Publications

Cognitive impairment, micro and macrovascular complications contribute to the high morbidity and mortality of type 1 diabetes (T1D) in an aging population. The dietary inflammatory index (DII), a validated measure of the inflammatory potential of dietary nutrients, has not been evaluated for its relationship to complications in T1D. To this end, validated semiquantitative food frequency questionnaires were administered at baseline to 591 individuals of the Joslin 50-year Medalist Study (“Medalists”), a well-characterized cohort having ≥50 years of T1D. The DII score was derived for each Medalist as a weighted summary score from 35 nutrients that have been associated with inflammatory markers in literature. A higher score indicated the pro-inflammatory potential of the diet. Logistic and linear regression models were applied to test cross-sectional relationships between the DII and complications. A higher DII was significantly (p<0.05) associated with 1.6 and 1.4 times increased odds of nephropathy (eGFR≤60 ml/min/1.7m2) and neuropathy (MNSI score >2) respectively, independent of glycemic control, diabetes duration, or other confounders. The DII was not associated with baseline self-report history of cardiovascular disease, nor with proliferative diabetic retinopathy (ETDRS >53). In a subset (n=69) who were given a cognitive battery, a higher DII was significantly associated (p=0.02) with worse working memory (Wechsler memory scale) but not with motor skills (Grooved Pegboard), executive function (Delis Kaplan) or immediate or delayed recall (Rey Auditory Verbal Learning Tests). To conclude, in aging adults with chronic T1D, a pro-inflammatory diet is associated with nephropathy, neuropathy and worse working memory, signaling a need for further studies examining diet and inflammation to eventually inform better strategies to lower morbidity in populations with long duration T1D. Disclosure H. Shah: None. E. Wolfson: None. M. Yu: None. F. Hu: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1DP3DK112192-01, 1DP3DK094333-01); Beatson Pledge Fund

In this paper, we identify the Young's modulus and residual stress state of a free-standing thin aluminum membrane, used in MEMS radio-frequency (rf) s

BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Abstract Background The Mediterranean diet and other dietary patterns rich in fruits and vegetables have been linked to lower risk of frailty in older adults. However, not all plant‐based diets are necessarily healthful, and no previous study has evaluated the role of the quality of plant‐based dietary patterns in frailty risk. Our aim was to assess the association between plant‐based diet quality and risk of frailty. Methods Prospective cohort consisted with 82 234 women aged ≥60 years from the Nurses' Health Study, who were followed from 1990 through 2014. The dates of analysis were April 14 to June 23, 2021. Dietary data were collected every 4 years using a validated semi‐quantitative food frequency questionnaire. The plant‐based diet quality was assessed with two indices (range 18–90 points): (a) healthful plant‐based diet index (hPDI), where healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, vegetable oils and tea/coffee) received positive scores, while less healthy plant foods (fruit juices, sweetened beverages, refined grains, potatoes, and sweets/desserts) and animal foods received reverse scores; and (b) unhealthful plant‐based diet index (uPDI) where positive scores were given to less healthy plant foods and reverse scores to healthy plant foods and animal foods. Frailty incidence was assessed every 4 years, being defined as having three or more of the following five criteria from the FRAIL scale: fatigue, low strength, reduced aerobic capacity, having ≥5 illnesses and weight loss ≥5%. Multivariable‐adjusted Cox proportional‐hazards models were used to estimate hazard ratios (HRs) and their 95% confidence interval (CI). Results We identified 12 910 incident cases of frailty over 1 176 401 person‐year follow‐up. In the multivariable analysis, the hPDI was inversely associated with the risk of frailty (hazard ratio [HR] for the highest vs. lowest quintile: 0.77, 95% confidence interval: 0.72–0.81; P trend <0.001). In addition, a 10‐unit increment in the hPDI was associated with a relative 15% lower risk of frailty. Conversely, a direct association was found between the uPDI and risk of frailty (HR highest vs. lowest quintile: 1.24 [1.17, 1.32], P trend <0.001). These associations were consistent for each frailty criterion, among participants with no frailty criteria at baseline, after excluding participants with diabetes, cancer and cardiovascular disease at baseline, for alternative versions of the plant‐based diet indices (PDIs), in subgroup analysis by categories of potential confounders, and in latency analysis. Conclusions A healthful plant‐based diet was associated with lower risk of frailty whereas an unhealthful plant‐based diet was associated with higher risk.

This paper describes the development of a new bivalent system comprising synthetic dimers of carbonic anhydrase linked chemically through thiol groups of cysteine residues introduced by site-directed mutagenesis. These compounds serve as models with which to study the interaction of bivalent proteins with ligands presented at the surface of mixed self-assembled monolayers (SAMs). Monovalent carbonic anhydrase (CA) binds to benzenesulfonamide ligands presented on the surface of the SAM with K(d)(surf) = 89 nM. The synthetic bivalent proteins--inspired by the structure of immunoglobulins--bind bivalently to the sulfonamide-functionalized SAMs with low nanomolar avidities (K(d)(avidity,surf) = 1-3 nM); this difference represents a ~50-fold enhancement of bivalent over monovalent association. The paper describes dimers of CA having (i) different lengths of the covalent linker that joined the two proteins and (ii) different points of attachment of the linker to the protein (either near the active site (C133) or distal to the active site (C185)). Comparison of the thermodynamics of their interactions with SAMs presenting arylsulfonamide groups demonstrated that varying the length of the linker between the molecules of CA had virtually no effect on the rate of association, or on the avidity of these dimers with ligand-presenting surfaces. Varying the point of attachment of the linker between monomeric CA's also had almost no effect on the avidity of the dimers, although changing the point of attachment affected the rates of binding and unbinding. These observations indicate that the avidities of these bivalent proteins, and by inference the avidities of structurally similar bivalent proteins such as IgG, are unexpectedly insensitive to the structure of the linker connecting them.

Fetuin-A interferes with insulin action in animal studies, but data on fetuin-A and diabetes risk in humans are sparse and the role of nonalcoholic fatty liver disease in this association is unknown. From 2000 to 2006, we prospectively identified 470 matched incident diabetes case-control pairs in the Nurses’ Health Study, for whom levels of plasma fetuin-A, alanine transaminase (ALT), and γ-glutamyltranspeptidase (GGT) were measured. After multivariate adjustment for covariates, including ALT and GGT, the odds ratio (OR) (95% CI) comparing extreme fetuin-A quintiles was 1.81 (1.07–3.06) (P for trend = 0.009). A mediational analysis showed that this positive association was largely (79.9%) explained by fasting insulin and hemoglobin A1c levels; after further adjustment of these factors, the OR (95% CI) comparing extreme quintiles was attenuated to 1.09 (0.56–2.10) (P for trend = 0.42). In addition, liver enzymes did not modify this association (P for interaction = 0.91 for ALT and 0.58 for GGT). When results from this study were pooled with those in three prior prospective investigations of the same association, a consistent, positive association was observed between high fetuin-A levels and diabetes risk: the relative risk (95% CI) comparing high versus low fetuin-A levels was 1.69 (1.39–2.05) (P for heterogeneity = 0.45). These findings suggest that plasma fetuin-A levels were independently associated with higher risk of developing type 2 diabetes.