Automated electronic reminders to facilitate primary cardiovascular disease prevention: randomised controlled trial.

Background: Primary care databases contain cardiovascular disease risk factor data, but practical tools are required to improve identification of at-risk patients.

Aim: To test the effects of a system of electronic reminders (the 'e-Nudge') on cardiovascular events and the adequacy of data for cardiovascular risk estimation.

Design Of Study: Randomised controlled trial.

Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate.

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

The direct impact of climate change on regional labor productivity.

Global climate change will increase outdoor and indoor heat loads, and may impair health and productivity for millions of working people. This study applies physiological evidence about effects of heat, climate guidelines for safe work environments, climate modeling, and global distributions of working populations to estimate the impact of 2 climate scenarios on future labor productivity. In most regions, climate change will decrease labor productivity, under the simple assumption of no specific adaptation.

Label-free high-throughput screening via mass spectrometry: a single cystathionine quantitative method for multiple applications.

Label-free mass spectrometric (MS) technologies are particularly useful for enzyme assay design for drug discovery screens. MS permits the selective detection of enzyme substrates or products in a wide range of biological matrices without need for derivatization, labeling, or capture technologies. As part of a cardiovascular drug discovery effort aimed at finding modulators of cystathionine beta-synthase (CBS), we used the RapidFire((R)) label-free high-throughput MS (HTMS) technology to develop a high-throughput screening (HTS) assay for CBS activity.

Pyrazole acids as niacin receptor agonists for the treatment of dyslipidemia.

Niacin is an effective drug for raising HDL cholesterol and reducing coronary risks, but patients show low compliance with treatment due to severe facial flushing upon taking the drug. A series of bicyclic pyrazole carboxylic acids were synthesized and tested for their ability to activate the niacin receptor. One analog, 23, showed improved potency and lacked flushing at doses that effectively altered the lipid profile of rats.

International patterns of practice in palliative radiotherapy for painful bone metastases: evidence-based practice?

Purpose: Multiple randomized controlled trials have demonstrated the equivalence of multifraction and single-fraction (SF) radiotherapy for the palliation of painful bone metastases (BM). However, according to previous surveys, SF schedules remain underused. The objectives of this study were to determine the current patterns of practice internationally and to investigate the factors influencing this practice.

Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.

Dexamethasone for the prophylaxis of radiation-induced pain flare after palliative radiotherapy for symptomatic bone metastases: a phase II study.

Aims: Pain flare occurs in over one-third of patients receiving palliative radiotherapy for bone metastases. A single dose of dexamethasone can decrease the incidence of pain flare during the first 2 days immediately after radiotherapy. We conducted a phase II prospective study to investigate the prophylactic role of prolonged dexamethasone.

Survey of the learning activities of Australasian radiation oncology specialist trainees.

Trainee radiation oncologists must master a substantial body of skills and knowledge to become competent specialists. The resources available to support this are limited. We surveyed the 90 registrars enrolled in the Royal Australian and New Zealand College of Surgeons (RANZCR) radiation oncology training programme to obtain a range of information about their learning activities (with a significant focus on part 1 teaching).

Hepatic encephalopathy in two goat kids with common paternity.

Two juvenile, intact, female mixed-breed goats from a common sire were presented for periodic neurologic deficits, seizures, and a generalized loss of body condition that occurred over a 4-6-week period. On physical examination, both goats were thin, obtunded, blind, and ataxic. Laboratory diagnostics revealed increased serum bile acids (95 micromol/l; reference interval: 0-50 micromol/l) in one of the goats.

Cue-based feeding for preterm infants: a prospective trial.

We set out to test whether premature infants were able to be fed orally on feeding cues and be discharged home earlier than infants fed by traditional feeding regimens. Attainment of adequate growth, adverse events, and nursing time to provide care were also assessed. After screening, the recruited premature infants (< 36 wks post-conceptual age [PCA]) were divided into two feeding regimens.

2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity.

The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.

Discovery of imidazole carboxamides as potent and selective CCK1R agonists.

High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.

Identifying individuals for primary cardiovascular disease prevention in UK general practice: priorities and resource implications.

Targeted cardiovascular disease prevention relies on risk-factor information held in primary care records. A risk algorithm, the 'e-Nudge', was applied to data from a population of >or=50-year-olds in 19 West Midlands practices, to identify those individuals at risk of cardiovascular disease. Altogether, 5.

Tetrahydro anthranilic acid as a surrogate for anthranilic acid: application to the discovery of potent niacin receptor agonists.

The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.

Minimally invasive techniques in colon surgery.

With the description of the first laparoscopic cholecystectomy in 1985, minimally invasive approaches have become the standard practice of surgeons in managing several disease processes. This has been mainly driven by the significant favorable impact of minimally invasive surgery on patient related outcomes. Smaller incisions lead to improved cosmesis, reduced postoperative pain and earlier return of gastrointestinal function.

Identifying undiagnosed diabetes: cross-sectional survey of 3.6 million patients' electronic records.

Background: Around 1% of the UK population has diabetes that is either undiagnosed or unrecorded on practice disease registers.

Aim: To estimate the number of people in UK primary care databases with biochemical evidence of undiagnosed diabetes. To develop simple practice-based search techniques to support early recognition of diabetes.

Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment--"Hypo Trial".

Background And Purpose: The primary purpose of the trial was to assess rate of tumour response to a hypofractionated course of radiotherapy in patients with incurable squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives included radiation toxicity, symptom control, quality of life (QoL) and progression-free and overall survival.

Patients And Methods: Patients were planned to receive 30 Gy in 5 fractions at 2/week, at least 3 days apart, with an additional boost of 6 Gy for small volume disease (< or =3 cm) in suitable patients.

Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.

Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.

Pulmonary arterial pressure testing for high mountain disease in cattle.

High mountain or brisket disease is an economically costly disease of cattle raised at elevations greater than 1500 m (5000 ft). It appears that no one breed is resistant to the effects of high-altitude hypoxia. Some breeds, and pedigrees within breeds, appear to be more naturally resistant to the effects of high altitude.