Comparative effectiveness of lifestyle interventions on cardiovascular risk factors among a Dutch overweight working population: A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Overweight (Body Mass Index [BMI] ≥ 25 kg/m²) and obesity (BMI≥ 30 kg/m²) are associated with increased cardiovascular risk, posing a considerable burden to public health. The main aim of this study was to investigate lifestyle intervention effects on cardiovascular risk factors in healthy overweight employees.</p> <p>Methods</p> <p>Participants were 276 healthy overweight employees (69.2% male; mean age 44.0 years [SD 9.2]; mean BMI 29.7 kg/m²[SD 3.1]). They were randomized to one of two intervention groups receiving a six month lifestyle intervention with behavior counseling by phone (phone group) or e-mail (Internet group), or to a control group receiving usual care. Body weight, height, waist circumference, sum of skinfolds, blood pressure, total cholesterol level and predicted aerobic fitness were measured at baseline, at 6 and at 24 months. Regression analyses included the 141 participants with complete data.</p> <p>Results</p> <p>At 6 months a significant favorable effect on total cholesterol level (-0.2 mmol/l, 95%CI -0.5 to -0.0) was observed in the phone group and a trend for improved aerobic fitness (1.9 ml/kg/min, 95%CI -0.2 to 3.9) in the Internet group. At two years, favorable trends for body weight (-2.1 kg, 95%CI -4.4 to 0.2) and aerobic fitness (2.3 ml/kg/min, 95%CI -0.2 to 4.8) were observed in the Internet group.</p> <p>Conclusions</p> <p>The intervention effects were independent of the used communication mode. However short-term results were in favor of the phone group and long-term results in favor of the internet group. Thus, we found limited evidence for our lifestyle intervention to be effective in reducing cardiovascular risk in a group of apparently healthy overweight workers.</p> <p>Trial registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN04265725">ISRCTN04265725</a></p

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated

ALIFE@Work: a randomised controlled trial of a distance counselling lifestyle programme for weight control among an overweight working population [ISRCTN04265725]

BACKGROUND: The prevalence of overweight is increasing and its consequences will cause a major public health burden in the near future. Cost-effective interventions for weight control among the general population are therefore needed. The ALIFE@Work study is investigating a novel lifestyle intervention, aimed at the working population, with individual counselling through either phone or e-mail. This article describes the design of the study and the participant flow up to and including randomisation. METHODS/DESIGN: ALIFE@Work is a controlled trial, with randomisation to three arms: a control group, a phone based intervention group and an internet based intervention group. The intervention takes six months and is based on a cognitive behavioural approach, addressing physical activity and diet. It consists of 10 lessons with feedback from a personal counsellor, either by phone or e-mail, between each lesson. Lessons contain educational content combined with behaviour change strategies. Assignments in each lesson teach the participant to apply these strategies to every day life. The study population consists of employees from seven Dutch companies. The most important inclusion criteria are having a body mass index (BMI) ≥ 25 kg/m(2 )and being an employed adult. Primary outcomes of the study are body weight and BMI, diet and physical activity. Other outcomes are: perceived health; empowerment; stage of change and self-efficacy concerning weight control, physical activity and eating habits; work performance/productivity; waist circumference, sum of skin folds, blood pressure, total blood cholesterol level and aerobic fitness. A cost-utility- and a cost-effectiveness analysis will be performed as well. Physiological outcomes are measured at baseline and after six and 24 months. Other outcomes are measured by questionnaire at baseline and after six, 12, 18 and 24 months. Statistical analyses for short term (six month) results are performed with multiple linear regression. Analyses for long term (two year) results are performed with multiple longitudinal regression. Analyses for cost-effectiveness and cost-utility are done at one and two years, using bootstrapping techniques. DISCUSSION: ALIFE@Work will make a substantial contribution to the development of cost-effective weight control- and lifestyle interventions that are applicable to and attractive for the large population at risk

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.C.L.R., G.D.S., G.S., J.L.M., K.B., M. Suderman, T.G.R. and T.R.G. are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/5). C.L.R. receives support from a Cancer Research UK Programme grant (no. C18281/A191169). G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). E.H. and J.M. were supported by MRC project grants (nos. MR/K013807/1 and MR/R005176/1 to J.M.) and an MRC Clinical Infrastructure award (no. MR/M008924/1 to J.M.). B.T.H. is supported by the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19, CVON2017-20). J.T.B. was supported by the Economic and Social Research Council (grant no. ES/N000404/1). The present study was also supported by JPI HDHL-funded DIMENSION project (administered by the BBSRC UK, grant no. BB/S020845/1 to J.T.B., and by ZonMW the Netherlands, grant no. 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians and the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J. Klughammer was supported by a DOC fellowship of the Austrian Academy of Sciences. Cohort-specific acknowledgements and funding are presented in the Supplementary Note

Accuracy of self-reported body weight, height and waist circumference in a Dutch overweight working population

<p>Abstract</p> <p>Background</p> <p>In population studies, body mass index (BMI) is generally calculated from self-reported body weight and height. The self-report of these anthropometrics is known to be biased, resulting in a misclassification of BMI status. The aim of our study is to evaluate the accuracy of self-reported weight, height and waist circumference among a Dutch overweight (Body Mass Index [BMI] ≥ 25 kg/m²) working population, and to determine to what extent the accuracy was moderated by sex, age, BMI, socio-economic status (SES) and health-related factors.</p> <p>Methods</p> <p>Both measured and self-reported body weight and body height were collected in 1298 healthy overweight employees (66.6% male; mean age 43.9 ± 8.6 years; mean BMI 29.5 ± 3.4 kg/m²), taking part in the ALIFE@Work project. Measured and self-reported waist circumferences (WC) were available for a sub-group of 250 overweight subjects (70.4% male; mean age 44.1 ± 9.2 years; mean BMI 29.6 ± 3.0 kg/m²). Intra Class Correlation (ICC), Cohen's kappa and Bland Altman plots were used for reliability analyses, while linear regression analyses were performed to assess the factors that were (independently) associated with the reliability.</p> <p>Results</p> <p>Body weight was significantly (p < 0.001) under-reported on average by 1.4 kg and height significantly (p < 0.001) over-reported by 0.7 cm. Consequently, BMI was significantly (p < 0.001) under-reported by 0.7 kg/m². WC was significantly (p < 0.001) over-reported by 1.1 cm. Although the self-reporting of anthropometrics was biased, ICC's showed high concordance between measured and self-reported values. Also, substantial agreement existed between the prevalences of BMI status and increased WC based on measured and self-reported data. The under-reporting of BMI and body weight was significantly (p < 0.05) affected by measured weight, height, SES and smoking status, and the over-reporting of WC by age, sex and measured WC.</p> <p>Conclusion</p> <p>Results suggest that self-reported BMI and WC are satisfactorily accurate for the assessment of the prevalence of overweight/obesity and increased WC in a middle-aged overweight working population. As the accuracy of self-reported anthropometrics is affected by measured weight, height, WC, smoking status and/or SES, results for these subgroups should be interpreted with caution. Due to the large power of our study, the clinical significance of our statistical significant findings may be limited.</p> <p>Trial Registration</p> <p>ISRCTN04265725</p

Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis

We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotyped lentiviral vector into a first-in-man CF trial in 2017

Identification of Enteroendocrine Regulators by Real-Time Single-Cell Differentiation Mapping

Homeostatic regulation of the intestinal enteroendocrine lineage hierarchy is a poorly understood process. We resolved transcriptional changes during enteroendocrine differentiation in real time at single-cell level using a novel knockin allele of Neurog3, the master regulator gene briefly expressed at the onset of enteroendocrine specification. A bi-fluorescent reporter, Neurog3Chrono, measures time from the onset of enteroendocrine differentiation and enables precise positioning of single-cell transcriptomes along an absolute time axis. This approach yielded a definitive description of the enteroendocrine hierarchy and its sub-lineages, uncovered differential kinetics between sub-lineages, and revealed time-dependent hormonal plasticity in enterochromaffin and L cells. The time-resolved map of transcriptional changes predicted multiple novel molecular regulators. Nine of these were validated by conditional knockout in mice or CRISPR modification in intestinal organoids. Six novel candidate regulators (Sox4, Rfx6, Tox3, Myt1, Runx1t1, and Zcchc12) yielded specific enteroendocrine phenotypes. Our time-resolved single-cell transcriptional map presents a rich resource to unravel enteroendocrine differentiation

Distinct localization of the complement C5b-9 complex on Gram-positive bacteria

The plasma proteins of the complement system fulfil important immune defence functions, including opsonization of bacteria for phagocytosis, generation of chemo-attractants and direct bacterial killing via the Membrane Attack Complex (MAC or C5b-9). The MAC is comprised of C5b, C6, C7, C8, and multiple copies of C9 that generate lytic pores in cellular membranes. Gram-positive bacteria are protected from MAC-dependent lysis by their thick peptidoglycan layer. Paradoxically, several Gram-positive pathogens secrete small proteins that inhibit C5b-9 formation. In this study, we found that complement activation on Gram-positive bacteria in serum results in specific surface deposition of C5b-9 complexes. Immunoblotting revealed that C9 occurs in both monomeric and polymeric (SDS-stable) forms, indicating the presence of ring-structured C5b-9. Surprisingly, confocal microscopy demonstrated that C5b-9 deposition occurs at specialized regions on the bacterial cell. On Streptococcus pyogenes, C5b-9 deposits near the division septum whereas on Bacillus subtilis the complex is located at the poles. This is in contrast to C3b deposition, which occurs randomly on the bacterial surface. Altogether, these results show a previously unrecognized interaction between the C5b-9 complex and Gram-positive bacteria, whichmight ultimately lead to a new model of MAC assembly and functioning