Placebo-controlled Randomized Clinical Trial Research Articles

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial

BackgroundConvalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy.Research QuestionIs rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19?Study Design and MethodsThis was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (illness severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality.ResultsAmong 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh SI [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58).InterpretationAmong adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes.Clinical Trial RegistrationClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov

Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light.

Background:Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted.Objective:A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE).Methods:The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next.Results:Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14).Conclusion:This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

The effects of a combination oral spray (Mucosamin®) for the prevention of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation: a double blind randomized clinical trial.

Oral mucositis (OM) is a frequent complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Damage to the nuclear and non-nuclear materials of the mucosal cells by the production of Reactive Oxygen Species (ROS) and proinflammatory cytokines could result to development and progression of OM. Previous studies have shown the effectiveness of Mucosamin® oral spray in the management of pain and acceleration of OM healing. The aims of the current study were to evaluate prophylactic effects of Mucosamin® oral spray in reducing the incidence and severity of OM in pediatric patients undergoing allogeneic HSCT. The current study was designed as a double-blind, placebo-controlled randomized clinical trial. Sixty patients were enrolled in the study and received placebo or Mucosamin® spray. Patients in both groups used sprays 4 times daily. Product application was begun at the time of initiation of conditioning regimen and was continued for 14days. Mucosamin® significantly reduced incidence and severity of OM compared to the placebo (P values: 0.027 and 0.035, respectively). This product could also decrease OM duration and delay OM onset (P values: 0.007 and 0.006, respectively). Mucosamin® could effectively reduce incidence, severity, and duration of OM and delay OM onset in pediatric patients undergoing allogeneic HSCT. The study protocol was registered in the Iranian Registry of Clinical Trials under the registry number IRCT20190917044805N1.

Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Type 2 Diabetes

Evidence of effective smoking cessation interventions in patients with diabetes is limited. The unique behavioral and metabolic characteristics of smokers with type 2 diabetes warrants a randomized clinical trial of the smoking cessation drug varenicline. To evaluate the efficacy and safety of varenicline in patients with type 2 diabetes with an intention to quit smoking. This multicenter, double-blind, placebo-controlled randomized clinical trial recruited patients from 6 outpatient clinics in 5 hospitals in Catania, Italy. Patients with type 2 diabetes, who were smoking at least 10 cigarettes a day, and who intended to quit smoking were screened for eligibility. Eligible patients were randomized to either varenicline or placebo treatment. The trial consisted of a 12-week treatment phase followed by a 40-week follow-up, nontreatment phase. Intention-to-treat data analysis was performed from December 2020 to April 2021. Varenicline, 1 mg, twice daily or matched placebo administered for 12 weeks. Patients in both treatment groups also received smoking cessation counseling. The primary efficacy end point of the study was the continuous abstinence rate (CAR) at weeks 9 to 24. Secondary efficacy end points were the CAR at weeks 9 to 12 and weeks 9 to 52 as well as 7-day point prevalence of abstinence at weeks 12, 24, and 52. A total of 300 patients (mean [SD] age, 57.4 [0.8] years; 117 men [78.0%] in varenicline group and 119 men [79.3%] in placebo group) were randomized to receive varenicline (n = 150) or placebo (n = 150). The CAR at weeks 9 to 24 was significantly higher for the varenicline than placebo group (24.0% vs 6.0%; odds ratio [OR], 4.95; 95% CI, 2.29-10.70; P < .001). The CARs at weeks 9 to 12 (31.3% vs 7.3%; OR, 5.77; 95% CI, 2.85-11.66; P < .001) and weeks 9 to 52 (18.7% vs 5.3%; OR, 4.07; 95% CI, 1.79-9.27; P < .001) as well as the 7-day point prevalence of abstinence at weeks 12, 24, and 52 were also significantly higher for the varenicline vs placebo group. The most frequent adverse events occurring in the varenicline group compared with the placebo group were nausea (41 [27.3%] vs 17 [11.4%]), insomnia (29 [19.4%] vs 19 [12.7%]), abnormal dreams (19 [12.7%] vs 5 [3.4%]), anxiety (17 [11.4%] vs 11 [7.3%]), and irritability (14 [9.4%] vs 8 [5.4%]). Serious adverse events were infrequent in both groups and not treatment-related. Results of this trial showed that inclusion of varenicline in a smoking cessation program is efficacious in achieving long-term abstinence without serious adverse events. Varenicline should be routinely used in diabetes education programs to help patients with type 2 diabetes stop smoking. ClinicalTrials.gov Identifier: NCT01387425.

Effect of Perioperative Dexmedetomidine on Delayed Graft Function Following a Donation-After-Cardiac-Death Kidney Transplant

Delayed graft function (DGF) is a risk factor for acute rejection and graft failure after kidney transplant. Previous studies have suggested that dexmedetomidine may be renoprotective, but whether the use of dexmedetomidine would improve kidney allograft function is unknown. To investigate the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant. This single-center, double-blind, placebo-controlled randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China. Adults (18 years or older) who were scheduled for DCD kidney transplant were enrolled between September 1, 2019, and January 28, 2021, and then randomized to receive either dexmedetomidine or normal saline (placebo). One-year postoperative outcomes were recorded. All analyses were based on the modified intention-to-treat population. Patients who were randomized to the dexmedetomidine group received a 24-hour perioperative dexmedetomidine intravenous infusion (0.4 μg/kg/h intraoperatively and 0.1 μg/kg/h postoperatively). Patients who were randomized to the normal saline group received an intravenous infusion of the placebo with the same dose regimen as the dexmedetomidine. The primary outcome was the incidence of DGF, defined as the need for dialysis in the first posttransplant week. The prespecified secondary outcomes were in-hospital repeated dialysis in the first posttransplant week, in-hospital acute rejection, and serum creatinine, serum cystatin C, estimated glomerular filtration rate, need for dialysis, and patient survival on posttransplant day 30. Of the 114 patients enrolled, 111 completed the study (mean [SD] age, 43.4 [10.8] years; 64 male patients [57.7%]), of whom 56 were randomized to the dexmedetomidine group and 55 to the normal saline group. Dexmedetomidine infusion compared with normal saline reduced the incidence of DGF (17.9% vs 34.5%; odds ratio [OR], 0.41; 95% CI, 0.17-0.98; P = .04) and repeated dialysis (12.5% vs 30.9%; OR, 0.32; 95% CI, 0.13-0.88; P = .02, which was not statistically significant after multiple testing corrections), without significant effect on other secondary outcomes. Dexmedetomidine vs normal saline infusion led to a higher median (IQR) creatinine clearance rate on postoperative days 1 (9.9 [4.9-21.2] mL/min vs 7.9 [2.0-10.4] mL/min) and 2 (29.6 [9.7-67.4] mL/min vs 14.6 [3.8-45.1] mL/min) as well as increased median (IQR) urine output on postoperative days 2 (106.5 [66.3-175.6] mL/h vs 82.9 [27.1-141.9] mL/h) and 7 (126.1 [98.0-151.3] mL/h vs 107.0 [82.5-137.5] mL/h) and at hospital discharge discharge (110.4 [92.8-121.9] mL/h vs 97.1 [77.5-113.8] mL/h). Three patients (5.5%) from the normal saline group developed allograft failure by the post hoc 1-year follow-up visit. This randomized clinical trial found that 24-hour perioperative dexmedetomidine decreased the incidence of DGF after DCD kidney transplant. The findings support the use of dexmedetomidine in kidney transplants. Chinese Clinical Trial Registry Identifier: ChiCTR1900025493.

Secondary hypertension and its treatment in cats

Secondary hypertension caused by an underlying disease is common in older cats, especially in those with chronic kidney disease and/or hyperthyroidism. Systolic blood pressure should be measured whenever an associated disease is diagnosed and persistent systolic blood pressure &gt;160mmHg should prompt treatment to prevent or reverse target organ damage. Amlodipine and telmisartan are licensed in the UK to treat feline hypertension and both drugs have been evaluated in prospective randomised placebo-controlled clinical trials in hypertensive cats with systolic blood pressure of 160–200mmHg that did not have evidence of target organ damage. Initial reductions of 20–30mmHg can be expected with either medication, and cats should be re-evaluated after 14 days and dose adjustments made as required. No studies have compared the performance of one drug against the other and either medication should be selected as the first-line treatment for feline hypertension. At present, there are more data in the literature to support the use of amlodipine in cats with severe hypertension (systolic blood pressure &gt;200mmHg), or with evidence of ocular or neurological target organ damage.

GP.2 Deep learning prediction of response to disease modifying therapy in primary progressive multiple sclerosis

Background: Only one disease modifying therapy (DMT), ocrelizumab, was found to slow disability progression in primary progressive multiple sclerosis (PPMS). Modeling the conditional average treatment effect (CATE) using deep learning could identify individuals more responsive to DMTs, allowing for predictive enrichment to increase the power of future clinical trials. Methods: Baseline clinical and MRI data were acquired as part of three placebo-controlled randomized clinical trials: ORATORIO (ocrelizumab), OLYMPUS (rituximab) and ARPEGGIO (laquinimod). Data from ORATORIO and OLYMPUS was separated into a training (70%) and testing (30%) set, while ARPEGGIO served as additional validation. An ensemble of multitask multilayer perceptrons was trained to predict the rate of disability progression on both treatment and placebo to estimate CATE. Results: The model could separate individuals based on their predicted treatment effect. The top 25% of individuals predicted to respond most have a larger effect size (HR 0.442, p=0.0497) than the entire group (HR 0.787, p=0.292). The model could also identify responders to laquinimod. A simulated study where the 50% most responsive individuals are randomized would require 6-times less participants to detect a significant effect. Conclusions: Individuals with PPMS who respond favourably to DMTs can be identified using deep learning based on their baseline clinical and imaging characteristics.

A randomized placebo-controlled double-blind study of dexmedetomidine on postoperative sleep quality in patients with endoscopic sinus surgery

BackgroundPostoperative sleep disorder is common and may cause aggravated postoperative pain, delirium, and poor prognosis. We accessed the effect of intraoperative intravenous dexmedetomidine on postoperative sleep quality in patients with endoscopic sinus surgery. MethodsThis single-center, double-blind, placebo-controlled randomized clinical trial enrolled a total of 110 participants aged 18 years to 65 years who were scheduled to receive endoscopic sinus surgery. Placebo (normal saline) or dexmedetomidine infusion (load dose 0.5 μg kg−1 over 10 min, followed by maintenance dose 0.2 ug kg−1 h−1) during surgery. The primary outcome was postoperative sleep quality. Secondary outcomes were postoperative Ramsay sedation scores, Visual Analog Scale (VAS) scores, serum cortisol, 5-hydroxytryptamine (5-HT) and hypocretin, delirium, and postoperative nausea and vomiting (PONV).ResultsAmong enrolled 110 patients, 55 were randomized to administer intraoperative dexmedetomidine and placebo. In total, 14 patients (7 in each group) were excluded because of protocol deviations, and 96 patients (48 in each group) were included in the per-protocol analysis. The dexmedetomidine group had a significantly higher sleep efficiency index(SEI) (66.85[3.00] vs 65.38[3.58]), the ratio of rapid eye movement sleep to total sleep(REM)(13.63[1.45] vs 12.38[2.11]) and lower arousal index (AI) (7.20[1.00] vs 8.07[1.29]), higher Ramsay sedation score at post-operation 1 h, 12 h point, lower VAS scores at post-operation 1 h, 12 h, 24 h point, lower cortisol, higher 5-HT and hypocretin in serum than the placebo group.ConclusionIn this randomized clinical trial, dexmedetomidine can improve the sleep quality of patients undergoing endoscopic sinus surgery. These results suggest that this therapy may be a viable strategy to enhance postoperative sleep quality in patients with endoscopic sinus surgery.Trial registrationThe study was approved by the Bethune International Peace Hospital Ethics Committee (2021-KY-129) and registered in the Chinese Clinical Trial Registry (www.chictr.org.cn/index.aspx, 28/09/2021).

Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy

Safe and effective prophylactic therapies for radiation-induced dermatitis (RID) remain an unmet need. To determine if epigallocatechin-3-gallate (EGCG) solution reduces the incidence of RID in patients undergoing radiotherapy after breast cancer surgery. This phase 2 double-blind, placebo-controlled randomized clinical trial enrolled 180 patients with breast cancer receiving postoperative radiotherapy at Shandong Cancer Hospital and Institute in Shandong, China, between November 2014 and June 2019. Data analysis was performed from September 2019 to January 2020. Participants were randomly assigned (2:1) to receive either EGCG solution (660 μmol/L) or placebo (0.9% NaCl saline) sprayed to the whole radiation field from day 1 of the radiation until 2 weeks after radiation completion. The primary end point was incidence of grade 2 or worse RID, defined by the Radiation Therapy Oncology Group scale. The secondary end points included RID index (RIDI), symptom index, changes in the skin temperature measured by infrared thermal images, and safety. A total of 180 eligible patients were enrolled, of whom 165 (EGCG, n = 111; placebo, n = 54) were evaluable for efficacy (median [range] age, 46 [26-67] years). The occurrence of grade 2 or worse RID was significantly lower (50.5%; 95% CI, 41.2%-59.8%) in the EGCG group than in the placebo group (72.2%; 95% CI, 60.3%-84.1%) (P = .008). The mean RIDI in the EGCG group was significantly lower than that in the placebo group. Furthermore, symptom indexes were significantly lower in patients receiving EGCG. Four patients (3.6%) had adverse events related to the EGCG treatment, including grade 1 pricking skin sensation (3 [2.7%]) and pruritus (1 [0.9%]). In this randomized clinical trial, prophylactic use of EGCG solution significantly reduced the incidence and severity of RID in patients receiving adjuvant radiotherapy for breast cancer. It has the potential to become a new choice of skin care for patients receiving radiotherapy. ClinicalTrials.gov Identifier: NCT02580279.

Regulation of NLRP3 inflammasome by zinc supplementation in Behçet's disease patients: A double-blind, randomized placebo-controlled clinical trial

BackgroundOverproduction of NLRP3 inflammasome complex is one of the causes of Behcet's disease's (BD) auto-inflammatory nature. The aim of current study was to examine the effect of zinc supplementation on NLRP3 inflammasome expression; as well as clinical manifestations of BD. MethodsIn this double-blind parallel placebo-controlled randomized clinical trial, 50 BD patients were randomly allocated into either zinc gluconate (30 mg/day elemental zinc) or placebo groups for 12 weeks. The mRNA expression of NLRP3 and caspase-1 in the leukocytes, serum level of zinc and IL-1β, anthropometric measures, and clinical manifestations of patients were collected at pre- and post-intervention phase. The Iranian Behçet's disease dynamic activity measure (IBDDAM) was scored to measure the treatment effect using the calculation of number needed to treat (NNT). Analysis of covariance was performed to obtain the corresponding effect sizes. ResultsZinc gluconate led to a significant improvement in genital ulcer (P = 0.019). Zinc supplementation decreased NLRP3 and caspase-1 genes expression compared with placebo group (baseline-adjusted P-value = 0.046 for NLRP3 and P-value = 0.003 for caspase-1), even after adjustment for the effect of confounding factors (baseline- and confounders-adjusted P-value = 0.032 for NLRP3 and P-value = 0.004 for caspase-1). Baseline and confounders adjusted effect size demonstrated that zinc was effective in reducing the serum level of IL-1β (P = 0.046). The NNT [95 %CI] for the rate of IBDDAM improvement was 3 [1.7–8.5]. ConclusionsZinc gluconate supplementation (30 mg/day) for a 3-month period can be considered as an adjuvant therapy in alleviating inflammation and genital ulcer among BD patients.

Evaluation of Nomacopan for Treatment of Bullous Pemphigoid

Bullous pemphigoid is a difficult-to-treat autoimmune blistering skin disease that predominantly affects older adults and is associated with an increased mortality rate. To examine the safety and therapeutic potential of nomacopan, an inhibitor of leukotriene B4 and complement C5, in patients with bullous pemphigoid. This multicenter, single-group, phase 2a nonrandomized controlled trial was conducted in the dermatology departments of universities in the Netherlands and Germany. Participants were enrolled between September 2018 and April 2020. Older adult patients (aged ≥55 years) with mild to moderate, new-onset or relapsing bullous pemphigoid were recruited into the study. Patients received nomacopan, 90 mg, subcutaneously on day 1 and 30 mg subcutaneously daily until day 42. The primary end point was the proportion of patients with grade 3 to 5 (severe) adverse events associated or possibly associated with nomacopan. Secondary end points included mean absolute and percentage changes in the Bullous Pemphigoid Disease Area Index (BPDAI) activity score, the BPDAI pruritus score, and the patient-reported outcome measures Dermatology Life Quality Index (DLQI) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL). A total of 9 patients (median [range] age, 75 [55-85] years) with bullous pemphigoid were included in the trial, of whom 5 were women (55.6%). No serious adverse events associated with nomacopan were found. The mean (90% CI) BPDAI activity score decreased from 32.0 (8.7) points on day 1 to 19.6 (9.0) points on day 42. Seven of 9 patients (77.8%) responded to nomacopan with a reduction in the BPDAI activity score of at least 8 points between days 1 and 42; in 3 responders, the reduction was 80% or greater. On day 42, the mean (90% CI) BPDAI pruritus score had decreased by 6.8 (4.6) points from 17.6 (4.0) points on day 1. The mean (90% CI) DLQI score decreased from 11.3 (4.2) points at baseline to 6.4 (3.8) points by day 42, and the mean (90% CI) TABQOL score decreased from 14.6 (5.4) points at baseline to 10.3 (5.0) points on day 42. Results of this nonrandomized controlled trial suggest that nomacopan can be well tolerated in older patients with bullous pemphigoid and may have therapeutic benefits for suppressing acute flares of this disease. A larger, placebo-controlled randomized clinical trial is warranted to confirm this safety profile and to establish nomacopan as a new therapeutic option for bullous pemphigoid. ClinicalTrials.gov Identifier: NCT04035733.

Percutaneous laser nucleoplasty at lumbar level: Literature review

The purpose of the study – to present an analysis of clinical trials to study the clinical efficacy and safety of the technique of percutaneous laser decompression of intervertebral discs based on a review of Russian and foreign studies.The review article presents modern literature data covering the issues of indications, contraindications, technique, efficacy and safety of percutaneous laser disc decompression in patients with degenerative disease of the lumbar intervertebral discs. The publication present modern data on the choice of the most rational tactics for surgical treatment of patients with this pathology. Relevant, unresolved issues are indicated, which dictates the need for large randomized placebo-controlled clinical trials, with the inclusion of the latter’s results in systematic reviews and meta-analyzes.

Effects of the Alpha, Beta, and Gamma Binaural Beat Brain Stimulation and Short-Term Training on Simultaneously Assessed Visuospatial and Verbal Working Memories, Signal Detection Measures, Response Times, and Intrasubject Response Time Variabilities: A Within-Subject Randomized Placebo-Controlled Clinical Trial.

Introduction Binaural beats (BBs) are phantom sound illusions perceived when two sounds of slightly different frequencies are separately transmitted to the ears. It is suggested that some BB frequencies might entrain the brain and enhance certain cognitive functions such as working memory or attention. Nevertheless, studies in this regard are very scarce, quite controversial, and merely covering a very small portion of this vast field of research (e.g., testing only a few BB frequencies), not to mention adopting some limited methodologies (e.g., no assessment of the loudness of the BB sound, adopting only between-subject analyses, and testing only one perceptual modality). Hence, we aimed to assess the potential effects of alpha, beta, and gamma BBs on cognitive-behavioral parameters of working memory and attention examined simultaneously in two different modalities (visuospatial and auditory-verbal). Methods This within-subject five-arm randomized placebo-controlled clinical trial included 155 trials in 31 healthy right-handed subjects (17 women, 14 men, 30.84 ± 6.16 years old). Each subject listened to 8-minute sessions of 10 Hz, 16 Hz, and 40 Hz binaural beats versus 240 Hz pure tone and silence (in random orders). In each 8-minute block, they played a dual 2-back task with feedback enabled. Their cognitive-behavioral parameters (working memory capacities, signal detection measures (hit rate, false alarm rate, sensitivity, and response bias), and reaction speed measures (response time and intrasubject response time variability)) were calculated. The effects of the sound interventions and short-term training on these working memory and attention measures were assessed statistically using mixed-model linear regressions, repeated-measures ANOVAs and ANCOVAs, Bonferroni post hoc tests, and one-sample t-tests (α = 0.05). Results The following are some major statistically significant findings (P ≤ 0.05): In the visuospatial modality, the 10 Hz BB reduced the response time and intrasubject response time variability and reduced the extent of decline over time in the case of visuospatial working memory, sensitivity, and hit rate. In the auditory-verbal modality, the 10 Hz intervention reduced the hit rate, false alarm rate, and sensitivity. The 10 Hz intervention also caused the lowest intermodality discrepancies in hit rates and false alarm rates, the highest response time discrepancies, and negative discrepancies in working memories and sensitivities (indicating the superiority of the visuospatial modality). The response biases tended to be liberal-to-neutral in the verbal modality and rather conservative in the visuospatial modality. Reactions were faster in the visuospatial modality than the auditory-verbal one, while the intrasubject variability of reaction times was smaller in the auditory-verbal modality. Short-term training can increase the hit rate, working memory, and sensitivity and can decrease the false alarm rate and response time. Aging and reduced sound intervention volume may slow down responses and increase the intrasubject variability of response time. Faster reactions might be correlated with greater hit rates, working memories, and sensitivities and also with lower false alarm rates. Conclusions The 8-minute alpha-band binaural beat entrainment may have a few, slight enhancing effects within the visuospatial modality, but not in both modalities combined. Short-term training can improve working memory and some cognitive parameters of attention. Some BB interventions can affect the intermodality discrepancies. There may be differences between the two modalities in terms of the response speeds and intrasubject response time variabilities. Aging can slow down the response, while increasing the volume of audio interventions may accelerate it.

Efficacy of Augmentation of Cognitive Behavioral Therapy With Transcranial Direct Current Stimulation for Depression

Major depressive disorder (MDD) affects approximately 10% of the population globally. Approximately 20% to 30% of patients with MDD do not sufficiently respond to standard treatment. Therefore, there is a need to develop more effective treatment strategies. To investigate whether the efficacy of cognitive behavioral therapy (CBT) for the treatment of MDD can be enhanced by concurrent transcranial direct current stimulation (tDCS). The double-blind, placebo-controlled randomized clinical trial PsychotherapyPlus was conducted at 6 university hospitals across Germany. Enrollment took place between June 2, 2016, and March 10, 2020; follow-up was completed August 27, 2020. Adults aged 20 to 65 years with a single or recurrent depressive episode were eligible. They were either not receiving medication or were receiving a stable regimen of antidepressant medication (selective serotonin reuptake inhibitor and/or mirtazapine). A total of 148 women and men underwent randomization: 53 individuals were assigned to CBT alone (group 0), 48 to CBT plus tDCS (group 1), and 47 to CBT plus sham-tDCS (group 2). Participants attended a 6-week group intervention comprising 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 mA for 30 minutes (anode over F3, cathode over F4). The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to posttreatment in the intention-to-treat sample. Scores of 0 to 6 indicate no depression; 7 to 19, mild depression; 20 to 34, moderate depression; and 34 and higher, severe depression. A total of 148 patients (89 women, 59 men; mean [SD] age, 41.1 [13.7] years; MADRS score at baseline, 23.0 [6.4]) were randomized. Of these, 126 patients (mean [SD] age, 41.5 [14.0] years; MADRS score at baseline, 23.0 [6.3]) completed the study. In each of the intervention groups, intervention was able to reduce MADRS scores by a mean of 6.5 points (95% CI, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time. However, there was no significant effect of group and no significant interaction of group × time, indicating the estimated additive effects were not statistically significant. There were no severe adverse events throughout the whole trial, and there were no significant differences of self-reported adverse effects during and after stimulation between groups 1 and 2. Based on MADRS score changes, this trial did not indicate superior efficacy of tDCS-enhanced CBT compared with 2 CBT control conditions. The study confirmed that concurrent group CBT and tDCS is safe and feasible. However, additional research on mechanisms of neuromodulation to complement CBT and other behavioral interventions is needed. ClinicalTrials.gov Identifier: NCT02633449.

Efficacy of using walnuts as statin adjuvants in hypertension management

ABSTRACT Background Due to the widespread unorthodox use of nuts to improve cardiovascular health, this clinical trial was carried out to evaluate the efficacy of walnut as an adjuvant statin in hypertensive subjects. Method A single-blind placebo-controlled randomized clinical trial that lasted for 3 months. Forty-five screened hypertensive subjects on treatment, aged 45–65 years, were randomized into intervention and placebo groups according to their blood pressure defined by the American Heart Association criteria. Fifteen (15) normotensive subjects were also recruited for this study. The participants in the intervention group included daily 7 g of boiled walnut taken as snacks. The study was not controlled for type of diet and frequency of meals in a day. Low-density lipoprotein cholesterol (LDLc) was the primary endpoint for this study. Results The mean LDLc levels of the intervention groups (84.6 mg/dl and 79.7 mg/dl, respectively) were significantly (p < .005) lower than the placebo (137.6 mg/dl). The high-density lipoprotein cholesterol (HDLc) levels of the intervention groups were significantly higher than the placebo. The mean total cholesterol levels of the intervention groups were significantly lower than the placebo group. The intervention groups recorded a significantly lower systolic and diastolic blood pressure compared to the placebo. The supplementation of walnut significantly decreased the apolipoprotein E (APOE), proprotein convertase subtilisin kexin 9 (PCSK9), and cholesteryl ester transfer protein (CETP) activities relative to the placebo. Conclusion The use of walnut as a statin adjuvant during hypertension treatment reduced LDLc levels within 42.1% and improved HDL levels by 33.6%, and the LDLc decrease related to reduced PCSK9 and APOE activities while the HDLc increase related to reduced CETP activities.

Magnesium Supplementation Affects the Expression of Sirtuin1, Tumor Protein P53 and Endothelial Nitric Oxide Synthase Genes in Patients with Atherosclerosis: A Double-Blind, Randomized, Placebo-Controlled Trial.

Magnesium seems to play a role in improving cardiovascular function, but its exact mechanism is unknown. In this study, we hypothesized that magnesium could modulate the expression of genes involved in atherosclerosis. The aim of the present investigation was to evaluate the effect of magnesium sulfate on the expression of sirtuin1 (SIRT1), tumor protein p53 (TP53), and endothelial nitric oxide synthase (eNOS) genes in patients with atherosclerosis. This study was a placebo-controlled double-blind randomized clinical trial on 56 patients with angiographically proven atherosclerosis. Participants were randomly divided into two groups receiving 300mg/day magnesium sulfate (n = 29) and placebo (n = 27) for three months (following up every month). Fasting blood samples were taken before and after the intervention and total RNA was extracted and used to evaluate the expression level of SIRT1, TP53, and eNOS genes by Real-Time PCR. The expression of eNOS gene was significantly increased (P < 0.0001) and the expression of TP53 gene was decreased (P = 0.02) in the magnesium sulfate group compared to the placebo group. But SIRT1 gene expression was not significantly different between the two groups. Our findings demonstrate that magnesium sulfate supplementation may have a protective role against the progression of atherosclerosis through upregulation of eNOS and downregulation of TP53 gene. Trial registration: This present clinical trial has been registered in the Iranian Registry of Clinical Trials (IRCT) with the registration code of "IRCT20151028024756N3", https://www.irct.ir/trial/29097?revision=114102. Registered on 16 December 2019.

Probiotic supplement as an adjunctive therapy with Ritalin for treatment of attention-deficit hyperactivity disorder symptoms in children: a double-blind placebo-controlled randomized clinical trial

PurposeAccumulating evidence highlights the importance of microbiota-directed intervention in neuropsychiatric disorders. This study aims to investigate the effects of probiotic supplements as an adjunct therapy in combination with Ritalin in children with attention-deficit hyperactivity disorder (ADHD).Design/methodology/approachChildren with ADHD, aged 6–12 years, who had an intelligent quotient of ≥70 were enrolled in the study. Participants were randomly assigned to either the group that received probiotics or the group that received the placebo in addition to the weight-adjusted dose of Ritalin. Parents were asked to complete the revised Conners Parent Rating Scale–short version (CPRS–RS), and the psychiatrist completed the seven-point Clinical Global Impression–Severity (CGI–S) scale. Two study groups were compared in three time points, including T1 (before intervention), T2 (at the end of fourth week) and T3 (at the end of the eighth week).FindingsA total of 38 participants completed the study. After eight weeks of intervention, the probiotic group had a significant improvement regarding CPRS–RS scores in T2 (9.4 unit, p = 0.014) and T3 (18.6 unit, p < 0.001), compared to placebo. In addition, children in the probiotic group had 0.7 unit lower CGI in T3 (p = 0.018) than the placebo group. A significant reduction of CGI scores was observed in each interval (T2 vs T1, T3 vs T2 and T3 vs T1; p < 0.05). This significant change in CGI score between intervals was also detected in the placebo group in T2 vs T1 (p = 0.002) and T3 vs T1 (p < 0.001). Mean CPRS scores of the groups were different in T2 and T3 (p = 0.011 and p < 0.001, respectively) and mean CGI scores of the two study groups were different in T3 (p = 0.018).Originality/valueEight weeks of supplementation with probiotics had a favorable effect on symptoms and severity of ADHD. Therefore, probiotics as an adjuvant treatment might have a promising efficacy regarding the management of ADHD.

The effect of menaquinone-7 supplementation on dp-ucMGP, PIVKAII, inflammatory markers, and body composition in type 2 diabetes patients: a randomized clinical trial

BackgroundType 2 diabetes mellitus (T2DM) is a common disorder that is characterized by chronic hyperglycemia and chronic inflammation, which also have a reinforcing effect on each other. The present research studied the effects of menaquinone (MK-7) supplementation on serum dp-ucMGP (dephospho uncarboxylated Matrix Gla Protein), PIVKAII (Prothrombin Induced by Vitamin K Absence), inflammatory markers and body composition indices in type 2 diabetes mellitus (T2DM) patients.MethodsThis 12-week double-blind placebo-controlled randomized clinical trial allocated 60 T2DM patients equally into a MK-7 (200 mcg/day) group or a placebo group. All patients also received dietary advice at the beginning of study and their dietary intakes were checked using a 3-day food record. The body composition of each patient was also measured and their vitamin K status was assessed using the ELISA method to measure serum dp-ucMGP and PIVKAII. In addition, inflammatory status indices were also measured, including hsCRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6) and TNF-α (tumor necrosis factor alpha). All measurements were made both before and after the intervention period.ResultsIn total 45 patients completed the trial (MK-7 group = 23 and placebo group = 22). The calorie and macronutrient intake of the two groups were similar pre and post intervention. There were statistically significant increases in dietary vitamin K intake for both groups over the course of the study (p < 0.05), but the intergroup differences were not significant. The body composition indices (i.e., body fat percentage, fat mass, fat free mass, muscle mass, bone mass and total body water) were not significantly different between groups or across the trial. The serum levels of the vitamin K markers, PIVKAII and dp-ucMGP, decreased significantly in the MK-7 group over the course of the study (p < 0.05), but there was no decrease in the placebo group. However, after adjusting for the baseline levels and changes in vitamin K intake, the between group differences were only significant for PIVKAII (p < 0.05). Following the intervention, the serum levels of the inflammatory markers (hsCRP, IL-6, and TNF-α) were significantly lower in the MK-7 group (p < 0.05), but not in the placebo group. However, the between group differences in the inflammatory markers were not statistically significant.ConclusionsAlthough further studies are needed, it appears that MK-7 supplementation can be effective in improving PIVKAII levels, but not for improving dp-ucMGP, inflammatory status or the body composition indices of T2DM patients.Trial registration numberThis study was prospectively registered at the Iranian Registry of Clinical Trials on the 20th of May 2019 (ID: IRCT20100123003140N22).

Immunomodulatory and clinical responses to zinc gluconate supplementation in patients with Behçet's disease: A double-blind, randomized placebo-controlled clinical trial

Toll-like receptor (TLR) 2 and 4 are involved in the pathogenesis of Behçet's disease (BD). The current study aimed to investigate the effect of zinc supplementation on TLR-2/4 expression and the clinical manifestations of BD. In this double-blind placebo-controlled randomized clinical trial, 50 BD patients were randomly allocated into either zinc gluconate (30mg/day) or placebo groups for 12 weeks. Before and after the intervention, the surface and mRNA expression level of TLR-2 and TLR-4 in the leukocytes, serum level of zinc and tumor necrosis factor-α (TNF-α), quality of life, anthropometric measures, and blood pressure of patients were collected. BD activity was studied using the nonocular Iranian Behçet's disease dynamic activity measure (IBDDAM), Behçet's disease current activity form (BDCAF), and total inflammatory activity index (TIAI) at the pre-and post-intervention phases. The effect sizes were compared between two groups using analysis of covariance. There were significant decrease in TLR-2 mRNA (P=0.038) and protein expression (P=0.034) and nonocular IBDDAM score (P=0.046) in the zinc group compared to placebo at the endpoint. The serum level of zinc was increased in the zinc group (P<0.001). Zinc supplementation significantly decreased the TLR-4 surface (P=0.012) and mRNA expression (P=0.028) within the group. However, this decrease was not significant compared to the placebo group. There was no significant difference between the two groups regarding the serum level of TNF-α, BDCAF, TIAI, quality of life, anthropometric measures, and blood pressure (P>0.05). The present study revealed that zinc supplementation significantly improved nonocular IBDDAM score and TLR-2 expression in BD patients. NCT05098678.

Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: a meta-analysis

BackgroundWe conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with diabetic kidney disease (DKD).MethodsWe searched electronic databases for major randomized placebo-controlled clinical trials published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes of SGLT2i in patients with DKD. DKD was defined as chronic kidney disease in individuals with type 2 diabetes. Random-effects meta-analysis models were used to estimate pooled hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes including major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke, and cardiovascular death), kidney composite outcomes (a combination of worsening kidney function, end-stage kidney disease, or death from renal or cardiovascular causes), hospitalizations for heart failure (HHF), deaths and safety events (mycotic infections, diabetic ketoacidosis [DKA], volume depletion, amputations, fractures, urinary tract infections [UTI], acute kidney injury [AKI], and hyperkalemia).ResultsA total of 26,106 participants with DKD from 8 large-scale trials were included (median age: 65.2 years, 29.7–41.8% women, 53.2–93.2% White, median follow-up: 2.5 years). SGLT2i were associated with reduced risks of MACE (HR 0.83, 95% CI 0.75–0.93), kidney composite outcomes (HR 0.66, 95% CI 0.58–0.75), HHF (HR 0.62, 95% CI 0.55–0.71), cardiovascular death (HR 0.84, 95% CI 0.74–0.96), MI (HR 0.78, 95% CI 0.67–0.92), stroke (HR 0.76, 95% CI 0.59–0.97), and all-cause death (HR 0.86, 95% CI 0.77–0.96), with no significant heterogeneity detected. Similar results were observed among participants with reduced estimated glomerular filtration rate (eGFR: < 60 mL/min/1.73m2). The relative risks (95% CI) for adverse events were 3.89 (1.42–10.62) and 2.50 (1.32–4.72) for mycotic infections in men and women respectively, 3.54 (0.82–15.39) for DKA, and 1.29 (1.13–1.48) for volume depletion.ConclusionsAmong adults with DKD, SGLT2i were associated with reduced risks of MACE, kidney outcomes, HHF, and death. With a few exceptions of more clear safety signals, we found overall limited data on the associations between SGLT2i and safety outcomes. More research is needed on the safety profile of SGLT2i in this population.