Decreasing the options' number in multiple choice questions in the assessment of senior medical students and its effect on exam psychometrics and distractors' function.

BACKGROUND: Studies that have investigated the effect options' number in MCQ tests used in the assessments of senior medical students are scarce. This study aims to compare exam psychometrics between three- and five-option MCQ tests in final-year assessments. METHODS: A cluster randomized study was applied. Participants were classified into three groups, according to their academic levels. Students in each of those levels were randomized into either the three- or five-option test groups. RESULTS: Mean time to finish the five-option test was 45 min, versus 32 min for the three-option group. Cronbach's alpha was 0.89 for the three-option group, versus 0.81 for the five-options, p-value = 0.19. The mean difficulty index for the three-option group was 0.75, compared to 0.73 for the five-option group, p-value = 0.57. The mean discriminating index was 0.53 for the three-option group, and 0.45 for the five-options, p-value = 0.07. The frequency of non-functioning distractors was higher in the five-option test, 111 (56%), versus 39 (39%) in the three-options, with p-value < 0.01. CONCLUSIONS: This study has shown that three-option MCQs are comparable to five-option MCQs, in terms of exam psychometrics. Three-option MCQs are superior to five-option tests regarding distractors' effectiveness and saving administrative time.

Combining factorial and multi-arm multi-stage platform designs to evaluate multiple interventions efficiently.

BACKGROUND: Factorial designs and multi-arm multi-stage (MAMS) platform designs have many advantages, but the practical advantages and disadvantages of combining the two designs have not been explored. METHODS: We propose practical methods for a combined design within the platform trial paradigm where some interventions are not expected to interact and could be given together. RESULTS: We describe the combined design and suggest diagrams that can be used to represent it. Many properties are common both to standard factorial designs, including the need to consider interactions between interventions and the impact of intervention efficacy on power of other comparisons, and to standard multi-arm multi-stage designs, including the need to pre-specify procedures for starting and stopping intervention comparisons. We also identify some specific features of the factorial-MAMS design: timing of interim and final analyses should be determined by calendar time or total observed events; some non-factorial modifications may be useful; eligibility criteria should be broad enough to include any patient eligible for any part of the randomisation; stratified randomisation may conveniently be performed sequentially; and analysis requires special care to use only concurrent controls. CONCLUSION: A combined factorial-MAMS design can combine the efficiencies of factorial trials and multi-arm multi-stage platform trials. It allows us to address multiple research questions under one protocol and to test multiple new treatment options, which is particularly important when facing a new emergent infection such as COVID-19.

A study protocol for a preliminary randomised controlled trial assessing the acceptability and effectiveness of two eating disorders prevention interventions in Switzerland: The HEIDI BP-HW project.

Because of the serious consequences of eating disorders on young women's lives and because of the lack of specialised care facilities, assessing and implementing evidence-based prevention interventions is necessary. Switzerland, like other Western countries, has high prevalence rates of eating disorders. However, no prevention interventions have been evaluated in this country so far. This paper presents the protocol of a preliminary study with the aim to evaluate the acceptability and effectiveness of two interventions, the Body Project (BP) and the Healthy Weight Program (HW), for female students from French-speaking Switzerland. These two interventions were chosen because they have been widely evaluated and they proved to be effective in various countries. They take place in groups and include four weekly sessions over one month. Because of the pandemic situation, the group sessions will take place online on an collaborative platform. The design is a three-arm randomised controlled study. Ninety female students aged 18-25 and presenting with at least moderate body dissatisfaction will be randomised into three groups: (1) one-month BP intervention, (2) one-month HW intervention, and (3) one-month waiting-list control group followed by the BP intervention. Assessments of body dissatisfaction, thin-ideal internalisation, dietary restraint, negative affect, and eating disorder psychopathology will be conducted before and after the interventions or waiting list and after a one-month follow-up. ANCOVA and ANOVA with repeated measures will be used to assess group differences and follow-up stability. Acceptability will be assessed with a questionnaire on participants' satisfaction with the interventions, group discussion at the end of the intervention, and with participants' rate of attendance to the group sessions. The study results will provide additional data on these two eating disorders prevention interventions and will suggest ways for their dissemination and further evaluation in Switzerland.

Efficacy comparison of intraperitoneal anaesthesia and post-operative analgesia regimens in laboratory rats.

INTRODUCTION: Effective and safe anesthesia for rodents has long been a leading concern among biomedical researchers. Intraperitoneal injection constitutes an alternative to inhalant anesthesia. PURPOSE: The aim of this study was to identify a safe, reliable, and effective anesthesia and postoperative analgesia protocol for laboratory rats exposed to painful procedures. MATERIAL AND METHODS: Twenty-seven female Wistar rats in an ongoing study that required surgery were randomized into groups for three different intraperitoneal anesthesia protocols and three different analgesia regimens. The anesthesia groups were (1) medetomidine + ketamine (MK), (2) ketamine + xylacine (KX), and (3) fentanyl + medetomidine (FM). Three analgesia groups were equally distributed among the anesthesia groups: (1) local mepivacaine + oral ibuprofen (MI), (2) oral tramadol + oral ibuprofen (TI), and (3) local tramadol + oral tramadol + + oral ibuprofen (TTI). A core was assigned to measure anesthesia (0-3) and analgesia (0-2) effectiveness; the lower the score, the more effective the treatment. RESULTS: The mean MK score was 0.44 versus 2.00 for FM and 2.33 for KX. Mean score for analgesia on the first postoperative day was TTI (4.66) TI (9.13), and MI (10.14). Mean score 48 hours after surgery was TTI (3.4), TI (6.71), and MI (9.5). These differences were statistically significant. CONCLUSION: MK was shown to be a reliable, safe, and effective method of anesthesia. The TTI analgesia regimen is strongly recommended in light of these results.

Clinical effectiveness and bacteriological eradication of three different Short-COurse antibiotic regimens and single-dose fosfomycin for uncomplicated lower Urinary Tract infections in adult women (SCOUT study): study protocol for a randomised clinical trial.

INTRODUCTION: Uncomplicated lower urinary tract infections (uLUTI) are a common problem in primary care. Current local guidelines recommend the use of a single 3 g dose of fosfomycin. However, most general practitioners (GP) prefer short-course therapies to single-dose therapy. No study has compared head-to-head short-course antimicrobial agents for uLUTIs. Therefore, the aim of this randomised clinical trial is to compare three different short-course antibiotic therapies with a single-dose of fosfomycin for these infections. METHODS AND ANALYSIS: This will be a pragmatic, multicentre, parallel group, open trial. Women aged 18 or older and with symptoms of uLUTI and a positive urine dipstick analysis will be randomised to one of the following four groups: a single dose of 3 g of fosfomycin, 2 days of 3 g of fosfomycin o.d., 3 days of pivmecillinam 400 mg three times per day (t.i.d) or 5 days of nitrofurantoin 100 mg t.i.d. A total sample of 1120 patients was calculated. The primary endpoint is clinical effectiveness at day 7, defined as cure of symptoms reported by the patients in a diary including four symptoms: dysuria, urgency, frequency and suprapubic pain, which will be scored on a 4-point severity scale (not present/mild/moderate/severe). Follow-up visits are scheduled at days 7 (phone call), 14 and 28 for assessing evolution. Urine samples will be collected in the three on-site visits and urine cultures performed. If positive, antibiograms for the three antibiotics studied will be performed. Bacterial eradication will be measured at days 14 and 28. ETHICS AND DISSEMINATION: The study was approved by the Ethical Board of IDIAP Jordi Gol (reference number: 21/173-AC) and Spanish Agency of Medicines and Medical Devices. The findings of this trial will be disseminated through research conferences and peer-review journals. TRIAL REGISTRATION NUMBER: NCT04959331; EudraCT Number: 2021-001332-26. TIME SCHEDULE: January 2022 to April 2023.

How can the utilisation of help for mental disorders be improved? A quasi-experimental online study on the changeability of stigmatising attitudes and intermediate variables in the process of utilisation.

BACKGROUND: Epidemiological studies show that even in highly developed countries many people with depression do not seek help for their mental health issues, despite promising prevention approaches encouraging people to seek help and reduce self-stigma. Therefore, an anti-stigma intervention study to support help-seeking behaviour will be developed on the basis of the newly explicated "Seeking Mental Health Care Model". METHODS: A quasi-experimental online study will be carried out to assess the effect of different intervention variables relevant for the help-seeking process. The study is conceived as a fractional factorial design. Participants will be screened for depressive complaints (PHQ-9 sum score ≥ 8) and current psychiatric/psychotherapeutic treatment. After baseline assessment the participants will be randomly allocated into one of the 24 study groups receiving different combinations of the vignette-based intervention aiming to reduce stigma and support help-seeking. Next, relevant outcome measures will be administered a second time. In a 3- and 6-month follow-up help-seeking behaviour will be measured. Gamified elements and avatar-choice techniques will be used to heighten study immersion and adherence. DISCUSSION: On the basis of the project results, promising research and intervention perspectives can be developed. Results, firstly, allow for a more detailed empirical investigation and conceptualisation of the stages of mental health care utilisation, as well as an examination of theoretical approaches to stigmatisation. Secondly, our online study could provide insights for an evidence-based design and evaluation of online interventions for people with a mental illness. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00023557 . Registered 11 December 2020. World Health Organization, Universal Trial Number: U1111-1264-9954. Registered 16 February 2021.

UK B.1.1.7 (Alpha) variant exhibits increased respiratory replication and shedding in nonhuman primates.

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, we compared African green monkeys infected intranasally with either the UK B.1.1.7 (Alpha) variant or its contemporary D614G progenitor. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases.

Experimental evidence that changing beliefs about mask efficacy and social norms increase mask wearing for COVID-19 risk reduction: Results from the United States and Italy.

In the absence of widespread vaccination for COVID-19, governments and public health officials have advocated for the public to wear masks during the pandemic. The decision to wear a mask in public is likely affected by both beliefs about its efficacy and the prevalence of the behavior. Greater mask use in the community may encourage others to follow this norm, but it also creates an incentive for individuals to free ride on the protection afforded to them by others. We report the results of two vignette-based experiments conducted in the United States (n = 3,100) and Italy (n = 2,659) to examine the causal relationship between beliefs, social norms, and reported intentions to engage in mask promoting behavior. In both countries, survey respondents were quota sampled to be representative of the country's population on key demographics. We find that providing information about how masks protect others increases the likelihood that someone would wear a mask or encourage others to do so in the United States, but not in Italy. There is no effect of providing information about how masks protect the wearer in either country. Additionally, greater mask use increases intentions to wear a mask and encourage someone else to wear theirs properly in both the United States and Italy. Thus, community mask use may be self-reinforcing.

Remdesivir is efficacious in rhesus monkeys exposed to aerosolized Ebola virus.

Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.

Effects of political versus expert messaging on vaccination intentions of Trump voters.

To increase COVID-19 vaccine uptake in resistant populations, such as Republicans, focus groups suggest that it is best to de-politicize the issue by sharing five facts from a public health expert. Yet polls suggest that Trump voters trust former President Donald Trump for medical advice more than they trust experts. We conducted an online, randomized, national experiment among 387 non-vaccinated Trump voters, using two brief audiovisual artifacts from Spring 2021, either facts delivered by an expert versus political claims delivered by President Trump. Relative to the control group, Trump voters who viewed the video of Trump endorsing the vaccine were 85% more likely to answer "yes" as opposed to "no" in their intention to get fully vaccinated (RRR = 1.85, 95% CI 1.01 to 3.40; P = .048). There were no significant differences between those hearing the public health expert excerpt and the control group (for "yes" relative to "no" RRR = 1.14, 95% CI 0.61 to 2.12; P = .68). These findings suggest that a political speaker's endorsement of the COVID-19 vaccine may increase uptake among those who identify with that speaker. Contrary to highly-publicized focus group findings, our randomized experiment found that an expert's factually accurate message may not be effectual to increase vaccination intentions.

Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets.

The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.

New Scoring System for Predicting Mortality in Patients with COVID-19.

PURPOSE: We aimed to develop a novel mortality scoring system for inpatients with COVID-19 based on simple demographic factors and laboratory findings. MATERIALS AND METHODS: We reviewed and analyzed data from patients who were admitted and diagnosed with COVID-19 at 10 hospitals in Daegu, South Korea, between January and July 2020. We randomized and assigned patients to the development and validation groups at a 70% to 30% ratio. Each point scored for selected risk factors helped build a new mortality scoring system using Cox regression analysis. We evaluated the accuracy of the new scoring system in the development and validation groups using the area under the curve. RESULTS: The development group included 1232 patients, whereas the validation group included 528 patients. In the development group, predictors for the new scoring system as selected by Cox proportional hazards model were age ≥70 years, diabetes, chronic kidney disease, dementia, C-reactive protein levels >4 mg/dL, infiltration on chest X-rays at the initial diagnosis, and the need for oxygen support on admission. The areas under the curve for the development and validation groups were 0.914 [95% confidence interval (CI) 0.891-0.937] and 0.898 (95% CI 0.854-0.941), respectively. According to our scoring system, COVID-19 mortality was 0.4% for the low-risk group (score 0-3) and 53.7% for the very high-risk group (score ≥11). CONCLUSION: We developed a new scoring system for quickly and easily predicting COVID-19 mortality using simple predictors. This scoring system can help physicians provide the proper therapy and strategy for each patient.

Stratified randomization for platform trials with differing experimental arm eligibility.

BACKGROUND: Platform trials facilitate efficient use of resources by comparing multiple experimental agents to a common standard of care arm. They can accommodate a changing scientific paradigm within a single trial protocol by adding or dropping experimental arms-critical features for trials in rapidly developing disease areas such as COVID-19 or cancer therapeutics. However, in these trials, efficacy and safety issues may render certain participant subgroups ineligible to some experimental arms, and methods for stratified randomization do not readily apply to this setting. METHODS: We propose extensions for conventional methods of stratified randomization for platform trials whose experimental arms may differ in eligibility criteria. These methods balance on a prespecified set of stratification variables observable prior to arm assignment that remains the same across experimental arms. To do so, we suggest modifying block randomization by including experimental arm eligibility as a stratifying variable, and we suggest modifying the imbalance score calculation in dynamic balancing by performing pairwise comparisons between each eligible experimental arm and standard of care arm participants eligible to that experimental arm. RESULTS: We provide worked examples to illustrate the proposed extensions. In addition, we also provide a formula to quantify the relative efficiency loss of platform trials with varying eligibility compared with trials with non-varying eligibility as measured by the size of the common standard of care arm. CONCLUSIONS: This article presents important extensions to conventional methods for stratified randomization in order to facilitate the implementation of platform trials with differing experimental arm eligibility.

[Acute kidney injury - Update 2021]. / Akute Nierenschädigung ­ Update 2021.

One in five hospitalized patients suffers acute kidney injury (AKI). Depending on its severity, AKI is associated with an up to 15-fold increased risk of mortality and constitutes a major risk factor for subsequent cardiovascular events and for the development of chronic kidney disease. This concise review summarizes recently published studies, focusing on 1.) automated AKI detection using electronic health records-based AKI alert systems, 2.) renal replacement therapy and its optimal timing and anticoagulation regimen, and 3.) coronavirus disease-2019 (COVID-19) associated AKI.

Deep learning with robustness to missing data: A novel approach to the detection of COVID-19.

In the context of the current global pandemic and the limitations of the RT-PCR test, we propose a novel deep learning architecture, DFCN (Denoising Fully Connected Network). Since medical facilities around the world differ enormously in what laboratory tests or chest imaging may be available, DFCN is designed to be robust to missing input data. An ablation study extensively evaluates the performance benefits of the DFCN as well as its robustness to missing inputs. Data from 1088 patients with confirmed RT-PCR results are obtained from two independent medical facilities. The data includes results from 27 laboratory tests and a chest x-ray scored by a deep learning model. Training and test datasets are taken from different medical facilities. Data is made publicly available. The performance of DFCN in predicting the RT-PCR result is compared with 3 related architectures as well as a Random Forest baseline. All models are trained with varying levels of masked input data to encourage robustness to missing inputs. Missing data is simulated at test time by masking inputs randomly. DFCN outperforms all other models with statistical significance using random subsets of input data with 2-27 available inputs. When all 28 inputs are available DFCN obtains an AUC of 0.924, higher than any other model. Furthermore, with clinically meaningful subsets of parameters consisting of just 6 and 7 inputs respectively, DFCN achieves higher AUCs than any other model, with values of 0.909 and 0.919.

E-cigarette-induced pulmonary inflammation and dysregulated repair are mediated by nAChR α7 receptor: role of nAChR α7 in SARS-CoV-2 Covid-19 ACE2 receptor regulation.

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.

Effects of Face Mask Use on Objective and Subjective Measures of Thermoregulation During Exercise in the Heat.

BACKGROUND: While increased face mask use has helped reduce COVID-19 transmission, there have been concerns about its influence on thermoregulation during exercise in the heat, but consistent, evidence-based recommendations are lacking. HYPOTHESIS: No physiological differences would exist during low-to-moderate exercise intensity in the heat between trials with and without face masks, but perceptual sensations could vary. STUDY DESIGN: Crossover study. LEVEL OF EVIDENCE: Level 2. METHODS: Twelve physically active participants (8 male, 4 female; age = 24 ± 3 years) completed 4 face mask trials and 1 control trial (no mask) in the heat (32.3°C ± 0.04°C; 54.4% ± 0.7% relative humidity [RH]). The protocol was 60 minutes of walking and jogging between 35% and 60% of relative VO2max. Rectal temperature (Trec), heart rate (HR), temperature and humidity inside and outside of the face mask (Tmicro_in, Tmicro_out, RHmicro_in, RHmicro_out) and perceptual variables (rating of perceived exertion (RPE), thermal sensation, thirst sensation, fatigue level, and overall breathing discomfort) were monitored throughout all trials. RESULTS: Mean Trec and HR increased at 30- and 60-minute time points compared with 0-minute time points, but no difference existed between face mask trials and control trials (P > 0.05). Mean Tmicro_in, RHmicro_in, and humidity difference inside and outside of the face mask (ΔRHmicro) were significantly different between face mask trials (P < 0.05). There was no significant difference in perceptual variables between face mask trials and control trials (P > 0.05), except overall breathing discomfort (P < 0.01). Higher RHmicro_in, RPE, and thermal sensation significantly predicted higher overall breathing discomfort (r2 = 0.418; P < 0.01). CONCLUSION: Face mask use during 60 minutes of low-to-moderate exercise intensity in the heat did not significantly affect Trec or HR. Although face mask use may affect overall breathing discomfort due to the changes in the face mask microenvironment, face mask use itself did not cause an increase in whole body thermal stress. CLINICAL RELEVANCE: Face mask use is feasible and safe during exercise in the heat, at low-to-moderate exercise intensities, for physically active, healthy individuals.

A new randomization procedure based on multiple covariates and applicable to parallel studies with simultaneous enrollment of all subjects prior to intervention.

BACKGROUND: Parallel intervention studies involving volunteers usually require a procedure to allocate the subjects to study-arms. Statistical models to evaluate the different outcomes of the study-arms will include study-arm as a factor along with any covariate that might affect the results. To ensure that the effects of the covariates are confounded to the least possible extent with the effects of the arms, stratified randomization can be applied. However, there is at present no clear-cut procedure when there are multiple covariates. METHODS: For parallel study designs with simultaneous enrollment of all subjects prior to intervention, we propose a D-optimal blocking procedure to allocate subjects with known values of the covariates to the study arms. We prove that the procedure minimizes the variances of the baseline differences between the arms corrected for the covariates. The procedure uses standard statistical software. RESULTS: We demonstrate the potential of the method by an application to a human parallel nutritional intervention trial with three arms and 162 healthy volunteers. The covariates were gender, age, body mass index, an initial composite health score, and a categorical indicator called first-visit group, defining groups of volunteers who visit the clinical centre on the same day (17 groups). Volunteers were allocated equally to the study-arms by the D-optimal blocking procedure. The D-efficiency of the model connecting an outcome with the study-arms and correcting for the covariates equals 99.2%. We simulated 10,000 random allocations of subjects to arms either unstratified or stratified by first-visit group. Intervals covering the middle 95% of the D-efficiencies for these allocations were [82.0, 92.0] and [93.2, 98.4], respectively. CONCLUSIONS: Allocation of volunteers to study-arms with a D-optimal blocking procedure with the values of the covariates as inputs substantially improves the efficiency of the statistical model that connects the response with the study arms and corrects for the covariates. TRIAL REGISTRATION: Dutch Trial Register NL7054 ( NTR7259 ). Registered May 15, 2018.