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In this case study, a self-described biofield therapy (BT) practitioner (participant) took part in multiple (n = 60) treatment and control (non-treatment) sessions under double-blind conditions. During the treatment phases, the participant provided BT treatment at a distance of about 12 inches from the cells, alternating with rest phases where no such efforts were made. Human pancreatic cancer cell activity was assessed using three markers – cytoskeleton changes (tubulin and β-actin) and Ca2+ uptake. The study examined changes in the participant’s physiological parameters including electroencephalogram (EEG) and heart rate measures during the treatment of: (1) live cells and (2) either dead cells or medium only with no cells (control group). Changes in cellular outcomes and if there was an association between the participant’s physiological parameters and cellular outcomes were examined. The experimental setup was a 2 × 2 design, contrasting cell type (live vs. control) against session type (treatment vs. non-treatment). Parallel sham-treated control cells were examined for changes in the cell parameters over time while controlling for the presence of a person in front of the cells mimicking the distance and movements of the participant. The participant’s physiological data, including 64-channel EEG and heart rate, were continuously monitored throughout these sessions. We observed significant (p < 0.01) spectral changes in the participant’s EEG during BT treatment in all frequency bands of interest, as well as in heart rate variability (HRV) (RMSSD measure; p < 0.01). We also observed significant differences in beta and gamma EEG and HRV (pNN50 measure) when the participant treated live but not control cells (p = 0.02). However, no interaction between treatment and cell type (live vs. dead cells/medium-no cells) was observed. We observed Ca2+ uptake increased over time during both BT and sham treatment, but the increase was significantly less for the BT group relative to the sham-treatment controls (p = 0.03). When using Granger causality to assess causal directional associations between cell markers and participant’s physiological parameters, EEG measurements showed significant bidirectional causal effects with cell metrics, especially β-actin and intracellular Ca2+ levels (p < 0.000001). These outcomes suggest a complex relationship between physiological responses and cellular effects during BT treatment sessions. Given the study’s limitations, follow-up investigations are warranted. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the efficacy and safety of traditional acupuncture for pain relief based on rigorously designed RCTs with double-blind. The findings seek to provide valuable insights for clinical practice and inform future research. Methods: A literature search was conducted in PubMed, Web of Science, Cochrane Library, and Embase databases for randomized controlled trials on traditional acupuncture for pain management using a double-blind design, published from database inception to November 22, 2023. The Risk of Bias 2 (RoB2) tool was used to assess potential biases in the included studies, followed by a comprehensive analysis to evaluate efficacy and safety. Results: The findings show a significant positive effect on pain improvement, evidenced by changes in visual analog scale scores (mean difference 0.97 [95% confidence interval (CI) 0.66–1.27]). Safety analysis showed no significant differences in adverse reactions between the acupuncture and control groups (relative risk 1.40 [95% CI 0.52–3.74]), with no serious adverse effects reported. Conclusion: Traditional acupuncture is effective and safe in pain management. This suggests that acupuncture can be a valuable approach in clinical practice. Future studies should explore optimal treatment durations and frequency, using larger sample sizes for more comprehensive insights. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbance has a prevalence of 30–78% in patients with advanced cancer. While pharmacotherapy is common, randomized controlled studies (RCTs) investigating available agents are limited. This study examines the efficacy and safety of temazepam or melatonin versus placebo for sleep in advanced cancer. Methods: This is a multicenter, randomized, double-blind, placebo-controlled study of temazepam, melatonin prolonged release (PR) or placebo for insomnia in patients with advanced cancer, and an insomnia severity index (ISI) score of >11. Results: Twenty-one participants were randomized: nine to temazepam, eight to melatonin, and four to placebo. Baseline characteristics between groups were similar. The adjusted mean difference in day 8 ISI score versus placebo was −9.1 (95% confidence interval [CI] −17.5, 0.7, p = 0.04) for temazepam and −9.6 (95% CI −18,−1.2, p = 0.03) for melatonin PR. There was no improvement in global quality of life. Both agents were well tolerated. Conclusion: Temazepam and melatonin PR were associated with a clinically significant improvement in patient-reported insomnia severity compared with placebo. Findings need confirmation with larger patient numbers. [ABSTRACT FROM AUTHOR]

Abstract In this case study, a self-described biofield therapy (BT) practitioner (participant) took part in multiple (n = 60) treatment and control (non-treatment) sessions under double-blind conditions. During the treatment phases, the participant provided BT treatment at a distance of about 12 inches from the cells, alternating with rest phases where no such efforts were made. Human pancreatic cancer cell activity was assessed using three markers – cytoskeleton changes (tubulin and β-actin) and Ca2+ uptake. The study examined changes in the participant’s physiological parameters including electroencephalogram (EEG) and heart rate measures during the treatment of: (1) live cells and (2) either dead cells or medium only with no cells (control group). Changes in cellular outcomes and if there was an association between the participant’s physiological parameters and cellular outcomes were examined. The experimental setup was a 2 × 2 design, contrasting cell type (live vs. control) against session type (treatment vs. non-treatment). Parallel sham-treated control cells were examined for changes in the cell parameters over time while controlling for the presence of a person in front of the cells mimicking the distance and movements of the participant. The participant’s physiological data, including 64-channel EEG and heart rate, were continuously monitored throughout these sessions. We observed significant (p

Abstract Background The World Health Organization (WHO) declared the end of the COVID-19 (SARS-CoV-2) global public health emergency on May 5, 2023, but its long-term consequences have still been haunting the global population. Post-acute sequelae of COVID-19 (PASC) and long-term COVID-19 are serious concerns and present with various symptoms. Intranasal chlorpheniramine (iCPM) has been shown to decrease the viral burden of SARS-COV-2. iCPM uses decreased COVID-19 disease progression and severity in Accelerating COVID-19 Clinical Recovery in an Outpatient Setting (ACROSS)-I & III randomized control trials (RCT). Methods This prospective survey study included 259 participants in ACROSS I and III RCTs. We compared the effect of iCPM versus placebo on the reduction of PASC symptoms. A PASC questionnaire containing 17 questions regarding the most common PASC symptoms was used in this study. T-test and Pearson chi-square statistics were performed according to continuous and categorical data using STATA 17.0 Basic Edition software. Findings The iCPM cohort had a lower proportion of patients with fatigue or tiredness vs. placebo (0 Vs 17, 21, p

Jiyang Li,1,&ast; Xinxing Fei,2,&ast; Shiqi Wang,3,4,&ast; Zhangyu Xu,5,6 Fangyuan Xu,5,6 Jianxiong Wang,5,6 Yaqian Gao,7 Yue Hu5,6 1Department of Rehabilitation Medicine, Sichuan Tianfu New Area People’s Hospital, Chengdu, People’s Republic of China; 2Department of Psychiatry, Chengdu Eighth People’s Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, People’s Republic of China; 3Department of Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan, People’s Republic of China; 5Department of Rehabilitation Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 6Rehabilitation Medicine and Engineering Key Laboratory of Luzhou, Luzhou, People’s Republic of China; 7Department of Rehabilitation Medicine, the First Affiliated Hospital of Chengdu Medical College, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaqian Gao; Yue Hu, Email 673509366@qq.com; huyue@swmu.edu.cnBackground: Many studies have been conducted on the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression. However, the overall trends in research publications in this field remain elusive. There is still little quantitative analysis of the literature in this field. Therefore, we conducted a bibliometric analysis to explore the research patterns surrounding SSRIs for depression, aiming to gain a deeper understanding of their development and impact.Methods: Publications about the use of SSRIs for the treatment of depression were identified in the Web of Science Core Collection. Visualization analysis was performed with Bibliometrix, VOSviewer, and CiteSpace.Results: A total of 1149 publications published from 1990 to 2024 were included in the bibliometric analysis. Since 1990, the annual number of published papers has increased annually, reaching the maximum value of output in 2004. Fitted curve showed that after 2004, the number of publications per year was essentially stable The United States dominates the field. Among these institutions, University of Pittsburgh excels in this field. Fava M has the highest scientific productivity and extensive academic influence. European Neuropsychopharmacology is the most active journal in this field. The three most relevant keywords were “fluoxetine”, “double-blind”, and “major depression”. The trend topics in recent years were “connectivity”, “c-reactive protein”, and “anhedonia”.Conclusion: Research on the use of SSRIs for the treatment of depression continues to receive increased attention but still requiraes further exploration and innovation. We further analyze the current research hotspots and frontiers in this field.Keywords: selective serotonin reuptake inhibitors, depression, bibliometrics, double-blind, fluoxetine, major depression

Abstract Background Evidence on ivermectin as a treatment for Covid-19 is controversial. A Cochrane review concluded that the efficacy and safety of ivermectin is uncertain (evidence up to April 2022) and WHO recommended its use only in the setting of clinical trials. This study aimed to assess the efficacy and safety of oral ivermectin in hospitalized patients with mild to moderate Covid-19. Trial design and methods A double-blind, randomized placebo-controlled clinical trial was conducted among RT-PCR-confirmed, adults, hospitalised within the first four days of symptoms. Patients received oral ivermectin 24 mg or placebo daily for five days. RT-PCR was repeated on days five and ten. Clinical progression was monitored using the World Health Organization Clinical Progression Scale. Serum ivermectin levels were measured on days three, five, and seven. The primary outcome was the difference in the viral load between day zero and ten in the two groups. Results Out of 1699 patients screened, 249 underwent randomization and 127 received ivermectin, and 122 placebo. D10 median viral load for E gene (IQR) was 2,000 copies/mL (100 − 20,500) with ivermectin (n = 80) and 4,100 copies/mL (1,000–65,600) with placebo (n = 81, p = 0.028), per protocol analysis. The difference in Log viral load between day zero and ten between ivermectin and placebo was 3.72 and 2.97 respectively (p = 0.022). There was no significant difference in the WHO clinical progression scale or the adverse effects. Ivermectin blood levels taken before or with meals were not significantly different. Only 7 and 17 patients achieved blood levels above 160ng/ML and 100ng/ML respectively and they did not achieve a significantly lower viral load. Conclusion Although ivermectin resulted in statistically significant lower viral load in patients with mild to moderate Covid-19, it had no significant effect on clinical symptoms. Trial registration number SLCTR/2021/020, Sri Lanka Clinical Trials Registry. 19/07/2021.

Background: Evidence on ivermectin as a treatment for Covid-19 is controversial. A Cochrane review concluded that the efficacy and safety of ivermectin is uncertain (evidence up to April 2022) and WHO recommended its use only in the setting of clinical trials. This study aimed to assess the efficacy and safety of oral ivermectin in hospitalized patients with mild to moderate Covid-19. Trial design and methods: A double-blind, randomized placebo-controlled clinical trial was conducted among RT-PCR-confirmed, adults, hospitalised within the first four days of symptoms. Patients received oral ivermectin 24 mg or placebo daily for five days. RT-PCR was repeated on days five and ten. Clinical progression was monitored using the World Health Organization Clinical Progression Scale. Serum ivermectin levels were measured on days three, five, and seven. The primary outcome was the difference in the viral load between day zero and ten in the two groups. Results: Out of 1699 patients screened, 249 underwent randomization and 127 received ivermectin, and 122 placebo. D10 median viral load for E gene (IQR) was 2,000 copies/mL (100 − 20,500) with ivermectin (n = 80) and 4,100 copies/mL (1,000–65,600) with placebo (n = 81, p = 0.028), per protocol analysis. The difference in Log viral load between day zero and ten between ivermectin and placebo was 3.72 and 2.97 respectively (p = 0.022). There was no significant difference in the WHO clinical progression scale or the adverse effects. Ivermectin blood levels taken before or with meals were not significantly different. Only 7 and 17 patients achieved blood levels above 160ng/ML and 100ng/ML respectively and they did not achieve a significantly lower viral load. Conclusion: Although ivermectin resulted in statistically significant lower viral load in patients with mild to moderate Covid-19, it had no significant effect on clinical symptoms. Trial registration number: SLCTR/2021/020, Sri Lanka Clinical Trials Registry. 19/07/2021. [ABSTRACT FROM AUTHOR]

Infra-low frequency neurofeedback training (ILF-NFT) has shown promise in addressing cognitive and affective distress symptoms across a range of psychiatric disorders. This study tested ILF-NFT's effects in a double-blinded, placebo-controlled longitudinal context in healthy psychology students. Across five weeks, forty-two healthy psychology students (aged 18–35) were randomly allocated into two groups, receiving ten sessions of 30 minutes of active and sham ILF-NFT. Dependent variables were measured before, following, and two months after the intervention and were comprised of: heartrate variability assessments as a measure of stress resilience; digit span, n-back, trail making and go-no-go task measures of executive functioning performance; and SCL-90-R, WHOQOL-Bref, and peak performance measures of subjective self-report. Statistical analysis was performed using an ANCOVA and compared across groups correcting for baseline differences and multiple comparisons. ANCOVA analyses revealed no significant differences across active and placebo groups in any dependent variables, when correcting for multiple comparisons. Thus, the remaining analyses focused on questionnaire correlations. Here, significant correlations were observed between the novel peak performance questionnaire with the SCL-90-R and WHOQOL-Bref, confirming its construct and retest validity. Despite several methodological limitations, including a potential type-2 error, this study highlights limited effects of ILF-NFT in healthy volunteers. Future research should thus focus on clinically driven experimental designs to explore ILF-NFT's potential in psychiatric contexts. Further research utilization of the novel peak performance questionnaire is recommended for measures of peak performance. • The present study intervention of infra-low frequency neurofeedback training: •did not beat placebo in physiological, cognitive performance or self-report domains •was compromised by several methodological limitations, including •ten rather than 20 ILF-NFT sessions administered by non-expert clinicians •which points towards further exploring its potential in clinical psychiatric contexts • A novel performance questionnaire significantly correlated with SCL-90-R and WHO [ABSTRACT FROM AUTHOR]

Introduction: There is large variation in response to diet in irritable bowel syndrome (IBS) and determinants for differential response are poorly understood. Objectives: Our aim was to investigate differential clinical and molecular responses to provocation with fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) and gluten in individuals with IBS. Methods: Data were used from a crossover study with week-long interventions with either FODMAPs, gluten or placebo. The study also included a rapid provocation test. Molecular data consisted of fecal microbiota, short chain fatty acids, and untargeted plasma metabolomics. IBS symptoms were evaluated with the IBS severity scoring system. IBS symptoms were modelled against molecular and baseline questionnaire data, using Random Forest (RF; regression and clustering), Parallel Factor Analysis (PARAFAC), and univariate methods. Results: Regression and classification RF models were in general of low predictive power (Q2 ≤ 0.22, classification rate < 0.73). Out of 864 clustering models, only 2 had significant associations to clusters (0.69 < CR < 0.73, p < 0.05), but with no associations to baseline clinical measures. Similarly, PARAFAC revealed no clear association between metabolome data and IBS symptoms. Conclusion: Differential IBS responses to FODMAPs or gluten exposures could not be explained from clinical and molecular data despite extensive exploration with different data analytical approaches. The trial is registered at www.clinicaltrials.gov as NCT03653689 31/08/2018. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance: Pelvic inflammatory disease (PID) is a frequently occurring gynecological disorder mainly caused by the inflammation of a woman's upper genital tract. Generally, antibiotics are used for treating PID, but prolonged use poses potential risks of gut bacterial imbalance, bacterial resistance, super bacteria production, and associated adverse reactions. Traditional Chinese medicine (TCM) has shown unique advantages in various ailments and has received widespread clinical research attention. Fuke Qianjin (FUKE) capsule is an approved National Medical Products Administration (NMPA License No. Z20020024) Chinese herbal prescription that has been widely used individually or in combination with other Western medicines for the treatment of various gynecological inflammatory diseases, including chronic cervicitis, endometritis, and chronic PID. Aim: This clinical trial was designed to assess the safety and efficacy of FUKE capsule in mild-to-moderate symptomatic PID patients. Materials and methods: This phase 2, randomized, double-blind, positive controlled clinical trial was conducted in mild-to-moderate symptomatic PID patients at a single center in Pakistan from 21 September 2021 to 11 March 2022. Eligible female participants were randomly assigned to a test and a control group with a ratio of 1:1. The test group subjects received two metronidazole (METRO) tablets and one doxycycline hyclate (DOXY) simulant at a time, twice daily for 14 days, and two Fuke Qianjin (FUKE) capsules, three times a day after a meal for 28 days. Subjects in the control group received two METRO tablets and one DOXY tablet at a time, twice daily for 14 days, and two FUKE simulant capsules, three times a day after meal for 28 days. The primary efficacy outcome was an improvement in pelvic pain symptoms assessed through a visual analog scale (VAS). The secondary outcomes were the improvement in secondary efficacy symptoms like local physical signs, clinical assessment of leucorrhea and cervical secretions through laboratory examination, and improvement in the maximum area of pelvic effusion assessed through gynecological ultrasound after the treatment. The safety outcomes were assessed through vital signs, laboratory tests, electrocardiogram findings, and adverse events/serious adverse events. Results: A total of 198 subjects with active PID were randomly assigned to a test group (n = 99) and a control group (n = 99). The baseline characteristics of the subjects in the two groups were similar. In the intention-to-treat analysis, the primary efficacy was 84.9% for the test group and 71.6% for the control group, with a statistically significant difference (p = 0.0370; 95% CI -0.2568 to -0.0088). The secondary clinical efficacy was 88.4% for the test group and 82.7% for the control group, with no significant difference (p = 0.2977; 95% CI -0.1632 to 0.0501). The improvement in local physical signs was 95.8% for the test group and 76.9% for the control group, with no significant difference (p = 0.0542; 95% CI -0.3697 to -0.0085). The inter-group non-inferiority comparison showed that the upper limit of the 95% CI was less than 0.15 and thus met the noninferiority requirements of the test group to the control group. The results of clinical signs of leucorrhea and cervical secretions showed that there was no difference in the rate of improvement between the test and control groups, indicating that FUKE was non-inferior to DOXY. A total of 14 adverse events in eight subjects were observed in the trial, with an incidence rate of 4.7%. Four subjects in each group experienced seven adverse events with 4.5% and 4.8% incidence rates of adverse reactions in the test and control groups, with no statistically significant differences (p = 0.2001). No serious adverse events occurred in the trial. Conclusion: The results of this trial indicate that the test drug (Fuke Qianjin capsule) is non-inferior to the control drug (doxycycline hyclate tablet) in treating mild-tomoderate PID patients with comparable efficacy, safety, and tolerability to the control drug. [ABSTRACT FROM AUTHOR]

Abstract Objective Given the findings of central effects of erenumab in the literature, we aimed to conduct a rigorous placebo-controlled, double-blind, randomized study to elucidate whether the observed changes are directly attributable to the drug. Methods We recruited 44 patients with migraine, randomly assigning them to either the erenumab 70 mg or the placebo group. 40 patients underwent fMRI scanning using a trigeminal nociceptive paradigm both, pre- and four weeks post-treatment. Participants kept a headache diary throughout the whole study period of two months in total. A clinical response was defined as a ≥30% reduction in headache frequency at follow-up. Details of this study have been preregistered in the open science framework: https://osf.io/ygf3t . Results Seven participants of the verum group (n=33.33%) and 4 of the placebo group (21.05%) experienced improvements in migraine activity, characterized by a minimum of 30% reduction in monthly headache frequency compared to baseline. The imaging data show an interaction between the verum medication and the response. Whilst numbers were too small for individual analyses (Verum vs. Placebo and Responder vs. Non-Responder), the variance-weighted analysis (Verum vs Placebo, scan before vs after weighted for response) revealed specific decrease in thalamic, opercular and putamen activity. Interpretation The central effects of erenumab could be reproduced in a placebo randomized design, further confirming its central role in migraine modulation. The mechanism, whether direct or secondary to peripheral mode of action, needs further exploration. It is important to note that the response rate to erenumab 70mg in this study was not as substantial as anticipated in 2019, when this study was planned. This resulted in a too small sample size for a subgroup analysis based on the responder status was associated with both the verum drug and the relative reduction in headache days.

Background: Wuhu Oral Liquid (WHOL) is a modified preparation derived from the famous Wuhu Powder, which has a long history of use in treating traumatic injuries. This preparation has anti-inflammatory and analgesic properties and accelerates recovery following acute soft tissue injuries. Aims: To evaluate the efficacy and safety of WHOL in treating acute soft tissue injury associated with qi stagnation and blood stasis syndrome and to provide a basis for applying for the protection of varieties of Chinese medicine for WHOL. Methods: This study was a randomized, controlled, double-blind, multicenter clinical trial in which Fufang Shang Tong Capsule (FFSTC) was selected as the control drug. A total of 480 subjects with acute soft tissue injury associated with qi stagnation and blood stasis syndrome were randomly divided into a test and control group in a 3:1 ratio. The duration of drug treatment was 10 days. The primary outcome was Visual Analogue Scale (VAS) score for pain (including pain at rest and pain on activity). Secondary outcomes included the disappearance time of the pain at rest and on activity; the curative effect of TCM syndrome and improvement in the individual symptoms of TCM (swelling, ecchymosis, and dysfunction); and changes in C-reactive protein (CRP) and interleukin-6 (IL-6) levels. Safety was assessed using vital signs, laboratory examinations, electrocardiograms, and physical examinations. Results: Patient compliance was satisfactory in both groups (all between 80% and 120%). After 4 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain at rest (-1.88 ± 1.13 vs. -1.60 ± 0.93, p < 0.05) and on activity (-2.16 ± 1.18 vs. -1.80 ± 1.07, p < 0.05). After 7 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain on activity (-3.87 ± 1.60 vs. -3.35 ± 1.30, p < 0.01) and improving swelling (cure rate: 60.4% vs. 46.2%, p < 0.05; obvious effective rate: 60.7% vs. 47.0%, p < 0.05). After 10 days of treatment, the WHOLgroup was superior to the FFSTC group in decreasing the levels of CRP (-0.13 ± 2.85 vs. 0.25 ± 2.09, p < 0.05) and improving the TCM syndrome (cure rate: 44.1% vs. 30.8%, p < 0.05) and swelling (cure rate: 75.6% vs. 67.5%, p < 0.01; obvious effective rate: 75.6% vs. 68.4%, p < 0.05; effective rate: 77.0% vs. 71.8%, p < 0.05). The disappearance time of pain at rest was 8 days in both groups and 9 days on activity in both groups. In addition, there was no statistical difference between the incidence of adverse events (4.5% vs. 2.6%, p > 0.05) and adverse reactions (0.3% vs. 0%, p > 0.05) between the WHOL group and the FFSTC group. No serious adverse events occurred in either group, and no subjects were withdrawn because of adverse events. Conclusion: WHOL relieves the symptoms caused by acute soft tissue injury associated with qi stagnation and blood stasis syndrome more rapidly than FFSTC, and it is effective and safe in the treatment of acute soft tissue injury. Future studies still need a larger sample size to verify its efficacy and safety. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj= 149531, Identifier ChiCTR2200056411. [ABSTRACT FROM AUTHOR]

Pycnogenol® French maritime pine bark extract is a well-known and thoroughly studied patented extract from the bark of Pinus pinaster Ait. ssp. Atlantica. In 39 randomized double-blind, placebo-controlled (RDP) human clinical trials including 2,009 subjects, Pycnogenol® French maritime pine bark extract supplementation for two weeks to six months has been shown to beneficially affect cardiovascular health, chronic venous insufficiency, cognition, joint health, skin health, eye health, women’s health, respiratory health and allergies, oral health and sports performance. The mechanisms of action that can explain the respective effects on different conditions in the human body are discussed as well. As investigated in several in vitro, in vivo and in clinical studies, Pycnogenol® French maritime pine bark extract showed antioxidative effects, anti-inflammatory abilities, beneficial effects on endothelial function and reinforcing effects on the extracellular matrix. The present review aims to give a comprehensive overview of currently available “gold standard” RDP trials of Pycnogenol®’s benefits across various health domains compared to placebo. In addition, some of the processes on which the presented effects of Pycnogenol® French maritime pine bark extract are based will be elucidated and discussed. This broad overview of RDP studies on Pycnogenol® in different health domains can be used as a basis for further research on applications and mechanisms of this unique French maritime pine bark extract.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. Methods The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. Discussion This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. Trial registration ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.

Background: Few studies have investigated tolerability, blinding, and double-blinding of High-Definition transcranial Direct Current Stimulation (HD-tDCS) at amplitudes above 2 milliamps (mA). Objective: We examined a) tolerability of HD-tDCS during stimulation sessions and b) blinding and double blinding of participants and study team members. Methods: Data from a mixed neurologic sample of 292 older adults were pooled from 3046 HD-tDCS sessions (2329 active; 717 sham). Per electrode amplitudes ranged from 1 mA to 4 mA with total currents up to 10 mA. Participants completed a standardized sensation (tolerability) questionnaire after each session. Participants and study team members stated whether the participant received active or sham stimulation at the end of various sessions. Data were collapsed into the presence/absence of a symptom due to low rates of positive responding and were analyzed for both differences and bioequivalency. Results: There were no safety-related adverse events. HD-tDCS was well tolerated with mostly no (“none”) or “mild” sensations reported across sessions, regardless of active or sham condition and in both stimulation naïve and experienced participants. There were no significant differences in side effects between active and sham, with some achieving bioequivalence. Tingling and itching were significantly more common after lower (

In this study, the effects of foods containing lipopolysaccharide (LPS) from Pantoea agglomerans (LPSp) on immunity were preliminarily investigated using a double-blind, placebo-controlled, randomized, parallel-group comparative study design. Thirty healthy subjects aged ≥ 20 years (four males and twenty-six females; mean age 49 ± 9.2 years) were randomly assigned to the LPS-containing food group (488 μg/day; LPS) or placebo group. Each food was consumed for 8 weeks, and a subjective survey of cold symptoms (Wisconsin Upper Respiratory Symptom Questionnaire) and allergic symptoms of the eyes and nose were conducted. Phagocytic capacity and lymphocyte counts were measured as indicators of immune function. There were no significant between-group differences with respect to any of the investigated items. On sub-group analysis of eye–nose allergy symptom score, confined only to subjects who reported eye–nose allergic symptoms in previous years, the LPS group showed a trend toward milder symptoms compared to the placebo group. In addition, when the symptom scores were compared only for subjects who developed eye–nose allergies during the study period, the LPS group showed significantly lower overall scores and eye symptom scores compared to the placebo group. These results suggest that the consumption of LPS-containing foods may alleviate or prevent eye–nose allergies. There were no statistically predominant changes in hematology and blood biochemistry tests, indicating that continued consumption of LPS-containing foods is safe. (UMIN000046154).

Background: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. Methods: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. Discussion: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. Trial registration: ClinicalTrials.gov NCT03800524. Registered on January 11, 2019. [ABSTRACT FROM AUTHOR]

Due to the scale of the phenomenon, food allergy constitute a significant health problem and significantly impair the quality of life of patients. Differential diagnostics, including skin tests, sIgE detection tests, basophil and mast cell activation tests as well as double-blind placebo-controlled food challenge tests, is the gold standard in the diagnosis of food allergy. Recently, increasing attention has been paid to the potential use of nasal provocation test in the diagnosis of food allergy. Allergen dose, protocol standardization, assessment of subjective complaints and objectivization of test results are important factors determining the applicability of provocation tests. [ABSTRACT FROM AUTHOR]

Objective To explore the efficacy of atorvastatin combined with compound probiotics in the treatment of hyperlipidemia. Methods From January 2019 to December 2019, 33 patients with hyperlipidemia were recruited from the People‘s Hospital of Inner Mongolia Autonomous Region and were randomly divided into the test group（n=18） and the control group（n=15） using a randomized, double-blind, controlled trial design. The 20mg atorvastatin （once a day） plus compound probiotics（once a day, 2g each time） was given in test group, and the same dose of atorvastatin plus placebo was given in control group. The blood lipid level was measured once every 4 weeks for 12 weeks to compare the blood lipid levels at each time point between two groups. Results There were no significant differences in the baseline data between two groups (P＞0.05). There were no significant differences in the levels of TC, TG, LDL-C and other blood lipid levels related to the treatment effects between two groups(P＞0.05). At the different time points, there were statistical differences in the levels of TC, TG, LDL-C and other blood lipids(P

Diet is considered a culprit for symptoms in irritable bowel syndrome (IBS), although the mechanistic understanding of underlying causes is lacking. Metabolomics, i.e., the analysis of metabolites in biological samples may offer a diet-responsive fingerprint for IBS. Our aim was to explore alterations in the plasma metabolome after interventions with fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) or gluten versus control in IBS, and to relate such alterations to symptoms. People with IBS (n = 110) were included in a double-blind, randomized, crossover study with 1-wk provocations of FODMAPs, gluten, or placebo. Symptoms were evaluated with the IBS severity scoring system (IBS-SSS). Untargeted metabolomics was performed on plasma samples using LC-qTOF-MS. Discovery of metabolite alterations by treatment was performed using random forest followed by linear mixed modeling. Associations were studied using Spearman correlation. The metabolome was affected by FODMAP [classification rate (CR) 0.88, P < 0.0001], but less by gluten intake CR 0.72, P = 0.01). FODMAP lowered bile acids, whereas phenolic-derived metabolites and 3-indolepropionic acid (IPA) were higher compared with placebo. IPA and some unidentified metabolites correlated weakly to abdominal pain and quality of life. Gluten affected lipid metabolism weakly, but with no interpretable relationship to IBS. FODMAP affected gut microbial-derived metabolites relating to positive health outcomes. IPA and unknown metabolites correlated weakly to IBS severity. Minor symptom worsening by FODMAP intake must be weighed against general positive health aspects of FODMAP. The gluten intervention affected lipid metabolism weakly with no interpretable association to IBS severity. Registration: www.clinicaltrials.gov as NCT03653689. [ABSTRACT FROM AUTHOR]

In this study, the effects of foods containing lipopolysaccharide (LPS) from Pantoea agglomerans (LPSp) on immunity were preliminarily investigated using a double-blind, placebo-controlled, randomized, parallel-group comparative study design. Thirty healthy subjects aged ≥ 20 years (four males and twenty-six females; mean age 49 ± 9.2 years) were randomly assigned to the LPS-containing food group (488 μg/day; LPS) or placebo group. Each food was consumed for 8 weeks, and a subjective survey of cold symptoms (Wisconsin Upper Respiratory Symptom Questionnaire) and allergic symptoms of the eyes and nose were conducted. Phagocytic capacity and lymphocyte counts were measured as indicators of immune function. There were no significant between-group differences with respect to any of the investigated items. On sub-group analysis of eye–nose allergy symptom score, confined only to subjects who reported eye–nose allergic symptoms in previous years, the LPS group showed a trend toward milder symptoms compared to the placebo group. In addition, when the symptom scores were compared only for subjects who developed eye–nose allergies during the study period, the LPS group showed significantly lower overall scores and eye symptom scores compared to the placebo group. These results suggest that the consumption of LPS-containing foods may alleviate or prevent eye–nose allergies. There were no statistically predominant changes in hematology and blood biochemistry tests, indicating that continued consumption of LPS-containing foods is safe. (UMIN000046154). [ABSTRACT FROM AUTHOR]

Few studies have investigated tolerability, blinding, and double-blinding of High-Definition transcranial Direct Current Stimulation (HD-tDCS) at amplitudes above 2 milliamps (mA). We examined a) tolerability of HD-tDCS during stimulation sessions and b) blinding and double blinding of participants and study team members. Data from a mixed neurologic sample of 292 older adults were pooled from 3046 HD-tDCS sessions (2329 active; 717 sham). Per electrode amplitudes ranged from 1 mA to 4 mA with total currents up to 10 mA. Participants completed a standardized sensation (tolerability) questionnaire after each session. Participants and study team members stated whether the participant received active or sham stimulation at the end of various sessions. Data were collapsed into the presence/absence of a symptom due to low rates of positive responding and were analyzed for both differences and bioequivalency. There were no safety-related adverse events. HD-tDCS was well tolerated with mostly no ("none") or "mild" sensations reported across sessions, regardless of active or sham condition and in both stimulation naïve and experienced participants. There were no significant differences in side effects between active and sham, with some achieving bioequivalence. Tingling and itching were significantly more common after lower (<2 mA) than higher (≥3 mA) amplitude active sessions, while skin redness was significantly more common after higher amplitudes. Blinding was effective at the participant and study team levels. HD-tDCS was well tolerated with center electrode amplitudes up to 4 mA. The bimodal ramp-up/down format of the sham was effective for blinding. These results support higher scalp-based amplitudes that enable greater brain-based current intensities in older adults. • In 3046 HD-tDCS sessions, tingling, itching and a burning sensation were common in older adults. • No statistically significant differences between active vs. sham in naïve older adults. • No statistically significant differences for active vs. sham across 3046 sessions. • HD-tDCS at or above 3 mA per channel was well tolerated. • HD-tDCS sham effectively blinds both participants and study team (double-blind). [ABSTRACT FROM AUTHOR]

Background: Glycemic variability in patients with type 2 diabetes mellitus (T2DM) may be associated with chronic complications of the disease. Melatonin is a hormone that plays a crucial role in biological rhythms. Previous studies have indicated that individuals with T2DM often exhibit reduced melatonin production. In this study, our objective was to investigate whether nighttime melatonin supplementation could mitigate glycemic variability in these patients. Methods: Crossover, double-blind, placebo-controlled, randomized study. A total of 30 patients were enrolled in this study. The study included 15 participants who followed the intervention sequence of placebo (7 days)—washout (7 days)—melatonin (3 mg) (7 days), and another 15 participants who followed the sequence of melatonin (3 mg) (7 days)—washout (7 days)—placebo (7 days). During the final three days of the first and third weeks, the participants measured their pre- and postprandial capillary blood glucose levels. This study was reported according to the CONSORT 2010 statement: extension to randomized crossover trials. Results: There was a significant absolute difference in the breakfast blood glucose levels (p = 0.016) on Day 7. The use of melatonin determined a greater positive variation between pre- and postprandial glycemia than the placebo. The difference in glycemic amplitude between post-dinner Day 6 and pre-breakfast Day 7 was also significantly higher in the melatonin group (p = 0.032). Conclusions: Melatonin increased glycemic variability in individuals with type 2 diabetes mellitus (T2DM). These results can be attributed to the residual daytime effects of melatonin, prospective proximal effects, and damage to the prospective distal effects of exogenous melatonin. Therefore, caution should be exercised when administering melatonin supplementation to patients with T2DM, taking into consideration factors such as dosage, duration of use and genetic considerations. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to clinically evaluate of a novel gelatin-based biodegradable sponge after mandibular posterior teeth extraction to assess its abilities in controlling bleeding, pain, and dry socket compared a commercial sponge. Trial design: In this study, 26 patients who needed the extraction of two mandibular molar teeth were selected and, in each patient, after tooth extraction, the prepared gelatin sponge was used in the test group and the commercial sponge was used in the control group in the form of a randomized, double-blind, split-mouth clinical trial. The sterile gauzes were used on top of each sponge to absorb the extra blood (unabsorbed blood of sponges) to assess the blood absorption amount. Also, the amount of bleeding was recorded for 1 and 4 h after extraction for two groups. The amount of pain was measured for 12, 24, and 48 h after tooth extraction by Visual Analogue Scale (VAS). All patients also returned for examination four days after extraction to assess the occurrence of dry socket. Results: The results showed that the average weight of absorbed blood by sterile gauze in the control group (6.32 ± 1.06 g) was higher than in test group (3.97 ± 1.1 g), e.g., the bleeding control was better for the test group (p < 0.05). Bleeding was observed to be significantly reduced in the test group within 1 h (p = 0.003), within 1–4 h (p = 0.002), and after 4 h (p = 0.042) post-operatively in comparison to the control group. The average pain decreased significantly over time in both groups and the reduction of the pain was significantly higher for the test group (p < 0.05). Just one dry socket case occurred in the control group. Conclusion: The prepared sponge is recommended for use in dental surgeries because of its abilities in bleeding, pain, and dry socket control. [ABSTRACT FROM AUTHOR]

Transcutaneous tibial nerve stimulation (TTNS) is a promising treatment for neurogenic lower urinary tract symptoms. However, the evidence is limited due to a general lack of randomised controlled trials (RCTs) and, also, inconsistency in the sham and blinding conditions. In the context of much-needed RCTs, we aimed to develop a suitable sham-control protocol for a clinical setting to maintain blinding but avoid meaningful stimulation of the tibial nerve. Three potential electrode positions (lateral malleolus/5th metatarsal/plantar calcaneus) and two electrode sizes (diameter: 2.5 cm/3.2 cm) were tested to determine which combination provided the optimal sham configuration for a TTNS approach, based on a visible motor response. Sixteen healthy volunteers underwent sensory and motor assessments for each sham configuration. Eight out of them came back for an extra TTNS visit. Sensory thresholds were present for all sham configurations, with linear regression models revealing a significant effect regarding electrode position (highest at plantar calcaneus) but not size. In addition, motor thresholds varied with the position—lowest for the 5th metatarsal. Only using this position and 3.2 cm electrodes attained a 100% response rate. Compared to TTNS, sensory and motor thresholds were generally higher for the sham configurations; meanwhile, perceived pain was only higher at the lateral malleolus. In conclusion, using the 5th metatarsal position and 3.2 cm electrodes proved to be the most suitable sham configuration. Implemented as a four-electrode setup with standardized procedures, this appears to be a suitable RCT protocol for maintaining blinding and controlling for nonspecific TTNS effects in a clinical setting. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of the present study was to assess the safety and efficacy of Diclofenac sodium (DS) 140 mg medicated plaster vs. Diclofenac epolamine (DIEP) 180 mg medicated plaster and placebo plaster, for the treatment of painful disease due to traumatic events of the limbs. PATIENTS AND METHODS: This was a multicenter, phase III study involving 214 patients, aged 18-65 years, affected by painful conditions due to soft tissue injuries. Patients were randomized to DS, DIEP or placebo arms and treated with once-daily application of the plaster for a total treatment period of 7 days. The primary objective was first to demonstrate the non-inferior efficacy of the DS treatment when compared to the reference DIEP treatment and second that both, test and reference treatments, were superior with respect to placebo. The secondary objectives included the evaluation of efficacy, adhesion, safety, and local tolerability of DS in comparison to both DIEP and placebo. RESULTS: The mean visual analog scale (VAS) score decrease for pain at rest was higher in the DS (-17.65 mm) and the DIEP group (-17.5 mm) than in the placebo (-11.3 mm). Both active formulation plasters were associated with a statistically significant pain reduction compared to placebo. No statistically significant differences were observed between DIEP and DS plasters efficacy in relieving pain. Secondary endpoint evaluations supported the primary efficacy results. No serious adverse events (SAEs) were registered, and the most commonly detected adverse events were skin reactions at the application site. CONCLUSIONS: The results showed that both the DS 140 mg plaster and the reference DIEP 180 mg plaster are effective in relieving pain and present a good safety profile. [ABSTRACT FROM AUTHOR]

Summary: Background: Severe eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remains the most relapsed subtype of uncontrolled CRSwNP. CM310, a humanised anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits IL-4 and IL-13 signaling which underlying eosinophilic inflammation. This study aims to evaluate the efficacy and safety of CM310 in patients with severe ECRSwNP. Methods: A multicentre, randomised, double-blind, and placebo-controlled phase 2 clinical trial was conducted. 56 eligible adult patients with severe ECRSwNP were randomised 1:1 to receive subcutaneously either CM310 (300 mg) or placebo every 2 weeks under the background therapy of mometasone furoate nasal spray (MFNS) for 16 weeks, with 8 weeks of follow-up. Coprimary endpoints included the changes from baseline in nasal polyp score (NPS) and nasal congestion score (NCS) at week 16. Key secondary endpoints included sinus Lund-Mackay CT score, change in sinus volume occupied by disease, University of Pennsylvania Smell Identification Test score, 22-item Sino-nasal Outcome Test score, and total symptom score. Safety, pharmacodynamics, and changes in type 2 inflammation biomarkers were assessed. This study is registered with ClinicalTrials.gov, NCT04805398. Findings: Between April 6, 2021, and March 18, 2022, 27 patients respectively in both the CM310 and placebo groups completed the study. Findings suggested that CM310 improved the coprimary efficacy endpoints of decreasing nasal polyp size and alleviating nasal congestion compared with the placebo. Least squares (LS) mean differences (CM310 vs placebo) of change from baseline in NPS and NCS at week 16 were −2.1 (95% CI −2.9, −1.4; p

Background: Opioid Use Disorder (OUD) is a serious public health problem, and the behavioral and physiological effects of opioid withdrawal can be a major impediment to recovery. Medication for OUD is currently the mainstay of treatment; however, it has limitations and alternative approaches are needed. Objective: The purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on behavioral and physiological manifestations of acute opioid withdrawal. Methods: Patients with OUD undergoing acute opioid withdrawal were randomly assigned to receive double blind active tcVNS (N = 10) or sham stimulation (N = 11) while watching neutral and opioid cue videos. Subjective opioid withdrawal, opioid craving, and anxiety were measured using a Visual Analogue Scale (VAS). Distress was measured using the Subjective Units of Distress Scale (SUDS), and pain was measured using the Numerical Rating Scale (NRS) for pain. Electrocardiogram signals were measured to compute heart rate. The primary outcomes of this initial phase of the clinical trial (ClinicalTrials.gov NCT04556552) were heart rate and craving. Results: tcVNS compared to sham resulted in statistically significant reductions in subjective opioid withdrawal (p = .047), pain (p = .045), and distress (p = .004). In addition, tcVNS was associated with lower heart rate compared to sham (p = .026). Craving did not significantly differ between groups (p = .11). Conclusions: tcVNS reduces behavioral and physiological manifestations of opioid withdrawal, and should be evaluated in future studies as a possible non-pharmacologic, easily implemented approach for adjunctive OUD treatment.

Abstract Background Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear. Methods ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care. Discussion Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. Trial registration ISRCTN ISRCTN48075063 . Registered on 7th June 2019.