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Concept: The Trial


The purpose this study was to examine the effects of caffeine ingestion on performance and energy expenditure (anaerobic and aerobic contribution) during a 4-km cycling time trial (TT) performed after a carbohydrate (CHO) availability-lowering exercise protocol. After preliminary and familiarization trials, seven amateur cyclists performed three 4-km cycling TT in a double-blind, randomized and crossover design. The trials were performed either after no previous exercise (CON), or after a CHO availability-lowering exercise protocol (DEP) performed in the previous evening, followed by either placebo (DEP-PLA) or 5 of caffeine intake (DEP-CAF) 1 hour before the trial. Performance was reduced (-2.1%) in DEP-PLA vs CON (421.0±12.3 vs 412.4±9.7 s). However, performance was restored in DEP-CAF (404.6±17.1 s) compared with DEP-PLA, while no differences were found between DEP-CAF and CON. The anaerobic contribution was increased in DEP-CAF compared with both DEP-PLA and CON (67.4±14.91, 47. 3±14.6 and 55.3±14.0 W, respectively), and this was more pronounced in the first 3 km of the trial. Similarly, total anaerobic work was higher in DEP-CAF than in the other conditions. The integrated electromyographic activity, plasma lactate concentration, oxygen uptake, aerobic contribution and total aerobic work were not different between the conditions. The reduction in performance associated with low CHO availability is reversed with caffeine ingestion due to a higher anaerobic contribution, suggesting that caffeine could access an anaerobic “reserve” that is not used under normal conditions.

Concepts: Oxygen, Cellular respiration, Cycling, Caffeine, The Trial, Aerobic exercise, Anaerobic exercise, Individual time trial


We report information about an unpublished 1970s study (“8-way” Bendectin Study) that aimed to evaluate the relative therapeutic efficacy of doxylamine, pyridoxine, and dicyclomine in the management of nausea and vomiting during pregnancy. We are publishing the trial’s findings according to the restoring invisible and abandoned trials (RIAT) initiative because the trial was never published.

Concepts: Epidemiology, Randomized controlled trial,, Efficacy, The Trial, Nausea, Trial, Morning sickness


BACKGROUND: Hypohydration and hyperthermia are factors that may contribute to fatigue and impairment of endurance performance. The purpose of this study was to investigate the effectiveness of combining glycerol hyperhydration and an established precooling technique on cycling time trial performance in hot environmental conditions. METHODS: Twelve well-trained male cyclists performed three 46.4-km laboratory-based cycling trials that included two climbs, under hot and humid environmental conditions (33.3 +/- 1.1[degree sign]C; 50 +/- 6% r.h.). Subjects were required to hyperhydrate with 25 body mass (BM) of a 4[degree sign]C beverage containing 6% carbohydrate (CON) 2.5 h prior to the time trial. On two occasions, subjects were also exposed to an established precooling technique (PC) 60 min prior to the time trial, involving 14 BM ice slurry ingestion and applied iced towels over 30 min. During one PC trial, 1.2 BM glycerol was added to the hyperhydration beverage in a double-blind fashion (PC+G). Statistics used in this study involve the combination of traditional probability statistics and a magnitude-based inference approach. RESULTS: Hyperhydration resulted in large reductions (-0.6 to -0.7[degree sign]C) in rectal temperature. The addition of glycerol to this solution also lowered urine output (330 ml, 10%). Precooling induced further small (-0.3[degree sign]C) to moderate (-0.4[degree sign]C) reductions in rectal temperature with PC and PC+G treatments, respectively, when compared with CON (0.0[degree sign]C, P<0.05). Overall, PC+G failed to achieve a clear change in cycling performance over CON, but PC showed a possible 2% (30 s, P=0.02) improvement in performance time on climb 2 compared to CON. This improvement was attributed to subjects' lower perception of effort reported over the first 10 km of the trial, despite no clear performance change during this time. No differences were detected in any other physiological measurements throughout the time trial. CONCLUSIONS: Despite increasing fluid intake and reducing core temperature, performance and thermoregulatory benefits of a hyperhydration strategy with and without the addition of glycerol, plus practical precooling, were not superior to hyperhydration alone. Further research is warranted to further refine preparation strategies for athletes competing in thermally stressful events to optimize health and maximize performance outcomes.

Concepts: Physiology, Thermoregulation, Temperature, Hyperthermia, Humidity, The Trial, Normal human body temperature, Individual time trial


Intellectual property is associated with the creative work needed to design clinical trials. Two approaches have developed to protect the intellectual property associated with multicentre trial protocols prior to site initiation.The ‘open access’ approach involves publishing the protocol, permitting easy access to the complete protocol. The main advantages of the open access approach are that the protocol is freely available to all stakeholders, permitting them to discuss the protocol widely with colleagues, assess the quality and rigour of the protocol, determine the feasibility of conducting the trial at their centre, and after trial completion, to evaluate the reported findings based on a full understanding of the protocol. The main potential disadvantage of this approach is the potential for plagiarism; however if that occurred, it should be easy to identify because of the open access to the original trial protocol, as well as ensure that appropriate sanctions are used to deal with plagiarism.The ‘restricted access’ approach involves the use of non-disclosure agreements, legal documents that must be signed between the trial lead centre and collaborative sites. Potential sites must guarantee they will not disclose any details of the study before they are permitted to access the protocol. The main advantages of the restricted access approach are for the lead institution and nominated principal investigator, who protect their intellectual property associated with the trial. The main disadvantages are that ownership of the protocol and intellectual property is assigned to the lead institution; defining who ‘needs to know’ about the study protocol is difficult; and the use of non-disclosure agreements involves review by lawyers and institutional representatives at each site before access is permitted to the protocol, significantly delaying study implementation and adding substantial indirect costs to research institutes. This extra step may discourage sites from joining a trial.It is possible that the restricted access approach may contribute to the failure of well-designed trials without any significant benefit in protecting intellectual property. Funding agencies should formalize rules around open versus restricted access to the study protocol just as they have around open access to results.

Concepts: Clinical trial,, Law, Clinical research, The Trial, Trial, Intellectual property law, Legal documents


Currently, observations of an agricultural land system (ALS) largely depend on remotely-sensed images, focusing on its biophysical features. While social surveys capture the socioeconomic features, the information was inadequately integrated with the biophysical features of an ALS and the applications are limited due to the issues of cost and efficiency to carry out such detailed and comparable social surveys at a large spatial coverage. In this paper, we introduce a smartphone-based app, called eFarm: a crowdsourcing and human sensing tool to collect the geotagged ALS information at the land parcel level, based on the high resolution remotely-sensed images. We illustrate its main functionalities, including map visualization, data management, and data sensing. Results of the trial test suggest the system works well. We believe the tool is able to acquire the human-land integrated information which is broadly-covered and timely-updated, thus presenting great potential for improving sensing, mapping, and modeling of ALS studies.

Concepts: Better, Sociology, Data, Observation, The Trial, Graphic design, Large


Two large cardiovascular outcome trials of canagliflozin, the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study - Renal (CANVAS-R). Accruing data for the sodium-glucose co-transporter 2 inhibitor (SGLT2i) class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses. These updates will ensure that the data from the CANVAS Program will maximise advances in scientific knowledge and patient care. The specification of the analysis strategy prior to knowledge of the trial results, their design by the independent scientific trial Steering Committee, the detailed a priori definition of the analysis plans and the external review provided by the US Food and Drug Administration, all provide for a maximally efficient and robust utilisation of the data. The CANVAS Program should significantly advance our understanding of the effects of canagliflozin, and the broader SGLT2i class, on a range of important efficacy and safety outcomes.

Concepts: Game theory, Scientific method, Thought, The Trial, Logic, A priori, A priori and a posteriori, Plan


Background We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry. Methods During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials. Results Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals. Conclusions Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT number, NCT01692379 .).

Concepts: Stroke, Intracranial pressure, Modified Rankin Scale, Odds ratio, Ischemia, The Trial, Disability, Barthel scale


Background Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery. Methods We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 μg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30-day mortality. Results The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30-day mortality between the levosimendan group and the placebo group (32 patients [12.9%] and 33 patients [12.8%], respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval [CI], -5.7 to 5.9; P=0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, -2 hours; 95% CI, -5 to 1; P=0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, -12 hours; 95% CI, -21 to 2; P=0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, -1 to 2; P=0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias. Conclusions In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH number, NCT00994825 .).

Concepts: Medical statistics, Statistical significance, Cardiac arrest, Addition, Placebo, Normal distribution, The Trial, Integer


Background Evidence for the management of chronic obstructive pulmonary disease (COPD) comes from closely monitored efficacy trials involving groups of patients who were selected on the basis of restricted entry criteria. There is a need for randomized trials to be conducted in conditions that are closer to usual clinical practice. Methods In a controlled effectiveness trial conducted in 75 general practices, we randomly assigned 2799 patients with COPD to a once-daily inhaled combination of fluticasone furoate at a dose of 100 μg and vilanterol at a dose of 25 μg (the fluticasone furoate-vilanterol group) or to usual care (the usual-care group). The primary outcome was the rate of moderate or severe exacerbations among patients who had had an exacerbation within 1 year before the trial. Secondary outcomes were the rates of primary care contact (contact with a general practitioner, nurse, or other health care professional) and secondary care contact (inpatient admission, outpatient visit with a specialist, or visit to the emergency department), modification of the initial trial treatment for COPD, and the rate of exacerbations among patients who had had an exacerbation within 3 years before the trial, as assessed in a time-to-event analysis. Results The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group. The numbers of other serious adverse events were similar in the two groups. Conclusions In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events. (Funded by GlaxoSmithKline; Salford Lung Study number, NCT01551758 .).

Concepts: Health care, Health care provider, Clinical trial, Asthma, Pneumonia, Chronic obstructive pulmonary disease, Efficacy, The Trial


Background Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. Methods We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. Results The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], -0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, -4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). Conclusions The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039 .).

Concepts: Pharmacology, Epidemiology, Clinical trial, Randomized controlled trial, Intensive care medicine, Clinical research, Placebo, The Trial