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1.
Nat Med ; 28(11): 2321-2332, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36357675

RESUMO

Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.


Assuntos
Erros Inatos do Metabolismo , Metaboloma , Humanos , Metaboloma/genética , Metabolômica , Plasma/metabolismo , Fenótipo , Erros Inatos do Metabolismo/genética , Proteínas de Membrana/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo
2.
Nat Med ; 28(11): 2293-2300, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36357677

RESUMO

The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications.


Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Humanos , Intolerância à Glucose/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Glicemia/metabolismo , Proteômica , Teste de Tolerância a Glucose , Jejum
3.
J Med Internet Res ; 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36194866

RESUMO

BACKGROUND: The COVID-19 pandemic accelerated the interest in implementing mHealth in population-based health studies, but evidence is lacking on engagement and adherence in studies. We conducted a fully remote study for over 6-months tracking COVID-19 digital biomarkers and symptoms using a smartphone app nested within an existing cohort of UK adults. OBJECTIVE: To investigate participant characteristics associated with initial and sustained engagement in digital biomarker collection from a bespoke smartphone app and if engagement changed over time or as a result of COVID-19 factors. To explore participants' reasons for consenting to the smartphone sub-study and experiences related to initial and continued engagement. METHODS: Participants in the Fenland COVID-19 study were invited to the app sub-study from August-October 2020 until study closure (30 April 2021). Participants were asked to complete digital biomarker modules (oxygen saturation, body temperature, resting heart rate (RHR)) and possible COVID-19 symptoms in the app three times/week. Participants manually entered measurements, except RHR measured using the smartphone camera. Engagement was categorised from median weekly frequency of completing the three digital biomarker modules (categories; 0, 1-2 and 3 or more/times per week). Socio-demographic and health characteristics of those who did or did not consent to the sub-study, and by engagement category were explored. Semi-structured interviews were conducted with 35 participants and data analysed thematically; 22 who consented to the app sub-study and 13 who did not consent, purposively sampled by sex, age, educational attainment and by engagement category. RESULTS: A total of 2,524 (63%) of Fenland COVID-19 study participants consented to the app sub-study. Of those, 90.2% completed the app onboarding process. Median time in the app sub-study was 34.5 weeks (IQR 34, 37) with no change in engagement from 0-3 months or 3-6 months. Completion rates (1/week) across the study between digital biomarkers were similar (RHR 72.8%, temperature 73.1%, oxygen saturation 73.5%). Older age groups, lower managerial and intermediate occupations were associated with higher engagement whilst working, being a current smoker, overweight or obese and high perceived stress were associated with lower engagement. Reasons for consenting included altruism, previous positive participation experiences and interest in health research, and non-consent was due to confusion regarding study invitation and perceived phone incompatibility. Continued engagement was facilitated by routine and personal motivation, poor engagement was caused by user error and app/equipment malfunctions preventing data input. From these results we developed key recommendations to improve engagement in population-based mHealth studies. CONCLUSIONS: This mixed-method study demonstrated both high initial and sustained engagement in a large mHealth COVID-19 study over at least 6-month period in UK adults. Being nested in a known cohort study enabled the identification of participant characteristics and factors associated with engagement, to inform future applications in population-based health research.

4.
Nutrients ; 14(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36014869

RESUMO

Hypertension is a significant and preventable cardiovascular disease risk factor. Growing evidence suggests legumes have blood-pressure (BP) lowering properties. However, there is little population-based research on legume intake and hypertension risk in Western populations. The objective was to investigate the relationship between legume intake and blood pressure by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk cohort. Further, to identify any potential legume intake that confers benefits in relation to blood pressure. We included participants who completed both 7-day food diaries to assess legume intake and undertook a first (1993-1997) and second (1998-2000) health check from the EPIC-Norfolk prospective study. Legume consumption was categorized using percentile cut off values. We used multivariate logistic regression models to calculate the odds ratio of hypertension (defined as >140 mmHg systolic and/or >90 mmHg diastolic blood pressure) at the second health check, stratified by legume intake, adjusting for antihypertensive medication use and demographic, socioeconomic and lifestyle covariates. A total of 7522 participants were included with mean age (± SD) of 58.0 ± 8.9 years. The follow-up time was 3.7 years (range: 2.1-6.6 years). Mean legume consumption was 17.3 ± 16.3 g/day. Participants in the 97th percentile of legume intake had the lowest odds of subsequent hypertension (OR: 0.71; 95% CI: 0.52, 0.96). Legume consumption between 55-70 g/day was associated with reduced odds of hypertension (OR: 0.57; 95% CI: 0.37, 0.88); sex-specific values for men and women were 0.64 (0.38, 1.03) and 0.32 (0.12, 0.88), respectively. In this UK population, legume intake of 55-70 g/day was associated with a lower subsequent risk of hypertension. Given the low legume intake in the UK and Western countries, dietary guidance to increase intake above 55 g/day may lower the burden of hypertension and associated diseases.


Assuntos
Fabaceae , Hipertensão , Neoplasias , Idoso , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertensão/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Verduras
5.
Diabetologia ; 65(11): 1796-1803, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35916901

RESUMO

It is well established from clinical trials that behavioural interventions can halve the risk of progression from prediabetes to type 2 diabetes but translating this evidence of efficacy into effective real-world interventions at scale is an ongoing challenge. A common suggestion is that future preventive interventions need to be more personalised in order to enhance effectiveness. This review evaluates the degree to which existing interventions are already personalised and outlines how greater personalisation could be achieved through better identification of those at high risk, division of type 2 diabetes into specific subgroups and, above all, more individualisation of the behavioural targets for preventive action. Approaches using more dynamic real-time data are in their scientific infancy. Although these approaches are promising they need longer-term evaluation against clinical outcomes. Whatever personalised preventive approaches for type 2 diabetes are developed in the future, they will need to be complementary to existing individual-level interventions that are being rolled out and that are demonstrably effective. They will also need to ideally synergise with, and at the very least not detract attention from, efforts to develop and implement strategies that impact on type 2 diabetes risk at the societal level.


Assuntos
Diabetes Mellitus Tipo 2 , Medicina de Precisão , Diabetes Mellitus Tipo 2/prevenção & controle , Humanos
6.
Nat Commun ; 13(1): 4484, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35970849

RESUMO

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10-6) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.


Assuntos
COVID-19 , Proteínas de Ligação a DNA , Fatores de Transcrição , Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Proteínas de Ligação a DNA/genética , Células Epiteliais/metabolismo , Humanos , Peptidil Dipeptidase A/metabolismo , Sistema Respiratório , SARS-CoV-2 , Fatores de Transcrição/genética
7.
Eur Heart J ; 43(30): 2867-2875, 2022 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-35863377

RESUMO

AIMS: A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. METHODS AND RESULTS: An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. CONCLUSION: The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP.


Assuntos
Doenças Cardiovasculares , Hipertensão , Sódio na Dieta , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Potássio , Sódio , Sódio na Dieta/efeitos adversos
9.
J Am Heart Assoc ; 11(13): e023727, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35730648

RESUMO

Background Experimental studies show that high-sodium intake affects the innate immune system, among others with increased circulating granulocytes. Whether this relationship exists on a population level and whether this relates to disease outcomes is unclear. We aimed to test the hypotheses that (1) sodium intake is associated with granulocytes on a population level; (2) granulocytes are associated with the presence of hypertension and both cardiovascular and renal outcomes; and (3) the relation between high-sodium intake and these outcomes is mediated by granulocytes. Methods and Results We performed an analysis in 13 804 participants from the prospective EPIC (European Prospective Investigation into Cancer)-Norfolk cohort, with a mean age of 58 years and median follow-up of 19.3 years. Analyses were carried out using calculated estimated sodium intake and sodium-to-potassium ratios from spot urines at baseline. The main outcomes were hypertension at baseline, and composite cardiovascular (mortality or cardiovascular events) and renal (mortality or renal events) outcomes during follow-up. Sodium intake and urine sodium-to-potassium ratio were positively associated with circulating granulocyte concentrations after adjustment for confounders (ß=0.03; P=0.028 and ß=0.06; P<0.001, respectively). Granulocytes significantly mediated the associations of, respectively, sodium intake and urine sodium-to-potassium ratio with hypertension at baseline, and cardiovascular and renal outcomes. Conclusions Sodium intake is positively associated with circulating granulocyte concentrations, and higher granulocyte concentrations associate with worse long-term cardiovascular and renal outcomes. Given the recently established immune-modulating effects of sodium and the role of immune cells in both cardiovascular and renal disease, causality for this pathway may need consideration in further studies.


Assuntos
Doenças Cardiovasculares , Hipertensão , Sódio na Dieta , Granulócitos , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Pessoa de Meia-Idade , Potássio , Estudos Prospectivos , Sódio , Sódio na Dieta/efeitos adversos
10.
Am J Clin Nutr ; 116(2): 511-522, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35754192

RESUMO

BACKGROUND: Self-reported meat consumption is associated with disease risk but objective assessment of different dimensions of this heterogeneous dietary exposure in observational and interventional studies remains challenging. OBJECTIVES: We aimed to derive and validate scores based on plasma metabolites for types of meat consumption. For the most predictive score, we aimed to test whether the included metabolites varied with change in meat consumption, and whether the score was associated with incidence of type 2 diabetes (T2D) and other noncommunicable diseases. METHODS: We derived scores based on 781 plasma metabolites for red meat, processed meat, and poultry consumption assessed with 7-d food records among 11,432 participants in the EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition-Norfolk) cohort. The scores were then tested for internal validity in an independent subset (n = 853) of the same cohort. In focused analysis on the red meat metabolite score, we examined whether the metabolites constituting the score were also associated with meat intake in a randomized crossover dietary intervention trial of meat (n = 12, Lyon, France). In the EPIC-Norfolk study, we assessed the association of the red meat metabolite score with T2D incidence (n = 1478) and other health endpoints. RESULTS: The best-performing score was for red meat, comprising 139 metabolites which accounted for 17% of the explained variance of red meat consumption in the validation set. In the intervention, 11 top-ranked metabolites in the red meat metabolite score increased significantly after red meat consumption. In the EPIC-Norfolk study, the red meat metabolite score was associated with T2D incidence (adjusted HR per SD: 1.17; 95% CI: 1.10, 1.24). CONCLUSIONS: The red meat metabolite score derived and validated in this study contains metabolites directly derived from meat consumption and is associated with T2D risk. These findings suggest the potential for objective assessment of dietary components and their application for understanding diet-disease associations.The trial in Lyon, France, was registered at clinicaltrials.gov as NCT03354130.


Assuntos
Diabetes Mellitus Tipo 2 , Carne Vermelha , Estudos de Coortes , Dieta , Humanos , Carne , Estudos Prospectivos , Fatores de Risco
11.
Lancet Diabetes Endocrinol ; 10(8): 561-570, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35636440

RESUMO

BACKGROUND: The Office for Health Improvement and Disparities, part of the UK Government Department of Health and Social Care, highlighted an emerging signal of increased non-COVID-19-related deaths in England between July and October, 2021, with a potentially disproportionate higher increase in people with diabetes. We aimed to substantiate and quantify this apparent excess mortality, and to investigate the association between diabetes routine care delivery and non-COVID-19-related-mortality in people with diabetes before and after the onset of the pandemic. METHODS: In this population-based parallel cohort study, we used the National Diabetes Audit (NDA) to identify people with diabetes in England. The primary outcome was non-COVID-19-related deaths between July 3, 2021, and Oct 15, 2021, in participants in the 2021 COVID-19 cohort (registered in the NDA in the periods Jan 1, 2019, to March 31, 2020, and Jan 1, 2020, to March 31, 2021) compared with deaths between June 29, 2019, and Oct 11, 2019 (the equivalent 15-week period in 2019) in the 2019 pre-COVID-19 comparator cohort (people registered in the NDA in the periods Jan 1, 2017, to March 31, 2018, and Jan 1, 2018 to March 31, 2019). In each cohort, multivariable logistic regression examined whether completion of eight diabetes care processes in each of the two years before the index mortality year was associated with non-COVID-19-related death, adjusting for diabetes type, age, sex, ethnicity, and socioeconomic deprivation. FINDINGS: There were 3 218 570 people in the 2021 cohort and 2 973 645 people in the 2019 comparator cohort. In the 2021 cohort, there were 30 118 non-COVID-19-related deaths in people with diabetes, compared with 27 132 in the comparator cohort, representing an 11% increase (95% CI 9-13). The unadjusted incidence rate ratio (IRR) for mortality in the 2021 cohort compared to the 2019 cohort was 1·026 (1·009-1·043; p=0·003), which was unchanged after adjustment for age, sex, ethnicity, socioeconomic deprivation, and diabetes type (IRR 1·023 (1·006-1·040); p=0·007). In the 2021 cohort, 853 660 (26·5%) people received all eight care processes in 2020-21 compared with 1 547 240 (48·1%) people in 2019-20; a 44·8% (95% CI 44·7-45·0) relative reduction. In the pre-COVID-19 comparator cohort, 1 370 315 (46·1%) people with diabetes received all eight care processes in 2018-19 compared with 1 437 740 (48·3%) in 2017-18; a 4·7% (95% CI 4·5-4·9) relative decrease. Non-COVID-19-related mortality in the 2021 cohort was highest in people who did not receive all eight care processes in either of the two previous years (OR 2·67 [95% CI 2·56-2·77]; p<0·001) compared with those who received all eight care processes in both previous years. Mortality was also significantly higher in those who received all eight care processes in 2019-20 but not in 2020-21 (OR 1·66 [95% CI 1·59-1·73]; p<0·001) or not in 2019-20 but in 2020-21 (OR 1·27 [1·20-1·35]; p<0·001). This pattern of association was similar in the 2019 pre-COVID-19 cohort. INTERPRETATION: Our results show an increased risk of mortality in those who did not receive all eight care processes in one or both of the previous two years. Our results provide evidence that the increased rate of non-COVID-19-related mortality in people with diabetes in England observed between July 3, and Oct 15 of 2021 is associated with a reduction in completion of routine diabetes care processes following the pandemic onset in 2020. FUNDING: None.


Assuntos
COVID-19 , Diabetes Mellitus , Estudos de Coortes , Diabetes Mellitus/epidemiologia , Inglaterra/epidemiologia , Humanos , Pandemias
12.
Eur J Nutr ; 61(7): 3649-3667, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35641800

RESUMO

PURPOSE: In several studies, exploratory dietary patterns (DP), derived by principal component analysis, were inversely or positively associated with incident type 2 diabetes (T2D). However, findings remained study-specific, inconsistent and rarely replicated. This study aimed to investigate the associations between DPs and T2D in multiple cohorts across the world. METHODS: This federated meta-analysis of individual participant data was based on 25 prospective cohort studies from 5 continents including a total of 390,664 participants with a follow-up for T2D (3.8-25.0 years). After data harmonization across cohorts we evaluated 15 previously identified T2D-related DPs for association with incident T2D estimating pooled incidence rate ratios (IRR) and confidence intervals (CI) by Piecewise Poisson regression and random-effects meta-analysis. RESULTS: 29,386 participants developed T2D during follow-up. Five DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, were associated with higher incidence of T2D. The strongest association was observed for a DP comprising these food groups besides others (IRRpooled per 1 SD = 1.104, 95% CI 1.059-1.151). Although heterogeneity was present (I2 = 85%), IRR exceeded 1 in 18 of the 20 meta-analyzed studies. Original DPs associated with lower T2D risk were not confirmed. Instead, a healthy DP (HDP1) was associated with higher T2D risk (IRRpooled per 1 SD = 1.057, 95% CI 1.027-1.088). CONCLUSION: Our findings from various cohorts revealed positive associations for several DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, adding to the evidence-base that links DPs to higher T2D risk. However, no inverse DP-T2D associations were confirmed.


Assuntos
Diabetes Mellitus Tipo 2 , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta , Humanos , Incidência , Estudos Prospectivos , Fatores de Risco
14.
J Telemed Telecare ; : 1357633X221093434, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538704

RESUMO

INTRODUCTION: The ability to collect blood samples remotely without the involvement of healthcare professionals is a key element of future telehealth applications. We developed and validated the application of the Drawbridge OneDraw device for use at home for blood sample collection. The device was then applied in a large population-based remote monitoring study to assess changes in SARS-CoV-2 IgG antibody levels. METHODS: We tested: (1) feasibility of participants using the device at home without a healthcare professional on the upper arm and thigh sites (2) stability of the dried blood sample collected remotely (3) participant acceptability of the device compared with finger-prick and venous blood samples and the validity of SARS-CoV-2 virus antibody measurement versus venous blood sample (4) application to the Fenland COVID-19 study in which 4023 participants at 3 timepoints across 6 months. RESULTS: Participant acceptability was high, with a significantly lower median perceived pain score and 76% of participants preferring the OneDraw device over the other blood collection methods. There was high level of agreement in SARS-CoV-2 virus antibody results with venous blood samples in 120 participants (Cohen's kappa 0.68 (95% CI 0.56, 0.83). In the Fenland COVID-19 study, 92% of participants returned a sample at baseline (3702/4023), 89% at 3 months (3492/3918) and 93% at 6 months (3453/3731), with almost all samples received successfully processed (99.9%). DISCUSSION: The OneDraw device enables a standardised blood sample collection at home by participants themselves. Due to its ease-of-use and acceptability the OneDraw device is particularly useful in telehealth approaches where multiple samples need to be collected.

15.
J Am Heart Assoc ; 11(9): e023845, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35470706

RESUMO

Background Emerging evidence suggests accruing sedentary behavior (SB) in relatively more prolonged periods may convey additional cardiometabolic risks, but few studies have examined prospective outcomes. We examined the association of SB accumulation patterns with incident cardiovascular disease (CVD), cancer, and all-cause mortality (ACM). Methods and Results Data were from 7671 EPIC-Norfolk (European Prospective Investigation Into Cancer and Nutrition-Norfolk) cohort middle- to older-aged adults who wore accelerometers on the right hip for 4 to 7 days. Cox proportional hazards regression modeled associations between 2 measures of SB accumulation and incident CVD, cancer, and ACM. These were usual SB bout duration (the midpoint of each individual's SB accumulation curve, fitted using nonlinear regression) and alpha (hybrid measure of bout frequency and duration, with higher values indicating relatively shorter bouts and fewer long bouts). Models were adjusted for potential confounders, then further for 24-hour time-use compositions. During mean follow-up time of 6.4 years, 339 ACM, 1106 CVD, and 516 cancer events occurred. Elevated rates of incident cancer and ACM were seen with more prolonged SB accumulation (lower alpha, higher usual SB bout duration) but not CVD. For usual SB bout duration and alpha, respectively, the confounder-adjusted hazard ratios per SD of the exposure were 1.12 (95% CI, 1.02-1.23) and 0.88 (95% CI, 0.79-0.98) with incident cancer and 1.16 (95% CI, 1.07-1.26) and 0.80 (95% CI, 0.72-0.89) with ACM (all P<0.05). Further adjustment for 24-hour time use weakened associations with ACM for usual bout duration (hazard ratio, 1.06; 95% CI, 0.97-1.16; P=0.209) and partially for alpha (hazard ratio, 0.87; 95% CI, 0.77-0.99; P=0.029). Conclusions Accruing SB in longer bout durations was associated with higher rates of incident cancer and ACM but not with incident CVD, with some evidence of direct SB accumulation effects independent of 24-hour time use. Findings provide some support for considering SB accumulation as an adjunct target of messaging to "sit less and move more."


Assuntos
Doenças Cardiovasculares , Neoplasias , Acelerometria , Adulto , Doenças Cardiovasculares/epidemiologia , Humanos , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Estudos Prospectivos , Comportamento Sedentário
16.
Eur J Prev Cardiol ; 29(12): 1618-1629, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-35403197

RESUMO

AIMS: This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. METHODS AND RESULTS: EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal).Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32-64%] and 21% (95%CI 2-44%), with hypercholesterolaemia were 80% (95%CI 55-108%) and 48% (95%CI 22-81%), with hypertension were 80% (95%CI 65-96%) and 49% (95%CI 28-74%), with diabetes were 142% (95%CI 63-260%), and 100% (95%CI 32-204%), and amongst smokers were 152% (95%CI 122-186%) and 109% (95%CI 74-150%). CONCLUSIONS: In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.


Assuntos
Doença das Coronárias , Hipercolesterolemia , Hipertensão , Adulto , Estudos de Coortes , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Exercício Físico , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/epidemiologia , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Incidência , Obesidade/diagnóstico , Obesidade/epidemiologia , Estudos Prospectivos , Fatores de Risco
17.
Pharmacol Res ; 180: 106237, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35487405

RESUMO

The significant growth in type 2 diabetes mellitus (T2DM) prevalence strikes a common threat to the healthcare and economic systems globally. Despite the availability of several anti-hyperglycaemic agents in the market, none can offer T2DM remission. These agents include the prominent incretin-based therapy such as glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors that are designed primarily to promote GLP-1R activation. Recent interest in various therapeutically useful gastrointestinal hormones in T2DM and obesity has surged with the realisation that enteroendocrine L-cells modulate the different incretins secretion and glucose homeostasis, reflecting the original incretin definition. Targeting L-cells offers promising opportunities to mimic the benefits of bariatric surgery on glucose homeostasis, bodyweight management, and T2DM remission. Revising the fundamental incretin theory is an essential step for therapeutic development in this area. Therefore, the present review explores enteroendocrine L-cell hormone expression, the associated nutrient-sensing mechanisms, and other physiological characteristics. Subsequently, enteroendocrine L-cell line models and the latest L-cell targeted therapies are reviewed critically in this paper. Bariatric surgery, pharmacotherapy and new paradigm of L-cell targeted pharmaceutical formulation are discussed here, offering both clinician and scientist communities a new common interest to push the scientific boundary in T2DM therapy.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Células L , Camundongos
18.
J Clin Endocrinol Metab ; 107(7): e2952-e2961, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35306566

RESUMO

BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. MAIN OUTCOME MEASURES: CHD, CHD risk factors, and ANM. RESULTS: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.


Assuntos
Doença das Coronárias , Estudo de Associação Genômica Ampla , Envelhecimento/genética , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único
19.
Nat Med ; 28(4): 814-822, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35314841

RESUMO

The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.


Assuntos
Corticosteroides , Asma , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Asma/tratamento farmacológico , Humanos
20.
Clin Epigenetics ; 14(1): 39, 2022 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-35279219

RESUMO

BACKGROUND: This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature. METHODS/RESULTS: We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, 6 months after bariatric surgery, revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. NETosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. CONCLUSIONS: We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features.


Assuntos
Lipodistrofia , Síndrome Metabólica , Obesidade Mórbida , Metilação de DNA , Epigênese Genética , Humanos , Síndrome Metabólica/genética , Obesidade Mórbida/cirurgia , Fenótipo
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