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Background Although recent studies have indicated that gut microbiome dysbiosis was significantly associated with the onset of type 2 diabetes mellitus (T2DM), information on the role of blood microbiome in T2DM development is scarce. Methods Fifty incident T2DM cases and 100 matched non‐T2DM controls were selected from a prospective cohort study of “135.” The composition of the blood microbiome was characterized using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing from pre‐diagnostic blood sample. The amplicons were normalized, pooled, and sequenced on the Illumina MiSeq instrument using a MiSeq Reagent Kit PE300 v3 kit. Results Totally, 3 000 391 and 6 244 227 high‐quality sequences were obtained from T2DM patients and non‐T2DM controls, respectively. The mean diversity of the blood microbiome (Simpson, Chao1 and Shannon indices) was not different between two groups at baseline. At genus level, the Aquabacterium, Xanthomonas, and Pseudonocardia were presented with lower abundance, while Actinotalea, Alishewanella, Sediminibacterium, and Pseudoclavibacter were presented with higher abundance among T2DM cases compared to those in non‐T2DM controls. As the results shown, participants carried the genus Bacteroides in blood were significantly associated with a decreased risk for T2DM development, with 74% vs 88% (adjusted OR: 0.367, 95% CI: 0.151‐0.894). However, participants carried the genus Sediminibacterium have an increased risk for T2DM, with adjusted OR (95% CI) being 14.098 (1.358, 146.330). Conclusions Blood microbiome may play an etiology role in the development of T2DM. These findings would be useful to develop microbiota‐based strategies for T2DM prevention and control.

Background Each year, an estimated 15 million babies are born preterm. Micronutrient deficiencies, including vitamin D deficiency (VDD), are common in many low- and middle-income countries (LMICs), and these conditions are often associated with adverse pregnancy outcomes. Bangladesh experiences a high prevalence of VDD. The country also has a high preterm birth (PTB) rate. Using data from a population-based pregnancy cohort, we estimated the burden of VDD during pregnancy and its association with PTB. Methods Pregnant women ( N  = 3,000) were enrolled after ultrasound confirmation of gestational age at 8–19 weeks of gestation. Trained health workers prospectively collected phenotypic and epidemiological data at scheduled home visits. Trained phlebotomists collected maternal blood samples at enrollment and 24 -28 weeks of gestation. Aliquots of serum were stored at -80 0 C. We conducted a nested case–control study with all PTB ( n  = 262) and a random sample of term births ( n  = 668). The outcome, PTB, was defined as live births < 37 weeks of gestation, based on ultrasound. The main exposure was vitamin D concentrations of 24–28 weeks maternal blood samples. The analysis was adjusted for other PTB risk factors. Women were categorized as VDD (lowest quartile of 25(OH)D; <  = 30.25 nmol/L) or not deficient (upper-three quartiles of 25(OH)D; > 30.25 nmol/L). We used logistic regression to determine the association of VDD with PTB, adjusting for potential confounders. Results The median and interquartile range of serum 25(OH)D was 38.0 nmol/L; 30.18 to 48.52 (nmol/L). After adjusting for co-variates, VDD was significantly associated with PTB [adjusted odds ratio (aOR) = 1.53, 95% confidence interval (CI) = 1.10 – 2.12]. The risk of PTB was also higher among women who were shorter (aOR = 1.81, 95% CI: 1.27–2.57), primiparous (aOR = 1.55, 95% CI = 1.12 – 2.12), passive smokers (aOR = 1.60, 95% CI = 1.09 – 2.34), and those who received iron supplementation during pregnancy (aOR = 1.66, 95% CI: 1.17, 2.37). Conclusion VDD is common in Bangladeshi pregnant women and is associated with an increased risk of PTB.

BackgroundStudies examining age-stratified risk factors for suicide among individuals with bipolar disorder in different stages of life are scant, possibly because of the insufficient number of suicide cases.AimThis study investigated suicide mortality rates and risk profiles of suicide mortality stratified by five age groups in individuals with bipolar disorder.MethodsThis study identified patients with a diagnosis of bipolar disorder between January 1, 2000, and December 31, 2021, from Taiwan’s National Health Insurance Research Database. The study population comprised 45,211 inpatients diagnosed with bipolar disorder, with 1,370 suicide cases during the study period. We calculated the standardized mortality ratio (SMR) of the bipolar cohort relative to the general population. In the age-stratified nested case–control study, risk set sampling was performed to match 1 suicide case with 10 living controls by age, sex, and the year of first diagnosis. The age-stratified risk associated with demographic characteristics, psychiatric and physical comorbidities was estimated using multivariable conditional logistic regression.ResultsThe highest SMR (47.0) for suicide was observed in individuals with bipolar disorder aged <30 years. SMR decreased with age; patients aged >60 years had an SMR of 9.5. Among those younger than 40 years, a higher percentage of unemployment was noted among suicide cases than among controls. A significantly increased risk of the depressive phase of bipolar disorder was noted shortly before suicide mortality among patients with bipolar disorder in all age groups. Drug-induced and alcohol-induced mental disorders were associated with suicide and were highly prevalent in patients aged <30 years. Other forms of heart disease were identified in patients aged <40 years, and pneumonia was detected in the 50–59 years age group.ConclusionsThese findings aid the development of health-care intervention strategies for preventing suicide among patients with bipolar disorder in various stages of life.

Aims/hypothesisWe aimed to examine the association between type 2 diabetes and major subtypes of heart disease, to assess the role of genetic and early-life familial environmental factors in this association and to explore whether and to what extent a healthy lifestyle mitigates the risk of heart disease related to type 2 diabetes.MethodsIn this prospective nested case–control study based on the Swedish Twin Registry, 41,463 twin individuals who were aged ≥40 and heart disease-free were followed up for 16 years (from 1998 to 2014) to detect incident heart disease. Type 2 diabetes was ascertained from self-report, the National Patient Registry and glucose-lowering medication use. Heart disease diagnosis (including coronary heart disease, cardiac arrhythmias and heart failure) and onset age were identified from the National Patient Registry. Healthy lifestyle-related factors consisted of being a non-smoker, no/mild alcohol consumption, regular physical activity and being non-overweight. Participants were divided into three groups according to the number of lifestyle-related factors: (1) unfavourable (participants who had no or only one healthy lifestyle factor); (2) intermediate (any two or three); and (3) favourable (four). Generalised estimating equation models for unmatched case–control design and conditional logistic regression for co-twin control design were used in data analyses.ResultsOf all participants, 2304 (5.5%) had type 2 diabetes at baseline. During the observation period, 9262 (22.3%) had any incident heart disease. In unmatched case–control analyses and co-twin control analyses, the multi-adjusted OR and 95% CI of heart disease related to type 2 diabetes was 4.36 (3.95, 4.81) and 4.89 (3.88, 6.16), respectively. The difference in ORs from unmatched case–control analyses vs co-twin control analyses was statistically significant (OR 1.57; 95% CI 1.42, 1.73; p < 0.001). In stratified analyses by type 2 diabetes, compared with an unfavourable lifestyle, an intermediate lifestyle or a favourable lifestyle was associated with a significant 32% (OR 0.68; 95% CI 0.49, 0.93) or 56% (OR 0.44; 95% CI 0.30, 0.63) decrease in heart disease risk among patients with type 2 diabetes, respectively. There were significant additive and multiplicative interactions between lifestyle and type 2 diabetes on heart disease.Conclusions/interpretationType 2 diabetes is associated with more than fourfold increased risk of heart disease. The association still remains statistically significant, even after fully controlling for genetic and early-life familial environmental factors. However, greater adherence to a healthy lifestyle may significantly mitigate the risk of heart disease related to type 2 diabetes.

To investigate whether retinal arterial narrowing is associated with incident carotid plaque in the general population. Individuals without carotid plaque in 2014 who developed new‐onset carotid plaque in 2018 were selected as cases (n = 156) for the atherosclerosis group and matched for age and sex in a ratio of 1:1 for the control group. The effects of the baseline central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), and arteriovenous ratio (AVR) on the risk of new‐onset carotid plaque were evaluated in multivariable conditional logistic regression models. Subgroup analyses were performed. The mean CRAE, CRVE, and AVR were 153.03 ± 12.77 µm, 232.41 ± 19.78 µm, and 0.66 ± 0.07, respectively. After adjusting for multiple variables, the risk of developing new‐onset carotid plaque increased by 4% (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02–1.07, p < 0.01) with each 1‐µm decrease in CRAE and 80% (OR 1.80, 95% CI 1.17–2.78, p < 0.01) with each 0.1‐point decline in AVR. When CRAE and AVR were considered as categorical variables, compared with subjects in the highest CRAE and AVR groups, those in the lowest CRAE and AVR groups had a 159% (OR 2.59, 95% CI 1.34–5.01, p < 0.01) and 93% (OR 1.93, 95% CI 1.08–3.46, p = 0.03) increase in risk of developing new‐onset carotid plaque, respectively. However, CRVE was not significantly related to new‐onset carotid plaque. Subgroup and interaction analyses were performed, and no significant modification effect was found. In conclusion, retinal arterial narrowing was strongly related to the risk of incident carotid plaque.

The nested case-control and case-cohort designs are two main approaches for carrying out a substudy within a prospective cohort. This article adapts multiple imputation (MI) methods for handling missing covariates in full-cohort studies for nested case-control and case-cohort studies. We consider data missing by design and data missing by chance. MI analyses that make use of full-cohort data and MI analyses based on substudy data only are described, alongside an intermediate approach in which the imputation uses full-cohort data but the analysis uses only the substudy. We describe adaptations to two imputation methods: the approximate method (MI-approx) of White and Royston (2009) and the \"substantive model compatible\" (MI-SMC) method of Bartlett et al. (2015). We also apply the \"MI matched set\" approach of Seaman and Keogh (2015) to nested case-control studies, which does not require any full-cohort information. The methods are investigated using simulation studies and all perform well when their assumptions hold. Substantial gains in efficiency can be made by imputing data missing by design using the full-cohort approach or by imputing data missing by chance in analyses using the substudy only. The intermediate approach brings greater gains in efficiency relative to the substudy approach and is more robust to imputation model misspecification than the full-cohort approach. The methods are illustrated using the ARIC Study cohort. Supplementary Materials provide R and Stata code.

Aims/hypothesisWe aimed to examine the association between midlife type 2 diabetes mellitus and cerebrovascular disease (CBD) in late life, and further to explore whether genetic and early-life familial environmental factors (such as shared childhood socioeconomic status and adolescent environment) play a role in this association.MethodsIn this prospective nested case−control study based on the Swedish Twin Registry, 33,086 twin individuals who were born in 1958 or earlier and were CBD-free before the age of 60 were included. Midlife (40–59 years) type 2 diabetes was ascertained from self-report, the National Patient Registry (NPR) and glucose-lowering medication use. CBD diagnosis (cerebral infarction, occlusion of cerebral arteries, subarachnoid haemorrhage, intracerebral haemorrhage and unspecified CBD) and onset age were identified from the NPR. Late-life CBD was defined as CBD onset age ≥60 years. Generalised estimating equation (GEE) models were used to analyse unmatched case−control data (adjusted for the clustering of twins within a pair). Conditional logistic regression was used in co-twin matched case−control analyses in CBD-discordant twin pairs.ResultsOf all the participants, 1248 (3.8%) had midlife type 2 diabetes and 3121 (9.4%) had CBD in late life. In GEE models adjusted for age, sex, education, BMI, smoking, alcohol consumption, marital status, hypertension and heart disease, the ORs (95% CIs) of type 2 diabetes were 1.29 (1.03, 1.61) for cerebral infarction, 2.03 (1.20, 3.44) for occlusion of cerebral arteries, 0.52 (0.12, 2.21) for subarachnoid haemorrhage and 0.78 (0.45, 1.36) for intracerebral haemorrhage. In multi-adjusted conditional logistic regression, the OR of the type 2 diabetes–cerebral infarction association was 0.96 (0.51, 1.80). The differences in ORs from the GEE and co-twin control analyses were not statistically significant (p = 0.780).Conclusions/interpretationMidlife type 2 diabetes is significantly associated with increased risk of cerebral infarction and occlusion of cerebral arteries, but not intracerebral haemorrhage or subarachnoid haemorrhage in late life. Genetic and early-life familial environmental factors do not appear to account for the type 2 diabetes–cerebral infarction association, but further clarification is needed.

This study aimed to investigate the association between the triglyceride-glucose (TyG) index and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes. In this nested case-control study, all diabetic participants were registered hospitalizations during 2012-2018, including 596 with DR as cases and three matching controls per case. DR was assessed using Early Treatment Diabetic Retinopathy Study criteria. The TyG index was calculated: Ln (fasting blood glucose [mg/dL] × fasting triglycerides [mg/dL] ÷ 2). Multivariate logistic regression, a receiver-operating characteristic (ROC) curve, linear regression models, and mediation analysis were used to explore associations. The TyG index was lower in DR and decreased as its severity advanced among 2,112 subjects ( =0.005). After confounders (sex, duration of diabetes, use of antidiabetic agents, heart rate, systolic blood pressure, pulse pressure, height, weight, body-mass index, and glycated hemoglobin) had been accounted for, there were significant associations between the TyG index and any-severity DR (OR 0.83, 95% CI 0.73-0.95; =0.006), as well as vision-threatening DR (VTDR; OR 0.53, 95% CI 0.36-0.76; =0.001). ROC analysis indicated that the TyG index showed significant discriminatory ability in any-severity DR (area under curve [AUC] 0.534, =0.015) and VTDR (AUC 0.624, =0.001). The TyG index was associated with the presence and severity of DR. Our findings suggest that the TyG index may become a useful biomarker in evaluating and following the presence of DR and VTDR.