Patient-doctor continuity and diagnosis of cancer:electronic medical records study in general practice

BACKGROUND: Continuity of care may affect the diagnostic process in cancer but there is little research. AIM: To estimate associations between patient–doctor continuity and time to diagnosis and referral of three common cancers. DESIGN AND SETTING: Retrospective cohort study in general practices in England. METHOD: This study used data from the General Practice Research Database for patients aged ≥40 years with a diagnosis of breast, colorectal, or lung cancer. Relevant cancer symptoms or signs were identified up to 12 months before diagnosis. Patient–doctor continuity (fraction-of-care index adjusted for number of consultations) was calculated up to 24 months before diagnosis. Time ratios (TRs) were estimated using accelerated failure time regression models. RESULTS: Patient–doctor continuity in the 24 months before diagnosis was associated with a slightly later diagnosis of colorectal (time ratio [TR] 1.01, 95% confidence interval [CI] =1.01 to 1.02) but not breast (TR = 1.00, 0.99 to 1.01) or lung cancer (TR = 1.00, 0.99 to 1.00). Secondary analyses suggested that for colorectal and lung cancer, continuity of doctor before the index consultation was associated with a later diagnosis but continuity after the index consultation was associated with an earlier diagnosis, with no such effects for breast cancer. For all three cancers, most of the delay to diagnosis occurred after referral. CONCLUSION: Any effect for patient–doctor continuity appears to be small. Future studies should compare investigations, referrals, and diagnoses in patients with and without cancer who present with possible cancer symptoms or signs; and focus on ‘difficult to diagnose’ types of cancer

Childhood overeating is associated with adverse cardiometabolic and inflammatory profiles in adolescence

Childhood eating behaviour contributes to the rise of obesity and related noncommunicable disease worldwide. However, we lack a deep understanding of biochemical alterations that can arise from aberrant eating behaviour. In this study, we prospectively associate longitudinal trajectories of childhood overeating, undereating, and fussy eating with metabolic markers at age 16 years to explore adolescent metabolic alterations related to specific eating patterns in the first 10 years of life. Data are from the Avon Longitudinal Study of Parents and Children (n = 3104). We measure 158 metabolic markers with a high-throughput (1H) NMR metabolomics platform. Increasing childhood overeating is prospectively associated with an adverse cardiometabolic profile (i.e., hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia) in adolescence; whereas undereating and fussy eating are associated with lower concentrations of the amino acids glutamine and valine, suggesting a potential lack of micronutrients. Here, we show associations between early behavioural indicators of eating and metabolic markers

The effect of a lifestyle intervention in obese pregnant women on gestational metabolic profiles: findings from the UK Pregnancies Better Eating and Activity Trial (UPBEAT) randomised controlled trial

Background: Pregnancy is associated with widespread change in metabolism, which may be more marked in obese women. Whether lifestyle interventions in obese pregnant women improve pregnancy metabolic profiles remains unknown. Our objectives were to determine the magnitude of change in metabolic measures during obese pregnancy, to indirectly compare these to similar profiles in a general pregnant population, and to determine the impact of a lifestyle intervention on change in metabolic measures in obese pregnant women. Methods: Data from a randomised controlled trial of 1158 obese (BMI ≥ 30 kg/m2) pregnant women recruited from six UK inner-city obstetric departments were used. Women were randomised to either the UPBEAT intervention, a tailored complex lifestyle intervention focused on improving diet and physical activity, or standard antenatal care (control group). UPBEAT has been shown to improve diet and physical activity during pregnancy and up to 6-months postnatally in obese women and to reduce offspring adiposity at 6-months; it did not affect risk of gestational diabetes (the primary outcome). Change in the concentrations of 158 metabolic measures (129 lipids, 9 glycerides and phospholipids, and 20 low-molecular weight metabolites), quantified three times during pregnancy, were compared using multilevel models. The role of chance was assessed with a false discovery rate of 5% adjusted p values. Results: All very low-density lipoprotein (VLDL) particles increased by 1.5–3 standard deviation units (SD) whereas intermediate density lipoprotein and specific (large, medium and small) LDL particles increased by 1–2 SD, between 16 and 36 weeks’ gestation. Triglycerides increased by 2–3 SD, with more modest changes in other metabolites. Indirect comparisons suggest that the magnitudes of change across pregnancy in these obese women were 2- to 3-fold larger than in unselected women (n = 4260 in cross-sectional and 583 in longitudinal analyses) from an independent, previously published, study. The intervention reduced the rate of increase in extremely large, very large, large and medium VLDL particles, particularly those containing triglycerides. Conclusion: There are marked changes in lipids and lipoproteins and more modest changes in other metabolites across pregnancy in obese women, with some evidence that this is more marked than in unselected pregnant women. The UPBEAT lifestyle intervention may contribute to a healthier metabolic profile in obese pregnant women, but our results require replication. Trial Registration: UPBEAT was registered with Current Controlled Trials, ISRCTN89971375, on July 23, 2008 (prior to recruitment)

Metabolic Profiling of Adiponectin Levels in Adults

Background - Adiponectin, a circulating adipocyte-derived protein, has insulin-sensitizing, anti-inflammatory, antiatherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown. Our aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile. Methods and Results - We applied multivariable regression in ≤5909 adults and Mendelian randomization (using cis-acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analyzing the causal effect of adiponectin in the metabolic profile of ≤37 545 adults. Participants were largely European from 6 longitudinal studies and 1 genome-wide association consortium. In the multivariable regression analyses, higher circulating adiponectin was associated with higher high-density lipoprotein lipids and lower very-low-density lipoprotein lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high-risk groups (defined by age and occurrence of previous cardiovascular event) and 1 study with admixed population. Conclusions - Our findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant

Associations between Blood Metabolic Profile at 7 Years Old and Eating Disorders in Adolescence:Findings from the Avon Longitudinal Study of Parents and Children

Eating disorders are severe illnesses characterized by both psychiatric and metabolic factors. We explored the prospective role of metabolic risk in eating disorders in a UK cohort (n = 2929 participants), measuring 158 metabolic traits in non-fasting EDTA-plasma by nuclear magnetic resonance. We associated metabolic markers at 7 years (exposure) with risk for anorexia nervosa and binge-eating disorder (outcomes) at 14, 16, and 18 years using logistic regression adjusted for maternal education, child's sex, age, body mass index, and calorie intake at 7 years. Elevated very low-density lipoproteins, triglycerides, apolipoprotein-B/A, and monounsaturated fatty acids ratio were associated with lower odds of anorexia nervosa at age 18, while elevated high-density lipoproteins, docosahexaenoic acid and polyunsaturated fatty acids ratio, and fatty acid unsaturation were associated with higher risk for anorexia nervosa at 18 years. Elevated linoleic acid and n-6 fatty acid ratios were associated with lower odds of binge-eating disorder at 16 years, while elevated saturated fatty acid ratio was associated with higher odds of binge-eating disorder. Most associations had large confidence intervals and showed, for anorexia nervosa, different directions across time points. Overall, our results show some evidence for a role of metabolic factors in eating disorders development in adolescence

Associations of central and peripheral blood pressure with cardiac structure and function in an adolescent birth cohort:the Avon Longitudinal Study of Parents and Children

LetterDiana L.S. Ferreira, Abigail Fraser, Laura D. Howe, Siana Jones, George Davey Smith, Debbie A. Lawlor, Robyn J. Tapp, Andy R. Ness, John E. Deanfield, Nish Chaturvedi, Alun D. Hughe

Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis

Funding Information: This work was supported by European Regional Development Fund (FEDER) through the Operational Program for Competitiveness Factors (COMPETE) [HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323, POCI-01-0145-FEDER-016385, POCI-01-0145-FEDER-007440 to CNC.IBILI, POCI-01-0145-FEDER-007274 to i3S/INEB and NORTE-01-0145-FEDER-000012 to T.L.L.]; national funds through the Portuguese Foundation for Science and Technology (FCT) [PTDC/SAU-ORG/119296/2010, PTDC/ NEU-OSD/0312/2012, PESTC/ SAU/UI3282/2013-2014, MITP-TB/ECE/0013/ 2013, FCT-UID/NEU/04539/2013], PD/BD/52294/2013 to T.M.R.R., SFRH/ BD/85556/2012 (co-financed by QREN) to V.C.S]; Lisboa Portugal Regional Operational Programme (LISBOA 2020) and Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement; and by INFARMED Autoridade Nacional do Medicamento e Produtos de Saúde, I.P. [FIS-FIS-2015-01_CCV_20150630-157]. Publisher Copyright: © 2017 The Author.Aims Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide and results from an obstruction in the blood supply to a region of the heart. In an attempt to replenish oxygen and nutrients to the deprived area, affected cells release signals to promote the development of new vessels and confer protection against MI. However, the mechanisms underlying the growth of new vessels in an ischaemic scenario remain poorly understood. Here, we show that cardiomyocytes subjected to ischaemia release exosomes that elicit an angiogenic response of endothelial cells (ECs). Methods and results Exosomes secreted by H9c2 myocardial cells and primary cardiomyocytes, cultured either in control or ischaemic conditions were isolated and added to ECs. We show that ischaemic exosomes, in comparison with control exosomes, confer protection against oxidative-induced lesion, promote proliferation, and sprouting of ECs, stimulate the formation of capillary-like structures and strengthen adhesion complexes and barrier properties. Moreover, ischaemic exosomes display higher levels of metalloproteases (MMP) and promote the secretion of MMP by ECs. We demonstrate that miR-222 and miR-143, the relatively most abundant miRs in ischaemic exosomes, partially recapitulate the angiogenic effect of exosomes. Additionally, we show that ischaemic exosomes stimulate the formation of new functional vessels in vivo using in ovo and Matrigel plug assays. Finally, we demonstrate that intramyocardial delivery of ischaemic exosomes improves neovascularization following MI. Conclusions This study establishes that exosomes secreted by cardiomyocytes under ischaemic conditions promote heart angiogenesis, which may pave the way towards the development of add-on therapies to enhance myocardial blood supply.publishersversionpublishe

Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns Findings From the Pregnancy and Childhood Epigenetics Consortium

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R-2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.Peer reviewe