Allowing for stratification in sample size planning of two-arm trials with continuous or binary outcome: Overview and tutorial

More often than not, clinical trials and even nonclinical medical experiments have to be run with observational units sampled from populations to be assumed heterogeneous with respect to covariates associated with the outcome. Relevant covariates which are known prior to randomization are usually categorical in type, and the corresponding subpopulations are called strata. In contrast to randomization which in most cases is performed in a way ensuring approximately constant sample size ratios across the strata, sample size planning is rarely done taking stratification into account. This holds true although the statistical literature provides a reasonably rich repertoire of testing procedures for stratified comparisons between two treatments in a parallel group design. For all of them, at least approximate methods of power calculation are available from which algorithms or even closed-form formulae for required sample sizes can be derived. The objective of this tutorial is to give a systematic review of the most frequently applicable of these methods and to compare them in terms of their efficiency under standard settings. Based on the results, recommendations for the sample size planning of stratified two-arm trials are given.

Efficacy of Sphincter Control Training and medical device in the treatment of premature ejaculation: A multicenter randomized controlled clinical trial

A new line of treatment for premature ejaculation (PE) based on the use of masturbation aid device in combination with behavioral techniques has emerged in recent years. We report a multicenter randomized clinical trial with a parallel group design to determine the effectiveness of an electronic device called Myhixel I© in the treatment of PE. Forty patients who met the criteria for the diagnosis of lifelong PE, were assigned to two treatment groups completed the Sphincter control training (SCT) program in eight weeks. The only difference between groups was the use of the device. The main measure was the “fold increase” (FI) of the intravaginal ejaculatory latency time (IELT). The geometric means of IELT show, at the end of the treatment at week 8, a superiority of the device group. The mean FI 4.27 (SD 2.59) at the end of treatment for the device group was clearly higher than obtained in the previous clinical trial, in which a specific medical device was not used. No side effects were observed and it required little therapeutic input and no partner involvement. The SCT program in combination with the Myhixel I© is an effective treatment for PE.

DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers

The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation—the key agent in trauma focused treatments—and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma.Trial registration: Addressing Heightened Levels of Aggression in Traumatized Offenders With Psychotherapeutic Means (ClinicalTrials.gov Identifier: NCT02992561, 14/12/2016).

Flexible vs. rigid dieting in resistance-trained individuals seeking to optimize their physiques: A randomized controlled trial

Background The purpose of this study was to compare a flexible vs. rigid diet on weight loss and subsequent weight regain in resistance-trained (RT) participants in a randomized, parallel group design. Methods Twenty-three males and females (25.6 ± 6.1 yrs; 170 ± 8.1 cm; 75.4 ± 10.3 kg) completed the 20-week intervention (consisting of a 10-week diet phase and a 10-week post-diet phase). Participants were randomized to a flexible diet (FLEX) comprised of non-specific foods or a rigid diet (RIGID) comprised of specific foods. Participants adhered to an ~20%kcal reduction during the first 10-weeks of the intervention and were instructed to eat ad libitum for the final 10-weeks. Body composition and resting metabolic rate were assessed 5 times: (baseline, 5, 10 [end of diet phase], 16, and 20 weeks). Results During the 10-week diet phase, both groups significantly reduced bodyweight (FLEX: baseline = 76.1 ± 8.4kg, post-diet = 73.5 ± 8.8 kg, ▲2.6 kg; RIGID: baseline = 74.9 ± 12.2 kg, post-diet = 71.9 ± 11.7 kg, ▲3.0 kg, p < 0.001); fat mass (FLEX: baseline = 14.8 ± 5.7 kg, post-diet = 12.5 ± 5.0 kg, ▲2.3 kg; RIGID: baseline = 18.1 ± 6.2 kg, post-diet = 14.9 ± 6.5 kg, ▲3.2 kg p < 0.001) and body fat% (FLEX: baseline = 19.4 ± 8.5%, post-diet = 17.0 ± 7.1%, ▲2.4%; RIGID: baseline = 24.0 ± 6.2%, post-diet = 20.7 ± 7.1%, ▲3.3%; p < 0.001). There were no significant differences between the two groups for any variable during the diet phase. During the post-diet phase, a significant diet x time interaction (p < 0.001) was observed for FFM with the FLEX group gaining a greater amount of FFM (+1.7 kg) in comparison with the RIGID group (−0.7 kg). Conclusions A flexible or rigid diet strategy is equally effective for weight loss during a caloric restriction diet in free-living, RT individuals. While post-diet FFM gains were greater in the FLEX group, there were no significant differences in the amount of time spent in resistance and aerobic exercise modes nor were there any significant differences in protein and total caloric intakes between the two diet groups. In the absence of a clear physiological rationale for increases in FFM, in addition to the lack of a standardized diet during the post-diet phase, we refrain from attributing the increases in FFM in the FLEX group to their diet assignment during the diet phase of the investigation. We recommend future research investigate additional physiological and psychological effects of flexible diets and weight regain in lean individuals.

Spontaneous and deliberate creative cognition during and after psilocybin exposure

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007.

Virtual Reality Tour to Reduce Perioperative Anxiety in an Operating Setting Before Anesthesia: Randomized Clinical Trial (Preprint)

BACKGROUND Perioperative anxiety is a major burden to patients undergoing surgeries with general anesthesia. OBJECTIVE This study investigated whether a virtual operating room tour (VORT) before surgery can be used to ameliorate perioperative anxiety. METHODS We employed a randomized parallel-group design with 2 study arms to compare VORT to the standard operation preparation procedure. The study included 84 patients. A validated inventory (state-trait operation anxiety-state) was used to assess perioperative state anxiety before (T1) and after (T2) surgery. In addition, trait operation anxiety was evaluated with an additional validated inventory (state-trait operation anxiety-trait). Moreover, user ratings on the usefulness of VORT were assessed with an evaluation questionnaire. Study arms were compared for perioperative state anxiety with two-tailed independent samples <i>t</i> tests. Subjective ratings were correlated with STOA-Trait values to investigate possible associations between perioperative anxiety with perceived usefulness. RESULTS There were no significant differences in perioperative state anxiety between VORT and standard operation preparation procedures before and after the surgery. Nonetheless, patients’ ratings of VORT overall were positive. The tour was perceived as useful and, therefore, showed acceptance for VR use. These ratings were unrelated to the degree of perioperative anxiety. CONCLUSIONS The subjective benefit of VORT could not be explained by a reduction of perioperative anxiety. Instead, VORT appears to serve the need for information and reduce uncertainty. In addition, VORT is perceived as beneficial regardless of the age of the patients. Considering this effect and the manageable organizational and financial effort toward implementation, the general use of VORT can be recommended. CLINICALTRIAL ClinicalTrials.gov NCT04579354; https://clinicaltrials.gov/ct2/show/NCT04579354

Integrative Nursing and Omaha System–Based Nursing Care Interventions in Older Women Feeling Loneliness (INOSEL): Study Protocol for a Randomized Controlled Trial

Purpose: This article presents the planned protocol for a study that investigates the effects of nursing care interventions based on Integrative Nursing (IN) and the Omaha System. The Omaha System is a nursing classification system focused on holistic care and used in determining nursing diagnoses and applying and evaluating interventions. Design: This study protocol describes a randomized controlled trial with a parallel group design. Method: Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Statement 2013 checklist is used in this study. The CONSORT (Consolidated Standards of Reporting Trials) flowchart is used in this protocol. After the level of loneliness of older women is determined by the Loneliness Scale for the Elderly in a family health center, women with high levels of loneliness will be randomly assigned to the intervention and control groups. Nursing care interventions consist of group-based (sightseeing, picnics, theater, cinema, group education, and charity activities) and person-centered interventions, according to IN and the Omaha System, for 12 weeks. Conclusions: This protocol will test the effectiveness of nursing care interventions that include a comprehensive (physical, psychological, social, and spiritual) evaluation. The results will help contribute to the provision of care in terms of IN and the Omaha System and guide health professionals and researchers.

Sulodexide in the treatment of patients with early stages of COVID-19: a randomised controlled trial

BackgroundTargeting endothelial cells has been suggested for the treatment of patients with COVID-19 and sulodexide has pleiotropic properties within the vascular endothelium that can prove beneficial to the same. We aimed to evaluate the effect of sulodexide when used in the early clinical stages of COVID-19.MethodsWe conducted a single-centre, outpatient setting, randomised controlled trial with a parallel-group design in Mexico. Including patients within three days of clinical symptom onset, who were at a high risk of severe clinical progression due to chronic comorbidities. Participants were randomly allocated to receive an oral dose of sulodexide (500 LRU twice a day) or the placebo for 21 days. Primary outcomes were need and length of hospitalisation, need and length of oxygen support.ResultsBetween June 5 and August 30, 2020, 243 patients were included in the “per-protocol” analysis. One hundred twenty-four of them received sulodexide, while 119 received placeboes. At 21 days follow-up, 22 of 124 patients required hospitalisation in the sulodexide group compared to 35 of 119 in the placebo group [relative risk (RR), 0·6; 95% confidence interval (CI), 0·37-0·96; p=0·03]. Fewer patients required oxygen support in the sulodexide group [37 of 124 vs. 50 of 119; RR, 0·71; 95% CI, 0·5 to 1; p=0·05], and for fewer days (9±7·2 in the sulodexide group vs. 11·5±9·6 in the placebo group; p=0·02). There was no between-group difference concerning the length of hospital stay.InterpretationEarly intervention in COVID-19 patients with sulodexide reduced hospital admissions and oxygen support requirements, although with no significant effect on mortality. This has beneficial implications in the patient well-being, making sulodexide a favourable medication until an effective vaccine or an antiviral becomes available.FundingResearcher independently initiated, partially funded by Alfasigma, Mexico.Listed in the ISRCTN registry under ID ISRCTN59048638.

A single dose of cannabidiol modulates medial temporal and striatal function during fear processing in people at clinical high risk for psychosis

Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.