacitinib substantially reduced the formation of ECM proteins in response to IL-13, while fibrogenesis in response to TNF-α or TGF-β1 was marginally inhibited. The in vitro findings were supported by clinical observations in patients with active rheumatoid arthritis, which had elevated serum type III collagen formation, indicating ongoing fibrogenesis during inflammation. After 48–60 weeks of tofacitinib treatment, type III collagen degradation, aswell as formation, were significantly decreased compared to baseline, highlighting dual anti-inflammatory and anti-fibrogenic effects of tofacitinib. In contrast, other anti-inflammatory treatments including methotrexate, adalimumab and tocilizumab demonstrated anti-inflammatory effects only. Our results highlight fibro-inflammatory profiles associated with TNF-α or IL-13 stimulation, both alone and in combination with TGF-β1, and support the use of tofacitinib as an anti-fibrogenic treatment in chronic inflammatory conditions.

BackgroundIn the general population, body mass index (BMI = weight (kg)/(height (m))2) shows a U-shaped relation to mortality, which is attributable to a combination of an inverse association with fat-free mass index (FFMI) and a direct association with fat mass index (FMI). However, preceding changes in body composition related to diseases, health behaviors, or social conditions that are also influencing later mortality may confound these associations.ObjectiveTo examine associations of FFMI and FMI, adjusted for preceding changes in FFMI and FMI over a 6 years period, with all-cause mortality in a healthy general population.MethodsThe study population was a random subset of adult Danes, participating in the Danish MONICA project; 989 men and 962 women, born 1922, 1932, 1942, and 1952, and examined in 1987–88 and 1993–94. They had no known major co-morbidities until start of follow-up in 1993–94, and were followed up for 18 years. Measures included height, weight, and bio-impedance, from which BMI, FFMI, and FMI were calculated, and information on educational level, smoking, alcohol drinking, leisure-time physical activity, which were obtained by questionnaires. We analyzed the relation between body composition and all-cause mortality by Cox proportional hazards model with splines, stratified by birth cohorts, and with adjustment for preceding changes in body composition and for the covariates including gender. We estimated hazard ratios (HR) with 95% confidence intervals (CI) relative to HR = 1.00 at the median values of BMI, FMI, and FFMI.ResultsDuring 18 years of follow-up, 286 men and 200 women died. BMI showed the well-known U-shaped association with mortality, and FMI was directly and FFMI inversely associated with mortality. Associations were not significantly modified by gender. Preceding changes in BMI, FMI, and FFMI were only weakly and not significantly associated with mortality. Associations for FMI and FFMI were monotonic, but curve-linear with a higher mortality above and below the respective median values of FMI and FFMI: at the 5th percentiles of FMI and FFMI, HRs were 0.80 (CI 0.57–1.13) and 2.01 (1.24–3.27), and at the 95th percentiles, HRs were 2.16 (1.38–3.38) and 0.81 (0.52–1.27), respectively.ConclusionsIn an apparently healthy general population, a large fat mass and a small fat-free mass are associated with greater risk of early mortality, also after adjusting for preceding changes in body composition, health behaviors, and educational level.

Objectives Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation in multiple articular joints, causing pain, joint damage, and loss of joint function. Despite the successful development of disease-modifying therapies, the heterogeneity of RA means that a significant proportion of patients respond poorly to treatment. This highlights the need for personalized medicine and predictive biomarkers to optimize treatment efficacy, safety, and cost. This study aimed to explore the relationship between type VI collagen (Col VI) remodeling and clinical response to anti-IL-6 receptor treatment. Methods Type VI collagen degradation was quantified using the C6M biomarker, a fragment of type VI collagen degraded by MMPs. Longitudinal differences in average biomarker levels between placebo and treatment groups were estimated using linear mixed models. The predictive capacity of the marker based on change from baseline to 4 weeks was analyzed using logistic regression. Results Both 4 mg and 8 mg doses of Tocilizumab (TCZ) reduced serum C6M concentrations compared to the placebo. Furthermore, C6M levels were more reduced in patients responding to treatment compared to early non-responders. A lower early reduction in C6M was associated with reduced odds of ACR treatment response and lowered disease activity. Conclusion These findings suggest that quantifying type VI collagen turnover may aid in identifying patients less likely to respond to treatment, indicating a new path towards optimizing patient care. Further studies are needed to validate these findings and explore the underlying mechanisms driving the observed relationships.

Purpose Intelligence has a strong influence on life capability, and thus, identifying early modifiable risk factors related to cognitive ability is of major public health interest. During pregnancy, vitamin D is transported from the mother to the fetus through the placenta in the form of 25-hydroxyvitamin D (25(OH)D). Levels of 25(OH)D have in some studies been associated with childhood neurodevelopment; however, results from all studies are not in agreement. We investigated if neonatal 25(OH)D 3 concentrations were associated with Børge Priens IQ test score (BPP) in young adulthood. Methods In this nested cohort study, 25(OH)D 3 concentrations were measured in dried blood spots from 818 newborns. We followed the children for their IQ BPP test scores in the Danish Conscription Register, which holds information on test results from the BPP test on individuals who have been recruited for Danish mandatory military draft board examination. Using general linear models, we investigated the crude and adjusted relationship between quintiles of 25(OH)D 3 concentrations and BPP IQ test results. Results The study population consisted of 95.8% men, with a mean age of 19.4 years. The median and range of the neonatal 25(OH)D 3  levels were 26.2 nmol/L (0–104.7 nmol/L). The overall Wald test did not show an association between neonatal 25(OH)D 3  levels and BPP IQ scores ( p  = 0.23); however, individuals within the 3rd (BPP IQ = 101.0, 98.0–103.9) and 4th (BPP IQ = 101.2, 99.1–104.3) quintiles had slightly higher BPP IQ scores than individuals from the first quintile (BPP IQ = 97.6, 94.6–100.6). Conclusions Our results support the hypothesis that individuals with the lowest levels of neonatal vitamin D might have slightly lower BPP. However, more studies are needed with larger study populations to confirm our results.

Activity trackers such as the Fitbit Charge 2 enable users and researchers to monitor physical activity in daily life, which could be beneficial for changing behaviour. However, the accuracy of the Fitbit Charge 2 in a free-living environment is largely unknown. To investigate the agreement between Fitbit Charge 2 and ActiGraph GT3X for the estimation of steps, energy expenditure, time in sedentary behaviour, and light and moderate-to-vigorous physical activity under free-living conditions, and further examine to what extent placing the ActiGraph on the wrist as opposed to the hip would affect the findings. 41 adults (n = 10 males, n = 31 females) were asked to wear a Fitbit Charge 2 device and two ActiGraph GT3X devices (one on the hip and one on the wrist) for seven consecutive days and fill out a log of wear times. Agreement was assessed through Bland-Altman plots combined with multilevel analysis. The Fitbit measured 1,492 steps/day more than the hip-worn ActiGraph (limits of agreement [LoA] = -2,250; 5,234), while for sedentary time, it measured 25 min/day less (LoA = -137; 87). Both Bland-Altman plots showed fixed bias. For time in light physical activity, the Fitbit measured 59 min/day more (LoA = -52;169). For time in moderate-to-vigorous physical activity, the Fitbit measured 31 min/day less (LoA = -132; 71) and for activity energy expenditure it measured 408 kcal/day more than the hip-worn ActiGraph (LoA = -385; 1,200). For the two latter outputs, the plots indicated proportional bias. Similar or more pronounced discrepancies, mostly in opposite direction, appeared when comparing to the wrist-worn ActiGraph. Moderate to substantial differences between devices were found for most outputs, which could be due to differences in algorithms. Caution should be taken if replacing one device with another and when comparing results.

BackgroundIdiopathic pulmonary fibrosis (IPF) is characterised by damage to the epithelial layer, closely associated with the alveolar basement membrane (BM). We aimed to investigate how type IV collagen (COL4) in the BM changes with the progression of IPF.MethodsCOL4 synthesis (PRO-C4) was detected in blood by the nordicPRO-C4 biomarker in patients with IPF from the two prospective, multicentre, observational, longitudinal cohorts, pulmonary fibrosis biomarker (PFBIO) and prospective observation of fibrosis in the lung clinical endpoints (PROFILE). PRO-C4 trajectories over 12 months were compared between progressors and non-progressors by linear mixed effects regression models. Rate of change in PRO-C4 and lung function were compared by Bayesian bivariate longitudinal models. Cox proportional hazards models analysed baseline PRO-C4 and 3 years mortality. COL4 staining in IPF and non-IPF lungs was evaluated by immunohistochemistry.ResultsIn PFBIO and PROFILE, 51/220 (23.2%) and 221/459 (48.1%) patients, respectively, had progressive disease at 12 months. Longitudinal PRO-C4 levels were higher in progressors versus non-progressors (average differences: PFBIO 21.5% (95% CI 3.4% to 42.9%, p=0.0184); PROFILE 10.9% (95% CI 0.8% to 22.1%; p=0.0340). Monthly rate of change in PRO-C4 was steeper in non-survivors versus survivors (mean difference up to 3.12% (95% CI 0.35% to 5.91%)) and was inversely correlated with the change in lung function. High baseline PRO-C4 was associated with increased mortality risk in PFBIO (HR 2.55 (95% CI 1.27 to 5.12), p=0.0083). COL4 staining was higher in IPF versus non-IPF lung but was less obvious in end-stage tissue.ConclusionsHigh and increasing serological PRO-C4 levels were prognostic for progression in two independent IPF cohorts. This study suggests that COL4 synthesis assessed by PRO-C4 is a pathologically relevant biomarker of alveolar BM repair in IPF.

Aims/hypothesisThe aim of this study was to examine the influence of neonatal vitamin D concentration on the development of early-onset type 2 diabetes in a large population sample.MethodsWe conducted a case-cohort study utilising data from the Danish biobank and registers. Neonatal vitamin D was assessed measuring 25-hydroxyvitamin D3 [25(OH)D3] concentrations on the dried blood spot samples from the Biological Specimen Bank for Neonatal Screening. Cases of type 2 diabetes (n = 731) were retrieved from the Danish National Patient Register for all individuals born in Denmark between 1 May 1981 and 31 December 1992. The sub-cohort (n = 1765) was randomly selected from all children born in the same period. We used a weighted Cox proportional hazard model assessing the hazard of first type 2 diabetes diagnoses by quintiles of 25(OH)D3 and restricted cubic spline.ResultsThe median 25(OH)D3 concentration (IQR) among cases was 21.3 nmol/l (13.3–34.1) and 23.9 nmol/l (13.7–35.7) in the sub-cohort. There was no indication of a potential lower risk of early-onset type 2 diabetes among individuals in the higher quintile of vitamin D concentration compared with the lowest (HRcrude 0.97 [95% CI 0.71, 1.33] p = 0.85; HRadjusted 1.29 [95% CI 0.92, 1.83] p = 0.14).Conclusions/interpretationThe results of this study do not support the hypothesis that higher neonatal vitamin D concentrations are associated with a lower risk of early-onset type 2 diabetes in adulthood.

Background Cortisol is often used as a biological marker for stress. When measured in urine or serum, representing a short-term measurement of the hormone, it has been associated with unfavorable sleep characteristics and both low and high physical activity levels. However, cortisol in hair represents a long-term stress measure and has been suggested as a promising new marker for chronic stress. Therefore, we aimed to examine the association between objectively measured sleep, physical activity and hair cortisol levels in preschool children. Methods In order to obtain objective measures of physical activity and sleep habits, 54 children aged 2–6 years wore an ActiGraph for 5 consecutive days and nights. For chronic stress measurements of each child, hair was cut from the back of the head close to the scalp for analysis of cortisol levels. Associations between measured sleep quality and quantity and level of physical activity and hair cortisol levels were estimated using linear regression analysis, presented as β. Results were adjusted for sex, age and BMI z-score. Results We found no significant association between log-transformed cortisol (pg/mg) and sleep duration (hours) (β = − 0.0016, p  = 0.99), sleep efficiency (β = − 3.1, p  = 0.18), sleep latency (β = 0.015, p  = 0.16) or physical activity level (100 counts per min) (β = 0.014, p  = 0.22). However, sleep latency (min) was directly associated with physical activity (counts per min) levels (β = 35.2, p  = 0.02), while sleep duration (hours) (β = − 142.1, p  = 0.55) and sleep efficiency (%) (β = − 4087, p  = 0.26) showed no significant associations. Conclusions In our study, a high physical activity level was associated with poorer sleep habits. Neither sleep quality nor physical activity were related to long term cortisol exposure. These results are among the first to study associations between objectively measured sleep, physical activity and chronic cortisol levels among preschool children. More and larger studies are therefore needed.

Objective To investigate if extracellular matrix (ECM) blood-based biomarkers reflect the pharmacodynamic effect and response to TNF-α inhibitor therapy (adalimumab, ADA), in patients with axial spondyloarthritis (axSpA). Methods We investigated ECM biomarkers in two randomized, double-blind, placebo-controlled trials of axSpA patients (DANISH and ASIM, n  = 52 and n  = 49, respectively) receiving ADA 40 mg or placebo every other week for 12 and 6 weeks, respectively, and thereafter ADA to week 48. Serum concentrations of degraded type I (C1M), II (C2M, T2CM), III (C3M), IV (C4M), VI (C6M), type X (C10C) collagen; metabolite of C-reactive protein (CRPM), prolargin (PROM), citrullinated vimentin (VICM), calprotectin (CPa9-HNE); and formation of type II (PRO‑C2), III (PRO‑C3), and VI (PRO‑C6) turnover of type IV collagen (PRO-C4) were measured at baseline and weeks 6 or 12, 24, and 48. The pharmacodynamic effect and treatment response to ADA was evaluated by linear mixed models, and correlations between biomarkers and clinical scores were assessed by Spearman’s correlation. Results C1M, C3M, C4M, C6M, CRP, PRO-C4, and CPa9-HNE levels declined after 6 or 12 weeks in patients receiving ADA compared to placebo (all p  < 0.05). Patients with AS Disease Activity Score C-reactive protein (ASDAS CRP) major improvement and/or clinically important improvement had significantly higher C1M, C3M, C4M, C6M, and PRO-C4 levels than patients with no/low improvement at baseline (all p  < 0.05). Baseline levels of biomarkers showed weak to moderate correlations with ASDAS and structural damage scores. Conclusion ECM metabolites showed a pharmacodynamic effect and were associated with ASDAS response during TNF-α inhibitor treatment in patients with axSpA.