Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes: the Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study.

Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes.

Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes.

Adverse events and overall health and well-being after COVID-19 vaccination: interim results from the VAC4COVID cohort safety study.

Objectives: To describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 vaccination.

Design: VAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease.

Setting: The study is conducted through a secure website (www.

Using trained dogs and organic semi-conducting sensors to identify asymptomatic and mild SARS-CoV-2 infections: an observational study.

Background: A rapid, accurate, non-invasive diagnostic screen is needed to identify people with SARS-CoV-2 infection. We investigated whether organic semi-conducting (OSC) sensors and trained dogs could distinguish between people infected with asymptomatic or mild symptoms, and uninfected individuals, and the impact of screening at ports-of-entry.

Methods: Odour samples were collected from adults, and SARS-CoV-2 infection status confirmed using RT-PCR.

Evaluating Diuretics in Normal Care (EVIDENCE): protocol of a cluster randomised controlled equivalence trial of prescribing policy to compare the effectiveness of thiazide-type diuretics in hypertension.

Introduction: Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines.

Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure-independent mechanisms in patients with or at risk of type 2 diabetes mellitus.

Aims: To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/doxazosin, to control for blood pressure (BP).

Methods: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging.

Impact of EMA regulatory label changes on hydroxyzine initiation, discontinuation and switching to other medicines in Denmark, Scotland, England and the Netherlands: An interrupted time series regression analysis.

Background: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands.

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries: Interrupted time series regression analysis.

Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations.

Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland.

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands.

Purpose: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland.

Methods: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac.

A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The VaSera trial testing dietary nitrate and spironolactone.

Aims: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure.

Methods: Daily spironolactone (≤50 mg) vs doxazosin (control ≤16 mg) and 70 mL beetroot juice (Beet-It ≤11 mmol nitrate) vs nitrate-depleted juice (placebo; 0 mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index (CAVI), a nominally pressure-independent stiffness measure (primary outcome), PWVart secondary, central systolic pressure and augmentation.

An Owner-Independent Investigation of Diabetes Alert Dog Performance.

To quantify Diabetes Alert Dog (DAD) performance by using owner-independent measures. Eight owners of accredited DADs used a FreeStyle Libre Flash Glucose Monitoring System (FGMS). Concurrent Closed Circuit Television (CCTV) footage was collected for between 5 and 14 days in each owner's home or workplace.

How effective are trained dogs at alerting their owners to changes in blood glycaemic levels?: Variations in performance of glycaemia alert dogs.

Aims: Domestic dogs are trained to a wide variety of roles including an increasing number of medical assistance tasks. Glycaemia alert dogs are reported to greatly improve the quality of life of owners living with Type 1 diabetes. Research into their value is currently sparse, on small numbers of dogs and provides conflicting results.

Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomized controlled VaSera trial.

Aims: The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure).

Methods: A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention.

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies.

Background: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.

Methods: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension.

Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double-Blind Randomized Controlled Trial.

Background: Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches.

Methods And Results: We performed a 1-year, double-blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0-16), patients were randomly assigned to initial monotherapy (losartan 50-100 mg or hydrochlorothiazide 12.

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records.

Clopidogrel efficacy is influenced by genetic variation of cytochrome P450 (CYP)2C19, however, few studies have considered patients who have a stroke. We used electronic medical records (EMRs) linked to a bioresource to examine real-world implications of clopidogrel pharmacogenetics in stroke. Patients hospitalized for any arterial thrombo-occlusive (ATO) event who subsequently redeemed clopidogrel prescriptions in the community were entered into the study (n = 651).

Serum neurofilament is associated with progression of brain atrophy and disability in early MS.

Objective: To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels.

Methods: Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay.

Acid-suppression medications and bacterial gastroenteritis: a population-based cohort study.

Aims: To investigate whether acid-suppression medicines (ASMs) increase the risk of bacterial gastroenteritis.

Methods: A population-based, propensity-score matched cohort study using a record-linkage database in Tayside, UK. The study consisted of 188 323 exposed to ASMs (proton-pump inhibitors and histamine-2 receptor antagonists) and 376 646 controls (a propensity-score matched cohort from the rest of population who were not exposed to ASMs) between 1999 and 2013.

Spironolactone use and risk of incident cancers: a retrospective, matched cohort study.

Aims: Spironolactone is widely used to treat heart failure, hypertension and liver disease with increased usage in recent years. Spironolactone has endocrine effects that could influence cancer risks and historical reports suggest possible links with increased risk of certain types of cancer. The aim of this study was to assess the effect of spironolactone exposure on cancer incidence.

Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial.

Background: Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control.

Methods: We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK.

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.

Background: Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.

Methods: In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK.

Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension.

Introduction: Resistant hypertension is inadequately controlled blood pressure (BP) despite treatment with at least three BP-lowering drugs. A popular hypothesis is that resistant hypertension is due to excessive Na(+)-retention, and that 'further diuretic therapy' will be superior to alternative add-on drugs.

Methods And Analysis: Placebo-controlled, random crossover study of fourth-line treatment when added to standard (A+C+D) triple drug therapy: ACE inhibitor or Angiotensin receptor blocker (A) +Calcium channel blocker (C)+Diuretic (D).