Analysis of English general practice level data linking medication levels, service activity and demography to levels of glycaemic control being achieved in type 2 diabetes to improve clinical practice and patient outcomes.

OBJECTIVE: Evaluate relative clinical effectiveness of treatment options for type 2 diabetes mellitus (T2DM) using a statistical model of real-world evidence within UK general practitioner practices (GPP), to quantify the opportunities for diabetes care performance improvement. METHOD: From the National Diabetes Audit in 2015-2016 and 2016-2017, GPP target glycaemic control (TGC-%HbA1c ≤58 mmol/mol) and higher glycaemic risk (HGR -%HbA1c results >86 mmol/mol) outcomes were linked using multivariate linear regression to prescribing, demographics and practice service indicators. This was carried out both cross-sectionally (XS) (within year) and longitudinally (Lo) (across years) on 35 indicators. Standardised ß coefficients were used to show relative level of impact of each factor. Improvement opportunity was calculated as impact on TGC & HGR numbers. RESULTS: Values from 6525 GPP with 2.7 million T2DM individuals were included. The cross-sectional model accounted for up to 28% TGC variance and 35% HGR variance, and the longitudinal model accounted for up to 9% TGC and 17% HGR variance. Practice service indicators including % achieving routine checks/blood pressure/cholesterol control targets were positively correlated, while demographic indicators including % younger age/social deprivation/white ethnicity were negatively correlated. The ß values for selected molecules are shown as (increased TGC; decreased HGR), canagliflozin (XS 0.07;0.145/Lo 0.04;0.07), metformin (XS 0.12;0.04/Lo -;-), sitagliptin (XS 0.06;0.02/Lo 0.10;0.06), empagliflozin (XS-;0.07/Lo 0.09;0.07), dapagliflozin (XS -;0.04/Lo -;0.4), sulphonylurea (XS -0.18;-0.12/Lo-;-) and insulin (XS-0.14;0.02/ Lo-0.09;-). Moving all GPP prescribing and interventions to the equivalent of the top performing decile of GPP could result in total patients in TGC increasing from 1.90 million to 2.14 million, and total HGR falling from 191 000 to 123 000. CONCLUSIONS: GPP using more legacy therapies such as sulphonylurea/insulin demonstrate poorer outcomes, while those applying holistic patient management/use of newer molecules demonstrate improved glycaemic outcomes. If all GPP moved service levels/prescribing to those of the top decile, both TGC/HGR could be substantially improved.

Antiepileptic drugs and the fetal epigenome.

Antiepileptic drugs (AEDs) can lower maternal folate and increase maternal homocysteine levels, which are known to affect the methyl cycle and hence DNA methylation levels. The influence of in utero exposure to AEDs on fetal DNA methylation was investigated. Genome-wide fetal epigenomic profiles were determined using the Infinium 27K BeadArray from Illumina (San Diego, CA, U.S.A.). The Infinium array measures approximately 27,000 CpG loci associated with 14,496 genes at single-nucleotide resolution. Eighteen cord blood samples (nine samples from babies exposed to AEDs and nine controls) from otherwise uncomplicated pregnancies were compared. Unsupervised hierarchic clustering was used to compare the calculated methylation profiles. A clear distinction between the methylation profiles of samples from babies exposed to AEDs in utero compared with controls was detected. These data provide evidence of an epigenetic effect associated with antenatal AED and high-dose folate supplementation during pregnancy. The differences in fetal DNA methylation of those exposed to AEDs shows that a genome-wide effect of methylation is evident. In addition, the epigenetic changes observed appear to be, in this limited sample, independent of extremes of birth weight centiles. These preliminary data highlight possible mechanisms by which AEDs might influence fetal outcomes and the potential of optimizing AED-specific folate supplementation regimens to offset these effects.

Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans.

Supplementation with folic acid during pregnancy is known to reduce the risk of neural tube defects and low birth weight. It is thought that folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. We examined the effects of folate on the human methylome using quantitative interrogation of 27,578 CpG loci associated with 14,496 genes at single-nucleotide resolution across 12 fetal cord blood samples. Consistent with previous studies, the majority of CpG dinucleotides located within CpG islands exhibited hypo-methylation while those outside CpG islands showed mid-high methylation. However, for the first time in human samples, unbiased analysis of methylation across samples revealed a significant correlation of methylation patterns with plasma homocysteine, LINE-1 methylation and birth weight centile. Additionally, CpG methylation significantly correlated with either birth weight or LINE-1 methylation were predominantly located in CpG islands. These data indicate that levels of folate-associated intermediates in cord blood reflect their influence and consequences for the fetal epigenome and potentially on pregnancy outcome. In these cases, their influence might be exerted during late gestation or reflect those present during the peri-conceptual period.

LINE-1 DNA methylation is inversely correlated with cord plasma homocysteine in man: a preliminary study.

Folic acid supplementation during pregnancy has known beneficial effects. It reduces risk of neural tube defects and low birth weight. Folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. However, most data on the effects of folate on the epigenome is derived from animal or in vitro models. We examined the relationship between cord blood methylation and maternal folic acid intake, cord blood folate and homocysteine using data from 24 pregnant women. Genome-wide methylation was determined by the level of methylation of LINE-1 repeats using Pyrosequencing. We show that cord plasma homocysteine (p = 0.001, r = -0.688), but not serum folate or maternal folic acid intake, is inverse correlated with LINE-1 methylation. This remained significant after correction for potential confounders (p = 0.004). These data indicate that levels of folate-associated intermediates in cord blood during late pregnancy have significant consequences for the fetal epigenome.

Associations between prostate cancer susceptibility and parameters of exposure to ultraviolet radiation.

Low sunlight exposure confers increased prostate cancer risk. In a study conducted in northern England, we investigated how combinations of exposure measures affect this risk. Recursive partitioning was used to identify combinations of exposure parameters that distinguished 453 prostate cancers from 312 benign hypertrophy patients. Sunbathing score most significantly defined cancer patients; 78.7% men with low scores (8.0) had cancer. These subgroups were stratified by childhood sunburning, holidays in a hot climate and skin type such that subgroups with a 13.0-fold increased risk of cancer were identified.

Prostate cancer risk and exposure to ultraviolet radiation: further support for the protective effect of sunlight.

Recent studies have suggested that exposure to ultraviolet (UV) radiation may be protective to some internal cancers including that in the prostate. We describe a confirmatory study in 212 prostatic adenocarcinoma and 135 benign prostatic hypertrophy patients designed to determine whether previous findings showing a protective effect for UV exposure could be reproduced. We used a validated questionnaire to obtain data on aspects of lifetime exposure to UV. The data confirmed that higher levels of cumulative exposure, adult sunbathing, childhood sunburning and regular holidays in hot climates were each independently and significantly associated with a reduced risk of this cancer.