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Integrating biomarkers into a comprehensive strategy is crucial for precise patient management, especially considering the significant healthcare costs associated with diseases. Current studies emphasize the urgent need for a paradigm shift in conceptualizing nonalcoholic fatty liver disease (NAFLD), now renamed metabolic dysfunction-associated steatotic liver disease (MASLD). Biomarkers are emerging as indispensable tools for accurate diagnosis, risk stratification, and monitoring disease progression. This review classifies biomarkers into conventional and novel categories, such as lipids, insulin resistance, hepatic function, and cutting-edge imaging/omics, and evaluates their potential to transform the approach to MASLD among individuals with type 2 diabetes mellitus (T2D). It focuses on the critical role of biomarkers in early MASLD detection, enhancing predictive accuracy, and discerning responses to interventions (pharmacological or lifestyle modifications). Amid this discussion, the complexities of the relationship between T2D and MASLD are explored, considering factors like age, gender, genetics, ethnicity, and socioeconomic background. Biomarkers enhance the effectiveness of interventions and support global initiatives to reduce the burden of MASLD, thereby improving public health outcomes. This review recognizes the promising potential of biomarkers for diagnostic precision while candidly addressing the challenges in implementing these advancements in clinical practice. The transformative role of biomarkers emerges as a central theme, promising to reshape our understanding of disease trajectories, prognosis, and the customization of personalized therapeutic strategies for improved patient outcomes. From a future perspective, identifying early-stage biomarkers, understanding environmental impact through exposomes, and applying a multiomics approach may reveal additional insight into MASLD development.
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Our study investigated the impact of genetic variations on metformin glycemic response in a cohort from the Rotterdam Study, comprising 14,926 individuals followed for up to 27 years. Among 1285 metformin users of European ancestry, using linear mixed models, we analyzed the association of single nucleotide polymorphisms (SNPs) and a Polygenic Risk Score (PRS) with glycemic response, measured by changes in metformin dosage or HbA1c levels. While individual genetic variants showed no significant association, rs622342 on SLC2A1 correlated with increased glycemic response only in metformin monotherapy patients (ß = -2.09, P-value < 0.001). The collective effect of variants, as represented by PRS, weakly correlated with changes in metformin dosage (ß = 0.023, P-value = 0.027). Synergistic interaction was observed between rs7124355 and rs8192675. Our findings suggest that while higher PRS correlates with increased metformin dosage, its modest effect size limits clinical utility, emphasizing the need for future research in diverse populations to refine genetic risk models.
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Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Metformina , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Relação Dose-Resposta a Droga , Hemoglobinas Glicadas/análise , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Metformina/farmacocinética , Metformina/uso terapêutico , Países Baixos , População Branca/genéticaRESUMO
Obesity and cardiometabolic disease often, but not always, coincide. Distinguishing subpopulations within which cardiometabolic risk diverges from the risk expected for a given body mass index (BMI) may facilitate precision prevention of cardiometabolic diseases. Accordingly, we performed unsupervised clustering in four European population-based cohorts (N ≈ 173,000). We detected five discordant profiles consisting of individuals with cardiometabolic biomarkers higher or lower than expected given their BMI, which generally increases disease risk, in total representing ~20% of the total population. Persons with discordant profiles differed from concordant individuals in prevalence and future risk of major adverse cardiovascular events (MACE) and type 2 diabetes. Subtle BMI-discordances in biomarkers affected disease risk. For instance, a 10% higher probability of having a discordant lipid profile was associated with a 5% higher risk of MACE (hazard ratio in women 1.05, 95% confidence interval 1.03, 1.06, P = 4.19 × 10-10; hazard ratio in men 1.05, 95% confidence interval 1.04, 1.06, P = 9.33 × 10-14). Multivariate prediction models for MACE and type 2 diabetes performed better when incorporating discordant profile information (likelihood ratio test P < 0.001). This enhancement represents an additional net benefit of 4-15 additional correct interventions and 37-135 additional unnecessary interventions correctly avoided for every 10,000 individuals tested.
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AIM: The guidelines recommend statins to prevent cardiovascular events in patients with type 2 diabetes (T2D) however, the importance of baseline LDL-Cholesterol (LDL-C) levels remains controversial. This study aimed to determine the association of statin use in T2D patients with major adverse cardiovascular events (MACE) and all-cause mortality and whether this association differs by baseline LDL-C levels. DATA SYNTHESIS: Medline, Embase, and Web of Science were systematically searched from inception until January 2022. Observational studies in patients with T2D comparing statin users vs non-users, with reports of the baseline LDL-C levels, were included. Random-effects meta-analysis and meta-regression were performed to estimate the overall effect on the risk of all-cause mortality and MACE (a composite of myocardial infarction, heart failure, stroke, and revascularization events) and the modification in the association by baseline LDL-C levels. We categorized studies according to their baseline LDL-C levels into 1) <100 mg/dl (2.59 mmol/l), 2) 100-130 mg/dl (2.59-3.37 mmol/l) and 3) >130 mg/dl (3.37 mmol/l) categories. A total of 9 cohort studies (n = 403,411 individuals) fulfilled our criteria. The follow-up duration ranged from 1.7 to 8 years. The overall combined estimate showed that statin therapy was associated with a significantly lower risk of MACE (Hazard Ratio (HR): 0.70 [95% CI 0.59 to 0.83], Absolute risk reduction percentage (ARR%): 3.19% [95%CI 0.88 to 5.50%) and all-cause mortality (HR: 0.60 [95% CI 0.46 to 0.79], ARR%: 5.23% [95% CI 2.18 to 8.28%), but varied, albeit not statistically significant, by baseline LDL-C levels. Studies with baseline LDL-C levels higher than 130 mg/dl had the greatest reduction of MACE (HR: 0.58 [95% CI 0.37 to 0.90]) and all-cause mortality risk (HR: 0.51 [95% CI [ 0.29 to 0.90]). The HRs of MACE in studies with LDL-C levels of 100-130 mg/dl and <100 mg/dl categories were respectively (0.70 [95% CI 0.59 to 0.83]) and (0.83 [95% CI [0.68 to 1.00]); and that of all-cause mortality were respectively (0.62 [95% CI 0.38 to 1.01]) and (0.67 [95% CI [0.44 to 1.02]). Statin use changes the HRs of MACE (0.99 [95%CI, 0.98 to 0.99]; P = 0.04) and all-cause mortality (0.99 [95% CI 0.98 to 1.01]; P = 0.8) per each mg/dl increase in baseline LDL-C level in meta-regression analyses. CONCLUSION: Statin therapy in patients with T2D was associated with reduced risk of MACE and all-cause mortality. Significant differences across studies with different baseline LDL-C levels were not observed.
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Biomarcadores , Doenças Cardiovasculares , LDL-Colesterol , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Estudos Observacionais como Assunto , Humanos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , LDL-Colesterol/sangue , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Medição de Risco , Biomarcadores/sangue , Feminino , Masculino , Resultado do Tratamento , Pessoa de Meia-Idade , Idoso , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/mortalidade , Dislipidemias/diagnóstico , Fatores de Proteção , Fatores de TempoRESUMO
Exercise can have a wide range of health benefits, including improving blood lipid profiles. For women to achieve optimal cardiovascular health, it is vital to determine the effect of exercise on their health and whether different exercise intensities can affect their blood lipid profile. A systematic review and meta-analysis were conducted to examine the effects of exercise on improving the lipid profile of healthy women. A database search was conducted using PubMed, Google Scholar, Embase, Scopus, and Web of Science from inception until July 2, 2021, for randomized controlled trials (RCTs) investigating exercise's effects on healthy women's blood lipid profiles. A total of 10 eligible articles (or 17 trials) with 576 participants were identified as eligible for the study. Overall, the meta-analysis shows that physical activity significantly improved total cholesterol (TC), triglycerides (TG), and high-density lipoprotein (HDL-C) levels: TC [WMD = -5.77 mg/dL, 95% CI: -10.41, -1.13, P < 0.01]; TG [WMD = -5.60 mg/dL, 95% CI: -8.96, -2.23, P < 0.01]; HDL [WMD = 4.49 mg/dL, 95% CI: 0.33, 8.65, P = 0.03]. Additionally, sub-group analyses indicated that combined exercise training improved TG and TC (p 0.05), and aerobic exercise significantly increased HDL. In this study, physical activity appears to be one of the most effective non-pharmacological means for improving HDL, TG, and TC in healthy women. In terms of TG and TC, CT was the most effective.
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AIMS: Common genetic variations in the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT-interval shortening in digoxin users. As QT-interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. METHODS: We included 11 377 individuals from the prospective population-based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time-dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose-dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non-users. RESULTS: The median baseline age of the total study population was 62 (interquartile range [IQR] 58-71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow-up of 11.5 (IQR 6.5-17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38-3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98-8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37-5.04] in the heterozygous TG and 2.56 [95%CI: 1.70-3.86] in the homozygous TT genotype groups. Compared to low- and moderate-dose, high-dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34-23.47]). CONCLUSIONS: Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin-associated risk of SCD in a population of European ancestry.
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Proteínas Adaptadoras de Transdução de Sinal , Morte Súbita Cardíaca , Digoxina , Genótipo , Humanos , Digoxina/efeitos adversos , Digoxina/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/epidemiologia , Idoso , Estudos Prospectivos , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Risco , Relação Dose-Resposta a Droga , Polimorfismo de Nucleotídeo Único , Países Baixos/epidemiologia , Cardiotônicos/efeitos adversos , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Síndrome do QT Longo/genética , Síndrome do QT Longo/induzido quimicamenteRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections (LRTIs) in infants. Maternal RSV vaccination is a preventive strategy of great interest, as it could have a substantial impact on infant RSV disease burden. In recent years, the clinical development of maternal RSV vaccines has advanced rapidly. OBJECTIVES: To assess the efficacy and safety of maternal respiratory syncytial virus (RSV) vaccination for preventing RSV disease in infants. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register and two other trials registries on 21 October 2022. We updated the search on 27 July 2023, when we searched MEDLINE, Embase, CENTRAL, CINAHL, and two trials registries. Additionally, we searched the reference lists of retrieved studies and conference proceedings. There were no language restrictions on our searches. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing maternal RSV vaccination with placebo or no intervention in pregnant women of any age. The primary outcomes were hospitalisation with clinically confirmed or laboratory-confirmed RSV disease in infants. The secondary outcomes covered adverse pregnancy outcomes (intrauterine growth restriction, stillbirth, and maternal death) and adverse infant outcomes (preterm birth, congenital abnormalities, and infant death). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods and assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (25 study reports) involving 17,991 pregnant women. The intervention was an RSV pre-F protein vaccine in four studies, and an RSV F protein nanoparticle vaccine in two studies. In all studies, the comparator was a placebo (saline, formulation buffer, or sterile water). We judged four studies at overall low risk of bias and two studies at overall high risk (mainly due to selection bias). All studies were funded by pharmaceutical companies. Maternal RSV vaccination compared with placebo reduces infant hospitalisation with laboratory-confirmed RSV disease (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.31 to 0.82; 4 RCTs, 12,216 infants; high-certainty evidence). Based on an absolute risk with placebo of 22 hospitalisations per 1000 infants, our results represent 11 fewer hospitalisations per 1000 infants from vaccinated pregnant women (15 fewer to 4 fewer). No studies reported infant hospitalisation with clinically confirmed RSV disease. Maternal RSV vaccination compared with placebo has little or no effect on the risk of congenital abnormalities (RR 0.96, 95% CI 0.88 to 1.04; 140 per 1000 with placebo, 5 fewer per 1000 with RSV vaccination (17 fewer to 6 more); 4 RCTs, 12,304 infants; high-certainty evidence). Maternal RSV vaccination likely has little or no effect on the risk of intrauterine growth restriction (RR 1.32, 95% CI 0.75 to 2.33; 3 per 1000 with placebo, 1 more per 1000 with RSV vaccination (1 fewer to 4 more); 4 RCTs, 12,545 pregnant women; moderate-certainty evidence). Maternal RSV vaccination may have little or no effect on the risk of stillbirth (RR 0.81, 95% CI 0.38 to 1.72; 3 per 1000 with placebo, no difference with RSV vaccination (2 fewer to 3 more); 5 RCTs, 12,652 pregnant women). There may be a safety signal warranting further investigation related to preterm birth. This outcome may be more likely with maternal RSV vaccination, although the 95% CI includes no effect, and the evidence is very uncertain (RR 1.16, 95% CI 0.99 to 1.36; 6 RCTs, 17,560 infants; very low-certainty evidence). Based on an absolute risk of 51 preterm births per 1000 infants from pregnant women who received placebo, there may be 8 more per 1000 infants from pregnant women with RSV vaccination (1 fewer to 18 more). There was one maternal death in the RSV vaccination group and none in the placebo group. Our meta-analysis suggests that RSV vaccination compared with placebo may have little or no effect on the risk of maternal death (RR 3.00, 95% CI 0.12 to 73.50; 3 RCTs, 7977 pregnant women; low-certainty evidence). The effect of maternal RSV vaccination on the risk of infant death is very uncertain (RR 0.81, 95% CI 0.36 to 1.81; 6 RCTs, 17,589 infants; very low-certainty evidence). AUTHORS' CONCLUSIONS: The findings of this review suggest that maternal RSV vaccination reduces laboratory-confirmed RSV hospitalisations in infants. There are no safety concerns about intrauterine growth restriction and congenital abnormalities. We must be careful in drawing conclusions about other safety outcomes owing to the low and very low certainty of the evidence. The evidence available to date suggests RSV vaccination may have little or no effect on stillbirth, maternal death, and infant death (although the evidence for infant death is very uncertain). However, there may be a safety signal warranting further investigation related to preterm birth. This is driven by data from one trial, which is not fully published yet. The evidence base would be much improved by more RCTs with substantial sample sizes and well-designed observational studies with long-term follow-up for assessment of safety outcomes. Future studies should aim to use standard outcome measures, collect data on concomitant vaccines, and stratify data by timing of vaccination, gestational age at birth, race, and geographical setting.
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Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Natimorto , Humanos , Gravidez , Feminino , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Lactente , Recém-Nascido , Natimorto/epidemiologia , Nascimento Prematuro/prevenção & controle , Nascimento Prematuro/epidemiologia , Complicações Infecciosas na Gravidez/prevenção & controle , Hospitalização/estatística & dados numéricos , Retardo do Crescimento Fetal/prevenção & controle , Resultado da Gravidez , Vacinação , Anormalidades Congênitas/prevenção & controle , Viés , Morte do Lactente/prevenção & controleRESUMO
OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Factors contributing to the development of hypertension exhibit significant variations across countries and regions. Our objective was to predict individuals at risk of developing hypertension within a 5-year period in a rural Middle Eastern area. METHODS: This longitudinal study utilized data from the Fasa Adults Cohort Study (FACS). The study initially included 10,118 participants aged 35-70 years in rural districts of Fasa, Iran, with a follow-up of 3,000 participants after 5 years using random sampling. A total of 160 variables were included in the machine learning (ML) models, and feature scaling and one-hot encoding were employed for data processing. Ten supervised ML algorithms were utilized, namely logistic regression (LR), support vector machine (SVM), random forest (RF), Gaussian naive Bayes (GNB), linear discriminant analysis (LDA), k-nearest neighbors (KNN), gradient boosting machine (GBM), extreme gradient boosting (XGB), cat boost (CAT), and light gradient boosting machine (LGBM). Hyperparameter tuning was performed using various combinations of hyperparameters to identify the optimal model. Synthetic Minority Over-sampling Technology (SMOTE) was used to balance the training data, and feature selection was conducted using SHapley Additive exPlanations (SHAP). RESULTS: Out of 2,288 participants who met the criteria, 251 individuals (10.9%) were diagnosed with new hypertension. The LGBM model (determined to be the optimal model) with the top 30 features achieved an AUC of 0.67, an f1-score of 0.23, and an AUC-PR of 0.26. The top three predictors of hypertension were baseline systolic blood pressure (SBP), gender, and waist-to-hip ratio (WHR), with AUCs of 0.66, 0.58, and 0.63, respectively. Hematuria in urine tests and family history of hypertension ranked fourth and fifth. CONCLUSION: ML models have the potential to be valuable decision-making tools in evaluating the need for early lifestyle modification or medical intervention in individuals at risk of developing hypertension.
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Hipertensão , Adulto , Humanos , Pressão Sanguínea , Teorema de Bayes , Estudos de Coortes , Seguimentos , Estudos Longitudinais , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Aprendizado de MáquinaRESUMO
Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.
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INTRODUCTION: The application of machine learning (ML) is increasingly growing in biomedical sciences. This study aimed to evaluate factors associated with type 2 diabetes mellitus (T2DM) and compare the performance of ML methods in identifying individuals with the disease in an Iranian setting. METHODS: Using the baseline data from Fasa Adult Cohort Study (FACS) and in a sex-stratified manner, we studied factors associated with T2DM by applying seven different ML methods including Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), K-Nearest Neighbours (KNN), Gradient Boosting Machine (GBM), Extreme Gradient Boosting (XGB) and Bagging classifier (BAG). We further compared the performance of these methods; for each algorithm, accuracy, precision, sensitivity, specificity, F1 score, and Area Under Curve (AUC) were calculated. RESULTS: 10,112 participants were recruited between 2014 and 2016, of whom 1246 had T2DM at baseline. 4566 (45%) participants were males, aged between 35 and 70 years. For males, age, sugar consumption, and history of hospitalization were the most weighted variables regarding their importance in screening for T2DM using the GBM model, respectively; these variables were sugar consumption, urine blood, and age for females. GBM outperformed other models for both males and females with AUC of 0.75 (0.69-0.82) and 0.76 (0.71-0.80), and F1 score of 0.33 (0.27-0.39) and 0.42 (0.38-0.46), respectively. GBM also showed a sensitivity of 0.24 (0.19-0.29) and a specificity of 0.98 (0.96-1.0) in males and a sensitivity of 0.38 (0.34-0.42) and specificity of 0.92 (0.89-0.95) in females. Notably, close performance characteristics were detected among other ML models. CONCLUSIONS: GBM model might achieve better performance in screening for T2DM in a south Iranian population.
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Diabetes Mellitus Tipo 2 , Adulto , Feminino , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Estudos de Coortes , Irã (Geográfico)/epidemiologia , Algoritmos , Aprendizado de Máquina , Açúcares da DietaRESUMO
PURPOSE OF REVIEW: This review aimed to determine the association between statin use and coronary artery calcification (CAC), as detected by computed tomography in the general population, in previously published observational studies (OSs) and randomized controlled trials (RCTs). RECENT FINDINGS: A systematic search until February 2022 identified 41 relevant studies, comprising 29 OSs and 12 RCTs. We employed six meta-analysis models, stratifying studies based on design and effect metrics. For cohort studies, the pooled ß of the association with CAC quantified by the Agatston score was 0.11 (95% CI = 0.05; 0.16), with an average follow-up time per person (AFTP) of 3.68 years. Cross-sectional studies indicated a pooled odds ratio of 2.11 (95% CI = 1.61; 2.78) for the presence of CAC. In RCTs, the pooled standardized mean differences (SMDs) for CAC, quantified by Agatston score or volume, over and AFTP of 1.25 years were not statistically significant (SMD = - 0.06, 95% CI = - 0.19; 0.06 and SMD = 0.26, 95% CI = - 0.66; 1.19), but significantly different (p-value = 0.04). Meta-regression and subgroup analyses did not show any significant differences in pooled estimates across covariates. The effect of statins on CAC differs across study designs. OSs demonstrate associations between statin use and higher CAC scores and presence while being prone to confounding by indication. Effects from RCTs do not reach statistical significance and vary depending on the quantification method, hampering drawing conclusions. Further investigations are required to address the limitations inherent in each approach.
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Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Calcificação Vascular , Humanos , Doença da Artéria Coronariana/complicações , Vasos Coronários/diagnóstico por imagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de Risco , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/tratamento farmacológico , Estudos Observacionais como AssuntoRESUMO
INTRODUCTION: Maternal vaccination is a promising strategy to reduce the burden of vaccine-preventable diseases for mothers and infants. We aimed to provide an up-to-date overview of the efficacy and safety of all available maternal vaccines. METHODS: We searched PubMed, Embase, CENTRAL and ClinicalTrials.gov on 1 February 2022, for phase III and IV randomised controlled trials (RCTs) that compared maternal vaccination against any pathogen with placebo or no vaccination. Primary outcomes were laboratory-confirmed or clinically confirmed disease in mothers and infants. Secondary safety outcomes included intrauterine growth restriction, stillbirth, maternal death, preterm birth, congenital malformations and infant death. Random effects meta-analysis were used to calculate pooled risk ratio's (RR). Quality appraisal was performed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). RESULTS: Six RCTs on four maternal vaccines, influenza, tetanus, diphtheria and pertussis (Tdap), pneumococcal and respiratory syncytial virus (RSV) were eligible. The overall risk of bias and certainty of evidence varied from low to high. Maternal influenza vaccination significantly reduced the number of laboratory-confirmed influenza cases (RR 0.58, 95% CI 0.42 to 0.79, event rate 57 vs 98, 2 RCTs, n=6003, I2=0%), and clinically confirmed influenza cases in mothers (RR 0.88, 95% CI 0.78 to 0.99, event rate 418 vs 472, 2 RCTs, n=6003, I2=0%), and laboratory-confirmed influenza in infants (RR 0.66, 95% CI 0.52 to 0.85, event rate 98 vs 148, 2 RCTs, n=5883, I2=0%), although this was not significant for clinically confirmed influenza in infants (RR 0.99, 95% CI 0.94 to 1.05, event rate 1371 vs 1378, 2 RCTs, n=5883, I2=0%). No efficacy data were available on maternal Tdap vaccination. Maternal pneumococcal vaccination did not reduce laboratory-confirmed and clinically confirmed middle ear disease (RR 0.49, 95% CI 0.24 to 1.02, event rate 9 vs 18, 1 RCT, n=133 and RR 0.88 95% CI 0.69 to 1.12, event rate 42 vs 47, 1 RCT, n=133, respectively), and clinically confirmed lower-respiratory tract infection (LRTI) (RR 1.08, 95% CI 0.82 to 1.43, event rate 18 vs 34, 1 RCT, n=70) in infants. Maternal RSV vaccination did not reduce laboratory-confirmed RSV LRTI in infants (RR 0.75, 95% CI 0.56 to 1.01, event rate 103 vs 71, 1 RCT, n=4527). There was no evidence of a significant effect of any of the maternal vaccines on the reported safety outcomes. CONCLUSIONS: The few RCTs with low event rates suggest that, depending on the type of maternal vaccine, the vaccine might effectively prevent disease and within its size does not show safety concerns in mothers and infants. PROSPERO REGISTRATION NUMBER: CRD42021235115.
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Vacinas contra Influenza , Influenza Humana , Infecções Respiratórias , Recém-Nascido , Feminino , Humanos , Lactente , Influenza Humana/prevenção & controle , Vacinas contra Influenza/uso terapêutico , Mães , Vacinação , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: Obesity represents a major and preventable global health challenge as a complex disease and a modifiable risk factor for developing other non-communicable diseases. In recent years, obesity prevalence has risen more rapidly in low- and middle-income countries (LMICs) compared to high-income countries (HICs). Obesity traits are shown to be modulated by an interplay of genetic and environmental factors such as unhealthy diet and physical inactivity in studies from HICs focused on populations of European descent; however, genetic heterogeneity and environmental differences prevent the generalisation of study results to LMICs. Primary research investigating gene-environment interactions (GxE) on obesity in LMICs is limited but expanding. Synthesis of current research would provide an overview of the interactions between genetic variants and environmental factors that underlie the obesity epidemic and identify knowledge gaps for future studies. Methods: Three databases were searched systematically using a combination of keywords such as "genes", "obesity", "LMIC", "diet", and "physical activity" to find all relevant observational studies published before November 2022. Results: Eighteen of the 1,373 articles met the inclusion criteria, of which one was a genome-wide association study (GWAS), thirteen used a candidate gene approach, and five were assigned as genetic risk score studies. Statistically significant findings were reported for 12 individual SNPs; however, most studies were small-scale and without replication. Conclusion: Although the results suggest significant GxE interactions on obesity in LMICs, updated robust statistical techniques with more precise and standardised exposure and outcome measurements are necessary for translatable results. Future research should focus on improved quality replication efforts, emphasising large-scale and long-term longitudinal study designs using multi-ethnic GWAS.
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Países em Desenvolvimento , Interação Gene-Ambiente , Humanos , Estudo de Associação Genômica Ampla , Estudos Longitudinais , Obesidade/epidemiologia , Obesidade/genéticaRESUMO
Background: Although common drugs for treating type 2 diabetes (T2D) are widely used, their therapeutic effects vary greatly. The interaction between the gut microbiome and glucose-lowering drugs is one of the main contributors to the variability in T2D progression and response to therapy. On the one hand, glucose-lowering drugs can alter gut microbiome components. On the other hand, specific gut microbiota can influence glycemic control as the therapeutic effects of these drugs. Therefore, this systematic review assesses the bi-directional relationships between common glucose-lowering drugs and gut microbiome profiles. Methods: A systematic search of Embase, Web of Science, PubMed, and Google Scholar databases was performed. Observational studies and randomised controlled trials (RCTs), published from inception to July 2023, comprising T2D patients and investigating bi-directional interactions between glucose-lowering drugs and gut microbiome, were included. Results: Summarised findings indicated that glucose-lowering drugs could increase metabolic-healthy promoting taxa (e.g., Bifidobacterium) and decrease harmful taxa (e.g., Bacteroides and Intestinibacter). Our findings also showed a significantly different abundance of gut microbiome taxa (e.g., Enterococcus faecium (i.e., E. faecium)) in T2D patients with poor compared to optimal glycemic control. Conclusions: This review provides evidence for glucose-lowering drug and gut microbiome interactions, highlighting the potential of gut microbiome modulators as co-adjuvants for T2D treatment.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Bacteroides , Bifidobacterium , Diabetes Mellitus Tipo 2/tratamento farmacológico , GlucoseRESUMO
BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (P<5.0×10-8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10-9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10-9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10-8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction (P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (P=1.0×10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.
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The spectrum of information related to precision medicine in diabetes generally includes clinical data, genetics, and omics-based biomarkers that can guide personalized decisions on diabetes care. Given the remarkable progress in patient risk characterization, there is particular interest in using molecular biomarkers to guide diabetes management. Metabolomics is an emerging molecular approach that helps better understand the etiology and promises the identification of novel biomarkers for complex diseases. Both targeted or untargeted metabolites extracted from cells, biofluids, or tissues can be investigated by established high-throughput platforms, like nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. Metabolomics is proposed as a valuable tool in precision diabetes medicine to discover biomarkers for diagnosis, prognosis, and management of the progress of diabetes through personalized phenotyping and individualized drug-response monitoring. This review offers an overview of metabolomics knowledge as potential biomarkers in type 2 diabetes mellitus (T2D) diagnosis and the response to glucose-lowering medications.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucose , Metabolômica/métodos , Biomarcadores/metabolismo , Espectrometria de Massas/métodosRESUMO
PURPOSE: Whether beverage quality affects changes in glycaemic traits and type 2 diabetes (T2D) risk is unknown. We examined associations of a previously developed Healthy Beverage Index (HBI) with insulin resistance, and risk of prediabetes and T2D. METHODS: We included 6769 participants (59% female, 62.0 ± 7.8 years) from the Rotterdam Study cohort free of diabetes at baseline. Diet was assessed using food-frequency questionnaires at baseline. The HBI included 10 components (energy from beverages, meeting fluid requirements, water, coffee and tea, low-fat milk, diet drinks, juices, alcohol, full-fat milk, and sugar-sweetened beverages), with a total score ranging from 0 to 100. A higher score represents a healthier beverage pattern. Data on study outcomes were available from 1993 to 2015. Multivariable linear mixed models and Cox proportional-hazards regression models were used to examine associations of the HBI (per 10 points increment) with two measurements of HOMA-IR (a proxy for insulin resistance), and risk of prediabetes and T2D. RESULTS: During follow-up, we documented 1139 prediabetes and 784 T2D cases. Mean ± SD of the HBI was 66.8 ± 14.4. Higher HBI score was not associated with HOMA-IR (ß: 0.003; 95% CI - 0.007, 0.014), or with risk of prediabetes (HR: 1.01; 95% CI 0.97, 1.06), or T2D (HR: 1.01; 95% CI 0.96, 1.07). CONCLUSION: Our findings suggest no major role for overall beverage intake quality assessed with the HBI in insulin resistance, prediabetes and T2D incidence. The HBI may not be an adequate tool to assess beverage intake quality in our population.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Estado Pré-Diabético , Humanos , Feminino , Masculino , Estado Pré-Diabético/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Bebidas , Dieta , Fatores de RiscoRESUMO
BACKGROUND: Post-marketing vaccine safety surveillance aims to monitor and quantify adverse events following immunization in a population, but little is known about their implementation in low- and middle-income countries (LMICs). We aimed to synthesize methodological approaches used to assess adverse events following COVID-19 vaccination in LMICs. METHODS: For this systematic review, we searched articles published from 1 December 2019 to 18 February 2022 in main databases, including MEDLINE and Embase. We included all peer-reviewed observational COVID-19 vaccine safety monitoring studies. We excluded randomized controlled trials and case reports. We extracted data using a standardized extraction form. Two authors assessed study quality using the modified Newcastle-Ottawa Quality Assessment Scale. All findings were summarized narratively using frequency tables and figures. RESULTS: Our search found 4254 studies, of which 58 were eligible for analysis. Many of the studies included in this review were conducted in middle-income countries, with 26 studies (45%) in lower-middle-income and 28 (48%) in upper-middle-income countries. More specifically, 14 studies were conducted in the Middle East region, 16 in South Asia, 8 in Latin America, 8 in Europe and Central Asia, and 4 in Africa. Only 3% scored 7-8 points (good quality) on the Newcastle-Ottawa Scale methodological quality assessment, while 10% got 5-6 points (medium). About 15 studies (25.9%) used a cohort study design and the rest were cross-sectional. In half of them (50%), vaccination data were gathered from the participants' self-reporting methods. Seventeen studies (29.3%) used multivariable binary logistic regression and three (5.2%) used survival analyses. Only 12 studies (20.7%) performed model diagnostics and validity checks (e.g., the goodness of fit, identification of outliers, and co-linearity). CONCLUSIONS: Published studies on COVID-19 vaccine safety surveillance in LMICs are limited in number and the methods used do not often address potential confounders. Active surveillance of vaccines in LMICs are needed to advocate vaccination programs. Implementing training programs in pharmacoepidemiology in LMICs is essential.
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BACKGROUND AND OBJECTIVES: The European Medicine Agency extended the use of Comirnaty, Spikevax, and Nuvaxovid in paediatrics; thus, these vaccines require additional real-world safety evidence. Herein, we aimed to monitor the safety of COVID-19 vaccines through Covid-19 Vaccine Monitor (CVM) and EudraVigilance surveillance systems and the published pivotal clinical trials. METHODS: In a prospective cohort of vaccinees aged between 5 and 17 years, we measured the frequency of commonly reported (local/systemic solicited) and serious adverse drug events (ADRs) following the first and second doses of COVID-19 vaccines in Europe using data from the CVM cohort until April 2022. The results of previous pivotal clinical trials and data in the EudraVigilance were also analysed. RESULTS: The CVM study enrolled 658 first-dose vaccinees (children aged 5-11 years; n = 250 and adolescents aged 12-17 years; n = 408). Local/systemic solicited ADRs were common, whereas serious ADRs were uncommon. Among Comirnaty first and second dose recipients, 28.8% and 17.1% of children and 54.2% and 52.2% of adolescents experienced at least one ADR, respectively; injection-site pain (29.2% and 20.7%), fatigue (16.1% and 12.8%), and headache (22.1% and 19.3%) were the most frequent local and systemic ADRs. Results were consistent but slightly lower than in pivotal clinical trials. Reporting rates in Eudravigilance were lower by a factor of 1000. CONCLUSIONS: The CVM study showed high frequencies of local solicited reactions after vaccination but lower rates than in pivotal clinical trials. Injection-site pain, fatigue, and headache were the most commonly reported ADRs for clinical trials, but higher than spontaneously reported data.