Early EEG correlates of word frequency and contextual predictability in reading

Previous research into written language comprehension has been equivocal as to whether word frequency and contextual predictability effects share an early time course of processing. Target word frequency (low, high) and its predictability from prior context (low, high) were manipulated across two-sentence passages. Context sentences were presented in full, followed by word-by-word presentation (300 ms SOA) of target sentences. ERPs were analysed across left-to-right and anterior-to-posterior regions of interest within intervals from 50 to 550 ms post-stimulus. The onset of significant predictability effects (50–80 ms) preceded that of frequency (P1, 80–120 ms), while both main effects were generally sustained through the N400 (350–550 ms). Critically, the frequency-predictability interaction became significant in the P1 and was sustained through the N400, although the specific configuration of effects differed across components. The pattern of findings supports an early, chronometric locus of contextual predictability in recognising words during reading

Synthesis of a Series of Diaminoindoles

[Image: see text] A selection of 3,4-diaminoindoles were required for a recent drug discovery project. To this end, a 10-step synthesis was developed from 4-nitroindole. This synthesis was subsequently adapted and used to synthesize 3,5-; 3,6-; and 3,7-diaminoindoles from the corresponding 5-, 6-, or 7-nitroindole. These novel intermediates feature orthogonal protecting groups that allow them to be further diversified. This is the first reported synthesis of these types of compounds

Oxidation of alkyl benzenes by a flavin photooxidation catalyst on nanostructured metal-oxide films

There are significant advantages in organic, interfacial photooxidation catalysis. Surface-bound catalysts on oxide interfaces offer highly reactive assemblies that minimize both catalyst and solution volume. We demonstrate here the oxygenation of alkyl benzenes by a flavin mononucleotide on nanoporous ZrO2 or TiO2 surfaces

Relationship between acute stress and clinical performance in medical students : a pilot simulation study

Funding: This study ran as part of the MBChB curriculum at the University of Aberdeen and no additional funding was required.Peer reviewedPostprin

Treating patients as persons : a capabilities approach to support delivery of person-centered care

Peer reviewedPublisher PD

Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial.

This is the final version of the article. It first appeared from BMJ via http://dx.doi.org/10.1136/bmjopen-2015-007645INTRODUCTION: Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. METHODS AND ANALYSIS: The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0-Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17-Week 32): Open-label combination therapy. Phase 3 (Week 33-Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. ETHICS AND DISSEMINATION: PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the results. TRIAL REGISTRATION NUMBER: UKCRN 4499 and EudraCT number 2008-007749-29 registered 27/08/2009.Funding statement The study is funded by a special project grant from the British Heart Foundation (number SP/08/002). Further funding is provided by Comprehensive Local Research Networks. The losartan and losartan-HCTZ were a generous gift from Dr Paul Robinson, Merck Sharpe Dohme, UK. Acknowledgements BW, PS, MC and MJB are NIHR Senior Investigators

Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis:protocol of the standard care versus celecoxib outcome trial (SCOT)

Introduction Cyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects. Data from randomised and observational studies suggest that celecoxib has similar cardiovascular toxicity to traditional NSAIDs. The overall safety balance of a strategy of celecoxib therapy versus traditional NSAID therapy is unknown. The European Medicines Agency  requested studies of the cardiovascular safety of celecoxib within Europe. The Standard care versus Celecoxib Outcome Trial (SCOT) compares the cardiovascular safety of celecoxib with traditional NSAID therapy in the setting of the European Union healthcare system. Methods and analysis SCOT is a large streamlined safety study conducted in Scotland, England, Denmark and the Netherlands using the Prospective Randomised Open Blinded Endpoint design. Patients aged over 60 years with osteoarthritis or rheumatoid arthritis, free from established cardiovascular disease and requiring chronic NSAID therapy, are randomised to celecoxib or their previous traditional NSAID. They are then followed up for events by record-linkage within their normal healthcare setting. The hypothesis is non-inferiority with a confidence limit of 1.4. The primary endpoint is the first occurrence of hospitalisation or death for the Anti-Platelet Trialists’ Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are (1) first hospitalisation or death for upper gastrointestinal ulcer complications (bleeding, perforation or obstruction); (2) first occurrence of hospitalised upper gastrointestinal ulcer complications or APTC endpoint; (3) first hospitalisation for heart failure; (4) first hospitalisation for APTC endpoint plus heart failure; (5) all-cause mortality and (6) first hospitalisation for new or worsening renal failure. Ethics and dissemination SCOT has been approved by the relevant ethics committees. The trial results will be published in a peer-reviewed scientific journal.</p

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

This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/S0140-6736(15)00257-3BACKGROUND: 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. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. FINDINGS: Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. INTERPRETATION: Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. FUNDING: The British Heart Foundation and National Institute for Health Research.The study was funded by a special project grant from the British Heart Foundation (number SP/08/002). Further funding was provided by the National Institute for Health Research (NIHR) Comprehensive Local Research Networks. BW, PS, MC, and MJB are NIHR Senior Investigators, and are supported by, respectively, the NIHR UCL/UCL Hospitals Biomedical Research Centre, the Biomedical Research Centre award to Imperial College Healthcare NHS Trust, the NIHR Cardiovascular Biomedical research Unit at St Bartholomew’s Hospital, London, and the NIHR Biomedical Research Centre award to Cambridge University Hospitals NHS Trust. Blinded medication was packed by Alan Wong and colleagues at the Royal Free Hospital pharmac