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IntroductionThe population-based Inter99 cohort has contributed extensively to our understanding of effects of a systematic screening and lifestyle intervention, as well as the multifactorial aetiology of type 2 diabetes (T2D) and cardiovascular disease. To understand causes, trajectories and patterns of early and overt cardiometabolic disease manifestations, we will perform a combined clinical deep phenotyping and registry follow-up study of the now 50–80 years old Inter99 participants.Methods and analysisThe Inter99 cohort comprises individuals aged 30–60 years, who lived in a representative geographical area of greater Copenhagen, Denmark, in 1999. Age-stratified and sex-stratified random subgroups were invited to participate in either a lifestyle intervention (N=13 016) or questionnaires (N=5264), while the rest served as a reference population (N=43 021). Of the 13 016 individuals assigned to the lifestyle intervention group, 6784 (52%) accepted participation in a baseline health examination in 1999, including screening for cardiovascular risk factors and prediabetic conditions. In total, 6004 eligible participants, who participated in the baseline examination, will be invited to participate in the deep phenotyping 20-year follow-up clinical examination including measurements of anthropometry, blood pressure, arterial stiffness, cardiometabolic biomarkers, coronary artery calcification, heart rate variability, heart rhythm, liver stiffness, fundus characteristics, muscle strength and mass, as well as health and lifestyle questionnaires. In a subsample, 10-day monitoring of diet, physical activity and continuous glucose measurements will be performed. Fasting blood, urine and faecal samples to be stored in a biobank. The established database will form the basis of multiple analyses. A main purpose is to investigate whether low birth weight independent of genetics, lifestyle and glucose tolerance predicts later common T2D cardiometabolic comorbidities.Ethics and disseminationThe study was approved by the Medical Ethics Committee, Capital Region, Denmark (H-20076231) and by the Danish Data Protection Agency through the Capital Region of Denmark’s registration system (P-2020-1074). Informed consent will be obtained before examinations. Findings will be disseminated in peer-reviewed journals, at conferences and via presentations to stakeholders, including patients and public health policymakers.Trial registration numberNCT05166447.

Background Imbalances of gut microbiota composition are linked to a range of metabolic perturbations. In the present study, we examined the gut microbiota of women with gestational diabetes mellitus (GDM) and normoglycaemic pregnant women in late pregnancy and about 8 months postpartum. Methods Gut microbiota profiles of women with GDM ( n  = 50) and healthy ( n  = 157) pregnant women in the third trimester and 8 months postpartum were assessed by 16S rRNA gene amplicon sequencing of the V1-V2 region. Insulin and glucose homeostasis were evaluated by a 75 g 2-h oral glucose tolerance test during and after pregnancy. Results Gut microbiota of women with GDM was aberrant at multiple levels, including phylum and genus levels, compared with normoglycaemic pregnant women. Actinobacteria at phylum level and Collinsella , Rothia and Desulfovibrio at genus level had a higher abundance in the GDM cohort. Difference in abundance of 17 species-level operational taxonomic units (OTUs) during pregnancy was associated with GDM. After adjustment for pre-pregnancy body mass index (BMI), 5 of the 17 OTUs showed differential abundance in the GDM cohort compared with the normoglycaemic pregnant women with enrichment of species annotated to Faecalibacterium and Anaerotruncus and depletion of species annotated to Clostridium (sensu stricto) and to Veillonella . OTUs assigned to Akkermansia were associated with lower insulin sensitivity while Christensenella OTUs were associated with higher fasting plasma glucose concentration. OTU richness and Shannon index decreased from late pregnancy to postpartum regardless of metabolic status. About 8 months after delivery, the microbiota of women with previous GDM was still characterised by an aberrant composition. Thirteen OTUs were differentially abundant in women with previous GDM compared with women with previous normoglycaemic pregnancy. Conclusion GDM diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with normoglycaemic pregnant women, and 8 months after pregnancy, differences in the gut microbiota signatures are still detectable. The gut microbiota composition of women with GDM, both during and after pregnancy, resembles the aberrant microbiota composition reported in non-pregnant individuals with type 2 diabetes and associated intermediary metabolic traits.

The present study examined the effect of intense intermittent running with 5 s sprints on body composition, fitness level, and performance in untrained subjects aged 36–53 years. For 7 weeks, the subjects carried out 3 days a week 5–10–15 training consisting of 3–9 blocks of 4 repetitions of 15, 10, and 5 s low-, moderate-, and high-speed running, respectively. Body fat mass was 4.3% lower (P < 0.01), and lean body mass and bone mineral density was 1.1 and 0.9% higher (P < 0.01), respectively, after compared to before the intervention period (INT). The plasma bone turnover markers osteocalcin increased (P < 0.01) by 147%, and procollagen-type I N propeptide and carboxy-terminal collagen crosslinks increased (P < 0.05) by 84 and 76%, respectively. Furthermore, the training improved performance in 1500 m (P < 0.001), 3 km (P < 0.001), Yo–Yo intermittent endurance test (P < 0.01), and incremental treadmill running (P < 0.001) by 8.1, 9.9, 17.2, and 23.9%, respectively. Furthermore, blood lactate after running at 85% of maximal aerobic speed was lower (P < 0.01) after compared to before the INT. Thus, 7 weeks of 5–10–15 training resulted in significant health beneficial changes and better performance in untrained subject.

Antiplatelet therapy is a cornerstone of secondary stroke prevention, but the responsiveness to antiplatelet medication varies among patients. Clopidogrel is a pro-drug that requires hepatic transformation to reach its active metabolite. Single nucleotide polymorphisms (SNPs) in key enzymes or the target adenosine diphosphate (ADP) receptor on the platelet surface are believed to be involved in clopidogrel-mediated platelet inhibition and decreased antiplatelet effect with high-on-treatment platelet reactivity (HTPR). This study investigated whether specific SNPs in key hepatic enzymes (CYP2C19*2, *3, *17, CYP3A4*1G, and NR1I2) or the ADP receptor (PR2Y12) are associated with HTPR to clopidogrel. This observational study included patients with ischemic stroke (IS) and transient ischemic attacks (TIAs) receiving clopidogrel at a dose of 75 mg/day. Patients were genotyped for eight different SNPs in the genes encoding CYP2C19, CYP3A4, NR1I2, and the P2Y12 receptor. Of the 103 patients that were included, 30.7% carried the CYP2C19*2 allele and had higher platelet reaction unit (PRU) values than non-carriers, but no patients showed HTPR. Carriers of the *17 allele had higher platelet inhibition but showed no difference in PRU values compared with non-carriers. The remaining SNPs were neither associated with PRU nor with platelet inhibition. Patients with IS and TIAs treated with 75 mg clopidogrel/day do not have HTPR. A genetic analysis of CYP2C19*2, *3, *17, CYP3A4*1G, and NR1I2 revealed no associations with clopidogrel HTPR. CYP2C19*2 carriers and patients with HTPR in the acute phase after ischemic stroke or transient ischemic attacks exhibit higher PRU values, but not long-term treatment HTPR.

Post-menopausal osteoporosis is a condition that affects millions worldwide and places a huge socio-economic burden on society. Previous research has shown an association of loss of function SNPs in the gene for the purinergic receptor P2X7R with low bone mineral density, increased rates of bone loss and vertebral fractures in post-menopausal women. In this study we use a mouse model of oestrogen deficiency-induced bone loss and the BALB/cJ P2X7R −/− to show that absence of the P2X7R resulted in increased bone loss. Osteoclast precursors were isolated from both BALB/cJ P2X7R −/− and BALB/cJ P2X7R +/+ mice and then cultured in vitro to form mature resorbing osteoclasts. The BALB/cJ P2X7R −/− derived precursors generated slightly more osteoclasts but with a significant reduction in the amount of resorption per osteoclast. Furthermore, when using modified culture conditions osteoclast activity was additionally increased in the absence of the P2X7R suggest that P2X7R may regulate the lifespan and activity of osteoclasts. Finally using mechanical loading as an anabolic stimulus for bone formation, we demonstrated that the increased oestrogen-deficient bone loss could be rescued, even in the absence of P2X7R. This study paves the way for clinical intervention for women with post-menopausal osteoporosis and P2XR7 loss of function polymorphisms.

Background Chronic low‐grade inflammation has been suggested as one of the key elements in the development of sarcopenia, but in contrast to disease‐related loss of muscle mass, the role of chronic low‐grade inflammation in age‐related (primary) sarcopenia is still not clear. The aim of this study was to investigate low‐grade inflammation in relation to age and the potential association between inflammatory biomarkers and body composition, muscle strength and physical performance in a healthy Danish cohort. Methods There were 1160 generally healthy men and women (range: 22–93 years) included. Appendicular lean mass (ALM) and visceral fat normalized to height (kg/m2) was assessed by dual‐energy X‐ray absorptiometry (iDXA, GE Lunar). Muscle strength and physical performance were evaluated by handgrip strength (HGS), 30 s sit‐to‐stand performance, and maximal gait speed (GS). Systemic levels of TNF‐α, IL‐6, IL‐1β, IL‐4, IL‐13, and IFN‐γ were measured using multiplex bead‐based immunoassays (Bio‐Rad). hsCRP was assessed using latex particle‐enhanced immunoturbidimetric assays (Roche Diagnostics). Results With age, ALM/h2, HGS, sit‐to‐stand performance and GS decreased, whereas visceral fat/h2 increased in both men and women (P < 0.05). Systemic levels of hsCRP, TNF‐α, IL‐4, and IFN‐γ increased with age in men and women (P < 0.05), while IL‐1β increased in women only (P < 0.01). Higher levels of hsCRP were associated with lower ALM/h2 in elderly (≥65 years) men and women (P < 0.001). Higher levels of hsCRP were associated with lower handgrip strength in elderly women (P < 0.05) whereas higher levels of hsCRP was not associated with lower HGS in elderly men (P = 0.056). Higher levels of hsCRP were associated with lower GS (P < 0.05), whereas IFN‐γ was positively associated with GS in elderly women (P < 0.05), but not elderly men. Visceral fat index was positively associated with hsCRP in elderly men and women (P < 0.001). Compared with elderly with normal HGS, elderly men and women with low HGS displayed higher levels of TNF‐α and hsCRP (P < 0.05). Conclusions With age, systemic levels of hsCRP, TNF‐α, IL‐4, and IFN‐γ increased, with hsCRP and TNF‐α being especially elevated in more physically frail elderly supporting the association between low‐grade systemic inflammation and poor physical function. In contrast, only high levels of hsCRP were weakly associated with low muscle mass and positively associated with visceral fat and low physical function, suggesting that chronic low‐grade inflammation is not the main driver of age‐related loss of muscle mass as previously suggested.

Earlier studies on the association between plasma lipid profiles and functional somatic disorders (FSD) are mainly small case control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study was to investigate the associations between various FSDs and plasma lipid profiles (total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides) in a large, unselected population. A cross-sectional general population-based study. The Danish Study of Functional Somatic Disorders (DanFunD) conducted in 2011-2015 in 10 municipalities in the western part of greater Copenhagen, Denmark. A total of 8,608 men and women aged 18-76 years were included in the analyses. Various delimitations of FSD such as chronic fatigue, chronic widespread pain, irritable bowel, and bodily distress syndrome were measured using validated self-administrated questionnaires. Lipid parameters were measured from fasting plasma samples using colorimetric slide methods with Vitros 4600/5600 Ortho Clinical Diagnostics. Logistic regression analyses were used to calculate possible associations between plasma lipids and the various delimitations of FSD. Associations are presented by OR (95% CI) and shown in boxplots. We found a positive association between bodily distress syndrome and triglycerides and non-HDL cholesterol and a negative association with HDL-cholesterol, but no consistent association with total cholesterol. A similar pattern was observed for persons with chronic fatigue, and to some degree for persons with chronic widespread pain, whereas persons with irritable bowel did not show a clear association with the lipid profiles. This is the first major study on plasma lipid profiles and FSD indicating an association between some delimitations of FSD and an unfavorable lipid profile. Due to the cross-sectional design, it cannot be determined whether the findings are consequences or determinants of FSD. Further studies-preferable prospective studies-are needed.

BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.

ObjectiveTo investigate the effect of whole-body vibration exercise (WBV) on fracture risk in adults ≥50 years of age.DesignA systematic review and meta-analysis calculating relative risk ratios, fall rate ratio and absolute weighted mean difference using random effects models. Heterogeneity was estimated using I2 statistics, and the Cochrane Collaboration’s risk of bias tool and the GRADE approach were used to evaluate quality of evidence and summarise conclusions.Data sourcesThe databases PubMed, Embase and the Cochrane Central Register from inception to April 2016 and reference lists of retrieved publications.Eligibility criteria for selecting studiesRandomised controlled trials examining the effect of WBV on fracture risk in adults ≥50 years of age. The primary outcomes were fractures, fall rates and the proportion of participants who fell. Secondary outcomes were bone mineral density (BMD), bone microarchitecture, bone turnover markers and calcaneal broadband attenuation (BUA).Results15 papers (14 trials) met the inclusion criteria. Only one study had fracture data reporting a non-significant fracture reduction (risk ratio (RR)=0.47, 95% CI 0.14 to 1.57, P=0.22) (moderate quality of evidence). Four studies (n=746) showed that WBV reduced the rate of falls with a rate ratio of 0.67 (95% CI 0.50 to 0.89, P=0.0006; I2=19%) (moderate quality of evidence). Furthermore, data from three studies (n=805) found a trend towards falls reduction (RR=0.76, 95% CI 0.48 to 1.20, P=0.24; I2=24%) (low quality of evidence). Finally, moderate to low quality of evidence showed no overall effect on BMD and only sparse data were available regarding microarchitecture parameters, bone turnover markers and BUA.ConclusionsWBV reduces fall rate but seems to have no overall effect on BMD or microarchitecture. The impact of WBV on fractures requires further larger adequately powered studies. This meta-analysis suggests that WBV may prevent fractures by reducing falls.PROSPERO registration number CRD42016036320; Pre-results.

A healthy skeleton depends on a continuous renewal and maintenance of the bone tissue. The process of bone remodeling is highly controlled and consists of a fine-tuned balance between bone formation and bone resorption. Biochemical markers of bone turnover are already in use for monitoring diseases and treatment involving the skeletal system, but novel biomarkers reflecting specific biological processes in bone and interacting tissues may prove useful for diagnostic, prognostic, and monitoring purposes. The Wnt-signaling pathway is one of the most important pathways controlling bone metabolism and consequently the action of inhibitors of the pathway such as sclerostin and Dickkopf-related protein 1 (DKK1) have crucial roles in controlling bone formation and resorption. Thus, they might be potential markers for clinical use as they reflect a number of physiological and pathophysiological events in bone and in the cross-talk with other tissues in the human body. This review focuses on the clinical utility of measurements of circulating sclerostin and DKK1 levels based on preanalytical and analytical considerations and on evidence obtained from published clinical studies. While accumulating evidence points to clear associations with a number of disease states for the two markers, and thus, the potential for especially sclerostin as a biochemical marker that may be used clinically, the lack of standardization or harmonization of the assays still hampers the clinical utility of the markers.