Efficient and Economic Utilization of Cellobiose for Glycosylation Modification by Regulating Carbon Source Supply and Metabolic Pathway In Vivo.

Glycosylation, one of the most common and significant modifications in nature, has prompted the development of a cellobiose phosphorolysis route for glycosylation in vivo. However, the process of glycosylation is hampered by the notably low conversion rate of cellobiose. In this work, regulation of the carbon source supply by changing the ratio of glucose to cellobiose improved the conversion rate of cellobiose, resulting in enhancing the efficiency of glycosylation and the production of vitexin. Moreover, three genes (pgm, agp, and ushA) involved in the degradation of UDP-glucose were knocked out to relieve the degradation and diversion of the cellobiose phosphorolysis route. Finally, through the optimization of conversion conditions, we observed a continuous enhancement in cellobiose conversion rate and vitexin production in BL21ΔushAΔagp-TcCGT-CepA, corresponding to an increased concentration of added glucose. The maximum production of vitexin reached 2228 mg/L with the addition of 2 g/L cellobiose and 6 g/L glucose, which was 312% of that in BL21-TcCGT-CepA with the addition of 2 g/L cellobiose. The conversion rate of cellobiose in BL21ΔushAΔagp-TcCGT-CepA reached 88%, which was the highest conversion rate of cellobiose to date. Therefore, this study presents a cost-effective and efficient method to enhance the conversion rate of cellobiose during the glycosylation process.

Engineering Escherichia coli for efficient and economic production of C-glycosylflavonoids by deleting YhhW and regulating pH.

C-glycosylflavonoids have a number of pharmacological activities. An efficient method for the preparation of C-glycosylflavonoids is through metabolic engineering. Thus, it is important to prevent the degradation of C-glycosylflavonoids for producing C-glycosylflavonoids in the recombinant strain. In this study, two critical factors for the degradation of C-glycosylflavonoids were clarified. The quercetinase (YhhW) gene from Escherichia coli BL21(DE3) was expressed, purified, and characterized. YhhW effectively degraded quercetin 8-C-glucoside, orientin, and isoorientin, while the degradation of vitexin and isovitexin was not significant. Zn2+ can significantly reduce the degradation of C-glycosylflavonoids by inhibiting the activity of YhhW. pH was another key factor causing the degradation of C-glycosylflavonoids, and C-glycosylflavonoids were significantly degraded with pH exceeding 7.5 in vitro or in vivo. On this basis, two strategies, deleting YhhW gene from the genome of E. coli and regulating pH during the bioconversion, were developed to relieve the degradation of C-glycosylflavonoids. Finally, the total degradation rates for orientin and quercetin 8-C-glucoside decreased from 100 to 28% and 65% to 18%, respectively. The maximum yield of orientin reached 3353 mg/L with luteolin as substrate, and the maximum yield of quercetin 8-C-glucoside reached 2236 mg/L with quercetin as substrate. Therefore, the method described herein for relieving the degradation of C-glycosylflavonoids may be widely used for the biosynthesis of C-glycosylflavonoids in recombinant strains.

Assessment of immune cell profiles among post-menopausal women in the Women's Health Initiative using DNA methylation-based methods.

BACKGROUND: Over the past decade, DNA methylation (DNAm)-based deconvolution methods that leverage cell-specific DNAm markers of immune cell types have been developed to provide accurate estimates of the proportions of leukocytes in peripheral blood. Immune cell phenotyping using DNAm markers, termed immunomethylomics or methylation cytometry, offers a solution for determining the body's immune cell landscape that does not require fresh blood and is scalable to large sample sizes. Despite significant advances in DNAm-based deconvolution, references at the population level are needed for clinical and research interpretation of these additional immune layers. Here we aim to provide some references for immune populations in a group of multi-ethnic post-menopausal American women. RESULTS: We applied DNAm-based deconvolution to a large sample of post-menopausal women enrolled in the Women's Health Initiative (baseline, N = 58) or the ancillary Long Life Study (WHI-LLS, N = 1237) to determine the reference ranges of 58 immune parameters, including proportions and absolute counts for 19 leukocyte subsets and 20 derived cell ratios. Participants were 50-94 years old at the time of blood draw, and N = 898 (69.3%) self-identified as White. Using linear regression models, we observed significant associations between age at blood draw and absolute counts and proportions of naïve B, memory CD4+, naïve CD4+, naïve CD8+, memory CD8+ memory, neutrophils, and natural killer cells. We also assessed the same immune profiles in a subset of paired longitudinal samples collected 14-18 years apart across N = 52 participants. Our results demonstrate high inter-individual variability in rates of change of leukocyte subsets over this time. And, when conducting paired t tests to test the difference in counts and proportions between the baseline visit and LLS visit, there were significant changes in naïve B, memory CD4+, naïve CD4+, naïve CD8+, memory CD8+ cells and neutrophils, similar to the results seen when analyzing the association with age in the entire cohort. CONCLUSIONS: Here, we show that derived cell counts largely reflect the immune profile associated with proportions and that these novel methods replicate the known immune profiles associated with age. Further, we demonstrate the value this methylation cytometry approach can add as a potential application in epidemiological studies.

The Burden of Psoriasis in China and Global Level from 1990 to 2019: A Systematic Analysis from the Global Burden of Disease Study 2019.

Objectives: Psoriasis is a skin disease thought to be related to immune system dysfunction. Our study is aimed at analyzing the prevalence of psoriasis in China in multiple different categories and compared the prevalence at the global level, in order to bring insights to policymakers for treating this disease. Methods: We analyzed psoriasis trends from 1990 to 2019 in China as well as around the globe with data from the Global Burden of Disease 2019 study. Multiple metrics such as age-standardized prevalence rates, percent change in age-standardized prevalence rates, disability-adjusted life years (DALYs), and age and sex patterns were included. We also predicted the trends of psoriasis prevalence and DALYs in the following 30 years. Results: In China, the age-specific prevalence cases showed a right shift in 2019 compared to 1990 with a peak between the ages of 50 and 54 years and an obvious surpass in males between 40 and 69. Though China still had the largest number of psoriasis cases in 2019, the increase rate was below global level. A positive linear relationship between psoriasis prevalence and comorbidities was seen with rheumatoid arthritis, diabetes mellitus, multiple sclerosis, nonrheumatic valvular heart disease, cardiomyopathy and myocarditis, nonmelanoma skin cancer, non-Hodgkin lymphoma, and multiple myeloma in China within the male group in 2019. Discussion. The burden of psoriasis, as measured by the absolute number of DALYs, continues to increase around the world. The scarcity of modifiable risks for most psoriasis burdens suggests that new knowledge is needed to develop effective prevention and treatment strategies.

Knowledge Gaps, Challenges, and Opportunities in Health and Prevention Research for Asian Americans, Native Hawaiians, and Pacific Islanders: A Report From the 2021 National Institutes of Health Workshop.

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.

Association of Premature Menopause With Risk of Abdominal Aortic Aneurysm in the Women's Health Initiative.

OBJECTIVE: To determine if premature menopause and early menarche are associated with increased risk of AAA, and to explore potential effect modification by smoking history. SUMMARY OF BACKGROUND DATA: Despite worse outcomes for women with AAA, no studies have prospectively examined sex-specific risk factors, such as premature menopause and early menarche, with risk of AAA in a large, ethnically diverse cohort of women. METHODS: This was a post-hoc analysis of Women's Health Initiative participants who were beneficiaries of Medicare Parts A&B fee-for-service. AAA cases and interventions were identified from claims data. Follow-up period included Medicare coverage until death, end of follow-up or end of coverage inclusive of 2017. RESULTS: Of 101,119 participants included in the analysis, the mean age was 63 years and median follow-up was 11.3 years. Just under 10,000 (9.4%) women experienced premature menopause and 22,240 (22%) experienced early men-arche. Women with premature menopause were more likely to be overweight, Black, have >20 pack years of smoking, history of cardiovascular disease, hypertension, and early menarche. During 1,091,840 person-years of follow-up, 1125 women were diagnosed with AAA, 134 had premature menopause (11.9%), 93 underwent surgical intervention and 45 (48%) required intervention for ruptured AAA. Premature menopause was associated with increased risk of AAA [hazard ratio 1.37 (1.14, 1.66)], but the association was no longer significant after multivariable adjustment for demographics and cardiovascular disease risk factors. Amongst women with ≥20 pack year smoking history (n = 19,286), 2148 (11.1%) had premature menopause, which was associated with greater risk of AAA in all models [hazard ratio 1.63 (1.24, 2.23)]. Early menarche was not associated with increased risk of AAA. CONCLUSIONS: This study finds that premature menopause may be an important risk factor for AAA in women with significant smoking history. There was no significant association between premature menopause and risk of AAA amongst women who have never smoked. These results suggest an opportunity to develop strategies for better screening, risk reduction and stratification, and outcome improvement in the comprehensive vascular care of women.

Lipoprotein(a) levels and risk of abdominal aortic aneurysm in the Women's Health Initiative.

OBJECTIVE: Few studies have prospectively examined the associations of lipoprotein(a) [Lp(a)] levels with the risk of abdominal aortic aneurysm (AAA), especially in women. Accounting for commonly recognized risk factors, we investigated the baseline Lp(a) levels and the risk of AAA among postmenopausal women participating in the ongoing national Women's Health Initiative. METHODS: Women's Health Initiative participants with baseline Lp(a) levels available who were beneficiaries of Medicare parts A and B fee-for-service at study enrollment or who had aged into Medicare at any point were included. Participants with missing covariate data or known AAA at baseline were excluded. Thoracic aneurysms were excluded owing to the different pathophysiology. The AAA cases and interventions were identified using the International Classification of Diseases, 9th and 10th revision, codes and Current Procedural Terminology codes from claims data. Hazard ratios were computed using Cox proportional hazard models according to the quintiles of Lp(a). RESULTS: The mean age of the 6615 participants included in the analysis was 65.3 years. Of the 6615 participants, 66.6% were non-Hispanic white, 18.9% were black, 7% were Hispanic and 4.7% were Asian/Pacific Islander. Compared with the participants in the lowest Lp(a) quintile, those in higher quintiles were more likely to be overweight, black, and former or current smokers, to have hypertension, hyperlipidemia, and a history of cardiovascular disease, and to use menopausal hormone therapy and statins. During 65,476 person-years of follow-up, with a median of 10.4 years, 415 women had been diagnosed with an AAA and 36 had required intervention. More than one half had required intervention for a ruptured AAA. We failed to find a statistically significant association between Lp(a) levels and incident AAA. Additional sensitivity analyses stratified by race, with exclusion of statin users and alternative categorizations of Lp(a) using log-transformed levels, tertiles, and a cutoff of >50 mg/dL, were conducted, which did not reveal any significant associations. CONCLUSIONS: We found no statistically significant association between Lp(a) levels and the risk of AAA in a large and well-phenotyped sample of postmenopausal women. Women with high Lp(a) levels were more likely to be overweight, black, and former or current smokers, and to have hypertension, hyperlipidemia, and a history of cardiovascular disease, or to use hormone therapy and statins compared with those with lower Lp(a) levels. These findings differ from previous prospective, case-control, and meta-analysis studies that had supported a significant relationship between higher Lp(a) levels and an increased risk of AAA. Differences in the association could have resulted from study limitations or sex differences.

Serum folate levels and cognitive performance in the ELSA-Brasil baseline assessment.

BACKGROUND: Most studies that analyze the association between serum folate levels and cognitive function either restrict their assessments to specific clinical scenarios or do not include middle-aged individuals, to whom strategies for preventing cognitive impairment may be more feasible. OBJECTIVE: To examine the association between serum folate levels and cognitive function in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment. METHODS: Data from 4,571 ELSA-Brasil participants who live in the state of São Paulo, aged 35-74 years, were analyzed. The word list learning, delayed recall, word recognition, verbal fluency, and Trail Making Test Part B consisted in the cognitive tests. For each test, age, sex, and education-specific standardized scores and a global cognitive score were calculated. Crude and adjusted linear regression models were used to examine the associations of serum folate levels with cognitive test scores. RESULTS: In multivariable-adjusted models, serum folate was not associated with global cognitive score (ß=-0.043; 95% confidence interval [95%CI] -0.135 to 0.050 for lowest vs. highest quintile group), nor with any cognitive test performance. We did not find associations between serum folate and global cognitive scores in subgroups stratified by age, sex, or use of vitamin supplements either. CONCLUSIONS: We did not find significant associations between serum folate and cognitive performance in this large sample, which is characterized by a context of food fortification policies and a consequent low frequency of folate deficiency. Positive results from previous studies may not apply to the increasingly common contexts in which food fortification is implemented, or to younger individuals.

Serum folate levels and cognitive performance in the ELSA-Brasil baseline assessment / Níveis séricos de folato e desempenho cognitivo na avaliação de linha de base do ELSA-Brasil

ABSTRACT Background: Most studies that analyze the association between serum folate levels and cognitive function either restrict their assessments to specific clinical scenarios or do not include middle-aged individuals, to whom strategies for preventing cognitive impairment may be more feasible. Objective: To examine the association between serum folate levels and cognitive function in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment. Methods: Data from 4,571 ELSA-Brasil participants who live in the state of São Paulo, aged 35-74 years, were analyzed. The word list learning, delayed recall, word recognition, verbal fluency, and Trail Making Test Part B consisted in the cognitive tests. For each test, age, sex, and education-specific standardized scores and a global cognitive score were calculated. Crude and adjusted linear regression models were used to examine the associations of serum folate levels with cognitive test scores. Results: In multivariable-adjusted models, serum folate was not associated with global cognitive score (β=-0.043; 95% confidence interval [95%CI] -0.135 to 0.050 for lowest vs. highest quintile group), nor with any cognitive test performance. We did not find associations between serum folate and global cognitive scores in subgroups stratified by age, sex, or use of vitamin supplements either. Conclusions: We did not find significant associations between serum folate and cognitive performance in this large sample, which is characterized by a context of food fortification policies and a consequent low frequency of folate deficiency. Positive results from previous studies may not apply to the increasingly common contexts in which food fortification is implemented, or to younger individuals.

RESUMO Introdução: A maioria dos estudos que analisam a associação entre os níveis séricos de folato e a função cognitiva restringem suas avaliações a cenários clínicos específicos ou não incluem indivíduos de meia idade, nos quais estratégias preventivas para a função cognitiva podem ser mais viáveis. Objetivo: Examinar a associação entre os níveis séricos de folato e a função cognitiva na avaliação inicial do Estudo Longitudinal da Saúde do Adulto (ELSA-Brasil). Métodos: Foram analisados dados de 4.571 participantes do ELSA-Brasil em São Paulo, com idades entre 35 e 74 anos. Os testes cognitivos foram aprendizagem, recordatório tardio e reconhecimento de lista de palavras; fluência verbal e teste de trilhas parte B. Calculamos, para cada teste e globalmente, escores padronizados para idade, sexo e educação. Foram utilizados modelos de regressão linear para examinar as associações dos níveis séricos de folato com o desempenho nos testes cognitivos. Resultados: Em modelos ajustados para múltiplas variáveis, o folato sérico não esteve associado ao escore cognitivo global (β=-0,043; intervalo de confiança de 95%: [IC95%] -0,135 a 0,050 para 1º vs. 5º quintil), ou desempenho em qualquer teste cognitivo. Também não encontramos associações entre folato sérico e escores cognitivos globais em subgrupos estratificados por idade, sexo ou uso de suplementos vitamínicos. Conclusões: Não encontramos associações significativas entre folato sérico e desempenho cognitivo nesta grande amostra, caracterizada por um cenário sob políticas de fortificação alimentar e consequente baixa frequência de deficiência de folato. Resultados positivos de estudos anteriores podem não se aplicar às situações cada vez mais comuns em que a fortificação de alimentos é implementada, ou a indivíduos mais jovens.

Epigenomic Assessment of Cardiovascular Disease Risk and Interactions With Traditional Risk Metrics.

Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics.

Genome-Wide Assessment for Resting Heart Rate and Shared Genetics With Cardiometabolic Traits and Type 2 Diabetes.

BACKGROUND: High resting heart rate (RHR) occurs in parallel with type 2 diabetes (T2D) and metabolic disorders, implying shared etiology between them. However, it is unknown if they are causally related, and no study has been conducted to investigate the shared mechanisms underlying these associations. OBJECTIVES: The objective of this study was to understand the genetic basis of the association between resting heart rate and cardiometabolic disorders/T2D. METHODS: This study examined the genetic correlation, causality, and shared genetics between RHR and T2D using LD Score regression, generalized summary data-based Mendelian randomization, and transcriptome wide association scan (TWAS) in UK Biobank data (n = 428,250) and summary-level data for T2D (74,124 cases and 824,006 control subjects) and 8 cardiometabolic traits (sample size ranges from 51,750 to 236,231). RESULTS: Significant genetic correlation between RHR and T2D (rg = 0.22; 95% confidence interval: 0.18 to 0.26; p = 1.99 × 10-22), and 6 cardiometabolic traits (fasting insulin, fasting glucose, waist-hip ratio, triglycerides, high-density lipoprotein, and body mass index; rg range -0.12 to 0.24; all p < 0.05) were observed. RHR has significant estimated causal effect on T2D (odds ratio: 1.12 per 10-beats/min increment; p = 7.79 × 10-11) and weaker causal estimates from T2D to RHR (0.32 beats/min per doubling increment in T2D prevalence; p = 6.14 × 10-54). Sensitivity analysis by controlling for the included cardiometabolic traits did not modify the relationship between RHR and T2D. TWAS found locus chr2q23.3 (rs1260326) was highly pleiotropic among RHR, cardiometabolic traits, and T2D, and identified 7 genes (SMARCAD1, RP11-53O19.3, CTC-498M16.4, PDE8B, AKTIP, KDM4B, and TSHZ3) that were statistically independent and shared between RHR and T2D in tissues from the nervous and cardiovascular systems. These shared genes suggested the involvement of epigenetic regulation of energy and glucose metabolism, and AKT activation-related telomere dysfunction and vascular endothelial aging in the shared etiologies between RHR and T2D. Finally, FADS1 was found to be shared among RHR, fasting glucose, high-density lipoprotein, and triglycerides. CONCLUSIONS: These findings provide evidence of significant genetic correlations and causation between RHR and T2D/cardiometabolic traits, advance our understanding of RHR, and provide insight into shared etiology for high RHR and T2D.

Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes: Assessment of Causal Relations.

While dietary factors are important modifiable risk factors for type 2 diabetes (T2D), the causal role of carbohydrate quality in nutrition remains controversial. Dietary glycemic index (GI) and glycemic load (GL) have been examined in relation to the risk of T2D in multiple prospective cohort studies. Previous meta-analyses indicate significant relations but consideration of causality has been minimal. Here, the results of our recent meta-analyses of prospective cohort studies of 4 to 26-y follow-up are interpreted in the context of the nine Bradford-Hill criteria for causality, that is: (1) Strength of Association, (2) Consistency, (3) Specificity, (4) Temporality, (5) Biological Gradient, (6) Plausibility, (7) Experimental evidence, (8) Analogy, and (9) Coherence. These criteria necessitated referral to a body of literature wider than prospective cohort studies alone, especially in criteria 6 to 9. In this analysis, all nine of the Hill's criteria were met for GI and GL indicating that we can be confident of a role for GI and GL as causal factors contributing to incident T2D. In addition, neither dietary fiber nor cereal fiber nor wholegrain were found to be reliable or effective surrogate measures of GI or GL. Finally, our cost-benefit analysis suggests food and nutrition advice favors lower GI or GL and would produce significant potential cost savings in national healthcare budgets. The high confidence in causal associations for incident T2D is sufficient to consider inclusion of GI and GL in food and nutrient-based recommendations.

[Assessment of hypoglycemic status among hospitalized elderly patients with type 2 diabetes].

OBJECTIVE: To investigate the hypoglycemic characteristics of hospitalized elderly patients with type 2 diabetes mellitus (T2DM). METHODS: From January, 2014 to December, 2015, the data of 58 565 blood measurements using a standard blood glucose monitoring system (BGMS) were collected from 1187 cases of patients with type 2 diabetes during hospitalization in the Department of Endocrinology, Guangdong General Hospital (Guangzhou, China). Stratified analyses were conducted by dividing the patients into 3 age groups, namely <45 years group (128 cases), 45-64 years group (594 cases), and ≥65 years group (465 cases). The incidence and time distribution of hypoglycemia in these patients were compared among the 3 age groups. RESULTS: The risk of hypoglycemia increased with age. Compared with those below 45 years of age, the patients beyond or equal to 65 years had a significantly increased hypoglycemic density (0.95% vs 0.40%, P<0.001), a higher proportion of patients with hypoglycemia (28.17% vs 10.94%, P<0.001), and greater patient-days with hypoglycemia (4.48% vs 1.76%, P<0.001). In the elderly patients, hypoglycemia occurred most frequently before dawn, at which time the hypoglycemic density was 2.66% in patients ≥65 years of age, significantly higher than that in patients below 45 years (1.09%, P<0.05) and between 45 and 64 years (1.90%, P<0.05); the proportion of patients with hypoglycemia was also significantly higher in the elderly patients (14.57%) than in those below 45 years (3.77%, P<0.02) and between 45 and 64 years (9.42%, P<0.02). The proportion of patients with recurrent hypoglycemia (≥2 times) was significantly higher in patients ≥65 years (13.33%) than in younger patients (2.34% in <45 years group and 9.43% in 45-64 years group, P<0.05). CONCLUSION: The hypoglycemic risk in hospitalized elderly patients with T2DM is significantly higher than that in younger patients, especially before dawn and in terms of recurrent hypoglycemia. Clinicians should develop differential blood glucose monitoring and management strategies for these elderly patients to improve the clinical safety.

Understanding the relation between socioeconomic position and inflammation in post-menopausal women: education, income and occupational prestige.

Background: The role of occupational prestige, a direct measure of the perceived status of job and job holder, in inflammation is unknown. To contribute to understanding the pathways by which socioeconomic position (SEP) is associated with inflammation, we aimed to estimate the direct effects of education, income and occupational prestige on C-reactive protein (CRP) and to describe the relationship between these markers and CRP. Methods: The study was based on 2026 post-menopausal women enrolled in the Women's Health Initiative-Observational Study. Occupational prestige was determined by linking a text description of longest held occupation with a social status item from the Occupational Information Network. Path analysis was employed to estimate direct and mediated effects. Results: The study suggests that higher levels of education, income, and occupational prestige are associated with 8% (95% CI as percentage change -12, -4), 5% [95% CI (-8, -2) and 4% (95% CI - 7, -1)] lower levels of CRP, respectively. The inverse association between education and CRP was explained by the effect of education on income and occupational prestige. The effect of occupational prestige on CRP was independent of mediators in the model. Conclusions: The findings indicate that education may work to influence CRP primarily through increasing income and occupational prestige and provides evidence that occupational prestige captures a unique aspect of SEP.

Use of Medicare data to identify coronary heart disease outcomes in the Women's Health Initiative.

BACKGROUND: Data collected as part of routine clinical practice could be used to detect cardiovascular outcomes in pragmatic clinical trials or clinical registry studies. The reliability of claims data for documenting outcomes is unknown. METHODS AND RESULTS: We linked records of Women's Health Initiative (WHI) participants aged ≥65 years to Medicare claims data and compared hospitalizations that had diagnosis codes for acute myocardial infarction or coronary revascularization with WHI outcomes adjudicated by study physicians. We then compared the hazard ratios for active versus placebo hormone therapy based solely on WHI-adjudicated events with corresponding hazard ratios based solely on claims data for the same hormone trial participants. Agreement between WHI-adjudicated outcomes and Medicare claims was good for the diagnosis of myocardial infarction (κ, 0.71-0.74) and excellent for coronary revascularization (κ, 0.88-0.91). The hormone:placebo hazard ratio for clinical myocardial infarction was 1.31 (95% confidence interval, 1.03-1.67) based on WHI outcomes and 1.29 (95% confidence interval, 1.00-1.68) based on Medicare data. The hazard ratio for coronary revascularization was 1.09 (95% confidence interval, 0.88-1.35) based on WHI outcomes and 1.10 (95% confidence interval, 0.89-1.35) based on Medicare data. The differences between hazard ratios derived from WHI and Medicare data were not significant in 1000 bootstrap replications. CONCLUSIONS: Medicare claims may provide useful data on coronary heart disease outcomes among patients aged ≥65 years in clinical research studies. CLINICAL TRIALS REGISTRATION INFORMATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00000611.

Racial/ethnic disparities in association between dietary quality and incident diabetes in postmenopausal women in the United States: the Women's Health Initiative 1993-2005.

OBJECTIVE: To examine the association of dietary quality and risk of incident diabetes overall and by race/ethnicity among postmenopausal women enrolled in the Women's Health Initiative (WHI). RESEARCH METHODS AND PROCEDURES: The WHI recruited 161,808 postmenopausal women between 1993 and 1998, and followed them until 2005. Incident diabetes was determined annually over an average of 7.6 years from enrollment. At baseline, all participants completed a Food Frequency Questionnaire (FFQ). Dietary quality was assessed by the Alternate Healthy Eating Index (AHEI), calculated from the baseline FFQ responses. RESULTS: There were 10,307 incident cases of self-reported treated diabetes over 1,172,761 person-years of follow-up. Most participants did not meet the AHEI dietary goals; that is, only 0.1% of women met or exceeded the recommended consumption of vegetables, and few (17.3%) met or exceeded the recommended level for total fiber. After adjusting for potential confounders, women in the highest quintile of the AHEI score were 24% less likely to develop diabetes relative to women in the lowest quintile of AHEI [hazard ratio (HR)=0.76 (95% CI: 0.70-0.82)]. This association was observed in Whites [HR=0.74 (95% CI: 0.68-0.82)] and Hispanics [HR=0.68 (95% CI: 0.46-0.99)], but not in Blacks [HR=0.85 (95% CI: 0.69-1.05)] or Asians [HR=0.88 (95% CI: 0.57-1.38)]. CONCLUSION: These findings support a protective role of healthful eating choices in reducing the risk of developing diabetes, after adjusting for other lifestyle factors, in White and Hispanic postmenopausal women. Future studies are needed to investigate the relationship between dietary quality and risk of diabetes among Blacks and Asians in relationship to other lifestyle factors.

Prenatal prescription corticosteroids and offspring diabetes: a national cohort study.

BACKGROUND: Foetal exposure to excess glucocorticoids has been associated with altered development of multiple foetal systems that may persist after birth and lead to an increased risk of diseases. The purpose of this study is to investigate the role of prenatal prescription corticosteroids for the development of diabetes among offspring. METHODS: We conducted a national birth cohort study of children from singleton pregnancies born in Denmark between 1 January 1997 and 31 December 2004 with follow-up through 31 December 2008. Four Danish nationwide administrative registries were linked to identify specific exposures, outcomes and covariates of interest among 505 386 children from singleton pregnancies born alive to 360 484 women. We calculated hazard ratios (HRs) comparing diabetes incidence (separately for type 1 and type 2 diabetes/elevated blood glucose) in children exposed vs unexposed to prescription corticosteroids prenatally. RESULTS: Prenatal exposure to prescription corticosteroids was associated with a small increase in offspring type 1 diabetes incidence rate [HR = 1.20, 95% confidence limits (CL) = 0.94, 1.53] and with a 51% increase in type 2 diabetes/elevated blood glucose hazard ratio when comparing children exposed prenatally to prescription corticosteroids with those unexposed (HR = 1.51, 95% CL = 0.69, 3.31). The data were consistent with a monotonic increase in overall diabetes hazard ratios with increasing strength of the corticosteroid. CONCLUSIONS: There may be a relation between prenatal prescription corticosteroid use and childhood diabetes but further studies with more extensive assessment of foetal exposures are warranted. If prenatal prescription corticosteroids contribute to the development of offspring diabetes, the public health implications could be substantial.

Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women's Health Initiative Observational Study.

OBJECTIVE: The homeostasis model assessment (HOMA), based on plasma levels of fasting glucose and insulin, has been widely validated and applied for quantifying insulin resistance and beta-cell function. However, prospective data regarding its relation to diabetes risk in ethnically diverse populations are limited. RESEARCH DESIGN AND METHODS: Among 82,069 women who were aged 50-79 years, free of cardiovascular disease or diabetes, and participating in the Women's Health Initiative Observational Study, we conducted a nested case-control study to prospectively examine the relations of HOMA of insulin resistance (HOMA-IR) and beta-cell function (HOMA-B) with diabetes risk. During a median follow-up period of 5.9 years, 1,584 diabetic patients were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. RESULTS: Baseline levels of fasting glucose, insulin, and HOMA-IR were each significantly higher among case compared with control subjects, while HOMA-B was lower (all P values <0.0001). After adjustment for matching factors and diabetes risk factors, all four markers were significantly associated with diabetes risk; the estimated relative risks per SD increment were 3.54 (95% CI 3.02-4.13) for fasting glucose, 2.25 (1.99-2.54) for fasting insulin, 3.40 (2.95-3.92) for HOMA-IR, and 0.57 (0.51-0.63) for HOMA-B. While no statistically significant multiplicative interactions were observed between these markers and ethnicity, the associations of both HOMA-IR and HOMA-B with diabetes risk remained significant and robust in each ethnic group, including whites, blacks, Hispanics, and Asians/Pacific Islanders. When evaluated jointly, the relations of HOMA-IR and HOMA-B with diabetes risk appeared to be independent and additive. HOMA-IR was more strongly associated with an increased risk than were other markers after we excluded those with fasting glucose > or = 126 mg/dl at baseline. CONCLUSIONS: High HOMA-IR and low HOMA-B were independently and consistently associated with an increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women. These data suggest the value of HOMA indexes for diabetes risk in epidemiologic studies.

Prevention of type 2 diabetes by diet and lifestyle modification.

Diabetes mellitus is an epidemic of our time. This disease affects nearly 150 million adults worldwide and nearly 11 million in the United States in 2000. Because of the prevalence of obesity and diabetes and associated vascular complications, preventing even a small proportion of cases would save thousands of lives and billions of dollars in healthcare costs and lost productivity. Researchers have made great strides in identifying many lifestyle and dietary factors associated with diabetes, but solidifying the scientific basis for prevention and control of this disease as well as implementation at a national level remains a difficult challenge. The literature on the influence of diet and lifestyle in the development of diabetes is reviewed here, with emphasis on epidemiologic data. We outline a systematic approach to primary and secondary prevention of this disease by evaluating and prioritizing risk factors for which intervention is effective and developing a framework for application of intervention strategies. Effective interventions must target not only the affected individuals but also families, workplaces, schools and communities. Prevention of this devastating disease calls for the identification of culture-sensitive measures that can be applied to the population in general and some high-risk minority groups in particular.

Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment.

BACKGROUND: Type 2 diabetes is an epidemic that is affecting an ever-increasing proportion of the US population. Although consumption of refined carbohydrates has increased and is thought to be related to the increased risk of type 2 diabetes, the ecologic effect of changes in the quality of carbohydrates in the food supply on the risk of type 2 diabetes remains to be quantified. OBJECTIVE: The objective was to examine the correlation between consumption of refined carbohydrates and the prevalence of type 2 diabetes in the United States. METHODS: In this ecologic correlation study, the per capita nutrient consumption in the United States between 1909 and 1997 obtained from the US Department of Agriculture was compared with the prevalence of type 2 diabetes obtained from the Centers for Disease Control and Prevention. RESULTS: In a univariate analysis, a significant correlation with diabetes prevalence was observed for dietary fat (r = 0.84, P < 0.001), carbohydrate (r = 0.55, P < 0.001), protein (r = 0.71, P < 0.001), fiber (r = 0.16, P = 0.03), corn syrup (r = 0.83, P < 0.001), and total energy (r = 0.75, P < 0.001) intakes. In a multivariate nutrient-density model, in which total energy intake was accounted for, corn syrup was positively associated with the prevalence of type 2 diabetes (beta = 0.0132, P = 0.038). Fiber (beta = -13.86, P < 0.01) was negatively associated with the prevalence of type 2 diabetes. In contrast, protein (P = 0.084) and fat (P = 0.79) were not associated with the prevalence of type 2 diabetes when total energy was controlled for. CONCLUSIONS: Increasing intakes of refined carbohydrate (corn syrup) concomitant with decreasing intakes of fiber paralleled the upward trend in the prevalence of type 2 diabetes observed in the United States during the 20th century.