The phenomenon of "one-trial tolerance" to the anxiolytic effect of chlordiazepoxide in the elevated plus-maze is abolished by the introduction of a motivational conflict situation.

A single exposure to the elevated plus-maze test of anxiety reduces or abolishes the anxiolytic efficacy of benzodiazepines. The present study was designed to examine whether this phenomenon of "one-trial tolerance" resulted from a motivational deficit on trial 2. We hypothesized that whereas there is a motivational conflict on trial 1 in relation to the open arms (exploration drive X natural fear of open spaces), there is no "reason" for an animal to explore it on trial 2. A motivational conflict was introduced on trial 2 by rendering the enclosed arms of the apparatus aversive on trial 1. Thus, every time rats entered the enclosed arms, an aversive situation (light and hot air blow) was produced until they left the arm. On trial 2, rats did not receive this aversive stimulation. Chlordiazepoxide significantly enhanced the percent open arm time as well as the percent open arm entries on trial 2 in rats that had been submitted to the aversive stimulation in the enclosed arms on trial 1, but was not effective in rats which had been exposed to the apparatus in the absence of the aversive stimulation on trial 1. In addition, there was no difference in the percent open arm time and entries on trial 2 between saline-treated rats submitted to the aversive or non-aversive condition on trial 1. The aversive condition on trial 1 did not modify the number of total arm entries on trial 2, either. The results suggest that the anxiolytic effect of chlordiazepoxide in the elevated plus-maze depends on the presence of a motivational conflict situation.     

Branched-Chain Amino Acids and Arginine Improve Performance in Two Consecutive Days of Simulated Handball Games in Male and Female Athletes: A Randomized Trial

The central nervous system plays a crucial role in the development of physical fatigue. The purpose of this study is to investigate the effect of combined supplementation of branched-chain amino acids (BCAA) and arginine on intermittent sprint performance in simulated handball games on 2 consecutive days. Methods: Fifteen male and seven female handball players consumed 0.17 g/kg BCAA and 0.04 g/kg arginine together (AA trial), or placebo (PB trial) before exercise. Each trial contained two 60-min simulated handball games on consecutive days. The game was consisted of 30 identical 2-min blocks and a 20 m all-out sprint was performed at the end of each block. The performance, measured by percentage changes of sprint time between day 1 and 2, was significantly better in the AA trial (first half: AA trial: -1.34±0.60%, PB trial: -0.21±0.69%; second half: AA trial: -1.68±0.58%, PB trial: 0.49±0.42%). The average ratings of perceive exertion throughout the 2-day trial was significantly lower in the AA trial (14.2±0.3) than the PB trial (15.1±0.4). Concurrently, post-exercise tryptophan/BCAA ratio on both days in the AA trial was significantly lower than the baseline. This study showed that BCAA and arginine supplementation could improve performance in intermittent sprints on the second consecutive day of simulated handball games in well-trained athletes by potentially alleviating central fatigue.     

门冬胰岛素、地特胰岛素、甘精胰岛素分别联合二甲双胍对糖尿病孕妇妊娠结局的影响

摘要 目的：探究门冬胰岛素、地特胰岛素、甘精胰岛素分别联合二甲双胍对糖尿病孕妇妊娠结局的影响。方法：随机抽取本院400例妊娠期糖尿病产妇为研究对象，按照简单随机法分为对照组（n=100例）、试验A组（n=100例）、试验B组（n=100例）和试验C组（n=100例）。对照组采用口服二甲双胍治疗，试验A、B、C组，分别采用门冬胰岛素、地特胰岛素、甘精胰岛素联合二甲双胍治疗。对比四组产妇的分娩方式，各产程时间，体重指数（BMI）、随机血糖、内脂素、脂联素的水平，妊娠并发症发生率，新生儿结局。结果：试验A、B、C组的自然分娩率均高于对照组（P<0.05），且试验A组的自然分娩率均高于试验B组、试验C组（P<0.05），试验B组、试验C组的自然分娩率对比无差异（P>0.05）；对照组、试验A、B、C组自然分娩产妇的第一产程、第二产程、第三产程时间对比无差异（P>0.05）；试验A、B、C组的BMI指数、随机血糖、内脂素、脂联素的水平均低于对照组（P<0.05），且试验A组的BMI指数、随机血糖、内脂素、脂联素的水平均低于试验B组、试验C组（P<0.05），试验B组、试验C组的BMI指数、随机血糖、内脂素、脂联素的水平对比无差异（P>0.05）；试验A、B、C组的妊娠并发症发生率均低于对照组（P<0.05），且试验A组的妊娠并发症发生率低于试验B组、试验C组（P<0.05），试验B组、试验C组的妊娠并发症发生率对比无差异（P>0.05）；试验A、B、C组的新生儿不良结局发生率均低于对照组（P<0.05），且试验A组的新生儿不良结局发生率低于试验B组、试验C组（P<0.05），试验B组、试验C组的新生儿不良结局发生率对比无差异（P>0.05）。结论：门冬胰岛素、地特胰岛素、甘精胰岛素分别联合二甲双胍均能够提高糖尿病孕妇妊娠的自然分娩率，降低BMI指数、随机血糖、内脂素、脂联素的水平，降低妊娠并发症发生率，改良新生儿不良结局，其中门冬胰岛素的疗效最好，具有较强的临床推广价值。     

How Often Does an Individual Trial Agree with Its Corresponding Meta-Analysis? A Meta-Epidemiologic Study

Objective

A meta-analysis may provide more conclusive results than a single trial. The major cost of meta-analysis is the time of waiting before the meta-analysis becomes available and resources spent on consequent trials that may not be necessary. The objective of this study is to address how often the result of a single trial, in particular the first trial, differs from that of its corresponding meta-analysis so as to reduce unnecessary waiting time and subsequent trials.

Study Design and Settings

A meta-epidemiologic study was conducted by collecting meta-analyses from the Cochrane Database of Systematic Reviews and five major medical journals. Effect size of a single trial was compared with that of its corresponding meta-analysis. The single trial includes the first trial, last trial and any trial randomly selected from the meta-analysis.

Results

647 meta-analyses are included and the median number of trials in a meta-analysis is 5. 233 (36.0%) meta-analyses have the first trial with a statistically significant result. When the first trial is statistically significant, 84.1% (95% CI: 79.4%, 88.8%) of the corresponding meta-analyses is both in the same direction and statistically significant. When the first trial is statistically insignificant, 57.9% (95% CI: 53.2%, 62.8%) of the meta-analysis is also statistically insignificant regardless of direction. The median number of years is 6.5 years from the first to the 5^th trial.

Conclusion

The conclusion of the first trial that the treatment is effective or harmful is mostly likely correct. A statistically significant trial agrees more often with its corresponding meta-analysis than a large trial. These findings imply that particularly in some urgent, life-saving or other critical circumstances for which no other effective methods are available, cautious recommendation based on the significant result of the first trial seems justifiable and could start use of an effective intervention by 5–8 years earlier.     

Incorporating Argumentation through Forensic Science

This article outlines how to incorporate argumentation into a forensic science unit using a mock trial. Practical details of the mock trial include: (1) a method of scaffolding students’ development of their argument for the trial, (2) a clearly outlined set of expectations for students during the planning and implementation of the mock trial, and (3) an example of how to use questioning to guide students through the planning of the mock trial. While a general forensic science unit is provided in the article, a teacher can use the details of the mock trial with any forensic science unit for either middle school or secondary science students.     

The phenomenon of one-trial tolerance to the anxiolytic effect of chlordiazepoxide in the elevated plus-maze test is abolished by previous administration of chlordiazepoxide or buspirone

It has been repeatedly reported that the anxiolytic action of benzodiazepines in the elevated plus-maze test is abolished in rats that have received a single prior experience of the test apparatus (one-trial tolerance effect). To analyze whether the one-trial tolerance effect of chlordiazepoxide can be influenced by administration of chlordiazepoxide or buspirone on trial 1, male Wistar rats received an IP injection of vehicle, chlordiazepoxide (8 mg/kg) or buspirone (2.5 mg/kg) 30 min. before testing for 5 min. in the plus-maze (trial 1). Seventy-two hours later, the rats received vehicle or chlordiazepoxide 30 min. before the re-exposure to the plus-maze for 5 min. (trial 2). Groups injected with chlordiazepoxide or buspirone on trial 1 and with chlordiazepoxide on trial 2 showed an anxiolytic effect of chlordiazepoxide on trial 2, as opposed to rats injected with vehicle on trial 1 and with chlordiazepoxide on trial 2. As opposed to previous studies, the present results suggest that the influence of prior experience with the plus-maze on the anxiolytic action of chlordiazepoxide during re-exposure seems to depend critically on the drug state in which trial 1 is experienced. These results are discussed with respect to the hypothesis proposed to explain the phenomenon of one-trial tolerance.     

Randomised controlled trial of treatment for mild hypertension: design and pilot trial. Report of Medical Research Council Working Party on Mild to Moderate Hypertension.

A multicentre pilot trial to assess the feasibility of undertaking a full-scale national trial of treatment for mild to moderate hypertension has been performed and is being continued. By February 1977 over 1800 patients had entered the trial and some have been under observation for three years. The results so far show that the definitive trial is administratively and scientifically feasible and ethically justified.     

Self-designing two-stage trials to minimize expected costs

In the design of clinical trials, the sample size for the trial is traditionally calculated from estimates of parameters of interest, such as the mean treatment effect, which can often be inaccurate. However, recalculation of the sample size based on an estimate of the parameter of interest that uses accumulating data from the trial can lead to inflation of the overall Type I error rate of the trial. The self-designing method of Fisher, also known as the variance-spending method, allows the use of all accumulating data in a sequential trial (including the estimated treatment effect) in determining the sample size for the next stage of the trial without inflating the Type I error rate. We propose a self-designing group sequential procedure to minimize the expected total cost of a trial. Cost is an important parameter to consider in the statistical design of clinical trials due to limited financial resources. Using Bayesian decision theory on the accumulating data, the design specifies sequentially the optimal sample size and proportion of the test statistic's variance needed for each stage of a trial to minimize the expected cost of the trial. The optimality is with respect to a prior distribution on the parameter of interest. Results are presented for a simple two-stage trial. This method can extend to nonmonetary costs, such as ethical costs or quality-adjusted life years.     

舟山眼镜蛇对光暗周期加热光源反应所导致的体温变化

用 7条舟山眼镜蛇 (Najaatra)研究动物对光暗周期加热光源反应所导致的体温变化。设计两项实验 ,每项实验历时 9d。实验一光照期覆盖整个白天 ,实验二光照期覆盖整个晚上。眼镜蛇仅在加热光源开启期间进行体温调节 ,但光照期内任何阶段都未发现所有个体同时处于热活动状态。两项实验中热活动个体百分比的时间变化显著 ,实验二热活动个体百分比波动相对大于实验一。在加热光源开启期间 ,实验一热活动眼镜蛇的百分比总体上大于实验二。在两项实验中 ,热活动眼镜蛇体温的时间变化都不显著。实验一热活动眼镜蛇的体温高于实验二 ,而两项实验中不处于热活动状态的眼镜蛇的平均体温无显著差异。实验一热活动眼镜蛇 (31 1±0 8°C)选择的体温上限高于实验二眼镜蛇 (2 6 0± 0 9°C)。在两项实验的任何时间段内 ,眼镜蛇的体温都不低于环境温度。     

Post‐trial obligations in the Declaration of Helsinki 2013: classification,reconstruction and interpretation

The general aim of this article is to give a critical interpretation of post‐trial obligations towards individual research participants in the Declaration of Helsinki 2013. Transitioning research participants to the appropriate health care when a research study ends is a global problem. The publication of a new version of the Declaration of Helsinki is a great opportunity to discuss it. In my view, the Declaration of Helsinki 2013 identifies at least two clearly different types of post‐trial obligations, specifically, access to care after research and access to information after research. The agents entitled to receive post‐trial access are the individual participants in research studies. The Declaration identifies the sponsors, researchers and host country governments as the main agents responsible for complying with the post‐trial obligations mentioned above. To justify this interpretation of post‐trial obligations, I first introduce a classification of post‐trial obligations and illustrate its application with examples from post‐trial ethics literature. I then make a brief reconstruction of the formulations of post‐trial obligations of the Declaration of Helsinki from 2000 to 2008 to correlate the changes with some of the most salient ethical arguments. Finally I advance a critical interpretation of the latest formulation of post‐trial obligations. I defend the view that paragraph 34 of ‘Post‐trial provisions’ is an improved formulation by comparison with earlier versions, especially for identifying responsible agents and abandoning ambiguous ‘fair benefit’ language. However, I criticize the disappearance of ‘access to other appropriate care’ present in the Declaration since 2004 and the narrow scope given to obligations of access to information after research.     

A parallel phase I/II clinical trial design for combination therapies

The use of multiple drugs in a single clinical trial or as a therapeutic strategy has become common, particularly in the treatment of cancer. Because traditional trials are designed to evaluate one agent at a time, the evaluation of therapies in combination requires specialized trial designs. In place of the traditional separate phase I and II trials, we propose using a parallel phase I/II clinical trial to evaluate simultaneously the safety and efficacy of combination dose levels, and select the optimal combination dose. The trial is started with an initial period of dose escalation, then patients are randomly assigned to admissible dose levels. These dose levels are compared with each other. Bayesian posterior probabilities are used in the randomization to adaptively assign more patients to doses with higher efficacy levels. Combination doses with lower efficacy are temporarily closed and those with intolerable toxicity are eliminated from the trial. The trial is stopped if the posterior probability for safety, efficacy, or futility crosses a prespecified boundary. For illustration, we apply the design to a combination chemotherapy trial for leukemia. We use simulation studies to assess the operating characteristics of the parallel phase I/II trial design, and compare it to a conventional design for a standard phase I and phase II trial. The simulations show that the proposed design saves sample size, has better power, and efficiently assigns more patients to doses with higher efficacy levels.     

Modification of cycling biomechanics during a swim-to-cycle trial

The aim of this study was to investigate the effects of drafting, i.e., swimming directly behind a competitor, on biomechanical adaptation during subsequent cycling. Eight well-trained male triathletes underwent three submaximal sessions in a counterbalanced order. These sessions comprised a 10-min ride on a bicycle ergometer at 75% of maximal aerobic power (MAP) at a freely chosen cadence. This exercise was preceded either by a 750-m swim performed alone at competition pace (SCA trial; swimming-cycling alone), a 750-m swim in a drafting position at the same pace as during SCA (SCD trial; swimming-cycling with drafting), or a cycling warm-up at 30% of MAP for the same duration as the SCA trial (CTRL trial). The results indicated that the decrease in metabolic load when swimming in a drafting position (SCD trial) was associated with a significantly lower pedal rate and significantly higher mean and peak resultant torques when compared to the SCA trial, p < 0.05. These results could be partly explained by the lower relative intensity during swimming in the SCD trial when compared with the SCA trial, involving a delayed manifestation of fatigue in the muscles of the lower limbs at the onset of cycling.     

Target populations for first-in-human embryonic stem cell research in spinal cord injury

Geron recently announced that it had begun enrolling patients in the world's first-in-human clinical trial involving cells derived from human embryonic stem cells (hESCs). This trial raises important questions regarding the future of hESC-based therapies, especially in spinal cord injury (SCI) patients. We address some safety and efficacy concerns with this research, as well as the ethics of fair subject selection. We consider other populations that might be better for this research: chronic complete SCI patients for a safety trial, subacute incomplete SCI patients for an efficacy trial, and perhaps primary progressive multiple sclerosis (MS) patients for a combined safety and efficacy trial.     

Sample Size Reassessment in Adaptive Clinical Trials Using a Bias Corrected Estimate

Point estimation in group sequential and adaptive trials is an important issue in analysing a clinical trial. Most literature in this area is only concerned with estimation after completion of a trial. Since adaptive designs allow reassessment of sample size during the trial, reliable point estimation of the true effect when continuing the trial is additionally needed. We present a bias adjusted estimator which allows a more exact sample size determination based on the conditional power principle than the naive sample mean does.     

Blood-brain barrier integrity may be threatened by exercise in a warm environment

Seven active men were recruited to examine changes in the serum concentration of S100beta, a proposed peripheral marker of blood-brain barrier permeability, following prolonged exercise in temperate (T) and warm (W) conditions. Subjects were seated immersed to the neck in water at 35.0 (0.1) degrees C (T) or 39.0 (0.1) degrees C (W) for 30 min. Subjects then entered a room maintained at either 18.3 (1.8) degrees C (T) or 35.0 (0.3) degrees C (W) and completed 60 min of cycle exercise at 60% peak oxygen uptake. Serum S100beta concentration was elevated after exercise in the W trial (+0.12 (0.10) microg/l; P = 0.02) but not after the T trial (P = 0.238). Water immersion and exercise elevated core temperature by 2.1 (0.5) degrees C to 39.5 (0.3) degrees C at the end of exercise in the W trial compared with a 0.9 (0.2) degrees C increase during the T trial (P < 0.001). Weighted mean skin temperature was higher throughout the W trial compared with the T trial (P < 0.001). Heart rate (P < 0.001) and blood glucose (P < 0.001) and lactate (P < 0.001) concentrations were elevated to a greater extent during exercise in the W trial than in the T trial. Ratings of perceived exertion (P < 0.001) and thermal comfort (P < 0.001) were markedly higher throughout the W trial than in the T trial. The results of this study demonstrate that serum S100beta was elevated after water immersion and prolonged exercise in a warm environment, suggesting that blood-brain barrier permeability may be altered.     

Enhancement of fat metabolism by repeated bouts of moderate endurance exercise.

This study compared the fat metabolism between "a single bout of prolonged exercise" and "repeated bouts of exercise" of equivalent exercise intensity and total exercise duration. Seven men performed three trials: 1) a single bout of 60-min exercise (Single); 2) two bouts of 30-min exercise, separated by a 20-min rest between exercise bouts (Repeated); and 3) rest. Each exercise was performed with a cycle ergometer at 60% of maximal oxygen uptake. In the Single and Repeated trials, serum glycerol, growth hormone, plasma epinephrine, and norepinephrine concentrations increased significantly (P<0.05) during the first 30-min exercise bout. In the Repeated trial, serum free fatty acids (FFA), acetoacetate, and 3-hydroxybutyrate concentrations showed rapid increases (P<0.05) during a subsequent 20-min rest period. During the second 30-min exercise bout, FFA and epinephrine responses were significantly greater in the Repeated trial than in the Single trial (P<0.05). Moreover, the Repeated trial showed significantly lower values of insulin and glucose than the Single trial. During the 60-min recovery period after the exercise, FFA, glycerol, and 3-hydroxybutyrate concentrations were significantly higher in the Repeated trial than in the Single trial (P<0.05). The relative contribution of fat oxidation to the energy expenditure showed significantly higher values (P<0.05) in the Repeated trial than in the Single trial during the recovery period. These results indicate that repeated bouts of exercise cause enhanced fat metabolism compared with a single bout of prolonged exercise of equivalent total exercise duration.     

Elacestrant in metastatic breast cancer: Is the “standard of care” meeting standard requirements?

The EMERALD trial was an open label phase 3 trial evaluating elacestrant, the first oral selective estrogen receptor degrader (SERD), as compared to “standard of care”, in ER+/HER2- (hormone receptor positive, no HER2 overexpression) advanced or metastatic breast cancer.The EMERALD trial restricted the “standard of care” control arm to limited options that may have led to a substandard control arm. We describe how the EMERALD trial protocol allowed different clinically inappropriate scenarios in the control arm, according to prior therapy. The main relevant question remains the potential advantage of elacestrant over fulvestrant in fulvestrant-naive patients.Analyzing outcomes in subgroups according to prior and per-protocol therapy would help analyzing trial results. However, these subgroup results may be non-significant, and another randomized trial will be needed. Trials should be designed to answer directly clinical questions that are relevant.     

Setting up a pragmatic clinical trial in a low-resource setting: A qualitative assessment of GoLBeT,a trial of podoconiosis management in Northern Ethiopia

BackgroundClinical trials are often perceived as being expensive, difficult and beyond the capacity of healthcare workers in low-resource settings. However, in order to improve healthcare coverage, the World Health Organization (WHO) World Health Report 2013 stated that all countries need to become generators as well as recipients of data. This study is a methodological examination of the steps and processes involved in setting up the Gojjam Lymphoedema Best Practice Trial (GoLBeT; ISRCTN67805210), a highly pragmatic clinical trial conducted in northern Ethiopia. Challenges to the trial and strategies used to deal with them were explored, together with the reasons for delays.Methodology and principal findingsQualitative research methods were used to analyse emails and reports from the period between trial inception and recruitment. This analysis was complemented by interviews with key informants from the trial operational team. The Global Health Research Process Map was used as a framework against which to compare the steps involved in setting up the trial. A mini-group discussion was conducted with the trial operational team after study completion for reflection and further recommendations.This study showed that the key areas of difficulty in setting up and planning this trial were: the study design, that is, deciding on the study endpoint, where and how best to measure it, and assuring statistical power; recruitment and appropriate training of staff; planning for data quality; and gaining regulatory approvals. Collaboration, for example with statisticians, the trial steering committee, the study monitors, and members of the local community was essential to successfully setting up the trial.Conclusions and significanceLessons learnt from this trial might guide others planning pragmatic trials in settings where research is not common, allowing them to anticipate possible challenges and address them through trial design, planning and operational delivery. We also hope that this example might encourage similar pragmatic studies to be undertaken. Such studies are rarely undertaken or locally led, but are an accessible and efficient way to drive improved outcomes in public health.     

Passive triceps surae stretch inhibits vasoconstriction in the nonexercised limb during posthandgrip muscle ischemia.

We investigated whether selective muscle mechanoreceptor activation in the lower limb opposes arm muscle metaboreceptor activation-mediated limb vasoconstriction. Seven subjects completed two trials: one control trial and one stretch trial. Both trials included 2 min of handgrip and 2 min of posthandgrip exercise muscle ischemia (PEMI). In the stretch trial, a 2-min sustained triceps surae stretch, by brief passive dorsiflexion of the right foot, was performed simultaneously during PEMI. Mean arterial pressure, heart rate, and forearm blood flow (FBF) in the nonexercised arm and forearm vascular conductance (FVC) in the nonexercised arm were measured. During PEMI in the control trial, mean arterial pressure was significantly greater and FBF and FVC were significantly lower than baseline values (P < 0.05 for each). In contrast, FBF and FVC during PEMI in the stretch trial exhibited different responses than in the control trial. FBF and FVC were significantly greater in the stretch trial than in the control trial (FBF, 5.5 +/- 0.4 vs. 3.8 +/- 0.4 ml x 100 ml(-1) x min(-1); FVC, 0.048 +/- 0.004 vs. 0.033 +/- 0.003 unit, respectively; P < 0.05). These results indicate that passive triceps surae stretch can inhibit vasoconstriction in the nonexercised forearm mediated via muscle metaboreceptor activation in the exercised arm.