Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials.

BACKGROUND: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms. METHODS: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI). RESULTS: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes. CONCLUSIONS: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

Seeing the Truth About Double Blinding.

Randomized clinical trials provide reassurances that confounding factors are balanced at baseline whereas blinding is essential to assure the balance of extraneous factors thereafter. This article provides a three-part taxonomy of pitfalls that can arise because of inadequate blinding in clinical trials. We introduce a cautionary framework for readers interpreting a blinded randomized trial for evidence-based medicine. Each pitfall is illustrated with a relevant example of a potential bias resulting from knowledge of group assignment. Several pitfalls occur during the conduct of the study including inadequate blinding of the intervention group, control group, or responsible clinicians. Additional pitfalls relate to data analysis including unsubstantiated assertions of blinding and subverted tests for blinding. Further pitfalls arise due to surrounding oversight including unblinding of research ethics boards and scientific reviewers. These caveats are sources of misunderstanding when observing the apparent connection between a clinical intervention and patient outcomes. An awareness of specific pitfalls might help advance the interpretation and application of blinded randomized clinical trials to inform evidence-based medical care.

Considerations for open-label randomized clinical trials: Design, conduct, and analysis.

Randomization and blinding are regarded as the most important tools to help reduce bias in clinical trial designs. Randomization is used to help guarantee that treatment arms differ systematically only by treatment assignment at baseline, and blinding is used to ensure that differences in endpoint evaluation and clinical decision-making during the trial arise only from the treatment received and not, for example, the expectation or desires of the people involved. However, given that there are times when it is not feasible or ethical to conduct fully blinded trials, we discuss what can be done to improve a trial, including conducting the trial as if it were a fully blinded trial and maintaining confidentiality of ongoing study results. In this article, we review how best to design, conduct, and analyze open-label trials to ensure the highest level of study integrity and the reliability of the study conclusions.

Treatment guesses in the Treatment for Adolescents with Depression Study: Accuracy, unblinding and influence on outcomes.

OBJECTIVE: We evaluated the presence and impact of unblinding during the influential Treatment for Adolescents with Depression Study (ClinicalTrials.gov Identifier: NCT00006286). METHOD: Our analysis was part of a Restoring Invisible and Abandoned Trials reanalysis. Treatment for Adolescents with Depression Study trialled fluoxetine, placebo, cognitive behaviour therapy or their combination, in treating adolescents with major depressive disorder. We analysed the accuracy of guesses of fluoxetine or placebo allocation, and their effects on change in Children's Depression Rating Scale-Revised at 12 weeks. RESULTS: Of 221 participants allocated to fluoxetine or placebo, 151 adolescents (68%) had their guess about pill-treatment-arm allocation recorded at week 6, and guesses were recorded for 154 independent evaluators, 159 parents and 164 pharmacotherapists. All of these groups guessed treatment allocation more accurately than would be expected by chance (60-66% accuracy; all p-values ⩽ 0.004). Guesses did not become more accurate between 6 and 12 weeks and were not predicted by adverse events, though event documentation was poor. Treatment guess had a substantial and statistically significant effect on outcome (Children's Depression Rating Scale-Revised change mean difference 9.12 [4.69; 13.55], ß = 0.334, p < 0.001), but actual treatment arm did not (1.53 [-2.83; 5.89], ß = 0.056, p = 0.489). Removing guess from the analysis increased the apparent effect of treatment arm, making it almost statistically significant at the conventional alpha-level of 0.05 (p = 0.06). CONCLUSIONS: For Treatment for Adolescents with Depression Study, treatment guesses strongly predicted outcomes and may have led to the exaggeration of drug effectiveness in the absence of actual effects. The integrity of double-blinding in trials should be routinely assessed and reported.

Meta-epidemiologic review: blinding and sham treatment in clinical trial design for osteopathic manipulative treatment research.

Objective: To analyze the consistency of study designs in osteopathic manipulative treatment (OMT) research, focusing on blinding protocols and the use of sham treatments. Data Source and Study Selection: PubMed and CINAHL were searched in January 2022. A total of 83 research studies between 2009 and 2021 were selected based on the presence of a double- or single-blind study design and/or sham treatment. Data Extraction and Analysis: Data regarding the primary outcome measures, blinding design, measures used to determine success of blinding, osteopathic technique used, and sham technique used for each eligible study were extracted and compared among different study designs. Results: A total of 5968 subjects participated in the 83 trials. The study population mainly consisted of asymptomatic individuals (25%) and chronic back pain patients (19%). Light touch was employed most commonly (49%) as the sham treatment, followed by unrelated sham (20%) and incomplete maneuvers (20%). Most studies blinded the subjects (80%) or the outcome evaluator/data analyzer (71%), while only 20% studies blinded the osteopathic physicians. Conclusions: Strict double-blinding is achievable for OMT clinical research by blinding the subjects and data collectors/analyzers rather than the osteopaths providing the actual treatment. The use of questionnaires to determine the success of blinding should be considered. Additionally, including OMT-naïve subjects is preferred to enhance blinding success. When designing a sham treatment, careful consideration should be given to blinding the data collector, accounting for the placebo effect, and incorporating an additional no-treatment control group to improve the rigor of the study design.

Success of blinding a procedural intervention in a randomised controlled trial in preterm infants receiving respiratory support.

BACKGROUND: Blinding of treatment allocation from treating clinicians in neonatal randomised controlled trials can minimise performance bias, but its effectiveness is rarely assessed. METHODS: To examine the effectiveness of blinding a procedural intervention from treating clinicians in a multicentre randomised controlled trial of minimally invasive surfactant therapy versus sham treatment in preterm infants of gestation 25-28 weeks with respiratory distress syndrome. The intervention (minimally invasive surfactant therapy or sham) was performed behind a screen within the first 6 h of life by a 'study team' uninvolved in clinical care including decision-making. Procedure duration and the study team's words and actions during the sham treatment mimicked those of the minimally invasive surfactant therapy procedure. Post-intervention, three clinicians completed a questionnaire regarding perceived group allocation, with the responses matched against actual intervention and categorised as correct, incorrect, or unsure. Success of blinding was calculated using validated blinding indices applied to the data overall (James index, successful blinding defined as > 0.50), or to the two treatment allocation groups (Bang index, successful blinding: -0.30 to 0.30). Blinding success was measured within staff role, and the associations between blinding success and procedural duration and oxygenation improvement post-procedure were estimated. RESULTS: From 1345 questionnaires in relation to a procedural intervention in 485 participants, responses were categorised as correct in 441 (33%), incorrect in 142 (11%), and unsure in 762 (57%), with similar proportions for each of the response categories in the two treatment arms. The James index indicated successful blinding overall 0.67 (95% confidence interval (CI) 0.65-0.70). The Bang index was 0.28 (95% CI 0.23-0.32) in the minimally invasive surfactant therapy group and 0.17 (95% CI 0.12-0.21) in the sham arm. Neonatologists more frequently guessed the correct intervention (47%) than bedside nurses (36%), neonatal trainees (31%), and other nurses (24%). For the minimally invasive surfactant therapy intervention, the Bang index was linearly related to procedural duration and oxygenation improvement post-procedure. No evidence of such relationships was seen in the sham arm. CONCLUSION: Blinding of a procedural intervention from clinicians is both achievable and measurable in neonatal randomised controlled trials.

Peer review practices in academic medicine: how the example of orthopaedic surgery may help shift the paradigm?

PURPOSE: To establish the current peer-reviewed practices in the discipline of orthopaedic surgery and correlate these to the journal's impact factor. Unfortunately, this is not receiving much attention and a critical literature gap in various disciplines; thus, determining the current practices in the discipline of orthopaedic surgery could provide valid insight that may be potentially applicable to other academic medicine disciplines as well. METHODS: Orthopaedic surgery journals belonging to the Journal Citation Reports were queried, and the following was extracted: impact factor (IF) and blinding practices: single (SBPR), double (DBPR), triple (TBPR), quadruple (QBPR), and open (OPR) blinding review process and possibility of author-suggested reviewer (ASR) and non-preferred reviewer (NPR) options. RESULTS: Of the 82 journals, four were excluded as they allowed submission by invitation only. In the remaining, blinding was as follows: SBPR nine (11.5%), DBPR 52 (66.7%), TBPR two (2.6%), QBPR zero (0%), and OPR three (3.8%), and in 12 (15.4%), this was unclear. ASR and NPR options were offered by 34 (43.6%) and 27 (34.6%) journals respectively, whereas ASR was mandatory in eight (10.2%). No correlation between IF and any other parameter was found. CONCLUSION: The rules of the "game" are unclear/not disclosed in a significant number of cases, and the SBPR system, along with the ASR (mandatory sometimes) and NPR, is still extensively used with questionable integrity and fairness. Several recommendations are provided to mitigate potentially compromising practices, along with future directions to address the scarcity of research in this critical aspect of science.

Current perspectives in Leber congenital amaurosis type 8 mouse modeling.

Mutations in the CRB1 (Crumbs homolog 1) cause rare retinal diseases like retinitis pigmentosa type 12 (RP12) and Leber congenital amaurosis type 8 (LCA8). RP12 results in progressively worsening peripheral vision, whereas LCA8 causes severe visual impairment at birth or in early life. While several mouse models have been proposed for RP12, few replicate the full spectrum of human LCA8 pathology, such as disorganized retinal layering, abnormal retinal thickening, pigmentary defects, hyperreflective lesions, and severely attenuated electroretinogram responses at birth. Six models have been proposed utilizing the Cre-loxP system to delete candidate genes in specific retinal cell types and developmental stages. The model ablating Crb1 and its homolog Crb2 (using mRx-Cre) from the beginning of the eye development is the most complete as it shows blindness during the eye-opening stage, pigmentary defects in the RPE, ganglion cell layer heterotopia, disruption of retinal lamination, and acellular patches. LCA8 represents a unique type of retinal dystrophy among LCA subtypes, driven by dysfunctional retinal progenitor cells during eye development. In contrast, other LCA types and RP12 are caused by photoreceptor defects. Therefore, the most accurate LCA8-like mouse model must target both alleles of the Crb1 and Crb2 genes in the optic vesicle or earlier.

Enhancing the Security of the BB84 Quantum Key Distribution Protocol against Detector-Blinding Attacks via the Use of an Active Quantum Entropy Source in the Receiving Station.

True randomness is necessary for the security of any cryptographic protocol, including quantum key distribution (QKD). In QKD transceivers, randomness is supplied by one or more local, private entropy sources of quantum origin which can be either passive (e.g., a beam splitter) or active (e.g., an electronic quantum random number generator). In order to better understand the role of randomness in QKD, I revisit the well-known "detector blinding" attack on the BB84 QKD protocol, which utilizes strong light to achieve undetectable and complete recovery of the secret key. I present two findings. First, I show that the detector-blinding attack was in fact an attack on the receiver's local entropy source. Second, based on this insight, I propose a modified receiver station and a statistical criterion which together enable the robust detection of any bright-light attack and thus restore security.

Acupuncture for Japanese Katakori (Chronic Neck Pain): A Randomized Placebo-Controlled Double-Blind Study.

Background and Objectives: Although acupuncture is listed as a beneficial treatment for neck/shoulder stiffness, which has increased with the spread of information technology, to date, evidence of its efficacy under double-blind conditions has not been shown. This study aimed to assess whether acupuncture treatment with superficial skin piercing is superior to placebo treatment. Materials and Methods: A randomized, double-blind (practitioner-patient) placebo-controlled trial was performed at a single center with four arms (ISRCTN76896018). Four hundred patients with essential neck/shoulder stiffness were randomly assigned to penetrating needle treatment (acupuncture ritual and skin penetration), skin-touch needle treatment (acupuncture ritual and skin touch), no-touch needle treatment (acupuncture ritual alone), and no-treatment control. Each of the six acupuncturists applied a needle to each of the four acupoints in the neck/shoulder of 50 patients. Results: Each of the three treatments significantly (p = 0.01) improved neck/shoulder stiffness compared with the no-treatment control immediately and 24 h after treatment. There was a significant improvement in penetrating needle treatment over no-touch needle treatment 24 h later. However, there was no significant difference between the penetrating and skin-touch and skin-touch vs. no-touch. Conclusions: All treatments that received the ritual of acupuncture were better than the no-treatment control. Only genuine acupuncture involves the specific effects of needle insertion into the body. The acupuncture ritual had a significant impact on the subjective improvement of neck/shoulder stiffness; however, improvement with ritual alone versions of placebo acupuncture was not maintained as with superficial skin piercing. Our study provides important evidence of acupuncture efficacy and information regarding inert no-touch placebo control in acupuncture research.

Expected-value bias in mid-trimester preterm birth screening.

OBJECTIVES: Cervical length (CL) measurement ≤ 25 mm on mid-trimester ultrasound scan is a known risk factor for preterm birth, for which vaginal progesterone is recommended. The aims of this study were to evaluate whether CL measurement is affected by observer bias and to assess the impact on short cervix prevalence of masking CL measurement during routine mid-trimester ultrasound scan. METHODS: This was a flash study designed for a 2-month period (October and November 2018) at Cruces University Hospital (Bizkaia, Spain), in which all CL measurements from routine mid-trimester scans were masked. During the study period, there was no modification of the routine screening method, and women with a short cervix were prescribed 200 mg vaginal progesterone daily as per usual. The control group included women examined in a 2-month period (April and May 2018) prior to the study, in which CL measurements were taken as usual by a non-blinded operator. The primary outcome was the prevalence of short cervix in each group. RESULTS: A total of 983 CL measurements were analyzed, including 457 in the blinded group and 526 in the control group. The prevalence of short cervix was 2.7% in the non-blinded group and 5.5% in the blinded group (P = 0.024). We identified a statistically significant difference in the incidence of CL of 24-25 mm between the two groups, with a lower prevalence in the non-blinded vs blinded group (0.6% vs 2.4%; P < 0.005). Moreover, the distribution of CL values was normal in the blinded group, in contrast to the non-blinded group, which was characterized by skewed distribution of CL values. CONCLUSIONS: Expected-value bias exists and should be taken into account when measuring CL in mid-trimester preterm birth screening. Blinding has demonstrated to be an effective strategy to improve the performance of CL screening in clinical practice. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Extracting drug-drug interactions from no-blinding texts using key semantic sentences and GHM loss.

The extraction of drug-drug interactions (DDIs) is an important task in the field of biomedical research, which can reduce unexpected health risks during patient treatment. Previous work indicates that methods using external drug information have a much higher performance than those methods not using it. However, the use of external drug information is time-consuming and resource-costly. In this work, we propose a novel method for extracting DDIs which does not use external drug information, but still achieves comparable performance. First, we no longer convert the drug name to standard tokens such as DRUG0, the method commonly used in previous research. Instead, full drug names with drug entity marking are input to BioBERT, allowing us to enhance the selected drug entity pair. Second, we adopt the Key Semantic Sentence approach to emphasize the words closely related to the DDI relation of the selected drug pair. After the above steps, the misclassification of similar instances which are created from the same sentence but corresponding to different pairs of drug entities can be significantly reduced. Then, we employ the Gradient Harmonizing Mechanism (GHM) loss to reduce the weight of mislabeled instances and easy-to-classify instances, both of which can lead to poor performance in DDI extraction. Overall, we demonstrate in this work that it is better not to use drug blinding with BioBERT, and show that GHM performs better than Cross-Entropy loss if the proportion of label noise is less than 30%. The proposed model achieves state-of-the-art results with an F1-score of 84.13% on the DDIExtraction 2013 corpus (a standard English DDI corpus), which fills the performance gap (4%) between methods that rely on and do not rely on external drug information.

Adverse effects of subcutaneous vs intravenous hydration in older adults: An assessor-blinded randomised controlled trial (RCT).

BACKGROUND: Hydration therapy is essential in the care of the older patient. Subcutaneous (SC) hydration is a relevant method for parenteral hydration, but clinical trials on the subject have methodological shortcomings compared to updated standards. DESIGN: Assessor-blinded, non-inferiority RCT to explore if SC is a safe alternative to intravenous (IV) hydration. PARTICIPANTS: Eligible patients were: Admitted patients 65 years or older with a need for parenteral hydration. The targeted sample size was 67 patients in each group. INTERVENTION: Patients were randomised to parenteral hydration via an IV or SC catheter during a 24 hours observation period. The non-randomised catheter (inactive) was placed as a sham on the patient, thereby blinding the caregivers and outcome assessors. MEASUREMENT: Our primary outcome was the proportion of patients reporting at least one adverse effect with a non-inferiority calculation using a 20% margin. RESULTS: We included 51 patients, with 24 randomised to SC and 27 to IV. We were unable to reach our target sample size due to challenges in recruitment, time limitation, and COVID-19. For the outcome of adverse effects, SC was non-inferior to IV (p = 0.012). Time spent on inserting the catheters was shorter with SC (p = 0.001). The groups did not differ by pain of insertion, discomfort during infusion, or the risk of developing delirium. CONCLUSION: SC is a safe alternative to IV hydration, is faster to place and should be an available method for parenteral hydration wherever older adults are cared for. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03710408.

Designing and implementing methodology for double-blind, placebo-controlled clinical trials using blood products within the Department of Veterans Affairs.

BACKGROUND: Success in conducting clinical trials during the coronavirus disease of 2019 pandemic requires the ability to innovate and adapt. There are well-established procedures for the blinding of investigational agents, especially medications, in placebo-controlled randomized clinical trials within the Veterans Health Administration. However, these procedures, managed by research pharmacists, may not apply to investigational agents that are not exclusively managed by pharmacy, such as blood products, including coronavirus disease of 2019 convalescent plasma (plasma). In the absence of established blinding procedures, such studies require special design considerations to minimize uncertainty or bias. METHODS: We describe the processes and procedures developed for blinding of plasma in "Veterans Affairs CoronavirUs Research and Efficacy Studies-1" as a prototypical study using this class of investigational therapeutic agents. Veterans Affairs CoronavirUs Research and Efficacy Studies-1 is an ongoing multicenter randomized clinical trial testing the efficacy of plasma added to conventional therapy for severe acute respiratory syndrome coronavirus-2 infection. RESULTS: We report the design of procedures to supply investigational blood products or 0.9% normal saline (saline) control while ensuring the integrity of the blind. Key aspects include workflow considerations, physical blinding strategies, and methods for engaging stakeholders. These procedures leverage the well-established Veterans Affairs research pharmacist's research infrastructure, and Blood Bank Services, which is responsible for blood-based investigational products. CONCLUSION: By describing the methods used to deliver blood products in a blinded manner in Veterans Affairs CoronavirUs Research and Efficacy Studies-1, we strive both to educate and to increase awareness to improve the implementation of these biological therapeutics for future, high-quality research studies.

Assessment of the quality of randomized controlled trials in surgery using Jadad score: Where do we stand?

Introduction: Quality assessment of randomized controlled trials (RCTs) is important to prevent clinical application of erroneous results. Materials and Methods: This was an assessment of published RCTs in surgical subspecialties during 2011-2018 based on MEDLINE and EMBASE search. The primary objective of the present study was to quantitatively and qualitatively analyze the RCTs published from India based on year of publication, geographical distribution, and subspecialty using the modified Jadad score (high quality if score is ≥3; or ≥2 if blinded design was not feasible). Its secondary objective was to identify factors affecting the quality of RCTs. Results: Among 1304 trials identified, 162 were analyzed. Of these 96 (59%) had a score of ≥3; and 104 (64.2%) were of high quality (score ≥2). Year-wise there was no significant quantitative (P = 0.329) or qualitative (P = 0.255) variation. Geographic regions had similar quantity (P = 0.206) and quality (P = 0.068). The RCTs among subspecialties too were comparable in quantity and quality. Higher impact factor of journal (P = 0.013) and assessment by Institute Review Board (IRB) (P = 0.004) were significantly associated with a better study quality. Type of institution, number of authors, centricity, assistance by a statistician, and source of funding did not affect the quality of RCTs. Conclusions: : The quantity and quality of surgical RCTs were stable and comparable over the years and across geographical regions and subspecialties. Higher impact factor of journal and review by IRB were significantly associated with a better study quality.

Assessment of patient perception of treatment assignment and patient-reported outcomes in a cannabis use disorder trial.

Background: Blinding is a cornerstone of trial methodology. Prior work indicates participant-perceived assignment may be associated with trial outcomes. Less is known about how perception changes over time and if this is associated with outcomes.Objectives: To evaluate if participants change their perception of assignment over time in a blinded trial, and if perception is associated with different types of patient-reported outcomes (PROs).Methods: This was a secondary analysis of data from the Achieving Cannabis Cessation-Evaluating N-Acetylcysteine Treatment (ACCENT) trial, which evaluated the efficacy of N-acetylcysteine (NAC) relative to placebo for treating cannabis use disorder. Participants (N = 234; 164 men, 70 women) were asked at weeks 5 and 9 what treatment (placebo or NAC) they believed they were receiving. We included PROs proximal (cannabis-associated problems, craving) and distal (anxiety) to the intervention. Analysis was by multiple linear regression and mixed models.Results: Approximately 20% of participants in both arms changed their perception over time. Relative to participants who consistently perceived assignment to placebo, participants who consistently perceived assignment to NAC did not always have comparatively better average scores (coefficient -3.3 [95% CI: -7.0, 0.5]). In some analyses, participants who switched to guessing NAC from placebo had comparatively better average scores (coefficient -3.0 [95% CI: -9.3, 3.4]), but this was inconsistent across outcomes or strata defined by actual assignment or guess accuracy.Conclusion: The study suggests that the proportion of individuals who switch their perception over time is modest. However, this group may influence the estimates of intervention effects on some PROs.

Analysis of the frequency, characteristics, and reasons for termination of shoulder- and elbow-related clinical trials.

BACKGROUND: Clinical trials are key to the advancement of products and procedures related to conditions of the shoulder and elbow. Unfortunately, many trials are terminated prior to completion. CLINICALTRIALS: gov is a registry and results database maintained by the National Library of Medicine that catalogs trial characteristics and tracks overall recruitment status (eg, ongoing, completed, terminated) for each study as well as reasons for termination. Reasons for trial termination have not been specifically evaluated for shoulder- and elbow-related clinical trials. The current study set out to quantify completed and terminated shoulder- and elbow-related clinical trials, assess reasons for termination, and determine independent predictors of termination by comparing characteristics of completed and terminated trials. METHODS: The ClinicalTrials.gov database was queried on August 6, 2021, for all completed and terminated interventional studies registered to date using all available shoulder- and elbow-related search terms. Trial characteristics and reason for termination were abstracted. Univariate and multivariate analyses were performed using trial characteristics to determine independent predictors for trial termination. RESULTS: For shoulder-related trials, a total of 662 completed or terminated trials were identified and characterized, of which 51 (8%) were noted to have been terminated. For elbow-related trials, a total of 126 completed or terminated were identified and characterized, of which 16 (13%) were terminated. Difficulties with participant recruitment and/or retention was the individual reason most frequently reported for trial termination, accounting for 51% of terminated shoulder-related trials and 38% of terminated elbow-related trials. For shoulder-related trials, multivariate analysis of primary trial characteristics demonstrated increased odds of trial termination for industry-sponsorship (odds ratio [OR] = 4.2, P = .001) relative to sponsorship from local groups, and blinded studies (OR = 45.8, P = .0003) relative to studies that did not implement any form of blinding. For elbow-related trials, logistic regression did not reveal any of the primary trial characteristics evaluated to be correlated with odds of termination. CONCLUSION: Shoulder- and elbow-related clinical trials were terminated at a rate of 8% and 13%, respectively. Difficulties in the recruitment and/or retention of participants were the reason most frequently reported for trial termination. For shoulder-related trials, industry sponsorship and studies with blinding were identified as independent predictors of termination. Given the ethical considerations and the opportunity costs associated with terminated studies, independent predictors and reasons for trial termination should be considered and addressed when possible to increase the rate of clinical trial completion.

Is There Someone in the Hereafter? Mediumship Accuracy of 100 Readings Obtained with a Triple Level of Blinding Protocol.

The accuracy of information obtained by 28 self-claimant mediums related to 100 readings obtained with a triple level of blinding was examined across three indices: percentage of correct reading identified by the sitters, global score of readings and percentage of difference between correct and incorrect information.All three indices showed statistical differences of the intended versus the control readings: correct identification 65%; global score: intended readings, mean = 2.4, SD = 1.5; control readings, mean = 1.7, SD = 1.2; percentage difference between correct and incorrect information: intended readings, mean = -7.9%, SD = 38.7%; control readings, mean = -27.3%, SD = 38%.Our results using a very large sample, confirm previous results, supporting the hypothesis that self-claimant mediums are able to retrieve correct information about deceased people without knowing and interacting with the sitters having access with only to the deceased persons' first name.

Women report more severe sensations from 2 mA and 4 mA transcranial direct current stimulation than men.

Interest in transcranial direct current stimulation (tDCS) to alter cortical excitability, facilitate neural plasticity, and improve performance is increasing. Subjects often report temporary stimulation-related sensations, which might distract from the task being performed or compromise blinding. tDCS is also prone to high outcome irregularity and one potential variability source is the biological sex of the subject. The purpose of this study was to re-analyze existing tolerability data to ascertain any sex differences in sensation severity and blinding guesses from tDCS at 2 mA and 4 mA. Each subject underwent tDCS at three randomly ordered intensities (sham, 2 mA, 4 mA), reported the severity sensations experienced, and guessed which tDCS condition they underwent (blinding). Women reported higher sensation severities than men from 2 mA and 4 mA tDCS and higher severities with increasing intensity (sham < 2 mA < 4 mA). Men reported similar severities in all stimulation conditions. Both sexes distinguished sham from 2 mA and 4 mA, and neither were able to discriminate between 2 mA from 4 mA. This study highlights differences in severity reports between women and men and adds to the growing body of literature, indicating that current sham methodologies might be inadequate to maintain blinding.