Placebo-controlled Randomized Trial Research Articles

In the new era of psychedelic assisted therapy: A systematic review of study methodology in randomized controlled trials.

Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatric disorders. A notable methodological challenge in psychedelic AT, however, is the complexity of blinding procedures. The lack of efficacious blinding can introduce considerable response bias, reduce internal validity, and compromise participant retention. This systematic review examines design and blinding techniques in RCTs utilizing psychedelics and placebo for the treatment of psychiatric disorders. The aim of this work is to identify factors that may inform future RTC design for conducting psychedelics research. We conducted a systematic review of PubMed, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Psycinfo, Embase, and Web of Science Core Collection to examine: (1) placebo selection, (2) study design, and (3) integrity of blinding measures. Sixteen publications were identified as meeting the criteria for a systematic review.Our findings suggest that traditional placebo administration is insufficient to control for expectancy confounds. Consequently, experimental methodology that limits personnel unblinding and the use of an active placebo are important considerations when designing prospective clinical studies involving psychedelics.

Preliminary Results from a Phase IV Surveillance Study of Medical Cannabis Use in Australian Patients With Advanced Cancer Receiving Palliative Care.

Introduction: Our research group is conducting three large randomized placebo-controlled trials of medicinal cannabis for cancer symptoms. All participants are invited to take part in a posttrial surveillance study. Methods: Participants were given the manufacturers dosing instructions and liberty to titrate to effect. Data were collected on symptoms (Edmonton Symptom Assessment Scale [ESAS] score), perceived benefits, adverse effects, satisfaction with the product, and dose/frequency. Results: Twenty-six percent of eligible participants consented to take part in the surveillance study. Most participants changed their self-titrated dose at least once. Pain, sleep, and mood were the most frequently cited symptoms which improved. Fatigue, nausea, and cognitive impairment were the most frequently mentioned adverse effects. Conclusion: Participants felt confident making changes to their medicinal cannabis dose within the limits suggested by the manufacturer of each product. A number of benefits and adverse effects were ascribed to the product. Benefits were similar to those described in previous studies.

Management of isolated distal deep vein thrombosis.

Isolated distal deep vein thrombosis (DVT) represents up to 50% of all lower limb DVT in ultrasound series and is a frequent medical condition, which management is not well established. Data arising from registries and non-randomized studies suggest that most distal DVTs do not extend to the proximal veins and have an uneventful follow-up when left untreated. This data had some impact on international recommendations like the American College of Chest Physicians (ACCP), whose last version stated that ultrasound surveillance might be an option for selected low-risk patients. However, robust data arising from randomized studies are scarce. Indeed, only seven randomized trials assessing the need for anticoagulation for calf DVT have been published. Many of these trials had an open-label design and were affected by methodological limitations. When considering randomized placebo-controlled trials, one included low-risk patients and was hampered by a limited statistical power (CACTUS study). Nevertheless, data from this trial tend to confirm that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE but is associated with a higher risk of bleeding. A second randomized placebo-controlled trial did not assess the necessity of anticoagulant treatment but rather the long-term risk of recurrence and compared 6 weeks versus 12 weeks of treatment with rivaroxaban (RIDTS study). Finally, the last available randomized trial compared a 3-month versus a 12-month edoxaban treatment in patients with cancer and mainly asymptomatic distal DVT, detected by systematic compression ultrasonography. Overall, available data suggest that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE. High risk patients (previous VTE, active cancer, inpatients) might benefit from a course of anticoagulant treatment. However, the optimal anticoagulant intensity and duration are uncertain and further studies are needed.

(028) Intracavernosal Injection of Platelet-Rich Plasma for the Treatment of Erectile Dysfunction: A Meta-Analysis of Randomized Placebo-Controlled Trials

Abstract Introduction Erectile dysfunction (ED) affects 3 to 76.5% of men globally. Appropriate treatments for ED patients are vital to ensure their quality of life. However, the present conservative ED treatments cannot reverse the underlying pathology and often lead to discontinuation due to the lack of efficacy. Regenerative therapies, including platelet-rich plasma (PRP), have been gaining increasing interest for the last few years. Preclinical studies suggest that growth factors in PRP may be beneficial in ED. With the increasing evidence of PRP, a meta-analysis has yet to be conducted to determine its efficacy and safety compared to a placebo. Objective To systematically evaluate PRP's efficacy and safety for treating ED based on randomized placebo-controlled trials (RCTs) results. Methods A comprehensive search on PubMed, Scopus, and EMBASE databases was conducted on June 2023 to find relevant articles following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RCTs in English evaluating PRP's efficacy and safety in treating ED were included. The primary outcomes were the International Index of Erectile Function-Erectile Function (IIEF-EF) score at 1-, 3-, and 6-months post-treatment. The secondary analysis includes the proportion of patients who met the minimal clinically important difference (MCID) of IIEF-EF score, IIEF score for sexual satisfaction and overall satisfaction, peak systolic velocity (PSV) in the cavernousal artery, and the complication rate after treatment. Quality of included studies was assessed using JADAD Score and Cochrane RoB2 tools. Meta-analysis with a random or fixed effects model based on the heterogeneity was performed using Revman 5.4. Results From 183 articles in initial research, three RCTs with low risk of bias were reviewed. We included 103 patients in the PRP group and 106 in the placebo group. The baseline of the evaluated score from both groups was comparable despite variable PRP protocol being used. The pooled analysis showed that PRP is associated with higher IIEF-EF scores at 1, 3, and 6 months follow up compared to placebo with a mean difference (MD) of 2.85 (95% CI, 1.68 – 4.03, p: <0.00001), 2.81 (95% CI, 1.57 – 4.05, p: <0.00001), 3.11 (95% CI, 1.96 – 4.27, p: <0.00001). Similarly, the proportion of patients who met MCID and PSV at follow-up also favoured the PRP group. On contrary, the IIEF score for sexual satisfaction and overall satisfaction domain, as well as VAS score post-injection were comparable between groups. No significant adverse event was reported in any study during follow-up. Conclusions The present meta-analysis suggests that PRP is effective and tolerable as a restorative therapy for managing ED patients compared to a placebo. Nevertheless, additional RCTs with more robust data from larger sample sizes and longer-term follow-ups are required to corroborate the findings. Disclosure No.

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.

Perioperative oral pregabalin or clonidine in patients undergoing lumbar spine posterior fusion: A randomized controlled trial

ABSTRACT Background Multiple techniques and pharmacological efforts have been tried to control intraoperative hemodynamic fluctuations, reduce perioperative blood loss and severe postoperative pain. This study aimed to assess the perioperative effects of oral premedication with pregabalin or clonidine for lumbar spine posterior fusion under general anesthesia (GA). Outcome measures: Perioperative blood loss, hemodynamics, anesthetics consumption, postoperative pain, and side effects Methods This is a prospective, triple blinded randomized placebo-controlled trial (RCT). Ninety-six adult ASA I-II patients of either sex undergoing lumbar spine posterior fusion were randomly assigned to obtain a placebo (group E), pregabalin 300 mg (group P), or clonidine 200 μg (group C) orally 90 minutes before induction of GA. Trial registration: www.pactr.org with (PACTR201710002416280). Results Preemptive oral pregabalin 300 mg and clonidine 200 μg optimized intraoperative hemodynamics, reduced perioperative blood loss than the placebo group (by 22.2% and 30.7%, respectively), reduced postoperative pain scores, and anesthetic and postoperative analgesic consumption. In addition, they prolonged the duration to the first postoperative analgesic request. There was no major complication in any group. Conclusion Premedication with pregabalin or clonidine reduced perioperative blood loss and optimized intraoperative and postoperative hemodynamics, with the preference for clonidine over pregabalin as well as both reduced postoperative pain scores, analgesic requirements, PONV, and shivering. Sedative drugs should be used in lower doses to avoid oversedation. Pregabalin-associated dizziness and visual disturbance may necessitate extra precautions and patient education.

Association of IL-17 Inhibitors with Hypertension in Patients with Autoimmune Diseases: A Systematic Review and Meta-analysis on Randomized Controlled Trials.

The influence of IL-17 inhibition on blood pressure in autoimmune disease patients remains inconclusive. Our objective is to examine the risk of hypertension in patients with autoimmune diseases undergoing IL-17 inhibition therapies via meta-analysis of randomized, placebo-controlled trials (RCTs). We obtained integrated data from PubMed, Embase, and ClinicalTrials.gov. Incident hypertension rates were calculated, and hazard ratios (HRs) with 95% confidence intervals (CIs) were analyzed, along with Ι^2 statistics to assess heterogeneity. Sequential analysis ensured conclusion reliability. In 30 RCTs involving 9,909 patients with diverse autoimmune diseases treated with anti-IL-17 agents, our meta-analysis revealed a significant increase in hypertension risk (RR 1.69, CI 1.24-2.31, p=0.001), robustly supported by trial sequential analysis. Among the four agents (secukinumab, ixekizumab, bimekizumab, and brodalumab), only secukinumab exhibited a notable association with hypertension. Patients with various primary autoimmune diseases, particularly those with psoriatic arthritis, had a higher likelihood of developing hypertension; in rheumatic arthritis patient cohorts, anti-IL-17 agents did not elevate hypertension risk. Prolonged treatment duration correlated with an increased hypertension risk. Stratifying by gender, studies with a female predominance demonstrated a higher risk ratio for hypertension compared to male-predominant studies. This highlights that anti-IL-17 treatment escalates hypertension risk, emphasizing the need for extra caution when managing autoimmune disease patients. (Registered by PROSPERO, CRD42016053112).

Botulinum toxin-A effects on pain, somatosensory and psychosocial features of patients with refractory masticatory myofascial pain: a randomized double-blind clinical trial

The antinociceptive effect of BoNT-A have been well documented in animal studies; however, results of few but well-designed randomized placebo-controlled clinical trials about BoNT-A efficacy in masticatory myofascial pain (MFP) are inconsistent. Therefore, the present randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of BoNT-A in patients with refractory MFP. Twenty-eight patients with pain reduction of less than 30% despite conservative treatment and with an average pain intensity of > 50 mm on the visual analogue scale (VAS) participated. Patients were randomly assigned to receive a total of 80 U of BoNT-A or saline solution (SS) injected into the masseter and anterior temporalis muscles. Pain intensity (VAS), quantitative sensory testing (QST), conditioned pain modulation (CPM), and psychosocial status were examined. Follow-up was performed at 1 and 6 months. For repeated-measure comparisons between evaluation times, Friedman test with Bonferroni correction was used for pain and somatosensory variables and the Wilcoxon test for the psychosocial variables. The Mann–Whitney test was used for all comparisons between groups. The BoNT-A group had a significant decrease in pain intensity at follow-ups compared with the SS group (p < 0.001). QST assessment revealed higher pressure pain threshold values in the masseter muscle for BoNT-A group compared to SS (p < 0.03) at all follow-ups. No differences were found for mechanical pain threshold and wind-up ratio values (p > 0.05) in the entire study. The BoNT-A group presented the most efficient CPM effect (p < 0.03) only at the 1 month follow-up in the masseter muscle. There was a significant time effect for BoNT-A in all psychosocial variables (p < 0.05) and a drug effect in the Central Sensitization Inventory (p < 0.01), Pittsburgh Sleep Quality Index (p < 0.004), and Healthy Survey 36 (p < 0.05) at 6 months follow-up. The study demonstrates that a single injection-session of BoNT-A has positive effects on the hall pain spectrum of patients with refractory masticatory myofascial pain.

Is it now appropriate to assert that creatine supplementation holds cognitive benefits for the elderly?

This paper explores the potential cognitive benefits of creatine supplementation for the elderly population. Creatine, known for its role in muscular and neuronal energy metabolism, is primarily obtained through dietary intake, particularly from meat sources. The literature underscores creatine's significance in neural tissue development and cognitive capacity, with deficiencies linked to impaired cognitive function, especially in infants. In the context of the aging global population, cognitive decline is a prevalent concern, and reduced creatine concentration is implicated in this process. While association studies suggest a connection between creatine intake and cognitive performance in the elderly, the absence of robust clinical trials calls for further investigation. Physiological plausibility supports the idea that increased creatine intake, combined with physical activities, could positively impact cognition in the elderly. However, the existing evidence remains inconclusive, and rigorous randomized placebo-controlled clinical trials are essential to establish a cause-and-effect relationship and elucidate underlying mechanisms. Confirmation of cognitive benefits could pave the way for determining optimal dosages to enhance cognitive function in the elderly.

Assessing effectiveness of adding niosomal atorvastatin 1% ointment to topical calcineurin inhibitor treatment in non-segmental vitiligo.

Treatment of vitiligo is still a big challenge for dermatologists. The efficacy of statins in the treatment of vitiligo is controversial. We studied possible therapeutic effect of topical 1% niosomal atorvastatin ointment combined with topical 0.1% tacrolimus in treatment of non-segmental vitiligo. This is a triple blind, pilot, randomized placebo-controlled trial (RCT) that was performed in dermatology clinic. All the patients used topical 0.1% tacrolimus cream twice daily (BD). Moreover, the intervention group participants used topical 1% niosomal atorvastatin ointment, and control group participants were prescribed placebo ointment, BD. Patients were evaluated using vitiligo area surface index (VASI) score and patients' satisfaction at baseline and after 3 months treatment. The mean patient satisfaction in the intervention and control groups were 5 ± 1.4 and 3.5 ± 1.9; the difference between groups was not statistically significant (p = 0.9). We found statistically significant difference in VASI score before and after treatment in both intervention and control groups (p = 0.01 and p = 0.03, respectively). However, comparison of the VASI score between groups was not statistically significant (p = 0.62). We also found no significant correlation between VASI score and other variables. The result of this study indicates that adding of niosomal atorvastatin 1% ointment to topical calcineurin inhibitor has no additional effect on non-segmental type of vitiligo. Further large studies with different combinations are recommended before any conclusive result can be concluded on efficacy of statins in vitiligo.

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.

Hyperuricemia: An Intriguing Connection to Metabolic Syndrome, Diabetes, Kidney Disease, and Hypertension.

Our review explores the epidemiology, physiology, and clinical data surrounding the connection between hyperuricemia and metabolic syndrome, chronic kidney disease, and hypertension. Compelling physiologic mechanisms have been proposed to explain a causal relationship between hyperuricemia and metabolic syndrome, chronic kidney disease, and hypertension but clinical studies have given mixed results in terms of whether intervening with hyperuricemia using urate-lowering therapy has any beneficial effects for patients with these conditions. Despite the large amount of research already put into this topic, more randomized placebo-controlled trials are needed to more firmly establish whether a cause-effect relationship exists and whether lowering uric acid levels in patients with these conditions is beneficial.

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.

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.

The Use of L-Menthol in Endoscopic Transpapillary Interventions. Prospective Randomized Dual-Center Study

Aim: to study the effect of L-menthol on duodenal peristalsis, the results of cannulation of the papilla, the effectiveness and safety of endoscopic retrograde transpapillary interventions (ERTI).Materials and methods. A prospective two-center randomized placebo-controlled trial was carried out from January to November 2022 in two centers. The study included 126 patients, 69 (54.8 %) men and 57 (45.2 %) women, mean age — 62.1 ± 1.8 years. The inclusion criteria were age 18–75 years, indications for ERTI, absence of previous endoscopic papillotomy, absence of allergy to menthol, consent to participate in the study. After randomization, the main group (“L”) included 70 patients, the control group — 56. Patients in group “L” were irrigated with 25 mL (160 mg) of L-menthol (Spectavium), patients in the control group — with 25 mL of saline solution. Peristaltic activity was studied before and three minutes after administration of the drug. The intensity of peristalsis was assessed according to a modified Hiki scale: 0 points — complete absence of peristalsis; 1 point — single peristaltic waves; 2 points — intense peristalsis, little amenable to straightening at maximum insufflation; 3 points — pronounced peristalsis.Results. Three minutes post-irrigation, the suppression of peristaltic waves was noted in the experimental group “L”: 0 points — 63 (90 %) patients, 1 point — 6 (8.6 %) patients, compared to the control, with no change in peristalsis (p &lt; 0.05). Successful selective cannulation was achieved in 64 (91.4 %) patients of group “L” and in 41 (73.2 %) — of the control group (p &lt; 0.05). Non-cannulation endoscopic papillotomy had to be used in 6 (8.5 %) cases in group “L” and in 14 (25 %) cases in the control group. In general, successful cannulation was achieved in 100 % of patients in group “L”, and in 94.5 % — in the control group (p &lt; 0.05). The duration of the intervention was significantly reduced in group “L” — 40 ± 2.5 vs. 50.3 ± 3.6 min. Among the complications, only intraoperative bleeding was registered (2 (2.9 %) — group “L”, 5 (8.9 %) — the control group), which was eliminated endoscopically in all cases.Conclusion. The use of L-menthol during ERTI helps to achieve noticeable inhibition of peristalsis, promotes successful cannulation, reduces the intervention time, minimizes the risk of intraoperative complications. Thus, L-menthol has demonstrated its effectiveness and safety, which makes it possible to use it in the arsenal of combating enhanced peristalsis during ERTI.

Efficacy of conditioned autologous serum therapy (Orthokine®) on the dorsal root ganglion in patients with chronic radiculalgia: study protocol for a prospective randomized placebo-controlled double-blind clinical trial (RADISAC trial)

BackgroundPulsed radiofrequency (PRF) treatment on the dorsal root ganglion (DRG) has been proposed as a good option for the treatment of persistent radicular pain based on its effect of neuromodulation on neuropathic pain. Autologous conditioned serum (ACS) therapy is a conservative treatment based on the patient’s own blood. The aim of this manuscript is to develop a study protocol using ACS on the DRG as a target for its molecular modulation.MethodsWe plan to conduct a randomized controlled study to compare the efficacy of PRF therapy plus ACS versus PRF therapy plus physiological saline 0.9% (PhS) on the DRG to reduce neuropathic pain in patients with persistent lower limb radiculalgia (LLR) and to contribute to the functional improvement and quality of life of these patients.Study participants will include patients who meet study the inclusion/exclusion criteria. Eligible patients will be randomized in a 1:1 ratio to one of treatment with PRF plus ACS (experimental group) or PRF plus PhS (placebo group). The study group will consist of 70 patients (35 per group) who have experienced radicular pain symptoms for ≥ 6 months’ duration who have failed to respond to any therapy. Both groups will receive PRF on the DRG treatment before the injection of the sample (control or placebo). Patient assessments will occur at baseline, 1 month, 3 months, 6 months, and 12 months after therapy.The primary efficacy outcome measure is Numeric Pain Rating Scale (NPRS) responders from baseline to 12 months of follow-up using validated minimal important change (MIC) thresholds. A reduction of ≥ 2 points in NPRS is considered a clinically significant pain relief.The secondary efficacy outcome measure is the proportion of Oswestry Low Back Pain Disability Scale (ODS) responders from baseline to 12 months of follow-up in the experimental group (PRF plus ACS) versus the placebo group (PRF plus PhS). ODS responders are defined as those patients achieving the validated MIC of ≥ 10-point improvement in ODS from baseline to 12 months of follow-up as a clinically significant efficacy threshold.DiscussionThis prospective, double-blind, randomized placebo-controlled study will provide level I evidence of the safety and effectiveness of ACS on neuropathic symptoms in LLR patients.Trial registration {2a}{2b}EUDRACT number: 2021–005124-38. Validation date: 13 November 2021. Protocol version {3}: This manuscript presents the 2nd protocol version.

Relaxin as a biological marker and therapeutic target in heart failure

An important task of modern cardiology is the search and study of new cardiovascular biological markers that can help in the early diagnosis of heart diseases, serve as a tool to assess the effectiveness of treatment, and act as a prognostic marker and risk stratification criterion. This literature review aimed to consider relaxin (RLN) as a new diagnostic and prognostic cardiovascular biological marker. RLN is a natural peptide hormone with a molecular weight of approximately 6000 daltons. RLN2 is the main circulating form of RLN in the blood. Although human RLN2 was originally discovered as a hormone mainly secreted by the corpus luteum of the ovary, it is also synthesized in various tissues in non-pregnant women and men and is considered one of the most pleiotropic hormones of the human body, which perform various activities beyond reproduction.&#x0D; The availability of serelaxin (a recombinant molecule identical to human RLN2) has made it possible to study the effects of RLN2 on the cardiovascular system, kidneys, liver, and brain and to evaluate it in several randomized placebo-controlled clinical trials. RLN2 exerts many cardioprotective effects on the heart and vessels and has been proposed as a therapeutic target for cardiovascular diseases such as heart failure, atrial fibrillation, coronary heart disease, myocardial infarction, and arterial hypertension. Through the activation of its cognate receptor and subsequent flow of several molecular signaling pathways in the cardiovascular system, RLN2 can induce vasodilation and angiogenesis, increase arterial compliance and cardiac output, reduce vascular resistance, exert antifibrotic effects through regulation and remodeling of extracellular matrix turnover, reduce inflammation and apoptosis, inhibit oxidative stress, induce chronotropic and inotropic effects, and inhibit ventricular and atrial ectopic activity.&#x0D; Further studies are needed to demonstrate the potential use of RLN as an additional laboratory tool for diagnosis, risk stratification, and prediction of cardiovascular events in patients with heart failure. The effects of relaxin on morbidity and mortality in patients with heart failure have yet to be evaluated in more detail.

Probiotics in bone fracture treatment? A narrative literature review

The recent recognition of the importance of the intestinal microbiome in host physiology has driven investigations of gut microbiome-directed therapeutics, with probiotics attracting increased attention in the treatment of a diversity of conditions. The application of probiotics has expanded beyond the treatment of intestinal tract disorders. Today, their capacity to treat a vast array of conditions arising also along the gut–bone axis is being studied. Therefore, in this study we have carried out a scoping literature review of the clinical trials evaluating the effect of probiotics in the treatment of bone fracture. In total, six articles were found for review, four randomized placebo-controlled trials on humans and two studies using animal models. Probiotics were found to have positive effects on fracture treatment. Probiotics were shown to improve not only bone regeneration but also decrease systemic inflammation and pain during conservative fracture treatment. However, this is a novel field and due to the limited number of studies only sparse conclusions can be made. Additional clinical trials on the possible role of probiotics in fracture treatment are necessary to fully evaluate their therapeutic potential.

Prescription psychostimulants for the treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of randomized placebo-controlled trials.

There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD. Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables. Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention. Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.

Acute effects of a chewable beetroot-based supplement on cognitive performance: a double-blind randomized placebo-controlled crossover clinical trial

BackgroundDietary nitrate (NO3−) has been shown to be useful as an ergogenic aid with potential applications in health and disease (e.g., blood pressure control). However, there is no consensus about the effects of dietary NO3− or beetroot (BR) juice supplementation on cognitive function.ObjectiveThe aim of this study was to evaluate the effects of a single dose of a chewable BR-based supplement on cognitive performance.MethodsA double-blind randomized placebo-controlled two-period crossover clinical trial was carried out based on the extension of the CONSORT guidelines for randomized crossover trials. A total of 44 participants (24 F; 20 M; 32.7 [12.5] years; 66.3 [9.0] kg; 170 [9.2] cm; 22.8 [1.4] kg/m2) were randomly allocated to receive first either four BR-based chewable tablets (BR-CT) containing 3 g of a Beta vulgaris extract (RedNite®) or four tablets of a placebo (maltodextrin). A 4-day washout period was used before crossover. Ninety minutes after ingestion of the treatments, a neuropsychological testing battery was administered in each period. The trial was registered at clinicaltrials.gov NCT05509075.ResultsSignificant improvements with moderate effect size were found on memory consolidation at the short and long term only after BR-CT supplementation via the Rey Auditory Verbal Learning Test immediate (+ 20.69%) and delayed (+ 12.34%) recalls. Likewise, enhancement on both frontal lobe functions (+ 2.57%) and cognitive flexibility (+ 11.16%) were detected after BR-CT. There was no significant change (p < 0.05) on verbal memory of short-term digits, working memory and information processing speed. Mixed results were found on mood and anxiety through the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI-Y1 and STAI-Y2); however, sequence and period effects were seen on STAI-Y2.ConclusionsThe acute administration of a chewable BR-based supplement improves certain aspects of cognitive function in healthy females and males, particularly memory capacity and frontal skills.