Search

Background and Objectives : The aim of this systematic review was to assess the efficiency of using allografts for sinus lift. Materials and Methods : This systematic review was written under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendation of the Cochrane Handbook for Systematic Reviews of Interventions. Three electronic databases were screened until October 2023. The risk of bias was assessed according to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines. Statistical analysis was performed for median bone volume and implant survival rate. Results : From 321 articles retrieved, 7 articles were included in this review. A comparison between freeze-dried bone allograft (FDBA) and deproteinized bovine bone (DBB) for mean bone volume indicated a weighted mean difference (WMD) of -0.17 [-0.69, 0.36] (95% confidence interval (CI)), p = 0.53. For implant survival rate, a comparison was made between FDBA and autogenous bone indicating a risk ratio (RR) of 1.00 [0.96, 1.05] (95% CI), p = 1.00. Conclusions : The available evidence suggested that allograft bone can be used in sinus lift procedures. The results obtained are insufficient to compare with other types of bone graft, requiring a longer follow-up time. Future clinical trials are needed in order to evaluate the advantages of using allograft bone.

Background: Robotic and navigated TKA procedures have been introduced to improve component placement precision in the hope of improving implant survivorship and other clinical outcomes. Although numerous comparative studies have shown enhanced precision and accuracy in placing components, most comparative studies have not shown that such interventions result in improved implant survival. Given what we know about effect sizes from large arthroplasty registries, large cohort studies, and large randomized controlled trials (RCTs), we wondered how large randomized trials would need to be to detect such small differences, and if the number is very high, what that would tell us about the value of these treatments for preventing revision surgery., Questions/purposes: In this simulation study, we asked: Given that survivorship differences between technology-assisted TKA (TA-TKA, which we defined as either navigated or robot-assisted TKA) and conventional TKA are either small or absent based on large arthroplasty registries, large cohort studies, and large RCTs, how large would randomized trials need to be to detect small differences between TA-TKA and conventional TKA if they exist, and how long would the follow-up period need to be to have a reasonable chance to detect those differences?, Methods: We used estimated effect sizes drawn from previous clinical and registry studies, combined with estimates of the accuracy and precision of various navigation and robotic systems, to model and simulate the likely outcomes of potential comparative clinical study designs. To characterize the ranges of patients enrolled and general follow-up times associated with traditional RCT studies, we conducted a structured search of previously published studies evaluating the effect of robotics and navigation on revision rates compared with that of conventional TKA. The structured search of the University of British Columbia's library database (which automatically searches medical publication databases such as PubMed, Embase, Medline, and Web of Science) and subsequent searching through included studies' reference lists yielded 103 search results. Only clinical studies assessing implant survival differences between patient cohorts of TA-TKA and conventional TKA were included. Studies analyzing registry data, using cadaver specimens, assessing revision TKA, conference proceedings, and preprint services were excluded. Twenty studies met all our inclusion criteria, but only one study reported a statistically significant difference between the conventional and robotic or navigated groups. Next, we generated a large set of patients with simulated TKA (1.5 million), randomly assigning each simulated patient a set of patient-specific factors (age at the index surgery, gender, and BMI) drawn from data from registries and published information. We divided this set of simulated procedures into four groups, each associated with a coronal alignment precision reported for different types of surgical procedures, and randomly assigned each patient an overall coronal alignment consistent with their group's precision. TA procedures were modeled based on the alignment precision that an intervention could deliver, regardless of whether the technology used was navigation- or robot-assisted. To evaluate the power associated with using different cohort sizes, we ran a Monte Carlo simulation generating 3000 simulated populations that were drawn (with replacement) from the large set of simulated patients with TKA. We simulated the time to revision for aseptic loosening for each patient, computed the corresponding Kaplan-Meier survival curves, and applied a log-rank test to each study for statistical differences in revision rates at concurrent follow-up timepoints (1-25 years). From each simulation associated with a given cohort size, we determined the percentage of simulated studies that found a statistically significant difference at each follow-up interval. For each alternative precision, we then also calculated the expected reduction in revision rates (effect size) attributable to TA-TKA intervention and the number needed to treat (NNT) using TA-TKA to prevent one revision at 2, 5, 10, and 15 years after index surgery for the entire set of Kaplan-Meier survival analyses., Results: The results from our simulation found survivorship differences favoring TA-TKA ranging from 1.4% to 2.0% at 15 years of follow-up. Comparative studies would need to enroll between 2500 and 4000 patients in each arm of the study, depending on the precision of the navigated or robotic procedure, to have an 80% chance of showing this reduction in revision rates at 15 years of follow-up. For the highest precision simulated intervention, the NNT using TA-TKA to prevent one revision was 1000 at 2 years, 334 at 5 years, 100 at 10 years, and 50 at 15 years post-index surgery., Conclusion: Based on these simulations, it appears that TA-TKA interventions could potentially result in a relative reduction in revision rates as large as 27% (from 7.5% down to about 5.5% at 15 years for the intervention with the most precise coronal alignment); however, since this 2% absolute reduction in revision rates is relatively small in comparison with the baseline success rate of TKA and would not be realized until 15 years after the index surgery, traditional RCT studies would require excessively large numbers of patients to be enrolled and excessively long follow-up times to demonstrate whether such a reduction actually exists., Clinical Relevance: Given that the NNTs to avoid revisions at various time points are predicted to be high, it would require correspondingly low system costs to justify broad adoption of TA-TKA based on avoided revision costs alone, though we speculate that technology assistance could perhaps prove to be cost effective in the care of patients who are at an elevated risk of revision., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2021 by the Association of Bone and Joint Surgeons.)

Choosing the most appropriate patient-reported outcome measure (PROM) for a clinical study is essential in order to achieve trustworthy results. This choice will depend on (a) the objective of the study and hence the research question; (b) the choice of a theoretical framework, such as the World Health Organization's International Classification of Functioning, Disability, and Health (ICF); (c) whether there currently is a PROM that possesses high content validity and high construct validity for the specific patient group and objective, and if not; (d) the decision on whether to use a suboptimal PROM or develop and validate a new PROM. This paper presents the steps that should be followed in order to assess the relevance of PROMs and suggests ways to enhance the choice depending on the goal of the study., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Neurorehabilitation relies on core principles of neuroplasticity to activate and engage latent neural connections, promote detour circuits, and reverse impairments. Clinical interventions incorporating these principles have been shown to promote recovery and demote compensation. However, many clinicians struggle to find interventions centered on these principles in our nascent, rapidly growing body of literature. Not to mention the immense pressure from regulatory bodies and organizational balance sheets that further discourage time-intensive recovery-promoting interventions, incentivizing clinicians to prioritize practical constraints over sound clinical decision making. Modern neurorehabilitation practices that result from these pressures favor strategies that encourage compensation over those that promote recovery. To narrow the gap between the busy clinician and the cutting-edge motor recovery literature, we distilled 5 features found in early-phase clinical intervention studies-ones that value the more enduring biological recovery processes over the more immediate compensatory remedies. Filtering emerging literature through this lens and routinely integrating promising research into daily practice can break down practical barriers for effective clinical translation and ultimately promote durable long-term outcomes. This perspective is meant to serve a new generation of mechanistically minded and caring clinicians, students, activists, and research trainees, who are poised to not only advance rehabilitation science, but also erect evidence-based policy changes to accelerate recovery-based stroke care.

The translation of preclinical results into successful clinical therapies remains a challenge in sepsis research. One reason for this lack of translation might be the discrepancy between preclinical models and the clinical reality: nonresuscitated young healthy rodents in contrast to elderly comorbid patients in an intensive care unit. We introduce the mouse intensive care unit (MICU) as a concept to address the lack of resuscitation in preclinical studies as one of the limiting issues in translational research. The MICU reflects standard procedures of the clinical intensive care unit: fluid resuscitation, lung-protective mechanical ventilation, and hemodynamic monitoring and management, all tailored to organ- and function-specific targets. Thus, the MICU gives an experimental animal the intermediate possibility of recovery and survival due to "patient" management, which is not reflected in less complex experimental scenarios, which either result in acute survival or death.

Objectives: To provide Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidance for the consideration of study limitations (risk of bias) due to missing participant outcome data for time-to-event outcomes in intervention studies., Study Design and Setting: We developed this guidance through an iterative process that included membership consultation, feedback, presentation, and iterative discussion at meetings of the GRADE working group., Results: The GRADE working group has published guidance on how to account for missing participant outcome data in binary and continuous outcomes. When analyzing time-to-event outcomes (e.g., overall survival and time-to-treatment failure) data of participants for whom the outcome of interest (e.g., death and relapse) has not been observed are dealt with through censoring. To do so, standard methods require that censored individuals are representative for those remaining in the study. Two types of censoring can be distinguished, end of study censoring and censoring because of missing data, commonly named loss to follow-up censoring. However, both types are not distinguishable with the usual information on censoring available to review authors. Dealing with individuals for whom data are missing during follow-up in the same way as individuals for whom full follow-up is available at the end of the study increases the risk of bias. Considerable differences in the treatment arms in the distribution of censoring over time (early versus late censoring), the overall degree of missing follow-up data, and the reasons why individuals were lost to follow-up may reduce the certainty in the study results. With often only very limited data available, review and guideline authors are required to make transparent and well-considered judgments when judging risk of bias of individual studies and then come to an overall grading decision for the entire body of evidence., Conclusion: Concern for risk of bias resulting from censoring of participants for whom follow-up data are missing in the underlying studies of a body of evidence can be expressed in the study limitations (risk of bias) domain of the GRADE approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: The objective of this scoping review was to examine the range of published evidence on recruitment approaches and outcomes of US adolescents and young adults (AYA) ages (18-29 years) into human immunodeficiency virus (HIV)-related behavioral research studies during the past 10 years., Recent Findings: Implementation of effective behavioral research strategies among HIV at-risk and infected AYA is key to ending the HIV epidemic and necessitates successful recruitment strategies. A comprehensive search was executed across four electronic databases. Of the 1697 identified studies, seven met inclusion criteria with six of these seven directed to HIV prevention. Most studies used online recruitment as part of a hybrid strategy, and combined field-based/in-person and online methods. Recruitment strategies and outcomes, resources and compensation, procedures for consent, and timelines varied among all seven studies. Our results highlight the need for development of recruitment models in alignment with behavioral strategies aimed to treat and prevent HIV among US AYA.

Over the past 20 years, recent advances in science technologies have dramatically changed the styles of clinical research. Currently, it has become more popular to use recent modern epidemiological techniques, such as propensity score, instrumental variable, competing risks, marginal structural modeling, mixed effects modeling, bootstrapping, and missing data analyses, than before. These advanced techniques, also known as modern epidemiology, may be strong tools for performing good clinical research, especially in large-scale observational studies, along with relevant research questions, good databases, and the passion of researchers. However, to use these methods effectively, we need to understand the basic assumptions behind them. Here, I will briefly introduce the concepts of these techniques and their implementation. In addition, I would like to emphasize that various types of clinical studies, not only large database studies but also small studies on rare and intractable diseases, are equally important because clinicians always do their best to take care of many kinds of patients who suffer from various kidney diseases and this is our most important mission.

Objective: To gain insight into neonatal care providers' perceptions of deferred consent for delivery room (DR) studies in actual scenarios., Methods: We conducted semistructured interviews with 46 neonatal intensive care unit (NICU) staff members of the Leiden University Medical Center (the Netherlands) and the Hospital of the University of Pennsylvania (USA). At the time interviews were conducted, both NICUs conducted the same DR studies, but differed in their consent approaches. Interviews were audio-recorded, transcribed and analysed using the qualitative data analysis software Atlas.ti V.7.0., Results: Although providers reported to regard the prospective consent approach as the most preferable consent approach, they acknowledged that a deferred consent approach is needed for high-quality DR management. However, providers reported concerns about parental autonomy, approaching parents for consent and ethical review of study protocols that include a deferred consent approach. Providers furthermore differed in perceived appropriateness of a deferred consent approach for the studies that were being conducted at their NICUs. Providers with first-hand experience with deferred consent reported positive experiences that they attributed to appropriate communication and timing of approaching parents for consent., Conclusion: Insight into providers' perceptions of deferred consent for DR studies in actual scenarios suggests that a deferred consent approach is considered acceptable, but that actual usage of the approach for DR studies can be improved on., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammation is commonly characterized as a defensive and protective reaction of the body to various exogenous or endogenous stimuli, which aims to maintain the body health. Punica granatum (pomegranate) and its constituent ellagic acid (EA) are recently more taken into accounts since their promising pharmacological effects. Therefore, we aimed to obtain a comprehensive review regarding antiinflammatory, anticancer, and antioxidant activities of both pomegranate and EA and their possible involved mechanisms. In the procedure, scientific databases, including Web of Science, PubMed, Scopus, and Google Scholar, were searched in the English language, until the end of January 2019. Pomegranate belonging to the Punicaceae has been used for medical purposes from ancient and in different cultures. Several studies have also supported that EA is the major active compound of pomegranate and possesses antimutagenic, antiinflammatory, antifibrosis, anticancer, and antiaging properties. It has been suggested that pomegranate and EA possess promising immunomodulatory effects in preclinical models as well as human studies through regulation of the T-cell function and suppressing humoral immunity. Hopefully, we wish that this review and information could be helpful for designing further experiments to investigate the potential protective effects of pomegranate and EA., (© 2020 John Wiley & Sons, Ltd.)

Challenges remain for policy adoption and implementation to tackle the unprecedented and relentless increase in obesity, diabetes and other non-communicable diseases (NCDs), especially in low- and middle-income countries. The aim of this mixed-methods study is to analyse the contextual relevance and applicability to low-resource settings of a sample of evidence-based healthy public policies, using local knowledge, perceptions and pertinent epidemiological data. Firstly, we will identify and prioritise policies that have the potential to reduce the burden of diabetes in low-resource settings with a scoping review and modified Delphi method. In parallel, we will undertake two cross-sectional population surveys on diabetes risk and morbidity in two low-resource settings in Ecuador. Patients, community members, health workers and policy makers will analyse the contextual relevance and applicability of the policy actions and discuss their potential for the reduction in inequities in diabetes risk and morbidity in their population. This study tackles one of the greatest challenges in global health today: how to drive the implementation of population-wide preventative measures to fight NCDs in low resource settings. The findings will demonstrate how local knowledge, perceptions and pertinent epidemiological data can be used to analyse the contextual relevance and applicability of potential policy actions.

Precision medicine has spurred new innovations in molecular pathology leading to recent advances in the analysis of exhaled breath as a non-invasive diagnostic tool. Volatile organic compounds (VOCs) detected in exhaled breath have the potential to reveal a wealth of chemical and metabolomic information. This study describes the development of a method for the analysis of breath, based on automated thermal desorption (TD) combined with flow modulated comprehensive two-dimensional gas chromatography (GC×GC) with dual flame ionisation and quadrupole mass spectrometric detection (FID and qMS). The constrained optimisation and analytical protocol was designed to meet the practical demands of a large-scale multi-site clinical study, while maintaining analytical rigour to produce high fidelity data. The results demonstrate a comprehensive method optimisation for the collection and analysis of breath VOCs by GC×GC, integral to the standardisation and integration of breath analysis within large clinical studies., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to investigate the potential added value of combining propensity score (PS) methods with multivariable linear regression (MLR) in estimating the average treatment effect on the treated (ATT) in nonrandomized studies with health-related quality of life (HRQoL) outcomes., Methods: We first used simulations to compare the performances of different PS-based methods, either alone or in combination with further MLR adjustment, in estimating ATT. PS methods were, respectively, optimal pair (OPM) and full (OFM) PS matching, subclassification on the PS (SBC), and the inverse probability of treatment weighting (IPTW). We simulated several scenarios, according to different sample sizes, proportions of treated vs untreated subjects, and types of HRQoL outcomes. We also applied the same methods to a real clinical data set., Results: OPM and IPTW provided the closest Type I error to the nominal threshold α = 0.05 across all scenarios. Overall, both methods showed also lower variability in estimates than SBC and OFM. SBC performed worst, generally providing the highest levels of bias. Further MLR adjustment lessened bias for all methods, however providing higher Type I error for SBC and OFM. In the real case, all methods provided similar ATT estimates except for one outcome., Conclusions: Our findings suggest that for sample sizes up to n = 200, OPM and IPTW are to be preferred to OFM and SBC in estimating ATT on HRQoL outcomes. Specifically, OPM performed best in sample sizes of n ≥ 80, IPTW for smaller sample sizes. Additional MLR adjustment can further improve ATT estimates., (© 2019 John Wiley & Sons, Ltd.)

Sarcopenia-the age-related loss of skeletal muscle mass and strength-is a major public health issue. Sarcopenia is associated with an increased risk of falls, disability, dependency, institutionalization, hospital stay and early death. Finding interventions to stabilize, reverse or prevent sarcopenia is therefore a key goal for clinical ageing research. If patients are to eventually benefit from discovery science on ageing skeletal muscle, we need to build a translational pipeline that facilitates progress from laboratory science and epidemiology, through feasibility testing to early-phase, and eventually late-phase clinical trials. A number of barriers need to be overcome to make this pipeline work-in particular challenges around identifying people with sarcopenia in routine clinical practice, ensuring that we study patients with clearly defined sarcopenia rather than related conditions such as functional impairment, developing capacity to run trials for older people, and selecting trial outcomes of relevance to older people with multimorbidity. A further key point is that interventions should ideally have pleiotropic actions-i.e. beneficial actions across multiple organ systems, rather than treating sarcopenia alone. Such pleiotropic interventions may be the only way to avoid the perils of polypharmacy and drug interactions that bedevil care for many older people. Maximising the potential for scientific discoveries in the biology of ageing muscle to improve health requires that discovery scientists, translational clinical scientists and clinicians come together to exchange findings and shape each others ideas within a shared culture.

Purpose: To overcome the constraint of common multiple-baseline designs that only one case per stagger position is permitted., Methods: Three alternative strategies for assigning more than one case to each stagger position are examined., Results: The three recommended strategies achieve the objective while maintaining the study's internal and statistical-conclusion validities., Conclusions: ExPRT, a freely available Excel-based randomization-test package, can be used to assist in both the design and statistical analysis associated with each of the strategies.

A number of analyses associated with the uncontrolled manifold (UCM) hypothesis have been used recently to investigate stability of actions across populations. We explored whether some of those methods have an advantage for clinical studies because they require fewer trials to achieve consistent findings. We compared the number of trials needed for the analysis of inter-trial variance, analysis of motor equivalence, and analysis in the space of referent coordinates. Young healthy adults performed four-finger accurate force production tasks under visual feedback with the right (dominant) and left hand over three days. Three methods [analytical (M1), experimental (M2), and cumulative mean (M3) methods] were used to define the minimal number of trials required to reach certain statistical criteria. Two of these methods, M1 and M2, showed qualitatively similar results. Fewer trials (M1: 5-13, M2: 4-10) were needed for analysis of motor equivalence compared to inter-trial variance analysis (M1: 14-24, M2: 10-14). The third method (M3) showed no major differences among the outcome variables. The index of synergy in the inter-trial variance analysis required a very small number of trials (M1, M2: 2-4). Variables related to referent coordinates required only a few trials (under 3), whereas the synergy index in this analysis required the largest number of trials (M1: 24-34, M2: 12-16). This is the first study to quantify the number of trials needed for UCM-based methods of assessing motor coordination broadly used in clinical studies. Clinical studies can take advantage of specific recommendations based on the current data regarding the number of trials needed for each analysis thus allowing minimizing the test session duration without compromising data reliability.

With the development of the methodology of clinical trials and the appearance of medical big data, the real-world study (RWS) presents its unique advantages, plays a role in clinical practice and research, and its importance is more and more recognized by scholars in recent years. In surgical research field, due to the specificity of surgical diseases and operational procedures, confounding factors and risk of bias are greatly higher than those of traditional medications. Therefore, using unique advantages of the RWS to solve the actual clinical problem in surgical field is the main goal of performing surgical RWS. This article will systematically elucidate how to perform the surgical RWS and the special matters of concern in carrying out surgical RWS.

In the paper a number of issues, including conceptual ones, related to the specific features of making statistical decisions, choosing tests and computing characteristics that will strengthen the evidence base of the conclusions obtained when analyzing data using methods of mathematical statistics, are considered. The paper aims not to describe the methods of mathematical statistics themselves, but to analyze the conditions and the need to apply the most common tests. In particular, the magnitude of the indicator of the statistical significance of the observed effects - p-value - and the sample size to obtain a significant effect are discussed, the effect of multiple comparisons, the application of the Bayesian approach, and others are considered.

Over one billion of the world's population are smokers, with increasing tobacco use in low- and middle-income countries. However, information about the methodology of studies on tobacco control is limited. We conducted a literature search to examine and evaluate the methodological designs of published tobacco research in Sub-Saharan Africa (SSA) over the past 50 years. The first phase was completed in 2015 using PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials. An additional search was completed in February 2017 using PubMed. Only tobacco/smoking research in SSA countries with human subjects and published in English was selected. Out of 1796 articles, 447 met the inclusion criteria and were from 26 countries, 11 of which had one study each. Over half of the publications were from South Africa and Nigeria. The earliest publication was in 1968 and the highest number of publications was in 2014 ( n = 46). The majority of publications used quantitative methods (91.28%) and were cross-sectional (80.98%). The commonest data collection methods were self-administered questionnaires (38.53%), interviews (32.57%), and observation (20.41%). Around half of the studies were among adults and in urban settings. We conclud that SSA remains a "research desert" and needs more investment in tobacco control research and training.

Background: Several meta-research studies and benchmarking activities have assessed how comprehensively and timely, academic institutions and private companies publish their clinical studies. These current "clinical trial tracking" activities differ substantially in how they sample relevant studies, and how they follow up on their publication. Methods: To allow informed policy and decision making on future publication assessment and benchmarking of institutions and companies, this paper outlines and discusses 10 variables that influence the tracking of timely publications. Tracking variables were initially selected by experts and by the authors through discussion. To validate the completeness of our set of variables, we conducted i) an explorative review of tracking studies and ii) an explorative tracking of registered clinical trials of three leading German university medical centres. Results: We identified the following 10 relevant variables impacting the tracking of clinical studies: 1) responsibility for clinical studies, 2) type and characteristics of clinical studies, 3) status of clinical studies, 4) source for sampling, 5) timing of registration, 6) determination of completion date, 7) timeliness of dissemination, 8) format of dissemination, 9) source for tracking, and 10) inter-rater reliability. Based on the description of these tracking variables and their influence, we discuss which variables could serve in what ways as a standard assessment of "timely publication". Conclusions: To facilitate the tracking and consequent benchmarking of how often and how timely academic institutions and private companies publish clinical study results, we have two core recommendations. First, the improvement in the link between registration and publication, for example via institutional policies for academic institutions and private companies. Second, the comprehensive and transparent reporting of tracking studies according to the 10 variables presented in this paper., Competing Interests: No competing interests were disclosed.

Children and young people are seen as fundamental to the design and delivery of clinical research as active and reflective participants. In Europe, involvement of children and young people in clinical research is promoted extensively in order to engage young people in research as partners and to give them a voice to raise their own issues or opinions and for their involvement in planning and decision making in addition to learning research skills. Children and young people can be trained in clinical research through participation in young person advisory groups (YPAGs). Members of YPAGs assist other children and young people to learn about clinical research and share their experience and point of view with researchers, thereby possibly influencing all phases of research including the development and prioritization of research questions, design and methods, recruitment plans, and strategies for results dissemination. In the long term, the expansion of YPAGs in Europe will serve as a driving force for refining pediatric clinical research. It will help in a better definition of research projects according to the patients' needs. Furthermore, direct engagement of children and young people in research will be favorable to both researchers and young people., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Objectives: Research on labor pain currently uses standard scores such as numerical scales as clinical outcomes, but no clear guidelines for such an assessment have appeared since a review published in 1998. We aimed to describe and estimate the quality of the methods used to assess and analyze such outcomes in a systematic review of 215 comparative studies published since then in 27 influential journals., Methods: In addition to a complete description, we created for each study a composite "analysis quality score" (AQS) on the basis of the methods of both measurement of pain/analgesia, and statistical analysis. AQS was tested against various factors, including a "design quality score" (DQS), created to estimate methodological quality (regardless of the analysis of pain intensity)., Results: Both the AQS and its "measurement" component increased with the year of publication, as well as the DQS. The impact factor correlated only with the statistical component of the AQS, and with the DQS. However, the mean AQS and DQS were, respectively, at 43% and 75% of their maximal possible value, and these 2 scores were not correlated. The intensity of labor pain (or pain relief) was the primary outcome in 19% of the studies. Although most of the studies actually used numerical scales, the methods of analysis were heterogeneous. When a cutoff point was determined to define analgesia, this was most often 30% of the maximal value., Discussion: This review points out the need for a better standardization of the methods in this field of research.

A comparison of 2 treatments with survival outcomes in a clinical study may require treatment randomization on clusters of multiple units with correlated responses. For example, for patients with otitis media in both ears, a specific treatment is normally given to a single patient, and hence, the 2 ears constitute a cluster. Statistical procedures are available for comparison of treatment efficacies. The conventional approach for treatment allocation is the adoption of a balanced design, in which half of the patients are assigned to each treatment arm. However, considering the increasing acceptability of responsive-adaptive designs in recent years because of their desirable features, we have developed a response-adaptive treatment allocation scheme for survival trials with clustered data. The proposed treatment allocation scheme is superior to the balanced design in that it allows more patients to receive the better treatment. At the same time, the test power for comparing treatment efficacies using our treatment allocation scheme remains highly competitive. The advantage of the proposed randomization procedure is supported by a simulation study and the redesign of a clinical study., (Copyright © 2018 John Wiley & Sons, Ltd.)

The purpose of a non-inferiority trial is to assert the efficacy of an experimental treatment compared with a reference treatment by showing that the experimental treatment retains a substantial proportion of the efficacy of the reference treatment. Statistical methods have been developed to test multiple experimental treatments in three-arm non-inferiority trials. In this paper, we report the development of procedures that simultaneously test the non-inferiority and the superiority of experimental treatments after the assay sensitivity has been established. The advantage of the proposed test procedures is the additional ability to identify superior treatments while retaining an non-inferiority testing power comparable to that of existing testing procedures. Single-step and stepwise procedures are derived and then compared with each other to determine their relative testing power and testing error in a simulation study. Finally, the suggested procedures are illustrated with two clinical examples.

Background: Understanding links between behaviour change techniques (BCTs) and mechanisms of action (the processes through which they affect behaviour) helps inform the systematic development of behaviour change interventions., Purpose: This research aims to develop and test a methodology for linking BCTs to their mechanisms of action., Methods: Study 1 (published explicit links): Hypothesised links between 93 BCTs (from the 93-item BCT taxonomy, BCTTv1) and mechanisms of action will be identified from published interventions and their frequency, explicitness and precision documented. Study 2 (expert-agreed explicit links): Behaviour change experts will identify links between 61 BCTs and 26 mechanisms of action in a formal consensus study. Study 3 (integrated matrix of explicit links): Agreement between studies 1 and 2 will be evaluated and a new group of experts will discuss discrepancies. An integrated matrix of BCT-mechanism of action links, annotated to indicate strength of evidence, will be generated. Study 4 (published implicit links): To determine whether groups of co-occurring BCTs can be linked to theories, we will identify groups of BCTs that are used together from the study 1 literature. A consensus exercise will be used to rate strength of links between groups of BCT and theories., Conclusions: A formal methodology for linking BCTs to their hypothesised mechanisms of action can contribute to the development and evaluation of behaviour change interventions. This research is a step towards developing a behaviour change 'ontology', specifying relations between BCTs, mechanisms of action, modes of delivery, populations, settings and types of behaviour.

Under the three-treatment three-period crossover design with simple carry-over effects, we derive the least-squares estimators for period effects, treatment effects and carry-over effects, as well as their covariance matrix in closed and explicit expressions. Using Monte Carlo simulation, we compare the test procedure adjusting carry-over with that ignoring carry-over with respect to Type I error and power. We further compare interval estimators adjusting carry-over with those ignoring carry-over with respect to the coverage probability and the average length. When the variation of responses within patients is small, the test procedure and interval estimators ignoring carry-over can lose accuracy in the presence of carry-over effects. When the variation of responses within patients is large, this loss of accuracy may become small or even minimal. We note that the loss of efficiency due to the adjustment of carry-over under the simple carry-over three-period crossover design is moderate, and is much less than that found for a two-period crossover design. We use the double-blind three-period crossover trial comparing formoterol solution aerosol and salbutamol suspension aerosol with a placebo for patients suffering from exercise-induced asthma on the forced expiratory volume in one second (FEV1) to illustrate the use of test procedures and interval estimators discussed here.

Rationale, Aims and Objectives: Evidence-based guidelines constitute a foundation for medical decision making. It is often unclear whether recommendations in general guidelines also apply to older people. This study aimed to develop a methodology to increase the focus on older people in the development of guidelines., Methods: The methodology distinguishes 4 groups of older people: (1) relatively healthy older people; (2) older people with 1 additional specific (interfering) comorbid condition; (3) older people with multimorbidity; and (4) vulnerable older people., Results: The level of focus on older people required may be determined by the prevalence of the disease or condition, level of suffering, social relevance, and the expectation that a guideline may improve the quality of care. A specialist in geriatric medicine may be involved in the guideline process via participation, provision of feedback on drafts, or involvement in the analysis of problem areas. Regarding the patient perspective, it is advised to involve organisations for older people or informal carers in the inventory of problem areas, and additionally to perform literature research of patient values on the subject. If the guideline focuses on older people, then the relative importance of the various outcome measures for this target group needs to be explicitly stated. Search strategies for all the 4 groups are suggested. For clinical studies that focus on the treatment of diseases that frequently occur in older people, a check should be made regarding whether these studies produce the required evidence. This can be achieved by verifying if there is sufficient representation of older people in the studies and determining if there is a separate reporting of results applying to this age group., (© 2017 John Wiley & Sons, Ltd.)

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation., (© 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: In healthcare research, outcomes with skewed probability distributions are common. Sample size calculations for such outcomes are typically based on estimates on a transformed scale (e.g. log) which may sometimes be difficult to obtain. In contrast, estimates of median and variance on the untransformed scale are generally easier to pre-specify. The aim of this paper is to describe how to calculate a sample size for a two group comparison of interest based on median and untransformed variance estimates for log-normal outcome data., Methods: A log-normal distribution for outcome data is assumed and a sample size calculation approach for a two-sample t-test that compares log-transformed outcome data is demonstrated where the change of interest is specified as difference in median values on the untransformed scale. A simulation study is used to compare the method with a non-parametric alternative (Mann-Whitney U test) in a variety of scenarios and the method is applied to a real example in neurosurgery., Results: The method attained a nominal power value in simulation studies and was favourable in comparison to a Mann-Whitney U test and a two-sample t-test of untransformed outcomes. In addition, the method can be adjusted and used in some situations where the outcome distribution is not strictly log-normal., Conclusions: We recommend the use of this sample size calculation approach for outcome data that are expected to be positively skewed and where a two group comparison on a log-transformed scale is planned. An advantage of this method over usual calculations based on estimates on the log-transformed scale is that it allows clinical efficacy to be specified as a difference in medians and requires a variance estimate on the untransformed scale. Such estimates are often easier to obtain and more interpretable than those for log-transformed outcomes.

Observational studies are often the only viable options in many clinical settings, especially when it is unethical or infeasible to randomly assign participants to different treatment régimes. In such case propensity score (PS) analysis can be applied to accounting for possible selection bias and thereby addressing questions of causal inference. Many PS methods exist, yet few guidelines are available to aid applied researchers in their conduct and evaluation of a PS analysis. In this article we give an overview of available techniques for PS estimation and application, balance diagnostic, treatment effect estimation, and sensitivity assessment, as well as recent advances. We also offer a tutorial that can be used to emulate the steps of PS analysis. Our goal is to provide information that will bring PS analysis within the reach of applied clinical researchers and practitioners., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Statistical training psychology focuses on frequentist methods. Bayesian methods are an alternative to standard frequentist methods. This article provides researchers with an introduction to fundamental ideas in Bayesian modeling. We use data from an electroencephalogram (EEG) and anxiety study to illustrate Bayesian models. Specifically, the models examine the relationship between error-related negativity (ERN), a particular event-related potential, and trait anxiety. Methodological topics covered include: how to set up a regression model in a Bayesian framework, specifying priors, examining convergence of the model, visualizing and interpreting posterior distributions, interval estimates, expected and predicted values, and model comparison tools. We also discuss situations where Bayesian methods can outperform frequentist methods as well has how to specify more complicated regression models. Finally, we conclude with recommendations about reporting guidelines for those using Bayesian methods in their own research. We provide data and R code for replicating our analyses., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

There have been numerous treatments in the clinical research literature about various design, analysis, and interpretation considerations when testing hypotheses about mechanisms and contingencies of effects, popularly known as mediation and moderation analysis. In this paper we address the practice of mediation and moderation analysis using linear regression in the pages of Behaviour Research and Therapy and offer some observations and recommendations, debunk some popular myths, describe some new advances, and provide an example of mediation, moderation, and their integration as conditional process analysis using the PROCESS macro for SPSS and SAS. Our goal is to nudge clinical researchers away from historically significant but increasingly old school approaches toward modifications, revisions, and extensions that characterize more modern thinking about the analysis of the mechanisms and contingencies of effects., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The last 20 years has seen an uptick in research on missing data problems, and most software applications now implement one or more sophisticated missing data handling routines (e.g., multiple imputation or maximum likelihood estimation). Despite their superior statistical properties (e.g., less stringent assumptions, greater accuracy and power), the adoption of these modern analytic approaches is not uniform in psychology and related disciplines. Thus, the primary goal of this manuscript is to describe and illustrate the application of multiple imputation. Although maximum likelihood estimation is perhaps the easiest method to use in practice, psychological data sets often feature complexities that are currently difficult to handle appropriately in the likelihood framework (e.g., mixtures of categorical and continuous variables), but relatively simple to treat with imputation. The paper describes a number of practical issues that clinical researchers are likely to encounter when applying multiple imputation, including mixtures of categorical and continuous variables, item-level missing data in questionnaires, significance testing, interaction effects, and multilevel missing data. Analysis examples illustrate imputation with software packages that are freely available on the internet., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

With the development of opioid abuse-deterrent formulations (ADFs), there is a need to conduct well-designed human abuse potential studies to evaluate the effectiveness of their deterrent properties. Although these types of studies have been conducted for many years, largely to evaluate inherent abuse potential of a molecule and inform drug scheduling, methodological approaches have varied across studies. The focus of this review is to describe current "best practices" and methodological adaptations required to assess abuse-deterrent opioid formulations for regulatory submissions. A literature search was conducted in PubMed® to review methodological approaches (study conduct and analysis) used in opioid human abuse potential studies. Search terms included a combination of "opioid," "opiate," "abuse potential," "abuse liability," "liking," AND "pharmacodynamic," and only studies that evaluated single doses of opioids in healthy, nondependent individuals with or without prior opioid experience were included. Seventy-one human abuse potential studies meeting the prespecified criteria were identified, of which 21 studies evaluated a purported opioid ADF. Based on these studies, key methodological considerations were reviewed and summarized according to participant demographics, study prequalification, comparator and dose selection, route of administration and drug manipulation, study blinding, outcome measures and training, safety, and statistical analyses. The authors recommend careful consideration of key elements (eg, a standardized definition of a "nondependent recreational user"), as applicable, and offer key principles and "best practices" when conducting human abuse potential studies for opioid ADFs. Careful selection of appropriate study conditions is dependent on the type of ADF technology being evaluated.

Introduction: A considerable number of clinical studies experience delays, which result in increased duration and costs. In multicentre studies, patient recruitment is among the leading causes of delays. Poor site selection can result in low recruitment and bad data quality. Site selection is therefore crucial for study quality and completion, but currently no specific guidelines are available., Material and Methods: Selection of sites adequate to participate in a prospective multicentre cohort study was performed through an open call using a newly developed objective multistep approach. The method is based on use of a network, definition of objective criteria and a systematic screening process., Illustrative Example of the Method at Work: Out of 266 interested sites, 24 were shortlisted and finally 12 sites were selected to participate in the study. The steps in the process included an open call through a network, use of selection questionnaires tailored to the study, evaluation of responses using objective criteria and scripted telephone interviews. At each step, the number of candidate sites was quickly reduced leaving only the most promising candidates. Recruitment and quality of data went according to expectations in spite of the contracting problems faced with some sites., Conclusion: The results of our first experience with a standardised and objective method of site selection are encouraging. The site selection method described here can serve as a guideline for other researchers performing multicentre studies., Trial Registration Number: ClinicalTrials.gov: NCT02297581., Competing Interests: Competing interests: AH-Ch, AJ and DH are AOCID employees and receive salary from the AO Foundation., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Extensive research has been conducted in the Multi-Regional Clinical Trial (MRCT) area. To effectively apply an appropriate approach to a MRCT, we need to synthesize and understand the features of different approaches. In this paper, examples are used to illustrate considerations regarding design, conduct, analysis and interpretation of result of MRCTs. We start with a brief discussion of region definitions and the scenarios where different regions have differing requirements for a MRCT. We then compare different designs and models as well as the corresponding interpretation of the results. We highlight the importance of paying special attention to trial monitoring and conduct to prevent potential issues associated with the final trial results. Besides evaluating the overall treatment effect for the entire MRCT, we also consider other key analyses including quantification of regional treatment effects within a MRCT, and assessment of consistency of these regional treatment effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Speech-language pathologists (SLPs) are increasingly required to read, interpret and create evidence regarding the effectiveness of interventions. This requires a good understanding of the strengths and weaknesses of different intervention study designs. This paper aims to take readers through a range of designs commonly used in speech-language pathology, working from those with the least to most experimental control, with a particular focus on how the more robust designs avoid some of the limitations of weaker designs. It then discusses the factors other than research design which need to be considered when deciding whether or not to implement an intervention in clinical practice. The final section offers some tips and advice on carrying out research in clinical practice, with the hope that more SLPs will become actively involved in creating intervention research.

Introduction: A proper understanding of study design is essential to creating successful studies. This is also important when reading or peer reviewing publications. In this article, we aimed to identify and summarize key papers that would be helpful for faculty members interested in learning more about study design in medical education research., Methods: The online discussions of the 2016-2017 Academic Life in Emergency Medicine Faculty Incubator program included a robust and vigorous discussion about education study design, which highlighted a number of papers on that topic. We augmented this list of papers with further suggestions by expert mentors. Via this process, we created a list of 29 papers in total on the topic of medical education study design. After gathering these papers, our authorship group engaged in a modified Delphi approach to build consensus on the papers that were most valuable for the understanding of proper study design in medical education., Results: We selected the top five most highly rated papers on the topic domain of study design as determined by our study group. We subsequently summarized these papers with respect to their relevance to junior faculty members and to faculty developers., Conclusion: This article summarizes five key papers addressing study design in medical education with discussions and applications for junior faculty members and faculty developers. These papers provide a basis upon which junior faculty members might build for developing and analyzing studies., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Development of effective treatments for alcohol use disorder (AUD) represents an important public health goal. This review provides a summary of completed preclinical and clinical studies testing pharmacotherapies for the treatment of AUD. We discuss opportunities for improving the translation from preclinical findings to clinical trial outcomes, focusing on the validity and predictive value of animal and human laboratory models of AUD. Specifically, while preclinical studies of medications development have offered important insights into the neurobiology of the disorder and alcohol's molecular targets, limitations include the lack of standardized methods and streamlined processes whereby animal studies can readily inform human studies. Behavioral pharmacology studies provide a less expensive and valuable opportunity to assess the feasibility of a pharmacotherapy prior to initiating larger scale clinical trials by providing insights into the mechanism of the drug, which can then inform recruitment, analyses, and assessments. Summary tables are provided to illustrate the wide range of preclinical, human laboratory, and clinical studies of medications development for alcoholism. Taken together, this review highlights the challenges associated with animal paradigms, human laboratory studies, and clinical trials with the overarching goal of advancing treatment development and highlighting opportunities to bridge the gap between preclinical and clinical research., (© 2016 Society for the Study of Addiction.)

Background: The conduct of oral food challenges as the preferred diagnostic standard for food allergy (FA) was harmonized over the last years. However, documentation and interpretation of challenge results, particularly in research settings, are not sufficiently standardized to allow valid comparisons between studies. Our aim was to develop a diagnostic toolbox to capture and report clinical observations in double-blind placebo-controlled food challenges (DBPCFC)., Methods: A group of experienced allergists, paediatricians, dieticians, epidemiologists and data managers developed generic case report forms and standard operating procedures for DBPCFCs and piloted them in three clinical centres. The follow-up of the EuroPrevall/iFAAM birth cohort and other iFAAM work packages applied these methods., Recommendations: A set of newly developed questionnaire or interview items capture the history of FA. Together with sensitization status, this forms the basis for the decision to perform a DBPCFC, following a standardized decision algorithm. A generic form including details about severity and timing captures signs and symptoms observed during or after the procedures. In contrast to the commonly used dichotomous outcome FA vs no FA, the allergy status is interpreted in multiple categories to reflect the complexity of clinical decision-making., Conclusion: The proposed toolbox sets a standard for improved documentation and harmonized interpretation of DBPCFCs. By a detailed documentation and common terminology for communicating outcomes, these tools hope to reduce the influence of subjective judgment of supervising physicians. All forms are publicly available for further evolution and free use in clinical and research settings., (© 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Tuberculous meningitis (TBM) remains a major cause of death and disability in tuberculosis-endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of TBM clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrollment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention TBM studies should improve the quality of future research outputs, can facilitate multicenter studies and meta-analyses of pooled data, and could provide the foundation for a global TBM data repository.

In recent years, there have been many scientific advances and new collaborations for rare diseases research and, ultimately, the health of patients living with rare diseases. However, for too many rare diseases, there still is no effective treatment, and our understanding of the incidence, prevalence, and underlying etiology is incomplete. To facilitate the studies needed to answer the many open questions there is a great need for the active involvement of all stakeholders, most importantly of patient groups. Also, the creation of streamlined infrastructure for performing multi-site clinical studies is critical, as is the engagement of multi-disciplinary teams with shared focus on a group of diseases. Another essential component of such efforts is to collect standardized data so that downstream meta-analyses and data sharing can be facilitated. To ensure high-quality protocols and datasets, a central data management and coordinating center is important. Since there are more than 6000 rare diseases, instead of focusing on single rare disease, it is more impactful to create platforms and methods that can support a group of rare diseases.

Introduction: Autologous haematopoietic cell transplantation (AHCT) is an evolving treatment avenue in multiple sclerosis (MS), which may be highly effective in controlling disease activity and improving disability. However, AHCT is associated with intrinsic toxicities and risks compared with conventional therapies. With growing experience in patient selection and treatment delivery, AHCT is increasingly considered an option in patients with aggressive disease that's responding poorly to disease modifying therapy. Areas covered: This article provides an introduction to AHCT and looks at its development as a treatment for MS over the last 20 years. It also highlights potential mechanisms of action, patient selection, and future trends for this treatment approach. Expert opinion: Currently published data suggest that AHCT's use is associated with significant reduction in MS disease activity and marked improvement in disability when used in patients with highly active relapsing remitting disease. Its long term safety and efficacy have not been fully evaluated but as increasing clinical trial data are published, its use is likely to grow. Further randomised controlled studies are needed to compare AHCT with standard disease modifying therapies and to optimise transplant regimens. Mechanistic studies may provide potential markers for response and a better understanding of disease pathogenesis.

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency., (Copyright © 2016. Published by Elsevier Inc.)