EEG functional connectivity as a Riemannian mediator: An application to malnutrition and cognition.

Mediation analysis assesses whether an exposure directly produces changes in cognitive behavior or is influenced by intermediate "mediators". Electroencephalographic (EEG) spectral measurements have been previously used as effective mediators representing diverse aspects of brain function. However, it has been necessary to collapse EEG measures onto a single scalar using standard mediation methods. In this article, we overcome this limitation and examine EEG frequency-resolved functional connectivity measures as a mediator using the full EEG cross-spectral tensor (CST). Since CST samples do not exist in Euclidean space but in the Riemannian manifold of positive-definite tensors, we transform the problem, allowing for the use of classic multivariate statistics. Toward this end, we map the data from the original manifold space to the Euclidean tangent space, eliminating redundant information to conform to a "compressed CST." The resulting object is a matrix with rows corresponding to frequencies and columns to cross spectra between channels. We have developed a novel matrix mediation approach that leverages a nuclear norm regularization to determine the matrix-valued regression parameters. Furthermore, we introduced a global test for the overall CST mediation and a test to determine specific channels and frequencies driving the mediation. We validated the method through simulations and applied it to our well-studied 50+-year Barbados Nutrition Study dataset by comparing EEGs collected in school-age children (5-11 years) who were malnourished in the first year of life with those of healthy classmate controls. We hypothesized that the CST mediates the effect of malnutrition on cognitive performance. We can now explicitly pinpoint the frequencies (delta, theta, alpha, and beta bands) and regions (frontal, central, and occipital) in which functional connectivity was altered in previously malnourished children, an improvement to prior studies. Understanding the specific networks impacted by a history of postnatal malnutrition could pave the way for developing more targeted and personalized therapeutic interventions. Our methods offer a versatile framework applicable to mediation studies encompassing matrix and Hermitian 3D tensor mediators alongside scalar exposures and outcomes, facilitating comprehensive analyses across diverse research domains.

The circadian clock protein REVERBα inhibits pulmonary fibrosis development.

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinß1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.

Early protein energy malnutrition impacts life-long developmental trajectories of the sources of EEG rhythmic activity.

Protein Energy Malnutrition (PEM) has lifelong consequences on brain development and cognitive function. We studied the lifelong developmental trajectories of resting-state EEG source activity in 66 individuals with histories of Protein Energy Malnutrition (PEM) limited to the first year of life and in 83 matched classmate controls (CON) who are all participants of the 49 years longitudinal Barbados Nutrition Study (BNS). qEEGt source z-spectra measured deviation from normative values of EEG rhythmic activity sources at 5-11 years of age and 40 years later at 45-51 years of age. The PEM group showed qEEGt abnormalities in childhood, including a developmental delay in alpha rhythm maturation and an insufficient decrease in beta activity. These profiles may be correlated with accelerated cognitive decline.

The change in glycaemic control immediately after COVID-19 vaccination in people with type 1 diabetes.

AIMS: Evidence suggests that some people with type 1 diabetes mellitus (T1DM) experience temporary instability of blood glucose (BG) levels after COVID-19 vaccination. We aimed to assess this objectively. METHODS: We examined the interstitial glucose profile of 97 consecutive adults (age ≥ 18 years) with T1DM using the FreeStyle Libre® flash glucose monitor in the periods immediately before and after their first COVID-19 vaccination. The primary outcome measure was percentage (%) interstitial glucose readings within the target range 3.9-10 mmol/L for 7 days prior to the vaccination and the 7 days after the vaccination. Data are mean ± standard error. RESULTS: There was a significant decrease in the % interstitial glucose on target (3.9-10.0) for the 7 days following vaccination (mean 52.2% ± 2.0%) versus pre-COVID-19 vaccination (mean 55.0% ± 2.0%) (p = 0.030). 58% of individuals with T1DM showed a reduction in the 'time in target range' in the week after vaccination. 30% showed a decrease of time within the target range of over 10%, and 10% showed a decrease in time within target range of over 20%. The change in interstitial glucose proportion on target in the week following vaccination was most pronounced for people taking metformin/dapagliflozin + basal bolus insulin (change -7.6%) and for people with HbA1c below the median (change -5.7%). CONCLUSION: In T1DM, we have shown that initial COVID-19 vaccination can cause temporary perturbation of interstitial glucose, with this effect more pronounced in people talking oral hypoglycaemic medication plus insulin, and when HbA1c is lower.

Vitamin D Deficiency at Diagnosis Increases All-Cause and Prostate Cancer-specific Mortality in Jamaican Men.

BACKGROUND: 25 hydroxyvitamin D [25(OH)D] and serum calcium have been associated with incident prostate cancer (PCa). However, there is limited data on whether these metabolites predict survival in men of African descent, a population disproportionately affected by PCa. We studied the relationship of 25(OH)D at PCa diagnosis with all-cause and cancer-specific mortality among Jamaican men and examined whether serum calcium modified any associations. METHODS: Serum 25(OH)D from 152 Jamaican men with incident PCa within the Prostate Cancer Risk Evaluation (PROSCARE) study were re-evaluated approximately 11 years after enrollment. 25(OH)D analyses were stratified using the using Holick criteria. PCa-specific and all-cause mortality were examined in Kaplan-Meier survival curves and Cox regression models adjusted for age, body mass index (BMI), smoking and Gleason score. Restricted cubic splines evaluated nonlinear associations. Serum calcium was assessed as an effect modifier of the association between 25(OH)D and mortality. RESULTS: Of cases with available 25(OH)D, 64 men with PCa survived, 38 deaths were PCa specific and 36 died of other causes. At baseline, 9.9% of cases were vitamin D deficient and 61.2% were vitamin D sufficient. Compared to 25(OH)D sufficient men, those with 25(OH)D <20.0 ng/mL concentrations were associated with higher PCa-specific mortality (adjusted HR, 4.95; 95% CI, 1.68, 14.63, P = .004) and all-cause mortality (adjusted HR, 2.40; 95%CI, 1.33, 4. 32, P = .003). Serum calcium was not associated with survival and did not modify any associations with 25(OH)D. CONCLUSIONS: 25(OH)D deficiency at PCa diagnosis predicted decreased survival for overall and PCa-specific cancer in Caribbean men of African ancestry.

Shift work is associated with positive COVID-19 status in hospitalised patients.

INTRODUCTION: Shift work is associated with lung disease and infections. We therefore investigated the impact of shift work on significant COVID-19 illness. METHODS: 501 000 UK Biobank participants were linked to secondary care SARS-CoV-2 PCR results from Public Health England. Healthcare worker occupational testing and those without an occupational history were excluded from analysis. RESULTS: Multivariate logistic regression (age, sex, ethnicity and deprivation index) revealed that irregular shift work (OR 2.42, 95% CI 1.92 to 3.05), permanent shift work (OR 2.5, 95% CI 1.95 to 3.19), day shift work (OR 2.01, 95% CI 1.55 to 2.6), irregular night shift work (OR 3.04, 95% CI 2.37 to 3.9) and permanent night shift work (OR 2.49, 95% CI 1.67 to 3.7) were all associated with positive COVID-19 tests compared with participants that did not perform shift work. This relationship persisted after adding sleep duration, chronotype, premorbid disease, body mass index, alcohol and smoking to the model. The effects of workplace were controlled for in three ways: (1) by adding in work factors (proximity to a colleague combined with estimated disease exposure) to the multivariate model or (2) comparing participants within each job sector (non-essential, essential and healthcare) and (3) comparing shift work and non-shift working colleagues. In all cases, shift work was significantly associated with COVID-19. In 2017, 120 307 UK Biobank participants had their occupational history reprofiled. Using this updated occupational data shift work remained associated with COVID-19 (OR 4.48 (95% CI 1.8 to 11.18). CONCLUSIONS: Shift work is associated with a higher likelihood of in-hospital COVID-19 positivity. This risk could potentially be mitigated via additional workplace precautions or vaccination.

Mortality in 98 type 1 diabetes mellitus and type 2 diabetes mellitus: Foot ulcer location is an independent risk determinant.

INTRODUCTION: We previously demonstrated in both a longitudinal study and in meta-analysis (pooled relative-risk RR, 2.45) that all-cause mortality is significantly higher in people with diabetes foot ulceration (DFU) than with those without a foot ulcer. In this prospective study, we looked at the factors linked to mortality after presentation to podiatry with DFU. METHODS: Ninety-eight individuals recruited consecutively from the Salford Royal Hospital Multidisciplinary Foot Clinic in Spring 2016 were followed up for up to 48 months. Data concerning health outcomes were extracted from the electronic patient record (EPR). RESULTS: Seventeen people (17) had type 1 diabetes mellitus, and 81 had type 2 diabetes mellitus. Thirty-one were women. The mean age (range) was 63.6 (28-90) years with maximum diabetes duration 45 years. Mean HbA1c was 72 (95% CI: 67-77) mmol/mol; 97% had neuropathy (International Working Group on the Diabetic Foot (IWGDF) monofilament); 62% had vascular insufficiency (Doppler studies); 69% of ulcers were forefoot, and 23% of ulcers were hind foot in location. Forty of 98 (40%) patients died in follow-up with 27% of death certificates including sepsis (not foot-related) and 35% renal failure as cause of death. Multivariate regression analysis indicated a 6.3 (95% CI: 3.9-8.1) fold increased risk of death with hind foot ulcer, independent of age/BMI/gender/HbA1c/eGFR/total cholesterol level. CONCLUSION: This prospective study has indicated a very high long-term mortality rate in individuals with DFU, greater for those with a hind foot ulcer and shown a close relation between risk of sepsis/renal failure and DFU mortality, highlighting again the importance of addressing all risk factors as soon as people present with a foot ulcer.

Longitudinal clinical trajectory analysis of individuals before and after diagnosis of Type 2 Diabetes Mellitus (T2DM) indicates that vascular problems start early.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) frequently associates with increasing multi-morbidity/treatment complexity. Some headway has been made to identify genetic and non-genetic risk factors for T2DM. However, longitudinal clinical histories of individuals both before and after diagnosis of T2DM are likely to provide additional insight into both diabetes aetiology/further complex trajectory of multi-morbidity. METHODS: This study utilised diabetes patients/controls enrolled in the DARE (Diabetes Alliance for Research in England) study where pre- and post-T2DM diagnosis longitudinal data was available for trajectory analysis. Longitudinal data of 281 individuals (T2DM n = 237 vs matched non-T2DM controls n = 44) were extracted, checked for errors and logical inconsistencies and then subjected to Trajectory Analysis over a period of up to 70 years based on calculations of the proportions of most prominent clinical conditions for each year. RESULTS: For individuals who eventually had a diagnosis of T2DM made, a number of clinical phenotypes were seen to increase consistently in the years leading up to diagnosis of T2DM. Of these documented phenotypes, the most striking were diagnosed hypertension (more than in the control group) and asthma. This trajectory over time was much less dramatic in the matched control group. Immediately prior to T2DM diagnosis, a greater indication of ischaemic heart disease proportions was observed. Post-T2DM diagnosis, the proportions of T2DM patients exhibiting hypertension and infection continued to climb rapidly before plateauing. Ischaemic heart disease continued to increase in this group as well as retinopathy, impaired renal function and heart failure. CONCLUSION: These observations provide an intriguing and novel insight into the onset and natural progression of T2DM. They suggest an early phase of potentially related disease activity well before any clinical diagnosis of diabetes is made. Further studies on a larger cohort of DARE patients are underway to explore the utility of establishing predictive risk scores.

Central adiposity at diagnosis may reduce prostate cancer-specific mortality in African-Caribbean men with prostate cancer: 10-year follow-up of participants in a case-control study.

PURPOSE: General and central adiposity are associated with the risk of developing prostate cancer (PCa), but the role of these exposures on PCa survival among men of African ancestry are less studied. This study aimed to investigate the association of anthropometry at diagnosis with all-cause and PCa-specific mortality and evaluate whether androgen deprivation therapy (ADT) modulated this risk. METHODS: Associations between body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) at diagnosis and mortality were examined in 242 men with newly diagnosed PCa enrolled between 2005 and 2007 and re-evaluated 10.9 years later. Multi-variable Cox proportional hazard models were used to examine associations of body size variables (using standard WHO cut-points and as continuous variables) with mortality, adjusted for sociodemographic characteristics, Gleason score, smoking, diabetes, primary treatment, and ADT therapy. RESULTS: A total of 139 deaths (all-cause mortality 6.98/100 person-years) occurred (PCa-specific deaths, 56; other causes, 66; causes unknown, 17). In multi-variable analysis BMI, WC and WHR categories at diagnosis were not associated with all-cause mortality even after adjusting for ADT. While WHR (but not BMI or WC) when included as a continuous variable predicted lower PCa-specific mortality (multi-variable adjusted WHR per 0.1 difference: HR, 0.50; 95%CI 0.28, 0.93), the effect disappeared with ADT covariance and excluding deaths within the first 2 years. CONCLUSION: Our study suggests that central adiposity as measured by WHR may improve long-term survival among men of African ancestry. Metabolic studies to understand the mechanism for this association are needed.

Personal protective equipment (PPE) and infection among healthcare workers - What is the evidence?

BACKGROUND: The worldwide outbreak of coronavirus disease-19 (COVID-19) has already put healthcare workers (HCWs) at a high risk of infection. The question of how to give HCWs the best protection against infection is a priority. METHODS: We searched systematic reviews and original studies in Medline (via Ovid) and Chinese Wan Fang digital database from inception to May, 2020, using terms 'coronavirus', 'health personnel', and 'personal protective equipment' to find evidence about the use of full-body PPEs and other PPEs by HCW exposed highly infectious diseases. RESULTS: Covering more of the body could provide better protection for HCWs. Of importance, it is not just the provision of PPE but the skills in donning and doffing of PPE that are important, this being a key time for potential transmission of pathogen to the HCW and in due time from them to others. In relation to face masks, the evidence indicates that a higher-level specification of face masks and respirators (such as N95) seems to be essential to protect HCWs from coronavirus infection. In community setting, the use of masks in the case of well individuals could be beneficial. Evidence specifically around PPE and protection from the COVID-19 virus is limited. CONCLUSION: Covering more of the body, and a higher-level specification of masks and respirators could provide better protection for HCWs. Community mask usecould be beneficial. High quality studies still need to examine the protection of PPE against COVID-19.

A phased approach to unlocking during the COVID-19 pandemic-Lessons from trend analysis.

BACKGROUND: The COVID-19 pandemic has led to radical political control of social behaviour. The purpose of this paper is to explore data trends from the pandemic regarding infection rates/policy impact, and draw learning points for informing the unlocking process. METHODS: The daily published cases in England in each of 149 Upper Tier Local Authority (UTLA) areas were converted to Average Daily Infection Rate (ADIR), an R-value - the number of further people infected by one infected person during their infectious phase with Rate of Change of Infection Rate (RCIR) also calculated. Stepwise regression was carried out to see what local factors could be linked to differences in local infection rates FINDINGS: By the 19th April 2020 the infection R has fallen from 2.8 on 23rd March before the lockdown and has stabilised at about 0.8, sufficient for suppression. However there remain significant variations between England regions. Regression analysis across UTLAs found that the only factor relating to reduction in ADIR was the historic number of confirmed number infection/000 population, There is however wide variation between Upper Tier Local Authorities (UTLA) areas. Extrapolation of these results showed that unreported community infection may be 150 times higher than reported cases, providing evidence that by the end of the second week in April, 26.8% of the population may already have had the disease and so have increased immunityExtrapolation of these results showed that unreported community infection may be 150 times higher than reported cases, providing evidence that by the end of the second week in April, 26.8% of the population may already have had the disease and so have increased immunity. INTERPRETATION: Analysis of current case data using infectious ratio has provided novel insight into the current national state and can be used to make better-informed decisions about future management of restricted social behaviour and movement.

The treatment rate of erectile dysfunction (ED) in younger men with type 2 diabetes is up to four times higher than the equivalent non-diabetes population.

INTRODUCTION: Erectile dysfunction (ED) is common in older age and in diabetes mellitus (DM). Phosphodiesterase type 5-inhibitors (PDE5-is) are the first-line for ED. We investigated how the type of diabetes and age of males affect the PDE5-i use in the primary care setting. METHODS: From 2018 to 2019, the general practice level quantity of all PDE5-i agents was taken from the general practice (GP) Prescribing Dataset in England. The variation in outcomes across practices was examined across one year, and for the same practice against the previous year. RESULTS: We included 5761 larger practices supporting 25.8 million men of whom 4.2 million ≥65 years old. Of these, 1.4 million had T2DM, with 0.8 million of these >65. About 137 000 people had T1DM. About 28.8 million tablets of PDE5-i were prescribed within the 12 months (2018-2019) period in 3.7 million prescriptions (7.7 tablets/prescription), at total costs of £15.8 million (£0.55/tablet). The NHS ED limit of one tablet/user/wk suggests that 540 000 males are being prescribed a PDE5-i at a cost of £29/y each. With approximately 30 000 GPs practising, this is equivalent to one GP providing 2.5 prescriptions/wk to overall 18 males. There was a 3x variation between the highest decile of practices (2.6 tablets/male/y) and lowest decile (0.96 tablets/male/y). The statistical model captured 14% of this variation and showed that T1DM males were the largest users, while men age <65 with T2DM were being prescribed four times as much as non-DM. Those T2DM >65 were prescribed 80% of the non-DM amount. CONCLUSION: There is a wide variation in the use of PDE5-is. With only 14% variance capture, other factors including wide variation in patient awareness, prescribing rules of local health providers, and recognition of the importance of male sexual health by GP prescribers might have a significant impact.

Controlling antibiotic usage-A national analysis of General Practitioner/Family Doctor practices links overall antibiotic levels to demography, geography, comorbidity factors with local discretionary prescribing choices.

INTRODUCTION: Ecological studies show association between antimicrobial resistance (AMR), and inappropriate oral antibiotics use. Moderating antibiotic prescribing requires an understanding of all drivers of local prescribing. The aim was to quantify how much is determined by external factors compared with discretionary clinical choices. METHODS: Oral antibiotic usage taken from England General Practitioner/Family Doctor practice prescribing data was aggregated using WHO/ATC defined daily doses (DDDs). The average annual antibiotic daily prescribing rate (AAADPR) in each practice was the total DDD of oral antibiotics divided by registered population and 365. The AAADPR of English practices in 2017_18 was linked by regression to factors including demographics, geography, medical comorbidities, clinical performance, patient satisfaction, medical workforce characteristics and prescribing selection. The regression coefficients for modifiable prescribing selection factors were applied to the difference between the median and top decile practice values to establish overall reduction opportunities through changing prescribing behaviour. RESULTS: Twenty five factors accounted for 58% of the AAADPR variation in 5889 practices supporting 49.8 million patients. Non-modifiable factors linked increased AAADPR to more northerly location, higher prevalence of diabetes, COPD, CHD, and asthma; higher white ethnicity; higher patient satisfaction and lower population density. Modifiable behaviour accounted for 11% of the variation in AAADPR, with increases associated with a wider range of antibiotics, higher proportion taken as liquids, higher doses in each prescription, lower guideline compliance, lower targeted antibiotics, lower spend/dose, and less seasonal variation. If all practices achieved the level of modifiable factors of the top decile, this model suggests that overall AAADPR could reduce by 31%. CONCLUSION: Such analysis is associative and does not infer causation. However, demographics, location, medical condition of the population, and prescribing selection are drivers of overall antibiotic prescribing. This analysis provides benchmarks for both non-modifiable and modifiable factors against which practices could evaluate their opportunities to reduce antibiotic prescribing.

Social deprivation modifies the association between incident foot ulceration and mortality in type 1 and type 2 diabetes: a longitudinal study of a primary-care cohort.

AIMS/HYPOTHESIS: The aim of this study was to determine whether social deprivation in the presence of diabetes is an independent predictor of developing a foot ulcer and separately of mortality. METHODS: This was a primary-care-based retrospective analysis of 13,955 adults with type 1 (n = 1370) or type 2 (n = 12,585) diabetes after a median follow-up of 10.5 years. Demographic characteristics, indices of social deprivation and clinical variables were assessed at baseline. The primary outcomes were new foot ulceration (in those without a previous history of foot ulcers) and all-cause mortality. Cox proportional hazard models were used to describe the associations among foot ulceration, social deprivation and mortality. RESULTS: The mean age of the population was 69.4 (range: 16-89) years. The incidence of foot ulceration was greater in individuals with type 2 (8.6%) compared with type 1 diabetes (4.8%). Occurrence was similar by sex, but increased with age and deprivation index. Individuals in the highest quintile of deprivation were 77% more likely to develop a foot ulcer compared with those in the lowest quintile (OR 1.77 [95% CI 1.45, 2.14], p < 0.0001). Overall, 2946 (21.1%) deaths were recorded. Compared with individuals without a foot ulcer, the development of a foot ulcer was associated with a higher age- and sex-adjusted mortality rate (25.9% vs 14.0%), and a 72% (HR 1.72 [95% CI 1.56, 1.90], p < 0.001) increased risk of mortality in those with type 2 diabetes. Risk of death increased by 14% per quintile of deprivation in a univariable analysis (HR 1.14 [95% CI 1.10, 1.17]). In multivariable Cox regression analyses, there was a 48% increased risk of mortality in individuals with a foot ulcer (HR 1.48 [95% CI 1.33, 1.66]) independent of the Townsend index score (HR 1.13 [95% CI 1.10, 1.17], per quintile), baseline age, sex, diabetes type, smoking status, hypertension, statin use, ß-blocker use, metformin use, HbA1c levels and insulin use. CONCLUSIONS/INTERPRETATION: This study confirms the high mortality rate in individuals with diabetes-related foot ulcers. In addition, socioeconomic disadvantage was found to be an independent effect modifier, contributing to an increased burden of mortality in people with diabetes who develop foot ulceration. In light of this, and as diabetes service configurations are orientated for the next 5-10 years, modelling of foot ulceration risk needs to take socioeconomic disadvantage into account.

Sodium-glucose co-transporter-2 inhibitors, the latest residents on the block: Impact on glycaemic control at a general practice level in England.

AIMS: To determine, using published general practice-level data, how differences in Type 2 diabetes mellitus (T2DM) prescribing patterns relate to glycaemic target achievement levels. METHODS: Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of different classes of medication in 2015/2016 and changes between that year and the year 2014/2015 in medication to proportion of patients achieving target glycaemic control (glycated haemoglobin A1c [HbA1c] ≤58 mmol/mol [7.5%]) and proportion of patients at high glycaemic risk (HbA1c >86 mmol/mol [10.0%]) for practices in the National Diabetes Audit with >100 people with T2DM on their register. RESULTS: Overall, HbA1c outcomes were not different between the years studied. Although, in percentage terms, most practices increased their use of sodium-glucose co-transporter-2 (SGLT2) inhibitors (96%), dipeptidyl peptidase-4 (DPP-4) inhibitors (76%) and glucagon-like peptide 1 (GLP-1) analogues (53%), there was wide variation in the use of older and newer therapies. For example, 12% of practices used >200% of the national average for some newer agents. In cross-sectional analysis, greater prescribing of metformin and analogue insulin were associated with a higher proportion of patients achieving HbA1c ≤58 mmol/mol; the use of SGLT2 inhibitors and metformin was associated with a reduced proportion of patients with HbA1c >86 mol/mol; otherwise associations for sulphonylureas, GLP-1 analogues, SGLT2 inhibitors and DPP-4 inhibitors were neutral or negative. In year-on-year analysis there was ongoing deterioration in glycaemic control, which was offset to some extent by increased use of SGLT2 inhibitors and GLP-1 analogues, which were associated with a greater proportion of patients achieving HbA1c levels ≤58 mmol/mol and a smaller proportion of patients with HbA1c levels >86 mmol/mol. SGLT2 inhibitor prescribing was associated with significantly greater improvements than those found for GLP-1 analogues. CONCLUSION: Greater use of newer agents was associated with improvement in glycaemic outcomes but was not sufficient to compensate for the prevailing decline. This may reflect wide variability in the prescribing of newer agents. We found that SGLT inhibitors may be superior to other oral agents in relation to HbA1c outcome. Serious consideration should be given to their use.

Real-world practice level data analysis confirms link between variability within Blood Glucose Monitoring Strip (BGMS) and glycosylated haemoglobin (HbA1c) in Type 1 Diabetes.

AIMS/HYPOTHESIS: Our aim was to quantify the impact of Blood Glucose Monitoring Strips variability (BGMSV) at GP practice level on the variability of reported glycated haemoglobin (HbA1cV) levels. METHODS: Overall GP Practice BGMSV and HbA1cV were calculated from the quantity of main types of BGMS being prescribed combined with the published accuracy, as % results within ±% bands from reference value for the selected strip type. The regression coefficient between the BGMSV and HbA1cV was calculated. To allow for the aggregation of estimated three tests/day over 13 weeks (ie, 300 samples) of actual Blood Glucose (BG) values up to the HbA1c, we multiplied HbA1cV coefficient by √300 to estimate an empirical value for impact of BGMSV on BGV. RESULTS: Four thousand five hundred and twenty-four practice years with 159 700 T1DM patient years where accuracy data were available for more than 80% of strips prescribed were included, with overall BGMSV 6.5% and HbA1c mean of 66.9 mmol/mol (8.3%) with variability of 13 mmol/mol equal to 19% of the mean. At a GP practice level, BGMSV and HbA1cV as % of mean HbA1c (in other words, the spread of HbA1c) were closely related with a regression coefficient of 0.176, P < 0.001. Thus, greater variability in the BGMS at a GP practice level resulted in a greater spread of HbA1C readings in T1DM patients. Applying this factor for BGMS to the national ISO accepted standard where 95% results must be ≤±15% from reference, revealed that for BG, 95% results would be ≤±45% from the reference value. Thus, the variation in BG is three times that of the BGMS. For a patient with BG target @10 mmol/L using the worst performing ISO standard strips, on 1/20 occasions (average 1/week) actual blood glucose value could be >±4.5 mmol/L from target, compared with the best performing BGMS with BG >±2.2 mmol/L from reference on 1/20 occasions. CONCLUSION: Use of more variable/less accurate BGMS is associated both theoretically and in practice with a larger variability in measured BG and HbA1c, with implications for patient confidence in their day-to-day monitoring experience.

Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.

BACKGROUND: The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established. However, the extent to which these effects differ by baseline blood pressure, presence of comorbidities, or drug class is less clear. We therefore performed a systematic review and meta-analysis to clarify these differences. METHOD: For this systematic review and meta-analysis, we searched MEDLINE for large-scale blood pressure lowering trials, published between Jan 1, 1966, and July 7, 2015, and we searched the medical literature to identify trials up to Nov 9, 2015. All randomised controlled trials of blood pressure lowering treatment were eligible for inclusion if they included a minimum of 1000 patient-years of follow-up in each study arm. No trials were excluded because of presence of baseline comorbidities, and trials of antihypertensive drugs for indications other than hypertension were eligible. We extracted summary-level data about study characteristics and the outcomes of major cardiovascular disease events, coronary heart disease, stroke, heart failure, renal failure, and all-cause mortality. We used inverse variance weighted fixed-effects meta-analyses to pool the estimates. RESULTS: We identified 123 studies with 613,815 participants for the tabular meta-analysis. Meta-regression analyses showed relative risk reductions proportional to the magnitude of the blood pressure reductions achieved. Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events (relative risk [RR] 0·80, 95% CI 0·77-0·83), coronary heart disease (0·83, 0·78-0·88), stroke (0·73, 0·68-0·77), and heart failure (0·72, 0·67-0·78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (0·87, 0·84-0·91). However, the effect on renal failure was not significant (0·95, 0·84-1·07). Similar proportional risk reductions (per 10 mm Hg lower systolic blood pressure) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure (all ptrend>0·05). There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history, except for diabetes and chronic kidney disease, for which smaller, but significant, risk reductions were detected. ß blockers were inferior to other drugs for the prevention of major cardiovascular disease events, stroke, and renal failure. Calcium channel blockers were superior to other drugs for the prevention of stroke. For the prevention of heart failure, calcium channel blockers were inferior and diuretics were superior to other drug classes. Risk of bias was judged to be low for 113 trials and unclear for 10 trials. Heterogeneity for outcomes was low to moderate; the I(2) statistic for heterogeneity for major cardiovascular disease events was 41%, for coronary heart disease 25%, for stroke 26%, for heart failure 37%, for renal failure 28%, and for all-cause mortality 35%. INTERPRETATION: Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities. Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease. FUNDING: National Institute for Health Research and Oxford Martin School.

Changes in metabolic parameters in patients with severe mental illness over a 10-year period: A retrospective cohort study.

BACKGROUND: Diabetes, obesity and metabolic syndrome are highly prevalent in patients with severe mental illness and can impose a major physical health burden. OBJECTIVE: To determine how anthropometric and metabolic features changed over time in a retrospective cohort of people with Severe Mental Illness living in Cheshire, UK. METHODS: In all, 1307 individuals on the severe mental illness Register were followed up between 2002 and 2012 in UK general practice. Subjects were identified through a pseudanonymised search of general practice registers. RESULTS: Baseline body mass index was 28.6 kg/m2 increasing to 31.0 at 10-year follow-up ( r2 = 0.84; p = 0.0002). There was a significant increase in fasting blood glucose from 5.72 to 6.79 mmol/L ( r2 = 0.48; p = 0.026). Correspondingly, there was a strong positive univariate relation between increase in body mass index and fasting blood glucose ( r2 = 0.54; p < 0.0001) taking into account all measurements. Fasting blood glucose also increased slightly with age ( p = 0.028). With increasing use of statins, total cholesterol fell from 4.5 to 3.9 mmol/L ( r2 = 0.88; p = 0.0001), as did low-density lipoprotein cholesterol from 3.43 to 2.35 mmol/L ( r2 = 0.94; p = 0.0001). In multivariate models, adjusting for age, gender, smoking and blood pressure, each unit increase in body mass index (odds ratio = 1.07 [1.01, 1.13]; p = 0.031) and triglycerides (odds ratio = 1.28 (1.06, 1.55); p = 0.009) was independently associated with an increased risk of having type 2 diabetes. CONCLUSION: Increasing body mass index relates to increasing rates of dysglycaemia over time. Measures to encourage weight reduction should be key strategies to reduce dysglycaemia rates in severe mental illness. Prescribing statins may have been effective in improving the lipid profile in this group.