Efficacy of decentralised home-based antihypertensive treatment in older adults with multimorbidity and polypharmacy (ATEMPT): an open-label randomised controlled pilot trial.

BACKGROUND: Older patients with multimorbidity and polypharmacy have been under-represented in clinical trials. We aimed to assess the effect of different intensities of antihypertensive treatment on changes in blood pressure, major safety outcomes, and patient-reported outcomes in this population. METHODS: ATEMPT was a decentralised, two-armed, parallel-group, open-label randomised controlled pilot trial conducted in the Thames Valley area, South East England. Individuals aged 65 years or older with multimorbidity (three or more chronic conditions) or polypharmacy (five or more types of medications) and a systolic blood pressure of 115-165 mm Hg were eligible for inclusion. Participants were identified through a search of national hospital discharge databases, identification of patients registered with an online pharmacy, and via targeted advertising on social media platforms. Participants were randomly assigned to receive up to two more classes versus up to two fewer classes of antihypertensive medications. Apart from routine home visits for conducting the baseline assessment, all communication, monitoring, and management of participants by the trial team was conducted remotely. The primary outcome was change in home-measured blood pressure. FINDINGS: Between Dec 15, 2020, and Aug 31, 2022, 230 participants were randomly assigned (n=126 to more vs n=104 to fewer antihypertensive medications). The frequency of serious adverse events was similar across both groups; no cardiovascular events occurred in the more antihypertensive drugs group, compared with six in the fewer antihypertensive drugs group, of which two were fatal. Over a 13-month follow-up period, the mean systolic blood pressure in the group allocated to receive more antihypertensive medications decreased from 134·5 mm Hg (SD 10·7) at baseline to 122·1 mm Hg (10·5). By contrast, in the group allocated to receive fewer antihypertensive medications, it remained relatively unchanged, moving from 134·8 mm Hg (SD 11·2) at baseline to 132·9 mm Hg (15·3); this corresponded to a mean difference of -10·7 mm Hg (95% CI -17·5 to -4·0). INTERPRETATION: Remotely delivered antihypertensive treatment substantially reduced systolic blood pressure in older adults who are often less represented in trials, with no increase in the risk of serious adverse events. The results of this trial will inform a larger clinical trial focusing on assessing major cardiovascular events, safety, physical functioning, and cognitive function that is currently in the planning stages. These results also underscore the efficiency of decentralised trial designs, which might be of broader interest in other settings. FUNDING: National Institute for Health Research Oxford Biomedical Research Centre and the Oxford Martin School.

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis.

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1ß inhibitor) and colchicine (ß-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1ß or ß-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45-0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51-1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99-592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management.

Sodium-based paracetamol: impact on blood pressure, cardiovascular events, and all-cause mortality.

BACKGROUND AND AIMS: Effervescent formulations of paracetamol containing sodium bicarbonate have been reported to associate with increased blood pressure and a higher risk of cardiovascular diseases and all-cause mortality. Given the major implications of these findings, the reported associations were re-examined. METHODS: Using linked electronic health records data, a cohort of 475 442 UK individuals with at least one prescription of paracetamol, aged between 60 and 90 years, was identified. Outcomes in patients taking sodium-based paracetamol were compared with those taking non-sodium-based formulations of the same. Using a deep learning approach, associations with systolic blood pressure (SBP), major cardiovascular events (myocardial infarction, heart failure, and stroke), and all-cause mortality within 1 year after baseline were investigated. RESULTS: A total of 460 980 and 14 462 patients were identified for the non-sodium-based and sodium-based paracetamol exposure groups, respectively (mean age: 74 years; 64% women). Analysis revealed no difference in SBP [mean difference -0.04 mmHg (95% confidence interval -0.51, 0.43)] and no association with major cardiovascular events [relative risk (RR) 1.03 (0.91, 1.16)]. Sodium-based paracetamol showed a positive association with all-cause mortality [RR 1.46 (1.40, 1.52)]. However, after further accounting of other sources of residual confounding, the observed association attenuated towards the null [RR 1.08 (1.01, 1.16)]. Exploratory analyses revealed dysphagia and related conditions as major sources of uncontrolled confounding by indication for this association. CONCLUSIONS: This study does not support previous suggestions of increased SBP and an elevated risk of cardiovascular events from short-term use of sodium bicarbonate paracetamol in routine clinical practice.

Sex-Specific Effects of Blood Pressure Lowering Pharmacotherapy for the Prevention of Cardiovascular Disease: An Individual Participant-Level Data Meta-Analysis.

BACKGROUND: Whether the relative effects of blood pressure (BP)-lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain. METHODS: We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data. RESULTS: We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89-0.95] for women and 0.90 [0.88-0.93] for men; P for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all P for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all P for interaction, ≥0.14). CONCLUSIONS: The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment.

Stratification of diabetes in the context of comorbidities, using representation learning and topological data analysis.

Diabetes is a heterogenous, multimorbid disorder with a large variation in manifestations, trajectories, and outcomes. The aim of this study is to validate a novel machine learning method for the phenotyping of diabetes in the context of comorbidities. Data from 9967 multimorbid patients with a new diagnosis of diabetes were extracted from Clinical Practice Research Datalink. First, using BEHRT (a transformer-based deep learning architecture), the embeddings corresponding to diabetes were learned. Next, topological data analysis (TDA) was carried out to test how different areas in high-dimensional manifold correspond to different risk profiles. The following endpoints were considered when profiling risk trajectories: major adverse cardiovascular events (MACE), coronary artery disease (CAD), stroke (CVA), heart failure (HF), renal failure (RF), diabetic neuropathy, peripheral arterial disease, reduced visual acuity and all-cause mortality. Kaplan Meier curves were plotted for each derived phenotype. Finally, we tested the performance of an established risk prediction model (QRISK) by adding TDA-derived features. We identified four subgroups of patients with diabetes and divergent comorbidity patterns differing in their risk of future cardiovascular, renal, and other microvascular outcomes. Phenotype 1 (young with chronic inflammatory conditions) and phenotype 2 (young with CAD) included relatively younger patients with diabetes compared to phenotypes 3 (older with hypertension and renal disease) and 4 (older with previous CVA), and those subgroups had a higher frequency of pre-existing cardio-renal diseases. Within ten years of follow-up, 2592 patients (26%) experienced MACE, 2515 patients (25%) died, and 2020 patients (20%) suffered RF. QRISK3 model's AUC was augmented from 67.26% (CI 67.25-67.28%) to 67.67% (CI 67.66-67.69%) by adding specific TDA-derived phenotype and the distances to both extremities of the TDA graph improving its performance in the prediction of CV outcomes. We confirmed the importance of accounting for multimorbidity when risk stratifying heterogenous cohort of patients with new diagnosis of diabetes. Our unsupervised machine learning method improved the prediction of clinical outcomes.

Systolic blood pressure, chronic obstructive pulmonary disease and cardiovascular risk.

OBJECTIVE: In individuals with complex underlying health problems, the association between systolic blood pressure (SBP) and cardiovascular disease is less well recognised. The association between SBP and risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD) was investigated. METHODS AND ANALYSIS: In this cohort study, 39 602 individuals with a diagnosis of COPD aged 55-90 years between 1990 and 2009 were identified from validated electronic health records (EHR) in the UK. The association between SBP and risk of cardiovascular end points (composite of ischaemic heart disease, heart failure, stroke and cardiovascular death) was analysed using a deep learning approach. RESULTS: In the selected cohort (46.5% women, median age 69 years), 10 987 cardiovascular events were observed over a median follow-up period of 3.9 years. The association between SBP and risk of cardiovascular end points was found to be monotonic; the lowest SBP exposure group of <120 mm Hg presented nadir of risk. With respect to reference SBP (between 120 and 129 mm Hg), adjusted risk ratios for the primary outcome were 0.99 (95% CI 0.93 to 1.05) for SBP of <120 mm Hg, 1.02 (0.97 to 1.07) for SBP between 130 and 139 mm Hg, 1.07 (1.01 to 1.12) for SBP between 140 and 149 mm Hg, 1.11 (1.05 to 1.17) for SBP between 150 and 159 mm Hg and 1.16 (1.10 to 1.22) for SBP ≥160 mm Hg. CONCLUSION: Using deep learning for modelling EHR, we identified a monotonic association between SBP and risk of cardiovascular events in patients with COPD.

Systolic Blood Pressure and Cardiovascular Risk in Patients With Diabetes: A Prospective Cohort Study.

BACKGROUND: Whether the association between systolic blood pressure (SBP) and risk of cardiovascular disease is monotonic or whether there is a nadir of optimal blood pressure remains controversial. We investigated the association between SBP and cardiovascular events in patients with diabetes across the full spectrum of SBP. METHODS: A cohort of 49 000 individuals with diabetes aged 50 to 90 years between 1990 and 2005 was identified from linked electronic health records in the United Kingdom. Associations between SBP and cardiovascular outcomes (ischemic heart disease, heart failure, stroke, and cardiovascular death) were analyzed using a deep learning approach. RESULTS: Over a median follow-up of 7.3 years, 16 378 cardiovascular events were observed. The relationship between SBP and cardiovascular events followed a monotonic pattern, with the group with the lowest baseline SBP of <120 mm Hg exhibiting the lowest risk of cardiovascular events. In comparison to the reference group with the lowest SBP (<120 mm Hg), the adjusted risk ratio for cardiovascular disease was 1.03 (95% CI, 0.97-1.10) for SBP between 120 and 129 mm Hg, 1.05 (0.99-1.11) for SBP between 130 and 139 mm Hg, 1.08 (1.01-1.15) for SBP between 140 and 149 mm Hg, 1.12 (1.03-1.20) for SBP between 150 and 159 mm Hg, and 1.19 (1.09-1.28) for SBP ≥160 mm Hg. CONCLUSIONS: Using deep learning modeling, we found a monotonic relationship between SBP and risk of cardiovascular outcomes in patients with diabetes, without evidence of a J-shaped relationship.

Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies.

AIMS: Evidence for the effect of elevated blood pressure (BP) on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic BP and the risk of VTE. METHODS AND RESULTS: Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5 588 280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432 173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104 017(1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic BP was associated with a 7% lower risk of VTE [hazard ratio: 0.93, 95% confidence interval (CI): (0.92-0.94)]. Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic BP and VTE, both in the one-sample [odds ratio (OR): 0.69, (95% CI: 0.57-0.83)] and two-sample analyses [OR: 0.80, 95% CI: (0.70-0.92)]. CONCLUSION: We found an increased risk of VTE with lower BP, and this association was independently confirmed in two Mendelian randomization analyses. The benefits of BP reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further BP reduction should be made cautiously.

Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis.

BACKGROUND: Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. METHODS: We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, ß blockers, calcium channel blockers, and thiazide diuretics, was estimated using a network meta-analysis framework. This study is registered with PROSPERO, CRD42018099283. FINDINGS: We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0-5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91-0·98]) compared with those without type 2 diabetes (0·89 [0·87-0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated. INTERPRETATION: Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted. FUNDING: British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.

Investigating the association of environmental exposures and all-cause mortality in the UK Biobank using sparse principal component analysis.

Multicollinearity refers to the presence of collinearity between multiple variables and renders the results of statistical inference erroneous (Type II error). This is particularly important in environmental health research where multicollinearity can hinder inference. To address this, correlated variables are often excluded from the analysis, limiting the discovery of new associations. An alternative approach to address this problem is the use of principal component analysis. This method, combines and projects a group of correlated variables onto a new orthogonal space. While this resolves the multicollinearity problem, it poses another challenge in relation to interpretability of results. Standard hypothesis testing methods can be used to evaluate the association of projected predictors, called principal components, with the outcomes of interest, however, there is no established way to trace the significance of principal components back to individual variables. To address this problem, we investigated the use of sparse principal component analysis which enforces a parsimonious projection. We hypothesise that this parsimony could facilitate the interpretability of findings. To this end, we investigated the association of 20 environmental predictors with all-cause mortality adjusting for demographic, socioeconomic, physiological, and behavioural factors. The study was conducted in a cohort of 379,690 individuals in the UK. During an average follow-up of 8.05 years (3,055,166 total person-years), 14,996 deaths were observed. We used Cox regression models to estimate the hazard ratio (HR) and 95% confidence intervals (CI). The Cox models were fitted to the standardised environmental predictors (a) without any transformation (b) transformed with PCA, and (c) transformed with SPCA. The comparison of findings underlined the potential of SPCA for conducting inference in scenarios where multicollinearity can increase the risk of Type II error. Our analysis unravelled a significant association between average noise pollution and increased risk of all-cause mortality. Specifically, those in the upper deciles of noise exposure have between 5 and 10% increased risk of all-cause mortality compared to the lowest decile.

The association of dietary insulin load and index with the risk of cancer and cancer mortality: a systematic review and meta-analysis.

Purpose: Insulin levels play an important role in cancer development. However, the link between an insulinogenic diet and cancer is still unclear. Therefore, we performed a systematic review with meta-analysis to investigate the association between dietary insulin index (II) and load (IL) with cancer risk and mortality. Methods: A comprehensive search between electronic databases (Web of Science, PubMed/Medline, Scopus, and Google Scholar) was conducted to identify relevant studies up to January 2022. The relative risks (RR) and Odds ratios (OR) were extracted from eligible studies, and meta-analysis was performed to calculate the pooled effect size. Result: 12 papers including 14 studies (10 cohorts and 4 case-control) were included for the meta-analysis. Among them, 10 studies reported effect size for the risk of cancer, and 4 studies reported effect size for cancer mortality. We observed no significant association between II and IL with cancer overall (RRII: 1.03, 95%CI: 0.91-1.17, RRIL: 1.16, 95%CI: 0.94-1.42) and in cohort studies, however, in case-control studies was related with higher odds of cancer (ORII: 2.30, 95%CI: 1.21-4.38, ORIL: 2.57, 95%CI: 1.64-4.02). Higher II and IL scores were associated with the increased risk of total (RRII: 1.29, 95%CI: 1.02-1.63) and (RRIL: 1.39, 95%CI: 1.06-1.83) and colorectal cancer mortality (RRII: 1.29, 95%CI: 1.13-1.48) and (RRIL: 1.37, 95%CI: 1.18-1.60). Conclusion: Higher dietary II and IL were not associated with cancer risk in overall and cohort studies, whereas related with a higher risk of cancer in case-control studies. We observed a significant positive relation of II and IL with cancer mortality, especially CRC mortality. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01013-3.

How Much Lowering of Blood Pressure Is Required to Prevent Cardiovascular Disease in Patients With and Without Previous Cardiovascular Disease?

PURPOSE OF REVIEW: To review the recent large-scale randomised evidence on pharmacologic reduction in blood pressure for the primary and secondary prevention of cardiovascular disease. RECENT FINDINGS: Based on findings of the meta-analysis of individual participant-level data from 48 randomised clinical trials and involving 344,716 participants with mean age of 65 years, the relative reduction in the risk of developing major cardiovascular events was proportional to the magnitude of achieved reduction in blood pressure. For each 5-mmHg reduction in systolic blood pressure, the risk of developing cardiovascular events fell by 10% (hazard ratio [HR] (95% confidence interval [CI], 0.90 [0.88 to 0.92]). When participants were stratified by their history of cardiovascular disease, the HRs (95% CI) in those with and without previous cardiovascular disease were 0.89 (0.86 to 0.92) and 0.91 (0.89 to 0.94), respectively, with no significant heterogeneity in these effects (adjusted P for interaction = 1.0). When these patient groups were further stratified by their baseline systolic blood pressure in increments of 10 mmHg from < 120 to ≥ 170 mmHg, there was no significant heterogeneity in the relative risk reduction across these categories in people with or without previous cardiovascular disease (adjusted P for interaction were 1.00 and 0.28, respectively). Pharmacologic lowering of blood pressure was effective in preventing major cardiovascular disease events both in people with or without previous cardiovascular disease, which was not modified by their baseline blood pressure level. Treatment effects were shown to be proportional to the intensity of blood pressure reduction, but even modest blood pressure reduction, on average, can lead to meaningful gains in the prevention of incident or recurrent cardiovascular disease.

ABCG2, SCN1A and CYP3A5 genes polymorphism and drug-resistant epilepsy in children: A case-control study.

PURPOSE: Drug Resistant -Epilepsy is still a major challenge in pharmacotherapy of epilepsy. Pharmacogenetic pathways are one of the most important elements that can help clinicians determine medication response and provide more efficient drug therapy, especially in cases of drug resistance. Genetic alterations in drug target and transporter proteins, in part, could explain the development of drug-resistant epilepsy. We sought to assess the association of CYP3A5 (rs776746), SCN1A (rs2298771) and ABCG2 (rs2231137) candidate polymorphisms with drug-resistant epilepsy among Iranian children with epilepsy. METHODS: In a hospital-based case-control study, 93 participants, including 45 men and 48 women aged 1.5 to 14 years old were recruited. Genotyping of CYP3A5 (rs776746), SCN1A (rs2298771) and ABCG2 (rs2231137) polymorphisms using the high-resolution melting (HRM) method were measured in 46 children with drug-resistant epilepsy and 47 healthy control subjects. The binary logistic regression model was used to estimate the odds ratio (OR) for each polymorphism per effect allele increase. RESULTS: The mean (standard deviation [SD]) age of the drug-resistant patients was 10.7 (9.0) years versus 7.3 (3.6) in the control group. In the case group, most of the patients with epilepsy were diagnosed with generalized seizure (about 87%) and negative epileptic history status (63%). Furthermore, idiopathic epilepsy was dominant in the case group (69%). There was a clinically meaningful increase in the chance of drug-resistant epilepsy in participants with candidate polymorphism in ABCG2 gene (per allele T increase, adjusted odds ratio [OR] 2.41, confidence interval [CI] 0.99 to 5.87, P=0.05). No significant association was found between CYP3A5 (per allele C increase, OR 0.92, CI 0.33 to 2.60, P= 0.88) and SCN1A (per allele *1 increase, OR 0.65, 95% CI 0.34 to 1.23, P= 0.19) with drug-resistant epilepsy. CONCLUSION: We found evidence for the relationship between the ABCG2 gene polymorphism and a higher chance of drug-resistant epilepsy in children. This finding may have important implications for understanding the role of ABCG2 gene polymorphism in children with drug-resistant epilepsy.

The Blood Pressure Lowering Treatment Trialists' Collaboration: methodological clarifications of recent reports.

Epidemiological evidence has consistently shown that people with higher systolic or diastolic blood pressure are at greater risk of cardiovascular diseases. However, there has been limited randomized evidence to determine the role of blood pressure level at treatment initiation in the reduction of cardiovascular diseases risk. The extent to which other characteristics of individuals, such as prior disease history, age or sex, should be taken into account has also been controversial. Furthermore, effects on less commonly reported efficacy and safety outcomes remain underexplored. The Blood Pressure Lowering Treatment Trialists' Collaboration has collected individual-level participant data from 52 randomized clinical trials, with more than 360 000 participants, and is now the largest source of individual-level data from randomized clinical trials of blood pressure-lowering treatment. This resource provides an unprecedented opportunity to address major areas of uncertainty relating to stratified efficacy and safety of antihypertensive therapy. Recent reports have demonstrated the power of pooled analyses of the Blood Pressure Lowering Treatment Trialists' Collaboration dataset in filling long-standing gaps in our knowledge. However, there have been some misconceptions regarding the methods underpinning the recent reports, which we clarify in this article.

Antihypertensive drug effects on long-term blood pressure: an individual-level data meta-analysis of randomised clinical trials.

OBJECTIVE: Evidence from randomised trials of pharmacological treatments on long-term blood pressure (BP) reduction is limited. We investigated the antihypertensive drug effects on BP over time and across different participant characteristics. METHODS: We conducted an individual patient-level data meta-analysis of 52 large-scale randomised clinical trials in the Blood Pressure Lowering Treatment Trialists' Collaboration using mixed models to examine treatment effects on BP over 4 years of mean follow-up. RESULTS: There were 363 684 participants (42% women), with baseline mean age=65 years and mean systolic/diastolic BP=152/87 mm Hg, and among whom 19% were current smokers, 49% had cardiovascular disease, 28% had diabetes and 69% were taking antihypertensive treatment at baseline. Drugs were effective in lowering BP showing maximal effect after 12 months and gradually attenuating towards later years. Based on measures taken ≥12 months postrandomisation, mean systolic/diastolic BP difference (95% CI) between more and less intense BP-lowering treatment was -11.1 (-11.3 to -10.8)/-5.6 (-5.7 to -5.4) mm Hg; between active treatment and placebo was -5.1 (-5.3 to -5.0)/-2.3 (-2.4 to -2.2) mm Hg; and between active and control arms for drug comparison trials was -1.4 (-1.5 to -1.3)/-0.6 (-0.7 to -0.6) mm Hg. BP reductions were observed across different baseline BP values and ages, and by sex, history of cardiovascular disease and diabetes and prior antihypertensive treatment use. CONCLUSION: These findings suggest that BP-lowering pharmacotherapy is effective in lowering BP, up to 4 years on average, in people with different characteristics. Appropriate treatment strategies are needed to sustain substantive long-term BP reductions.

High-Frequency Rheological and Piezo-Voltage Waveform Characterization of Inkjet-Printed Polymer-Based Dopant-Source Inks.

This work focuses on developing an understanding of the rheological properties of polymer-based dopant-source inks at the timescales relevant to inkjet printing and their corresponding roles in determining the production of defect-free droplets. Ink-specific optimization of printing processes for phosphorus and boron dopant-source inks with different compositions is demonstrated. Rheological flow curves measured by a piezo axial vibrator (PAV) were used to study the changes in complex viscosity (η*) and in the elastic (G') and viscous (G″) components of the shear modulus (G*) with respect to changes in frequency (from fmin = 1 kHz to fmax = 10 kHz) to obtain an insight into the high-frequency behaviour of inks, as well as the effects of temperature (25 °C and 45 °C) and the natural aging time of the inks. Inks demonstrating complex viscosity η*min ≥ 2 mPas to η*max ≤ 20 mPas and an elastic modulus G' ≤ 20 Pa, produced droplets with negligible defects. Of the three rheological parameters (η*, G' and G″), the elastic component (G') of the shear modulus was observed to have the greatest significance in determining the stability and homogeneity of ink droplets, thus dictating the quality of the printed structures. The reliability and stability of droplet formation were further investigated through voltage waveform simulation using an oscilloscope.

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis.

BACKGROUND: Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials. METHODS: We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons. FINDINGS: 145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84-0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76-0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76-0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of ß blockers (RR 1·48 [1·27-1·72]) and thiazide diuretics (RR 1·20 [1·07-1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92-1·13]). INTERPRETATION: Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes. FUNDING: British Heart Foundation, National Institute for Health Research, and Oxford Martin School.