Double-blind Randomized Trial Research Articles

Vitis vinifera seed extract versus micronized purified flavonoid fraction for patients with chronic venous disease: a randomized, non-inferiority trial

BackgroundVenoactive drugs (VADs) based on Vitis vinifera extract are widely used in Korea. However, studies on the clinical effects and head-to-head comparisons with other groups of VADs are limited. This trial aimed to evaluate whether Vitis vinifera seed extract was non-inferior to the micronized purified flavonoid fraction (MPFF) in relieving venous symptoms and improving quality of life in patients with chronic venous disease (CVD). MethodsIn this double-blind prospective randomized trial, patients from 13 hospitals, who were diagnosed with venous incompetence by duplex ultrasound and classified as clinical class 1, 2, or 3 in the Clinical, Etiological, Anatomical, and Pathophysiological classifications were enrolled. The primary outcome was the change in the Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-20) score at 8 weeks from baseline. Secondary outcomes included changes in the Aberdeen Varicose Vein Questionnaire (AVVQ), visual analog scale (VAS), and Venous Clinical Severity Score (VCSS) at 4- and 8 weeks from baseline. Moreover, the change in leg circumferences was measured at 8 weeks and compared to baseline. ResultsIn total, 303 patients were enrolled and randomly assigned to receive either Vitis vinifera seed extract (n = 154) or MPFF (n = 149). The CIVIQ-20 scores at 8 weeks were significantly reduced compared to those at baseline in both groups. No significant inter-group difference in the change of CIVIQ-20 at 8 weeks from baseline was observed (-8.31 ± 14.63 vs. -10.35 ± 14.38, P = 0.29, 95% confidence interval [CI] -1.65 to 5.72). The lower limit of the 95% CI was within the predefined noninferiority margin of 6.9. Furthermore, the AVVQ, VAS, and VCSS scores significantly decreased at 4- and 8 weeks after randomization compared with baseline in both groups. No significant differences were observed in the reduction of each score between groups. The calf circumference measured at 8 weeks was significantly reduced compared to that at baseline in patients receiving Vitis vinifera seed extract. ConclusionsVitis vinifera seed extract was non-inferior to MPFF in relieving venous symptoms and improving the quality of life in patients with CVD.

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation – Clinical and safety results

IntroductionWe investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methodsPatients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. ResultsTwenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01).Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DiscussionOur results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Efficacy of acupuncture and rehabilitation therapy on brain function activation area and neurological function in ischemic stroke: A systematic review and meta-analysis.

The probability of motor deficits after stroke is relatively high. At the same time many studies have reported that acupuncture and rehabilitation therapy have a significant effect on the treatment of stroke. This systematic review and meta-analysis aimed to evaluate the clinical value of acupuncture and rehabilitation therapy on brain eloquent areas and neurological function in ischemic stroke. Seven databases were electronically searched to screen randomized controlled trials (RCTs) of different intervention methods (acupuncture, rehabilitation) in the treatment of ischemic stroke. The search time is from January 1, 2000 to April 20, 2023, and the search languages are limited to Chinese and English. Two researchers independently screened literature and extracted data. The methodological quality of the studies was assessed using the Cochrane Handbook for Systematic Reviews of Interventions. A total of 17 randomized controlled studies were included, including 699 patients, with a maximum sample size of 144 cases and a minimum sample size of 11 cases. Among them, 3 studies reported the brain function in SM1 area. The effective rate of the experimental group was higher than that of the control group [relative risk (OR) = 3.24, 95%CI: 1.49 to 7.05, P < 0.05]. The FMA score of patients in the experimental group was higher than that in the control group [mean difference (MD) = 4.79, 95% CI: 3.86 to 5.71, P < 0.00001]. The NIHSS score of patients in the experimental group was lower than that in the control group [mean difference (MD) = -4.12, 95% CI: -6.99 to -1.26, P < 0.05].None of studies reported adverse events. Acupuncture rehabilitation for ischemic stroke can activate corresponding brain functional areas and improve neurological deficits. The therapeutic effect of acupuncture rehabilitation treatment is better than that of basic western medicine treatment, and it is more effective in improving neurological deficits. At the same time, clinical research needs to use high-quality randomized double-blind controlled trials with more detailed and larger sample designs, long-term efficacy evaluation and evidence-based research methods.

Maternal mood, anxiety and mental health functioning after combined myo-inositol, probiotics, micronutrient supplementation from preconception: Findings from the NiPPeR RCT

Observational studies have reported associations between nutrition during pregnancy and mental wellbeing. As secondary outcomes, the NiPPeR double-blind randomized trial in women planning conception investigated whether a myo-inositol, probiotics and enriched micronutrients formulation (intervention) taken preconception and throughout pregnancy could improve mental wellbeing during pregnancy and post-delivery, compared with a standard micronutrient supplement (control). Mood and anxiety symptoms were ascertained (Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI-state)) at preconception (baseline), 7, 28 and 34 weeks gestation, 3-weeks and 6-months post-delivery. EPDS>=13 was categorised as low mood; STAI-state>=45 as high anxiety. Change in mental health functioning was assessed as difference between preconception baseline and 6-month post-delivery 12-item Short-Form Health Survey (SF-12v2) mental component scores. Adjusting for site, ethnicity and baseline scores, there were no robust differences in EPDS and STAI-state scores between intervention and control groups across pregnancy (n = 630) and post-delivery (n = 532). Compared to controls, intervention group women averaged a 1.21 (95 %CI 0.04,2.39) higher change in SF-12v2 mental component score from preconception to 6-months post-delivery. Taking a myo-inositol, micronutrient and probiotic supplement during preconception/pregnancy had no effect on mood and anxiety, but there was evidence of a modest improvement in mental health functioning from preconception to 6-months post-delivery.

Effect of Lower Extremity Nerve Decompression in Patients with Painful Diabetic Peripheral Neuropathy: The DNND Randomized, Observation Group- and Placebo Surgery-controlled Clinical Trial.

Evaluate the effect of nerve decompression on pain in patients with lower extremity painful Diabetic Peripheral Neuropathy (DPN). Currently, no treatment provides lasting relief for patients with DPN. Benefits of nerve decompression remain inconclusive. This double-blinded, observation- and same-patient sham surgery-controlled randomized trial enrolled patients aged 18-80 years with lower extremity painful DPN who failed one-year of medical treatment. Patients were randomized to nerve decompression- or observation-group (2:1). Decompression-group patients were further randomized and blinded to nerve decompression in either right or left leg and sham surgery in the opposite leg. Pain (11-point Likert score) was compared between decompression and observation groups and between decompressed versus sham legs at 12 and 56 months. Of 2987 screened patients, 78 were randomized. At 12 months, compared with controls (n=37), both right-decompression-group (n=22) and left-decompression-group (n=18) reported lower pain (mean difference for both, -4.46; [95% CI, -6.34 to -2.58 and -6.48 to -2.45 respectively]; P<0.0001). Decompressed and sham legs equally improved. At 56 months, compared with controls (n=14), pain was lower in both the right-decompression-group (n=20) (mean difference, -7.65; [95% CI, -9.87 to -5.44]; P<0.0001) and left-decompression-group (n=16) (mean difference, -7.26; [95% CI, -9.60 to -4.91]; P<0.0001). Mean pain score was lower in decompressed versus sham legs (mean difference, 1.57 [95% CI, 0.46 to 2.67]; P=0.0002). Although nerve decompression was associated with reduced pain, the benefit of surgical decompression needs further investigation since a placebo effect may be responsible for part or all of these effects.

Combining transcranial direct current stimulation with hand robotic rehabilitation in chronic stroke patients: a double blind randomized clinical trial.

This study aimed to assess the impact of combining transcranial direct current stimulation (tDCS) with end-effector robot-assisted treatment (RAT) on upper limb function, spasticity, and hand dexterity in chronic stroke patients. This was a prospective, double-blind randomized trial with 20 equally allocated stroke patients. The experimental group received dual-tDCS (anode over affected M1, cathode over contralateral M1) alongside RAT, while the control group received sham tDCS with the same electrode placement + RAT. Each patient underwent 20 combined tDCS and RAT sessions. The primary outcome measure was the Fugl Meyer Upper Limb motor score (mFM-UL), with secondary outcomes including AMADEO® kinematic measures, Action Research Arm Test (ARAT), and Functional Independence Measure (FIM). Assessments were conducted at baseline, post-rehabilitation, and three months later. Combining bilateral tDCS with RAT did not yield additional improvements in mFM-UL, FIM, or ARAT scores among stroke patients. However, the real tDCS group showed enhanced finger flexion in the affected hand based on AMADEO® kinematic measures. The addition of tDCS to RAT did not result in significant overall functional improvements in chronic stroke patients. However, a benefit was observed in finger flexion of the affected hand.

Phosphatidylserine enriched with polyunsaturated n-3 fatty acid supplementation for attention-deficit hyperactivity disorder in children and adolescents with epilepsy: Arandomized placebo-controlled trial.

Attention-deficit hyperactivity disorder (ADHD) is a frequent comorbidity in children with epilepsy, which management mostly relies on the usual treatments of ADHD, especially methylphenidate. Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed as an alternative therapeutic approach in ADHD without epilepsy but has never been evaluated in epilepsy-associated ADHD. A multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA, in eicosapentaenoic- and docosahexaenoic-acid form, conjugated to a phospholipid vector (PS-Omega3) in children aged >6 and <16-years old, and suffering from any type of epilepsy and ADHD (inattentive or combined type) according to DSM-V. After a 4-week baseline period, patients were allocated (1:1) either to placebo group or to PS-Omega 3 group and entered a 12 week-double-blind treatment period which was followed by a 12 week-open-label treatment period. The primary outcome was the reduction of the ADHD-rating scale IV attention-deficit subscore after 12 weeks of treatment. The study was stopped early because of lack of eligible participants and the expected sample size was not reached. Seventy-four patients were randomized, 44 in PS-Omega3, and 30 in the placebo group. The reduction after 12 weeks of treatment in the inattention subscore of the ADHD-IV scale was -1.57 in the PS-Omega3 group, and -2.90 in the placebo group (p = 0.33, α = 5%). Results were similar after 24 weeks of treatment and for all other ADHD-related secondary outcomes, with no difference between placebo and PS-Omega3. Our study remaining underpowered, no formal conclusion about the effect of Ps-Omega3 could be drawn. However, our data strongly suggested that the PS-Omega 3 formulation used in the current study did not improve ADHD symptoms in children with epilepsy. Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed in ADHD but has never been evaluated in patients with both epilepsy and ADHD. To address this issue, we conducted a multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA in children with epilepsy and ADHD. The study was stopped early because of lack of eligible participants, hampering formal conclusion. However, the evolution of the ADHD symptoms at 12 and 24 weeks did not differ between placebo and PUFA supplementation, strongly suggesting that PUFA did not improve ADHD symptoms in children with epilepsy.

Efficacy of ultrasound-guided erector spinae plane block on analgesia and quality of recovery after minimally invasive direct coronary artery bypass surgery: protocol for a randomized controlled trial

BackgroundMinimally invasive direct coronary artery bypass (MIDCAB) surgery offers an effective option for coronary artery disease (CAD) patients with the avoidance of median sternotomy and fast postoperative recovery. However, MIDCAB is still associated with significant postoperative pain which may lead to delayed recovery. The erector spinae plane block (ESPB) is a superficial fascial plane block. There have not been randomized controlled trials evaluating the effects of ESPB on analgesia and patient recovery following MIDCAB surgery. We therefore designed a double-blind prospective randomized placebo-controlled trial, aiming to prove the hypothesis that ESPB reduces postoperative pain scores in patients undergoing MIDCAB surgery.MethodsThe study protocol has been reviewed and approved by the Ethical Review Committee of Peking University People’s Hospital. Sixty adult patients of either sex scheduled for MIDCAB surgery under general anesthesia (GA) will be included. Patients will be randomly allocated to receive either a preoperative single-shot ESPB with 30 mL of ropivacaine 0.5% (ESPB group) or normal saline 0.9% (control group). The primary outcomes are the difference between the two groups in numeric rating scale (NRS) scores at rest at different time points (6, 12, 18, 24, 48 h) after surgery. The secondary outcomes include NRS scores on deep inspiration within 48 h, postoperative hydromorphone consumption, and quality of patient recovery at 24 h and 48 h, using the Quality of Recovery-15 (QoR-15) scale. The other outcomes include intraoperative fentanyl requirements, the need for additional postoperative rescue analgesics, time to tracheal extubation and chest tube removal after surgery, incidence of postoperative nausea and vomiting (PONV) and postoperative cognitive dysfunction (POCD), intensive care unit (ICU) length of stay (LOS), hospital discharge time, and 30-day mortality. Adverse events will be also evaluated.DiscussionThis is a novel randomized controlled study evaluating a preoperative ultrasound-guided single-shot unilateral ESPB on analgesia and quality of patient recovery in MIDCAB surgery. The results of this study will characterize the degree of acute postoperative pain and clinical outcomes following MIDCAB. Our study may help optimizing analgesia regimen selection and improving patient comfort in this specific population.Trial registrationThe study was prospectively registered with the Chinese Clinical Trial Registry (trial identifier: ChiCTR2100052810). Date of registration: November 5, 2021.

Topical and subconjunctival anesthesia versus topical anesthesia alone in patients with senile cataracts undergoing phacoemulsification: a double-blind randomized controlled trial

BackgroundThis study compared topical anesthesia to a combination of topical anesthesia and subconjunctival anesthesia for phacoemulsification.MethodsThis double-blinded parallel placebo-controlled randomized trial involved senile cataract patients scheduled for phacoemulsification between May and December 2022. Patients were randomly assigned to receive either topical anesthesia with 0.5% tetracaine hydrochloride and subconjunctival balanced salt solution injection (Control group) or topical anesthesia and subconjunctival injection with 2% lidocaine (Lidocaine group). Baseline parameters, cataract grades, and various outcomes were recorded, including pain scores at specific time points, patient cooperation scores, requests for additional anesthesia, and complications. Statistical methods included Fisher’s exact test, the t-test, ordinal logistic regression, and linear regression with robust standard errors.ResultsIn total, 176 patients were included in the study after excluding 33 patients. A significant reduction in immediate postoperative pain was achieved in the Lidocaine group (p < 0.001) and was maintained for 2 h (p = 0.011). Additionally, better cooperation was observed in this group (p = 0.038). However, patients in the Lidocaine group experienced more pain during the subconjunctival injection (p = 0.001) and a significant increase in subconjunctival hemorrhage related to the injection (p < 0.001). Despite this, the rates of surgical complications were comparable between the groups, and all phacoemulsification procedures were successfully completed using the assigned anesthetic technique.ConclusionsThe addition of subconjunctival lidocaine injection to topical anesthesia reduced postoperative pain and improved patient cooperation during phacoemulsification. However, the lidocaine injection was painful, and it carried a higher risk of spontaneous-relief subconjunctival hemorrhage.Trial registrationTrial Registration Number: TCTR20220804003, date of registration August 4, 2022, retrospectively registered.

Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial

Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L.reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L.reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L.reuteri combination yields significant improvements in social functioning that generalized across different measures. Interestingly, ATCC-PTA-6475, but not the parental strain of DSM-17938, reverses the social deficits in a preclinical mouse model for ASD. Collectively, our findings show that L.reuteri enhances social behavior in children with ASD, thereby warranting larger trials in which strain-specific effects should also be investigated.

Evaluation of a low-level laser protocol for the control of postoperative pain, trismus, and edema in retained third molar surgeries

This split mouth double-blind randomized trial was aimed to evaluate the effect of low‑level laser therapy (LLLT) on pain, trismus, and swelling used in the postoperative period of surgery of third molars retained. Fifteen patients with symmetrically impacted mandibular third molars were randomized in two groups: LLLT group received only single‑dose intraoral and extraoral immediately after surgery; another group, received LLLT placebo on the other side. They were evaluated on the second and seventh days after surgery, the pain was evaluated in the first day too. There was no statistical difference in trismus, edema and pain between groups when examining data in the postoperative period of one, two or seven days. The pain level was significantly lower from the first day to seventh day in both groups. The laser group presented a delay or decreasing use of analgesics in the first postoperative day. Despite the statistically insignificant difference results, clinically it has been observed improvement of symptoms of discomfort related by patients. The results suggest that further studies are necessary for protocols consolidation and suggest explore combinations of photodynamic therapies.

Comments by Microbiologists for Interpreting Antimicrobial Susceptibility Testing and Improving the Appropriateness of Antibiotic Therapy in Community-Acquired Urinary Tract Infections: A Randomized Double-Blind Digital Case-Vignette Controlled Superiority Trial.

In primary care, urinary tract infections (UTIs) account for the majority of antibiotic prescriptions. Comments from microbiologists on interpreting the antimicrobial susceptibility testing (AST) profile for urinalysis were made to improve the prescription of antibiotics. We aimed to explore the added value of these comments on the quality of antibiotic prescribing by a superior double-blind digital randomized case-vignette trial among French general practitioners (GPs). One case vignette with (intervention) or without (control) a 'comment' after AST was randomly assigned to GPs. Among 815 participating GPs, 64.7% were women, at an average age of 37 years. Most (90.1%) used a computerized decision support system for prescribing antibiotics. Empirical antibiotic therapy was appropriate in 71.9% (95% CI, 68.8-75.0) of the cases, without differences between arms. The overall appropriateness of targeted antibiotic therapy (primary outcome) was not significantly increased when providing 'comments': 83.4% vs. 79.9% (OR = 1.26, 95% CI, 0.86-1.85). With the multivariate analysis, the appropriateness was improved by 2-folds (OR = 2.38, 95% CI, 1.02-6.16) among physicians working in healthcare facilities. Among digital-affine young general practitioners, the adjunction of a 'comment' by a microbiologist to interpret urinalysis in community-acquired UTIs did not improve the overall level of appropriateness of the targeted antibiotic.

The efficacy of the dental Water Jet, orthodontic, and conventional toothbrushes in plaque removal around orthodontic braces in adolescents: A randomized controlled trial.

Orthodontic treatment improves both masticatory function and the aspects of facial esthetics through the correct alignment of the teeth. If oral hygiene is neglected during fixed orthodontic treatment, it may lead to plaque accumulation and gingivitis. The aim of this randomized controlled trial was to evaluate the effectiveness of the dental Water Jet (DWJ), and orthodontic toothbrush (O-TH) in removing dental plaque around the orthodontic braces compared to conventional toothbrush (C-TH) in adolescents. This was a three-arm, double-blind, and parallel-group randomized active-controlled trial. Forty-five patients were randomly allocated into three groups: DWJ, the O-TH, and the C-TH (control group). The primary outcome measure was dental plaque accumulation change from the baseline (t0 ) to post-cleaning (t1 ), and plaque scores were recorded using the Orthodontic Plaque Index (OPI). The current clinical trial was registered and approved by Australian New Zealand Clinical Trials Registry (ACTRN12623000524695). A statistically significant difference was noted in the OPI scores between different time points in the DWJ group, the O-TH group, and the C-TH group (p < .05). However, no significant difference was noted between the groups after the cleaning procedure (p > .05). The level of oral hygiene was not satisfactory in patients undergoing fixed orthodontic treatment. In addition, the efficacy of the DWJ was not superior to O-TH nor to C-TH in plaque removal.

Sodium Bicarbonate for Metabolic Acidosis in the ICU: Results of a Pilot Randomized Double-Blind Clinical Trial.

To identify the best population, design of the intervention, and to assess between-group biochemical separation, in preparation for a future phase III trial. Investigator-initiated, parallel-group, pilot randomized double-blind trial. Eight ICUs in Australia, New Zealand, and Japan, with participants recruited from April 2021 to August 2022. Thirty patients greater than or equal to 18 years, within 48 hours of admission to the ICU, receiving a vasopressor, and with metabolic acidosis (pH < 7.30, base excess [BE] < -4 mEq/L, and Paco2 < 45 mm Hg). Sodium bicarbonate or placebo (5% dextrose). The primary feasibility aim was to assess eligibility, recruitment rate, protocol compliance, and acid-base group separation. The primary clinical outcome was the number of hours alive and free of vasopressors on day 7. The recruitment rate and the enrollment-to-screening ratio were 1.9 patients per month and 0.13 patients, respectively. Time until BE correction (median difference, -45.86 [95% CI, -63.11 to -28.61] hr; p < 0.001) and pH correction (median difference, -10.69 [95% CI, -19.16 to -2.22] hr; p = 0.020) were shorter in the sodium bicarbonate group, and mean bicarbonate levels in the first 24 hours were higher (median difference, 6.50 [95% CI, 4.18 to 8.82] mmol/L; p < 0.001). Seven days after randomization, patients in the sodium bicarbonate and placebo group had a median of 132.2 (85.6-139.1) and 97.1 (69.3-132.4) hours alive and free of vasopressor, respectively (median difference, 35.07 [95% CI, -9.14 to 79.28]; p = 0.131). Recurrence of metabolic acidosis in the first 7 days of follow-up was lower in the sodium bicarbonate group (3 [20.0%] vs. 15 [100.0%]; p < 0.001). No adverse events were reported. The findings confirm the feasibility of a larger phase III sodium bicarbonate trial; eligibility criteria may require modification to facilitate recruitment.

Efficacy and Safety of Plasma Exchange Combined with Hemoperfusion in the Treatment of Organophosphorus Poisoning: A Meta-Analysis

Introduction: The aim of the study was to systematically evaluate the efficacy and safety of plasma exchange combined with hemoperfusion in the treatment of organophosphorus poisoning. Methods: PubMed, Embase, the Cochrane Library, China National Knowledge Internet, Wanfang database, and Weipu database were searched for articles about this subject. Literature screening and selection were conducted in strict accordance with the inclusion and exclusion criteria. Results: 14 randomized controlled trials with 1,034 participants were included in this meta-analysis study, including 518 cases in plasma exchange combined with hemoperfusion group (the combination treatment group) and 516 cases in hemoperfusion group (the control group). Compared with the control group, the combination treatment group was associated with a higher effective rate (relative risk [RR] = 1.20, 95% confidence interval [CI] [1.11, 1.30], p < 0.00001) and lower fatality rate (RR = 0.28, 95% CI [0.15, 0.52], p< 0.0001); reduced TNF-α (standardized mean difference [SMD] = −1.95, 95% CI [−2.42, −1.48], p < 0.00001), IL-6 (SMD = −1.94, 95% CI [−3.08, −0.80], p = 0.0009), and C-reactive protein (CRP) (SMD = −1.94, 95% CI [−2.86, −1.03], p < 0.0001); shorten coma time (SMD = −1.99, 95% CI [−2.75, −1.24], p < 0.00001), recovery time of cholinesterase activity (SMD = −1.71, 95% CI [−1.90, −1.53], p < 0.00001), and hospital stay (SMD = −1.29, 95% CI [−1.59, −0.98], p < 0.00001). The incidence of complications in the combination treatment group such as liver and kidney damage (RR = 0.30, 95% CI [0.18, 0.50], p < 0.00001), pulmonary infection (RR = 0.29, 95% CI [0.18, 0.47], p < 0.00001), and intermediate syndrome (RR = 0.32, 95% CI [0.21, 0.49], p < 0.00001) was lower than that in the control group. Conclusions: The current evidence suggests that the combination of plasma exchange with hemoperfusion therapy can reduce the mortality of patients with organophosphorus poisoning, shorten the recovery time of cholinesterase activity and the time of coma, reduce the average length of hospital stay, and reduce the levels of IL-6, TNF-α, and CRP, but high-quality randomized double-blind controlled trials are still required to confirm the current findings in the future.

Which trial do we need? Mannitol therapy in hospitalized adult patients with tick-borne encephalitis and brain oedema: a double-blind placebo-controlled multicentre randomized trial

Tick-borne encephalitis (TBE) is an infection of the central nervous system (CNS) caused by tick-borne encephalitis virus (TBEV) [ 1 Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: Disease severity and long-term prognosis. Clinical Infectious Diseases. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (179) Google Scholar , 2 Ruzek D. Avšič Županc T. Borde J. Chrdle A. Eyer L. Karganova G. et al. Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res. 2019; 164: 23-51https://doi.org/10.1016/j.antiviral.2019.01.014 Crossref PubMed Scopus (173) Google Scholar ]. In 2020, there were 3734 confirmed cases of TBE in Europe (Russian Federation excluded) and Slovenia had one of the highest incidence rates with 8.9 confirmed TBE cases per 100,000 population [ 3 ECDC. Tick-borne encephalitis: Annual Epidemiological Report for 2020. Stockholm; 2020. Google Scholar ]. The virus is transmitted to humans principally through tick bites. There are three known subtypes of TBEV: European (EU-TBEV), Siberian and Far Eastern. Of all three subtypes, EU-TBEV causes the mildest disease [ 1 Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: Disease severity and long-term prognosis. Clinical Infectious Diseases. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (179) Google Scholar , 2 Ruzek D. Avšič Županc T. Borde J. Chrdle A. Eyer L. Karganova G. et al. Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res. 2019; 164: 23-51https://doi.org/10.1016/j.antiviral.2019.01.014 Crossref PubMed Scopus (173) Google Scholar ]. The majority of infections caused by EU-TBEV are asymptomatic (70-90%). Among symptomatic cases, approximately 40-50% develop meningitis, 50% meningoencephalitis, and 10% meningoencephalomyelitis [ 4 Kaiser R. Tick-borne encephalitis. Infect Dis Clin N Am. 2008; 22: 561-575https://doi.org/10.1016/j.idc.2008.03.013 Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar ]. The case-fatality rate in EU-TBE ranges from 0.5 to 2%, whereas 30‒46% of patients report incomplete recovery (residual neurological deficit) manifesting as residual symptoms/signs such as headache, memory and concentration disorders, fatigue, emotional lability, coordination disorders, tremor, hearing loss/tinnitus, and flaccid paresis [ 1 Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: Disease severity and long-term prognosis. Clinical Infectious Diseases. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (179) Google Scholar , 5 Velušček M. Blagus R. Kišek T.C. Ružić-Sabljić E. Avšič-županc T. Bajrović F.F. et al. Antibiotic Use and Long-Term Outcome in Patients with Tick-Borne Encephalitis and Co-Infection with Borrelia Burgdorferi Sensu Lato in Central Europe. A Retrospective Cohort Study. J Clin Med. 2019; 8: 1740https://doi.org/10.3390/jcm8101740 Crossref Scopus (4) Google Scholar , 6 Taba P. Schmutzhard E. Forsberg P. Lutsar I. Ljøstad U. Mygland et al. EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis. Eur J Neurol. 2017; 24: 1214-e61https://doi.org/10.1111/ene.13356 Crossref Scopus (115) Google Scholar , 7 Bogovič P. Stupica D. Rojko T. Lotrič-Furlan S. Avšič-Županc T. Kastrin A. et al. The long-term outcome of tick-borne encephalitis in Central Europe. Ticks Tick Borne Dis. 2018; 9: 369-378https://doi.org/10.1016/j.ttbdis.2017.12.001 Crossref Scopus (35) Google Scholar ]. These symptoms/signs decline over time and their frequency stabilises 12 months after the acute illness [ 7 Bogovič P. Stupica D. Rojko T. Lotrič-Furlan S. Avšič-Županc T. Kastrin A. et al. The long-term outcome of tick-borne encephalitis in Central Europe. Ticks Tick Borne Dis. 2018; 9: 369-378https://doi.org/10.1016/j.ttbdis.2017.12.001 Crossref Scopus (35) Google Scholar ].

The effect of bromelain in periodontal surgery: a double-blind randomized placebo-controlled trial

BackgroundPeriodontitis is a persistent inflammatory condition. Eliminating the infection and reducing its risk factors are the first steps in treating periodontitis. When the anti-infective therapy is complete, there may still be deep periodontal pockets and prolonged inflammation. Surgical pocket reduction or elimination is indicated under these circumstances. We aimed to evaluate the effect of bromelain on bleeding on probing (BOP), gingival index (GI), and plaque index (PI) after pocket elimination surgery.MethodsThis double-blind randomized placebo-controlled trial included 28 candidates for pocket elimination surgery referred to the private office of a periodontist in Bandar Abbas, Iran, from April 18 to August 18, 2021. Patients’ general characteristics, such as age and sex, were recorded. Additionally, periodontal indices including BOP, PI, GI, and pocket probing depth (PPD) were evaluated in all subjects. All patients underwent pocket elimination surgery. Afterwards, they were randomized into two groups. The first group received 500 mg Anaheal (bromelain) capsules twice a day before meal for one week. The second group received placebo, prepared in similar shape and color by the same pharmaceutical company. BOP, PI, GI, and PPD were assessed four weeks after completion of the treatment course (five weeks after surgery).ResultsFour weeks after intervention, BOP was significantly lower with Anaheal compared to placebo (0% vs. 35.7%, P = 0.014). However, there was no significant difference in GI between groups (P = 0.120). Mean PI was lower (17.71 ± 2.12 vs. 18.28 ± 2.49) and mean PPD higher (3.10 ± 0.71 vs. 2.64 ± 0.45) in the Anaheal group, but the differences did not reach statistically significant levels (P = 0.520 and P = 0.051, respectively).ConclusionsOne-week treatment with Anaheal at a dose of 1 g/d after pocket elimination surgery resulted in significantly lower BOP compared to placebo.Trial registrationIranian Registry of Clinical Trials (IRCT), IRCT20201106049289N1. Registered 06/04/2021. Registered prospectively, https://www.irct.ir/trial/52181.

Intra-articular mm-ii, a novel suspension of large empty multilamellar liposomes, in painful knee osteoarthritis: a 26 week phase 2b placebo-controlled double blind randomized trial

Intra-articular mm-ii, a novel suspension of large empty multilamellar liposomes, in painful knee osteoarthritis: a 26 week phase 2b placebo-controlled double blind randomized trial

OA25 Identification of biomarkers to stratify response to combination therapy with belimumab and rituximab in a randomized trial, BEAT-LUPUS for systemic lupus erythematosus

Abstract Background/Aims The BEAT-lupus double-blind randomised trial demonstrated that belimumab (anti-BAFF antibody) reduced the number of severe-flares (compared to placebo) after B-cell depletion (rituximab) in patients with systemic lupus erythematosus (SLE)(1). We longitudinally immune profiled patients recruited to the trial to identify which patients would benefit most from belimumab after rituximab combination therapy. Methods We constructed two models (because the number of patients who provided serum/blood RNA samples and peripheral blood mononuclear cells differed) using baseline data to predict a major clinical response (MCR)(2) to belimumab after rituximab at 52-weeks utilising conventional and machine learning approaches: A) Model 1: serum autoantibodies and cytokines, peripheral blood RNA expression, clinical data, and routinely collected laboratory-markers (10 responders, 11 non-responders). B) Model 2: B-cell flow-cytometry (8 responders, 8 non-responders). The emerging key variables were then used as effect modifiers comparing response to belimumab and placebo after rituximab. Results Baseline serum IgA2 anti-dsDNA antibody levels emerged from model 1 as the key predictor of MCR with an AUROC (area under the curve of the receiver operator characteristic) of 0.81 (95% CI: 0.70-0.96) in predicting an MCR by 52-weeks in the belimumab arm. An optimal cut point of serum IgA2 anti-dsDNA antibody (10.7 AU/arbitrary unit), derived from AUROC, was applied as an effect modifier which improved the delta between response to belimumab vs placebo from 13% (without the effect modifier) to 48% (95% CI: 10-70; p = 0.021) (Belimumab - 64% [9 responders, 5 non-responders], placebo - 16% [2 responders, 10 non-responders]). Belimumab significantly reduced serum IgA2 anti-dsDNA antibody levels compared to placebo at 52-weeks (difference: 20 AU; 95% CI: 13-27; p &amp;lt; 0.001) only in those patients who achieved an MCR, falling by 60% from baseline (difference: 23 AU; 95% CI: 11-35; p &amp;lt; 0.001, compared to non-response). Prediction model 2 identified the frequency of T-bet+CD11c+DNM-2 (double negative memory B-cell, type-2: CD11c+T-bet+CD38-CD27-IgD-CD21-CD24-) as the strongest predictor of MCR by 52-weeks in the belimumab arm with an AUROC of 1.00 (95% CI: 1.00-1.00). Using T-bet+CD11c+DNM-2 as an effect modifier (optimal cut point: 14.2% of total B-cells) the delta improved from 13% to 71% (95% CI: 23-92; p = 0.007) (Belimumab - 100% [8 responders, 0 non-responders], placebo - 29% [2 responders, 5 non-responders]). The frequency of T-bet+CD11c+DNM-2 was significantly lower in the belimumab arm at 52-weeks compared to placebo (difference: 6%; 95% CI: 3-11; p = 0.001), and dropped by 48% from baseline in belimumab responders (difference with non-responders: 11%; 95% CI: 6-15; p &amp;lt; 0.001). Conclusion High baseline serum IgA2 anti-dsDNA antibody and peripheral blood T-bet+CD11c+DNM-2 B-cell frequency could guide patient selection for belimumab after rituximab combination therapy thereby improving outcomes and access to targeted therapies for patients with SLE. Exploration of the underlying mechanisms and confirmation of these results including combining the two prediction models in a larger clinical trial are required. Reference 1. Shipa M, et al. Annals of Internal Medicine. 2021;174:1647-57. 2. McDonald S, et al. Lupus Sci Med. 2022;9:e000584. Disclosure M. Shipa: Grants/research support; Versus arthritis, LUPUS-UK. M. Parvaz: None. D. Nguyen: None. L. Santos: None. D.A. Isenberg: Consultancies; Astra Zeneca, Eli Lilly, Merck Serono, Servier and UCB. C. Gordon: Consultancies; Center for Disease Control and Prevention, AbbVie, Amgen, Astra-Zeneca, EMD Serono, MGP, Sanofi and UCB. M.R. Ehrenstein: Consultancies; GSK. Grants/research support; Versus arthritis.

Booster course of antenatal corticosteroids after preterm prelabor rupture of membranes: a double-blind randomized trial

Preterm prelabor rupture of membranes is a leading cause of preterm birth and is responsible for 18% to 20% of perinatal deaths in the United States. An initial course of antenatal corticosteroids has been shown to reduce morbidity and mortality in patients with preterm prelabor rupture of membranes. For patients who remain undelivered for 7 days or more after the initial course of antenatal corticosteroids, it is uncertain whether a booster course of antenatal corticosteroids reduces neonatal morbidity or increases the infection risk. The American College of Obstetricians and Gynecologists has concluded that the current evidence is insufficient to make a recommendation. This study aimed to evaluate if a single booster course of antenatal corticosteroids improves neonatal outcomes after preterm prelabor rupture of membranes. We conducted a multicenter, placebo-controlled randomized clinical trial. The inclusion criteria were preterm prelabor rupture of membranes, gestational age of 24.0 to 32.9 weeks, singleton, initial antenatal corticosteroid course administered at least 7 days before randomization, and planned expectant management. Consenting patients were randomized in gestational age blocks to either receive booster antenatal corticosteroids (12 mg betamethasone every 24 hours for 2 days) or a saline placebo. The primary outcome was composite neonatal morbidity or death. A sample size of 194 patients was calculated to yield 80% power at P<.05 to detect a reduction in primary outcome from 60% in placebo group to 40% in antenatal corticosteroids group. From April 2016 through August 2022, 194 patients consented and were randomized (47% of 411 eligible patients). Intent-to-treat analysis was performed on 192 patients (2 placebo patients left hospital, outcomes unknown). The groups had similar baseline characteristics. The primary outcome occurred in 64% of patients who received booster antenatal corticosteroids vs in 66% of patients who received the placebo (odds ratio, 0.82; 95% confidence interval, 0.43-1.57; gestational age-stratified Cochran-Mantel-Haenszel test). Individual components of the primary outcome and secondary neonatal and maternal outcomes were not significantly different between the antenatal corticosteroids and placebo groups. Specifically, chorioamnionitis (22% vs 20%), postpartum endometritis (1% vs 2%), wound infections (2% vs 0%), and proven neonatal sepsis (5% vs 3%) were not different between the groups. A booster course of antenatal corticosteroids at least 7 days after the first antenatal corticosteroids course in patients with preterm prelabor rupture of membranes did not improve neonatal morbidity or any other outcome in this adequately-powered, double-blind randomized clinical trial. Booster antenatal corticosteroids did not increase maternal or neonatal infection.