Background: Randomization is the foundation of any clinical trial involving treatment comparison. It helps mitigate selection bias, promotes similarity of treatment groups with respect to important known and unknown confounders, and contributes to the validity of statistical tests. Various restricted randomization procedures with different probabilistic structures and different statistical properties are available. The goal of this paper is to present a systematic roadmap for the choice and application of a restricted randomization procedure in a clinical trial.Methods: We survey available restricted randomization procedures for sequential allocation of subjects in a randomized, comparative, parallel group clinical trial with equal (1:1) allocation. We explore statistical properties of these procedures, including balance/randomness tradeoff, type I error rate and power. We perform head-to-head comparisons of different procedures through simulation under various experimental scenarios, including cases when common model assumptions are violated. We also provide some real-life clinical trial examples to illustrate the thinking process for selecting a randomization procedure for implementation in practice.Results: Restricted randomization procedures targeting 1:1 allocation vary in the degree of balance/randomness they induce, and more importantly, they vary in terms of validity and efficiency of statistical inference when common model assumptions are violated (e.g. when outcomes are affected by a linear time trend; measurement error distribution is misspecified; or selection bias is introduced in the experiment). Some procedures are more robust than others. Covariate-adjusted analysis may be essential to ensure validity of the results. Special considerations are required when selecting a randomization procedure for a clinical trial with very small sample size.Conclusions: The choice of randomization design, data analytic technique (parametric or nonparametric), and analysis strategy (randomization-based or population model-based) are all very important considerations. Randomization-based tests are robust and valid alternatives to likelihood-based tests and should be considered more frequently by clinical investigators.

Randomization is considered to be a key feature to protect against bias in randomized clinical trials. Randomization induces comparability with respect to known and unknown covariates, mitigates selection bias, and provides a basis for inference. Although various randomization procedures have been proposed, no single procedure performs uniformly best. In the design phase of a clinical trial, the scientist has to decide which randomization procedure to use, taking into account the practical setting of the trial with respect to the potential of bias. Less emphasis has been placed on this important design decision than on analysis, and less support has been available to guide the scientist in making this decision. We propose a framework that weights the properties of the randomization procedure with respect to practical needs of the research question to be answered by the clinical trial. In particular, the framework assesses the impact of chronological and selection bias on the probability of a type I error. The framework is applied to a case study with a 2-arm parallel group, single center randomized clinical trial with continuous endpoint, with no-interim analysis, 1:1 allocation and no adaptation in the randomization process. In so doing, we derive scientific arguments for the selection of an appropriate randomization procedure and develop a template which is illustrated in parallel by a case study. Possible extensions are discussed. The proposed ERDO framework guides the investigator through a template for the choice of a randomization procedure, and provides easy to use tools for the assessment. The barriers for the thorough reporting and assessment of randomization procedures could be further reduced in the future when regulators and pharmaceutical companies employ similar, standardized frameworks for the choice of a randomization procedure.

Purpose: Very high or low temperatures will lead to bone damage. The objective of this review was to analyze threshold values for thermal bone necrosis. Methods: Histological animal studies evaluating thermal effects on bone necrosis were selected via electronic and hand searches in English and German language journals until 1 November 2019. The outcome measures were temperature-exposure intervals and laser settings effecting bone damage. Furthermore, investigated parameters were the bone-to-implant contact ratios (BIC) and infrabony pockets around dental implants after thermal treatment. For quality assessment of studies, the CAMARADES study quality checklist was applied. Results: A total of 455 animals in 25 animal studies were included for data extraction after screening of 45 titles from 957 selected titles of the MEDLINE (PubMed), The Cochrane Library, Embase and Web of Science search. The threshold values for bone necrosis ranged between 47 °C and 55 °C for 1 min. A threshold value for cryoinsult and laser treatment has not yet been defined. However, temperatures in the vicinity of 3.5 °C produce a histologically proven effect on the bone and in the surrounding tissue. At 50 °C for 1 min, BIC values significantly decreased and infrabony pockets increased. Bone quality had an influence on the outcome, as cancellous bone suffered higher bone damage from thermal treatment compared to cortical bone. Conclusion: No clear threshold value for bone necrosis is available according to the current literature for warm and cold stimuli. More in-depth and clinical studies are required to provide further insights in assessing the potential of thermal necrosis for implant removal.

The quality of external chest compressions (ECC) is of primary importance within basic life support (BLS). Recent guidelines delineate the so-called 4"-step approach" for teaching practical skills within resuscitation training guided by a certified instructor. The objective of this study was to evaluate whether a "media-supported 4-step approach" for BLS training leads to equal practical performance compared to the standard 4-step approach. After baseline testing, 220 laypersons were either trained using the widely accepted method for resuscitation training (4-step approach) or using a newly created "media-supported 4-step approach", both of equal duration. In this approach, steps 1 and 2 were ensured via a standardised self-produced podcast, which included all of the information regarding the BLS algorithm and resuscitation skills. Participants were tested on manikins in the same mock cardiac arrest single-rescuer scenario prior to intervention, after one week and after six months with respect to ECC-performance, and participants were surveyed about the approach. Participants (age 23 ± 11, 69% female) reached comparable practical ECC performances in both groups, with no statistical difference. Even after six months, there was no difference detected in the quality of the initial assessment algorithm or delay concerning initiation of CPR. Overall, at least 99% of the intervention group (n = 99; mean 1.5 ± 0.8; 6-point Likert scale: 1 = completely agree, 6 = completely disagree) agreed that the video provided an adequate introduction to BLS skills. The "media-supported 4-step approach" leads to comparable practical ECC-performance compared to standard teaching, even with respect to retention of skills. Therefore, this approach could be useful in special educational settings where, for example, instructors' resources are sparse or large-group sessions have to be prepared.

Purpose: To identify risk factors that may lead to reoperations following primary vitrectomy (PV) and scleral buckling surgery (SB) for rhegmatogenous retinal detachment (RRD). Methods: Analysis of the association between distinct parameters and the necessity for reoperations in the ‘Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment study’ (SPR Study) using an Andersen–Gill‐mean intensity model. Results: The risk for recurrent reoperations is significantly reduced by primary vitrectomy (PV) compared to scleral buckling (SB) in pseudophakic eyes (p = 0.0009) and increased after PV compared to SB in phakic eyes (p < 0.0001). Additional significant risk factors were in the pseudophakic group preoperative deterioration of visual acuity (p = 0.0226), YAG capsulotomy (p = 0.0043), large breaks (p = 0.0290), number of affected quadrants (p = 0.0387), retinal incarceration during surgery (p = 0.0115), number of breaks (p < 0.0001) and symptomatic visual field defect (p = 0.0463). In the phakic group, associated risk factors were low intraocular pressure (p = 0.0013) and persistent intraoperative detachment at the buckle (p = 0.0184). Conclusion: Reoperations are used as an indicator for the quality and efficacy of surgical techniques. Using a refined multivariate survival model, distinct factors were identified and associated with one or more reoperations after PV or SB in RRD surgery. This information should be useful in the decision process regarding the surgical approach.