What is meant by intention to treat analysis? Survey of published randomised controlled trials

ObjectivesTo assess the methodological quality of intention to treat analysis as reported in randomised controlled trials in four large medical journals.DesignSurvey of all reports of randomised controlled trials published in 1997 in the BMJ, Lancet, JAMA, and New England Journal of Medicine.Results119 (48%) of the reports mentioned intention to treat analysis. Of these, 12 excluded any patients who did not start the allocated intervention and three did not analyse all randomised subjects as allocated. Five reports explicitly stated that there were no deviations from random allocation. The remaining 99 reports seemed to analyse according to random allocation, but only 34 of these explicitly stated this. 89 (75%) trials had some missing data on the primary outcome variable. The methods used to deal with this were generally inadequate, potentially leading to a biased treatment effect. 29 (24%) trials had more than 10% of responses missing for the primary outcome, the methods of handling the missing responses were similar in this subset.ConclusionsThe intention to treat approach is often inadequately described and inadequately applied. Authors should explicitly describe the handling of deviations from randomised allocation and missing responses and discuss the potential effect of any missing response. Readers should critically assess the validity of reported intention to treat analyses.

Key messages

• Intention to treat gives a pragmatic estimate of the benefit of a change in treatment policy rather than of potential benefit in patients who receive treatment exactly as planned
• Full application of intention to treat is possible only when complete outcome data are available for all randomised subjects
• About half of all published reports of randomised controlled trials stated that intention to treat was used, but handling of deviations from randomised allocation varied widely
• Many trials had some missing data on the primary outcome variable, and methods used to deal with this were generally inadequate, potentially leading to bias
• Intention to treat analyses are often inadequately described and inadequately applied

     

Ethics of randomised controlled trials – not yet time to give up on equipoise

In this commentary on Fries and Krishnan's argument that 'design bias' undermines the status of equipoise as the ethical justification for randomised controlled trials, it is argued that their argument is analogous to Bayesian arguments for the use of informative priors in trial design, but that this does not undermine the importance of equipoise. In particular, mismatches between the outcomes of interest to industrial sponsors of research and outcomes of interest to patients and clinicians ensure that in many cases industry-sponsored trials can fail to reflect the reasonable equipoise of working clinicians.     

What happens to the DNA vaccine in fish? A review of current knowledge

The primary function of DNA vaccines, a bacterial plasmid DNA containing a construct for a given protective antigen, is to establish specific and long-lasting protective immunity against diseases where conventional vaccines fail to induce protection. It is acknowledged that less effort has been made to study the fate, in terms of cellular uptake, persistence and degradation, of DNA vaccines after in vivo administration. However, during the last year some papers have given new insights into the fate of DNA vaccines in fish. By comparing the newly acquired information in fish with similar knowledge from studies in mammals, similarities with regard to transport, blood clearance, cellular uptake and degradation of DNA vaccines have been found. But the amount of DNA vaccine redistributed from the administration site after intramuscular administration seems to differ between fish and mammals. This review presents up-to-date and in-depth knowledge concerning the fate of DNA vaccines with emphasis on tissue distribution, cellular uptake and uptake mechanism(s) before finally describing the intracellular hurdles that DNA vaccines need to overcome in order to produce their gene product.     

Can testing clinical significance reduce false positive rates in randomized controlled trials? A snap review

Objective

The use of minimum clinically important difference in the hypothesis formulation for superiority trials is similar in principle to the concept of non-inferiority or equivalence trial. However, most clinical trials are analysed testing zero clinical difference. Since the minimum clinically important difference is pre-defined for power calculation, it is important to incorporate it in both the hypothesis testing and the interpretation of findings from clinical trials.

Results

We reviewed a set of 50 publications (25 with binary outcome, and 25 with survival time outcome). 20% of the 50 published trials that were statistically significant, were also clinically significant based on the minimum clinically important risk differences (or hazard ratio) used for their power calculations. This snap review seems to suggest that most published trials with statistically significant results were less likely to be clinically significant, which may partly explain the high false positive findings associated with findings from superiority trials. Furthermore, none of the reviewed publications explicitly used minimum clinically important difference in the interpretation of their findings. However, a systematic review is needed to critically appraise the impact of the current practice on false positive rate in published trials with significant findings.

     

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

Background aimsEvidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs.MethodsA systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19.ResultsEight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42–0.94, P = 0.02, I² = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB.ConclusionsMSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.     

Long acting β2 agonists for stable chronic obstructive pulmonary disease with poor reversibility: a systematic review of randomised controlled trials

Background

The long acting β2-agonists, salmeterol and formoterol, have been recommended, by some, as first line treatment of stable chronic obstructive pulmonary disease (COPD). We reviewed evidence of efficacy and safety when compared with placebo or anticholinergic agents in patients with poorly reversible COPD.

Methods

After searching MEDLINE, EMBASE, HealthSTAR, BIOSIS Previews, PASCAL, ToxFile, SciSearch, the Cochrane Library, and PubMed, as well as Web sites, selected journals, reference lists, and contacting drug manufacturers, two reviewers independently screened reports of randomised controlled trials of parallel or crossover design lasting four weeks or longer and including patients with a forced expiratory volume in one second (FEV1) ≤ 75% of predicted, a ratio of FEV1 to forced vital capacity (FVC) ≤ 88% of predicted, and < 15% improvement from baseline FEV1 after a dose of a β2 agonist. We included trials comparing salmeterol or formoterol with placebo or with ipratropium bromide and reporting one of these outcomes: lung function; exercise capacity; quality of life scores; dyspnea; exacerbations; rescue inhaler use; incidence of tachycardia, hypokalemia, or dry mouth. Two reviewers assessed the quality of included reports using the Jadad scale and allocation concealment, and abstracted data.

Results

Twelve trials satisfied our inclusion criteria; eight were high quality (Jadad score >2) and four were low quality (≤ 2). The adequacy of allocation concealment was unclear in all of them. We did not perform a meta-analysis due to differences in trial design and how outcomes were reported. Two trials comparing salmeterol with ipratropium did not detect differences; one trial comparing formoterol and ipratropium described greater improvement with formoterol in morning PEFR (15.3 versus 7.1 l/min, p = 0.040). Of twelve trials comparing long acting β2 agonists with placebo, six reported no improvement in exercise capacity, eleven reported improvements in FEV1 lung function (one reported no improvement), six reported less rescue inhaler usage (one reported no difference) and five reported improved dyspnea scores (two reported no improvement). Differences in quality of life were detected in one salmeterol trial ; however, two salmeterol, and one formoterol trial reported no differences. Adverse effects of interest were not reported.

Conclusion

In terms of clinical outcomes and safety, we could not find convincing evidence that salmeterol and formoterol have demonstrated advantages to ipratropium, a less expensive drug, for patients with stable COPD and poor reversibility. Compared to placebo, we found evidence of reduced rescue inhaler usage and improved spirometric outcomes without a significant impact on quality of life or exercise capacity.     

Does dietary fat affect inflammatory markers in overweight and obese individuals?—a review of randomized controlled trials from 2010 to 2016

Background

Obesity, a major cause of death and disability, is increasing worldwide. Obesity is characterized by a chronic, low-grade inflammatory state which is suggested to play a critical role in the development of obesity-related diseases like cardiovascular diseases and type 2 diabetes. In fact, in the hours following consumption of a meal, a transient increase in inflammatory markers occurs, a response that is exaggerated in obese subjects. Dietary composition, including content of dietary fatty acids, may affect this inflammatory response both acutely and chronically, and thereby be predictive of progression of disease. The aim of the review was to summarize the literature from 2010 to 2016 regarding the effects of dietary fat intake on levels of inflammatory markers in overweight and obesity in human randomized controlled trials.

Methods and results

We performed a literature search in MEDLINE, EMBASE, and PubMed databases. The literature search included human randomized controlled trials, both postprandial and long-term interventions, from January 2010 to September 2016. In total, 37 articles were included. Interventions with dairy products, vegetable oils, or nuts showed minor effects on inflammatory markers. The most consistent inflammatory-mediating effects were found in intervention with whole diets, which suggests that many components of the diet reduce inflammation synergistically. Furthermore, interventions with weight reduction and different fatty acids did not clearly show beneficial effects on inflammatory markers.

Conclusion

Most interventions showed either no or minor effects of dietary fat intake on inflammatory markers in overweight and obese subjects. To progress our understanding on how diet and dietary components affect our health, mechanistic studies are required. Hence, future studies should include whole diets and characterization of obese phenotypes at a molecular level, including omics data and gut microbiota.

     

What affects mRNA levels in leaves of field-grown aspen? A study of developmental and environmental influences

We have analyzed the abundance of mRNAs expressed from 11 nuclear genes in leaves of a free-growing aspen (Populus tremula) tree throughout the growing season. We used multivariate statistics to determine the influence of environmental factors (i.e. the weather before sampling) and developmental responses to seasonal changes at the mRNA level for each of these genes. The gene encoding a germin-like protein was only expressed early in the season, whereas the other tested genes were expressed throughout the season and showed mRNA variations on a day-to-day basis. For six of the genes, reliable models were found that described the mRNA level as a function of weather, but the leaf age was also important for all genes except one encoding an early light-inducible protein (which appeared to be regulated purely by environmental factors under these conditions). The results confirmed the importance of several environmental factors previously shown to regulate the genes, but we also detected a number of less obvious factors (such as the variation in weather parameters and the weather of the previous day) that correlated with the mRNA levels of individual genes. The study shows the power of multivariate statistical methods in analyzing gene regulation under field conditions.     

What makes a species vulnerable to extinction? Comparative life-history traits of two sympatric snakes

Although it is well known that species vary in their vulnerability to extinction, the reasons are poorly understood. Theory predicts that long-lived species with slow life histories (small litters, slow growth, late maturation) should be at greater risk than short-lived species with high potential rates of increase. This hypothesis was tested by comparing life-history traits of two species of sympatric, elapid snakes: the endangered broad-headed snake, Hoplocephalus bungaroides, and common small-eyed snake, Cryptophis nigrescens. From 1992 to 2000 a mark–recapture study of both species was undertaken in Morton National Park, south-eastern Australia, and this information was used to construct transition matrices for each species. The endangered H. bungaroides was found to mature late (6 years of age), had a high juvenile (54.7%) and adult (81.6%) survival rate, and a long generation length (10.4 years). In striking contrast, the common C. nigrescens matured early (within 3 years), had a lower juvenile (30.4%) and adult (74.4%) survival rate (but higher recruitment rate), and a substantially shorter generation length (5.9 years). Elasticity analyses revealed that H. bungaroides was considerably more sensitive to survival past the age of 2 years (68.6%) than C. nigrescens (37.4%). These results provide support for the hypothesis that species with slow life histories are more vulnerable to extinction.     

The effects of temperature on the circadian rhythms of flashing and glow in Gonyaulax polyedra: are the two rhythms controlled by two oscillators?

Circadian rhythms of flashing and glow were recorded simultaneously in Gonyaulax polyedra by determining maximum and minimum light emission at each measured interval of 28 sec. In constant light, the two rhythms in some cases showed different period lengths (tau), the glow rhythm being up to 1 hr shorter than the flashing rhythm. Lower temperatures shortened the tau of the glow rhythm more than that of the flashing rhythm. The amplitude of the flashing rhythm decreased when the temperature was increased from 15 degrees C to 25 degrees C, whereas that of the glow rhythm was increased. These results may indicate that the two rhythms are controlled by two separate oscillators.     

What are the sleep characteristics of elite female athletes? A systematic review with meta-analysis

With the recent growth in female sport, practitioners need to be able to provide specific support to female athletes to ensure their sleep, health and athletic performance are optimised. Examine the patterns, duration and quality of sleep among elite female athletes, and consider the impact of situational challenges and their effects on the sleep of elite female athletes. Data was located through a search of SPORTDiscus, MEDLINE and Scopus from inception up to May 2021. Studies needed to be peer-reviewed research reporting quantitative sleep outcomes for female athletes ≥ 18 years of age and competing at a predefined elite level. A meta-analysis was performed on habitual sleep outcomes (e.g. total sleep time [TST] and sleep efficiency [SE]) measured with actigraphy. A total of 38 studies were included. Meta-analysis showed habitual TST (n = 14) was 7.8 h [7.4, 8.2] (mean [95% CI]), and SE was 86.7% [84.7, 88.6], with high variability among studies (I² = 97.8–98.2%). Subjective sleep complaints are common before a competition, as do post-training sleep disturbances (63% studies report TST decrease), and post-competition sleep disturbances (75% studies report TST decrease). Female athletes achieve satisfactory objective sleep quantity and quality during habitual periods, but experience sleep disturbances pre- and post-situational challenges. There is high variability of objective sleep outcomes, demonstrating the individual nature of habitual female athlete sleep. Overall, future research must focus on optimising the sleep appraisal methods and creating high-quality study designs in a broader number of sports.     

How to select a probiotic? A review and update of methods and criteria

International competition within the dairy market and increasing public awareness about the importance of functional food consumption are providing new challenges for innovation in the probiotic sector. In this context, countless references are currently dedicated to the selection and characterization of new species and more specific strains of probiotic bacteria. In general, these studies adopt basic selection criteria established by the World Health Organization (WHO), including host-associated stress resistance, epithelium adhesion ability, and antimicrobial activity. These aspects are applied to ensure that the candidate probiotic could withstand the stressful conditions of the human digestive system and exert functional proprieties. However, it cannot be assumed that these novel microbial strains are capable of offering several biological benefits attributed to probiotics. Additionally, safety-associated selection criteria, such as plasmid-associated antibiotic resistance spreading and enterotoxin production, are often neglected. This article reviews the recent developments in the processes, strategies, and methods, such as anticarcinogenic, antidepression, antianxiety, antiobesity, antidiabetic, immunostimulatory, and cholesterol-lowering assessments, to select probiotic strains with the ultimate objective of assisting future probiotic microbe evaluation studies.     

What has transcranial magnetic stimulation taught us about neural adaptations to strength training? A brief review

The evidence for neural mechanisms underpinning rapid strength increases has been investigated and discussed for over 30 years using indirect methods, such as surface electromyography, with inferences made toward the nervous system. Alternatively, electrical stimulation techniques such as the Hoffman reflex, volitional wave, and maximal wave have provided evidence of central nervous system changes at the spinal level. For 25 years, the technique of transcranial magnetic stimulation (TMS) has allowed for noninvasive supraspinal measurement of the human nervous system in a number of areas such as fatigue, skill acquisition, clinical neurophysiology, and neurology. However, it has only been within the last decade that this technique has been used to assess neural changes after strength training. The aim of this brief review is to provide an overview of TMS, discuss specific strength training studies that have investigated changes, after short-term strength training in healthy populations in upper and lower limbs, and conclude with further research suggestions and the application of this knowledge for the strength and conditioning coach.