Randomised Controlled Trials May Underestimate Drug Effects: Balanced Placebo Trial Design

Background

It is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment.

Objective

To test the assumption of additivity. The primary hypothesis was that the total treatment effect is smaller than the sum of the drug effect and the placebo effect. The secondary hypothesis was that non-additivity was most pronounced in participants with large placebo effects.

Methods

We used a within-subject randomised blinded balanced placebo design and included 48 healthy volunteers (50% males), mean (SD) age 23.4 (6.2) years. Experimental pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections with hypertonic saline along with lidocaine or matching placebo in randomised order: A: received hypertonic saline/told hypertonic saline; B: received hypertonic saline+lidocaine/told hypertonic saline; C: received hypertonic saline+placebo/told hypertonic saline+pain killer; D: received hypertonic saline+lidocaine/told hypertonic saline+pain killer. The primary outcome measure was the area under the curve (AUC, mm²) of pain intensity during injections.

Results

There was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm² (95% CI, 4936–7622)) and the total treatment effect (mean AUC 5455 mm² (95% CI, 4585–6324)) (P = 0.049). This difference was larger for participants with large versus small placebo effects (P = 0.015), and the difference correlated significantly with the size of the placebo effect (r = 0.65, P = 0.006).

Conclusion

Although this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, particularly in studies reporting large placebo responses. The implications for randomised controlled trials and systematic reviews need to be discussed.     

On the Construction of Balanced and Partially Balanced Ternary Design

A method of constructing balanced and partially balanced ternary designs from balanced and partially balanced incomplete block designs, respectively, and two methods of constructing partially balanced ternary designs from association schemes are obtained. Two new and efficient balanced ternary designs having K < V and R ≦ 20 are obtained by the first method.     

Nausea and Vomiting following Balanced Xenon Anesthesia Compared to Sevoflurane: A Post-Hoc Explorative Analysis of a Randomized Controlled Trial

ObjectiveLike other inhalational anesthetics xenon seems to be associated with post-operative nausea and vomiting (PONV). We assessed nausea incidence following balanced xenon anesthesia compared to sevoflurane, and dexamethasone for its prophylaxis in a randomized controlled trial with post-hoc explorative analysis.Methods220 subjects with elevated PONV risk (Apfel score ≥2) undergoing elective abdominal surgery were randomized to receive xenon or sevoflurane anesthesia and dexamethasone or placebo after written informed consent. 93 subjects in the xenon group and 94 subjects in the sevoflurane group completed the trial. General anesthesia was maintained with 60% xenon or 2.0% sevoflurane. Dexamethasone 4mg or placebo was administered in the first hour. Subjects were analyzed for nausea and vomiting in predefined intervals during a 24h post-anesthesia follow-up.ResultsLogistic regression, controlled for dexamethasone and anesthesia/dexamethasone interaction, showed a significant risk to develop nausea following xenon anesthesia (OR 2.30, 95% CI 1.02–5.19, p = 0.044). Early-onset nausea incidence was 46% after xenon and 35% after sevoflurane anesthesia (p = 0.138). After xenon, nausea occurred significantly earlier (p = 0.014), was more frequent and rated worse in the beginning. Dexamethasone did not markedly reduce nausea occurrence in both groups. Late-onset nausea showed no considerable difference between the groups.ConclusionIn our study setting, xenon anesthesia was associated with an elevated risk to develop nausea in sensitive subjects. Dexamethasone 4mg was not effective preventing nausea in our study. Group size or dosage might have been too small, and change of statistical analysis parameters in the post-hoc evaluation might have further contributed to a limitation of our results. Further trials will be needed to address prophylaxis of xenon-induced nausea.

Trial Registration

EU Clinical Trials EudraCT-2008-004132-20ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00793663","term_id":"NCT00793663"}}NCT00793663     

The Effects of Thiethylperazine Dimaleate (Torecan) on Nausea and Vomiting

A double-blind study of thiethylperazine dimaleate (Torecan) and a placebo, given intramuscularly, was carried out on 40 patients with nausea and/or vomiting due to a variety of causes. No effect on these symptoms was noted in five patients who received the drug and in six who received the placebo. Thiethylperazine dimaleate was judged to have a good effect in 14 patients and the placebo in five patients. The placebo had a slight effect in nine patients and the drug in one.     

AMF和PGPR对生姜青枯病的影响

丛枝菌根真菌(Arbuscular mycorrhizal fungi,AMF)与植物根围促生细菌(Plant growth-promoting rhizobacteria,PGPR)占据相近的生态位,对植物病原物及其所致病害的发生与发展具有重要影响。本试验旨在于温室盆栽条件下探索AMF摩西管柄囊霉(Funneliformis mosseae,Fm)、根内球囊霉(Glomus intraradices,Gi)和地表球囊霉(Glomus versiforme,Gv)与PGPR假单胞菌(Pseudomonus sp.)S1-10菌株和S3-11菌株的相互作用及其对生姜(Zingiber officinale)青枯病(Ralstonia solanacearum,RS1)的影响。试验结果表明Gv显著增加假单胞菌S3-11菌株在生姜根围的定殖数量(P0.05),除生姜幼苗期外Fm则能促进S3-11菌株和S1-10菌株在根围内的定殖。PGPR S1-10和S3-11显著促进发棵期和块茎膨大期生姜AMF的侵染;发棵期S1-10显著提高了Gi的侵染率,但显著降低了Gv的侵染率(P0.05);块茎膨大期S3-11对Gv侵染(64%)的促进作用最大。AMF或/和PGPR(除S1-10外)接种处理均不同程度地促进了生姜的生长,其中Gv+S3-11组合处理的生姜生长量最大,其次为Fm+S3-11组合。无论是单接种还是双接种,供试PGPR和AMF均显著提高叶片防御性酶超氧物歧化酶(SOD)、过氧化物酶(POD)、苯丙氨酸(PAL)和过氧化氢酶(CAT)活性,降低丙二醛(MDA)含量和生姜青枯病的病情指数,其中,以Gv+S3-11组合处理的病情指数最低(25.5),且防效最高(71%)。研究结果表明AMF地表球囊霉与PGPR假单胞菌S3-11菌株组合能够相互促进、协同抑制生姜青枯病菌、诱导生姜抗病性、促进生姜生和增加产量,是适宜生姜生长的优良AMF+PGPR组合。     

Behavioural and Physiological Effects of Finely Balanced Decision-Making in Chickens

In humans, more difficult decisions result in behavioural and physiological changes suggestive of increased arousal, but little is known about the effect of decision difficulty in other species. A difficult decision can have a number of characteristics; we aimed to monitor how finely balanced decisions, compared to unbalanced ones, affected the behaviour and physiology of chickens. An unbalanced decision was one in which the two options were of unequal net value (1 (Q1) vs. 6 (Q6) pieces of sweetcorn with no cost associated with either option); a finely balanced decision was one in which the options were of equal net value (i.e. hens were "indifferent" to both options). To identify hens'' indifference, a titration procedure was used in which a cost (electromagnetic weight on an access door) was applied to the Q6 option, to find the individual point at which hens chose this option approximately equally to Q1 via a non-weighted door. We then compared behavioural and physiological indicators of arousal (head movements, latency to choose, heart-rate variability and surface body temperature) when chickens made decisions that were unbalanced or finely balanced. Significant physiological (heart-rate variability) and behavioural (latency to pen) differences were found between the finely balanced and balanced conditions, but these were likely to be artefacts of the greater time and effort required to push through the weighted doors. No other behavioural and physiological measures were significantly different between the decision categories. We suggest that more information is needed on when best to monitor likely changes in arousal during decision-making and that future studies should consider decisions defined as difficult in other ways.     

网隔栽培法对生姜姜瘟病防治及产量的影响

姜瘟病是由青枯雷尔氏菌(Ralstoniasolanacearum)引起的一种细菌性病害,被称为生姜种植产业的“癌症”.本试验设计了一种“网隔栽培法”,并探索其对土传姜瘟病发病率和生姜产量的影响.结果表明,经过连续3年的田间验证,相比传统栽培法,“网隔栽培法”种植可显著降低姜瘟病的发病率,平均减少了6.08个百分点,平均防治效果达到了48.33%;同时,生姜产量平均增加了13.21%.这种“短行播种、纵横开沟、深沟隔病”的“网隔栽培法”为姜瘟病的绿色防控提供了新方案,也为其他蔬菜、中药材等植物的土传病害防治提供了新的借鉴思路.     

Beneficial Effects of Jejeunoileostomy on Compulsive Eating and Associated Psychiatric Symptoms

During a study of 72 patients submitted to jejeunoileostomy for obesity seven were found in whom compulsive, episodic overeating was associated with depressive mood disturbance. When followed up nine to 27 months after operation all seven had lost weight and had also lost the habit of compulsive eating. In all cases psychiatric symptoms improved or disappeared, and symptom substitution was not observed. Obesity rather than psychiatric disorder is usually the main problem in such patients. The implications for psychoanalytic and other concepts of obesity are discussed.     

The Effects of a Problem Solving-Based Intervention on Depressive Symptoms and HIV Medication Adherence Are Independent

Depression and depressive symptoms predict poor adherence to medical therapy, but the association is complex, nonspecific, and difficult to interpret. Understanding this association may help to identify the mechanism explaining the results of interventions that improve both medical therapy adherence and depressive symptoms as well as determine the importance of targeting depression in adherence interventions. We previously demonstrated that Managed Problem Solving (MAPS) focused on HIV medication adherence improved adherence and viral load in patients initiating a new antiretroviral regimen. Here, we assessed whether MAPS improved depressive symptoms and in turn, whether changes in depressive symptoms mediated changes in adherence and treatment outcomes. We compared MAPS to usual care with respect to presence of depressive symptoms during the trial using logistic regression. We then assessed whether MAPS’ effect on depressive symptoms mediated the relationship between MAPS and adherence and virologic outcomes using linear and logistic regression, respectively. Mediation was defined by the disappearance of the mathematical association between MAPS and the outcomes when the proposed mediator was included in regression models. Although MAPS participants had a lower rate of depressive symptoms (OR = 0.45, 95% confidence interval 0.21–0.93), there was no evidence of mediation of the effects of MAPS on adherence and virological outcome by improvements in depression. Thus, interventions for medication adherence may not need to address depressive symptoms in order to impact both adherence and depression; this remains to be confirmed, however, in other data.     

Placebo in the treatment of pain

Placebo is the use of the substance or procedure without specific activity for the condition that is trying to be healed. In medicine, benefits of placebo effect are used since 1985 and 1978 placebo effect was first scientifically confirmed. It was found that placebo induced analgesia depends on the release of endogenous opiates in the brain and that the placebo effect can be undone using the opiates antagonist naloxone. Functional magnetic resonance imaging of the brain showed that placebo analgesia was obtained regarding the activation and increased functional relationship between ant. cingulate, prefrontal, orbitofrontal, and insular cortex, nucleus accumlens, amygdala, periaqueduktalne gray matter and spinal cord. Placebo also facilitates descending inhibition of nociceptive reflexes through periacvaeductal gray substance. Placebo effect can be achieved in several ways: by using pharmacological preparations or simulation of operating or other procedures. This phenomenon is associated with perception and expectation of the patient. To achieve the effect of placebo it is essential degree of the suggestions of the person who prescribe a placebo, and the degree of belief of the person receiving the placebo. Expected effect of placebo is to achieve the same effect as the right remedy. Achieved placebo effect depends on the way of presentation. If a substance is presented as harmful, it may cause harmful effects, called 'nocebo" effect. Placebo effect is not equal in all patients, same as the real effect of the drug is not always equal in all patients. Application of placebo in terms of analgesia will cause a positive response in 35% of patients. Almost the same percentage (36%) of patients will respond to treatment with morphine in medium doses (6-8 mg). Therefore, one should remember that response to placebo does not mean that a person simulates the pain and then it is unethical to withhold the correct treatment especially in light of findings that the prefrontal cortex is activated expecting liberation of pain and how this action reduce activities in brain regions responsible for sensation of pain (thalamus, somatosensory cortex and other parts of the cortex). However, the use of placebos is ethically, legally and morally very dubious. The basis for the placebo effect is deception. It undermines honest relationship and trust between doctor and patient which is extremely important for successful treatment. Consciously giving placebos to patients for a condition that can be adequately treated, with prejudice the right of patients to the best care possible, opens up many bioethical issues. Despite all the current knowledge level, placebo effect remains still a scientific mystery.     

Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity

Objective

Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3).

Method

Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33).

Results

We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity.

Conclusions

We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis.     

A Comparison of the Effects of Chlorothiazide,Quinethazone and Placebo on Student Volunteers and on Rats: A Teaching Exercise

Medical student participation in a controlled doubleblind clinical bioassay provides an effective introduction to clinical pharmacology and perhaps the best stimulus to the future rational evaluation and use of drugs. In one such exercise, 27 volunteers were divided into three groups: one received 50 mg. quinethazone, one 500 mg. chlorothiazide and the third a lactose placebo. Urine was collected for three 90-minute periods, volume and pH being recorded; sodium and potassium were measured with a flame photometer, and chloride by the Volhard technique. Although this study was primarily a comparative bioassay of two established diuretics against a placebo, no previous direct comparisons of these diuretics could be found in the literature. The diuretic activity of chlorothiazide and quinethazone compared to placebo therapy was confirmed in both humans and rats, the use of controls was illustrated, and a higher mean sodium-potassium ratio for quinethazone than for chlorothiazide was demonstrated.     

生姜脱菌快繁研究进展

生姜是重要的经济作物 ,可用作香料、药物和调味品 ,它主要通过地下根状茎繁殖。自 1 977年生姜脱菌组培获得成功以来 ,在外植体的选择、培养基和培养条件等脱菌快繁技术上都有较大改进 ,培养效率明显提高 ,平均每个芽可增殖 7.7个芽 ,移栽成活率高达 95 %以上。就生姜脱菌快繁技术的发展及其应用前景 ,诸如创造遗传变异、离体种质保存、脱菌种子包衣和离体小块茎生产等作了综述。