Double-blind Study Research Articles

Quantitative Analysis of Factors of Attrition in a Double-blind rTMS Study for Alzheimer Treatment.

Attrition is a particular concern in studies examining the efficacy of a treatment for Alzheimer disease. Analyzing reasons for withdrawal in Alzheimer studies is crucial to ruling out attrition bias, which can undermine a study's validity. In contrast, attrition in studies using repetitive transcranial magnetic stimulation (rTMS) has received much less attention. Our goal was to identify any commonalities between participants who withdrew for the same reasons. Three independent coders rated each response concerning the reasons for withdrawal, and frequency tables were generated to characterize the participants within each category. This study was conducted on the 28 withdrawn cases from a 7-month study investigating the short-term and long-term therapeutic effects of rTMS for Alzheimer disease among 156 participants across 3 sites of the study. Seven reasons for withdrawal were identified, with health and medical changes being the most commonly reported reason (7 participants). Personal issues involving family or caregivers were the next most common (5 participants), and the remaining 5 categories consisted of 3 participants each. Although the limited sample size prevented the use of inferential statistics, our findings highlight the need for more transparent reporting of attrition rates and withdrawal reasons by rTMS researchers.

The Effect of Low-Dose Colchicine on the Phenotype and Function of Neutrophils and Monocytes in Patients with Chronic Coronary Artery Disease: A Double-Blind Randomized Placebo-Controlled Cross-Over Study.

Recent landmark trials showed that colchicine provides a substantial benefit in reducing major cardiovascular events in patients with coronary artery disease. Yet, its exact mechanism of action is still poorly understood. This study aimed to unravel the effect of colchicine on monocyte and neutrophil phenotype and function. A randomized double-blind placebo-controlled cross-over intervention study was executed in patients with a history of myocardial infarction. In neutrophils, colchicine treatment decreased CD62L expression and NGAL release upon ex vivo stimulation and increased PMA-induced ROS production. The effects of colchicine on monocytes were limited to a decrease in HLA-DR expression in the intermediate and nonclassical monocytes. Also, on the level of RNA expression, colchicine did not affect monocyte phenotype, while affecting various immunomodulating genes in neutrophils. Overall, our study suggests that treatment with colchicine affects neutrophil function, particularly by reducing neutrophil recruitment, lowering concentrations of NGAL, and changing the expression of various genes with immunomodulatory potential, whereas the effect on monocytes is limited.

Efficacy and Safety of Dexmedetomidine in the Prone Position in Elderly Patients with Pneumonia: A Prospective, Double-Blind, Randomized Controlled Study.

We aimed to identify a safe and effective method to assist older adults with pneumonia in tolerating the prone position for a longer duration. This was a randomized, controlled, double-blinded study performed at the Shanghai Fourth People's Hospital. Eighty patients with pneumonia aged ≥ 65years were included. The patients were able to spontaneous breath in the prone position and were administered intravenous dexmedetomidine or an isotonic sodium chloride solution. The cumulative daily durations of prone positioning for all patients in the two groups were recorded. The primary outcome was the percentage of patients who completed ≥ 9h/day in the prone position. The secondary outcomes included the incidence of complications in the prone position and patient outcomes. Eighty patients were included (average age: 79.6 ± 8.9years). The percentage of patients who completed ≥ 9h/day in the prone position was significantly higher in the dexmedetomidine group than in the placebo group (P = 0.011). The percentage of patients who completed ≥ 12h/day in the prone position was also significantly greater in the dexmedetomidine group than in the placebo group (P = 0.008). There were no significant differences in other variables between the two groups. The results of this study demonstrate that intravenous dexmedetomidine injection can significantly prolong the duration of spontaneous breathing in the prone position in elderly pneumonia patients without obvious adverse events. We provide a safe and effective method to help patients with pneumonia, especially those with delirium or cognitive impairment, who cannot tolerate the length of time needed for spontaneous breathing in the prone position to be effective. The study was registered with the Chinese Clinical Trial Center (registration number: ChiCRT2300067383) on 2023-01-05.

Systemic acupuncture application does not change muscle performance parameters in women: A randomized, controlled, double-blind pilot study

Background/objectiveAcupuncture is used for therapeutic purposes. The possible beneficial role of this therapy may be as an ergogenic resource for the performance of fitness variables in exercise and sports. To date, acupuncture has been associated with increases in muscle strength, aerobic power, and vertical jump performance, but the evidence is still inconclusive. This study aimed to verify the immediate effects of a single session of acupuncture on lower-limb muscle performance in 31 young, physically active women. MethodsThis randomized, controlled, double-blind pilot study was approved by the Research Ethics Committee and in the Brazilian Registry of Randomized Clinical Trials. After warming up on a treadmill, the participants underwent the vertical jump test, followed by an isometric strength test of the extensor muscles of both knees. Immediately after the tests, participants were randomly divided into the following groups: sham (SG), acupuncture (AG), and control (CG). After each intervention, all participants repeated the warm-up and functional tests. ResultsThere was a significant decrease in the mean and peak values of vertical jump height, in the sham and acupuncture groups, respectively. Furthermore, none of the groups showed changes in isometric muscle strength. ConclusionIt was concluded that the proposed acupuncture protocol did not promote improve in lower-limb muscle performance parameters in young, physically active women.

Infinity: A Prospective Trial for Safety and Accuracy of Navigated Posterior Cervical and Thoracic Instrumentation in long-segment Fusions.

Unblinded single-arm prospective clinical trial. Evaluate safety and accuracy of navigation for placement of posterior cervicothoracic instrumentation. Computer assisted stereotactic navigation for placement of spinal instrumentation has been widely studied and implemented in the thoracic and lumbar spine. However less literature exists regarding the use of computer assisted navigation for posterior cervical instrumentation, particularly with lateral mass fixation. Here we present the first prospective study of navigated cervical lateral mass screw placement for cervicothoracic fusion. Patients who met indications for posterior cervical fusion were screened, consented, and enrolled preoperatively for instrumentation with Medtronic Infinity Occipital-Cervical-Thoracic implants, with use of intraoperative O-arm and stereotactic Stealth navigation. Postoperative CTs of the instrumented levels were obtained during the same hospital admission. Primary outcome of the trial was safety. Secondary outcomes were screw accuracy assessed by Gertzbein-Robbins grade, neurologic exams, and patient reported outcomes on the PROMIS 29 questionnaire. A total of 50 patients underwent surgery, and 557 screws were placed. There were no adverse events related to the use of navigation or screw malposition. Gertzbein-Robbins grade A or B placement comprised 95% of navigated screws. There was a decrease in positive Hoffmann sign rate postoperatively, and sensory and motor exams remained stable. There was improvement in patient reported pain and sleep domains. Navigation for cervicothoracic instrumentation is safe overall and leads to high rates of accurately placed screws. Longer term follow up could provide more insight to whether the use of this technology results in durable improvement in spinal alignment parameters and patient reported outcomes. 3.

Randomized double-blind placebo-controlled study to evaluate the effect of long-acting mesalamine on postinfectious irritable bowel syndrome with diarrhea.

A subset of patients with irritable bowel syndrome (IBS) develop their symptoms after gastroenteritis, referred to as postinfectious IBS (PI-IBS). PI-IBS is associated with low-grade intestinal inflammation. Previous studies have evaluated mesalamine, an anti-inflammatory drug, in patients with IBS. We evaluated the efficacy of long-acting mesalamine in patients with PI-IBS. Sixty-one patients who developed diarrhea-predominant IBS (IBS-D) after gastroenteritis were randomized to receive either 2.4 g of long-acting mesalamine or placebo daily for 8-weeks. The symptoms assessed were abdominal pain, bloating, stool frequency, stool consistency, severity of diarrhea and constipation, satisfaction with bowel habits, and IBS affecting or interfering with life. Quality-of-life (QOL) was assessed using the IBS-QOL questionnaire. The prespecified primary outcome variable was the overall bowel symptom score (BSS) after 8-weeks of treatment. Effect sizes were expressed as standardized mean differences (Cohen's d). Fifty-four patients completed the 8-week treatment (n = 28 mesalamine, n = 26 placebo), 49 (91%) were male, and age range 23-71 years (mean ± SD 43 ± 13). Mesalamine demonstrated superior efficacy compared to placebo on the primary outcome variable, overall BSS (Cohen's d = 0.57, p = 0.042). Mesalamine was also superior for the secondary outcome of how much IBS affects your life in general (d = 0.72, p = 0.01). For the secondary outcomes of IBS symptoms, 7 of the 7 symptoms had trends of mesalamine superiority. For the secondary outcomes of IBS-QOL subscales, 8 of 9 had trends of mesalamine superiority. In patients with PI-IBS, long-acting mesalamine demonstrated to be effective in reducing IBS symptoms and improving QOL.

45 INTerpath-004: A phase 2, randomized, double-blind study of pembrolizumab with V940 (mRNA-4157) or placebo in the adjuvant treatment of renal cell carcinoma

Abstract Background The PD-1 inhibitor pembrolizumab is approved as monotherapy for the adjuvant treatment of patients with renal cell carcinoma (RCC) who are at increased risk of recurrence following nephrectomy or nephrectomy and resection of metastatic lesions based on results from the phase 3 KEYNOTE-564 trial. Novel combination strategies could provide further clinical benefit in the adjuvant setting. V940 (mRNA-4157) is an individualized neoantigen therapy that is hypothesized to increase the antitumor activity of T cells and enhance the activity of pembrolizumab. V940 plus pembrolizumab showed improved clinical outcomes for stage III/IV melanoma compared with pembrolizumab alone in the phase 2b KEYNOTE-942 study. INTerpath-004 is a global, multicenter, randomized, double-blind, phase 2 trial (NCT06307431) designed to evaluate the efficacy and safety of adjuvant pembrolizumab with V940 or placebo in patients with RCC who have undergone nephrectomy. Methods Eligible patients are adults with histologically or cytologically confirmed RCC with clear cell or papillary histology (intermediate-high risk [pT2 Gr4, N0, M0 or pT3 Gr3/4, N0, M0], high-risk [pT4, N0, M0 or pT any stage, N1, M0], or M1 NED [solid, isolated, soft tissue metastases that can be completely resected at the time of nephrectomy or ≤2 years from nephrectomy]) with or without sarcomatoid features. Patients must have undergone nephrectomy and/or metastasectomy ≤12 weeks prior to randomization and be tumor-free as assessed by investigator. Patients must not have received prior systemic therapy ≤4 weeks or radiotherapy ≤2 weeks prior to randomization. Approximately 272 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg intravenously every 6 weeks for up to 9 cycles in combination with either V940 1 mg or placebo intramuscularly every 3 weeks for up to 9 doses or treatment discontinuation due to unacceptable toxicity, disease recurrence, patient withdrawal, or investigator decision. Randomization will be stratified by histology (clear cell vs papillary) and disease risk (intermediate-high vs high vs M1 NED). Imaging assessments (computed tomography or magnetic resonance imagery) will be performed every 12 weeks through year 2, every 16 weeks in years 3-5, and every 24 weeks in year 6 and beyond. The primary endpoint is disease-free survival by investigator assessment. Secondary endpoints include distant metastasis-free survival, overall survival, and safety parameters including adverse events (AEs), laboratory test results, and vital signs. AEs will be monitored throughout the study and for 30 days after the last dose of treatment (90 for serious AEs) and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Efficacy will be assessed in all randomly assigned patients, and safety will be assessed in all patients who received ≥1 dose of study intervention. Recruitment is ongoing.

Plantar Compartment Block Improves Enhanced Recovery after Hallux Valgus Surgery: A Randomized Comparative Double-Blind Study.

Walking ability is a key factor in enhanced recovery after foot ambulatory surgery. Plantar compartment block offers an analgesic alternative to popliteal sciatic nerve block (PSNB) for hallux valgus surgery. The objective of this study was to compare these two regional anesthesia strategies on patients' ability to recover a painless unaided walk. This prospective double-blinded (patient; observing anesthesiologist) randomized study compared patients scheduled for hallux valgus surgery receiving PSNB with 1% mepivacaine, then combined plantar and peroneal nerve blocks (PCB group) with ropivacaine 0.5% and dexamethasone, or PSNB with ropivacaine 0.5% and dexamethasone (control group). The primary outcome was the patient's ability to walk unaided 6 h after PSNB. The test was performed on a GAITRite® spatio-temporal gait analysis mat. During three days, the number of patient steps, pain levels, rescue analgesics, patient's experience and adverse events were assessed. Sixty patients were included and 59 were analyzed. The number of patients walking unaided on the GAITRite® mat was significantly higher in the PCB group (21/30, 70%) than in the control group (4/29, 13.8%; p<0.001). Gait quality using the Functional Ambulation Profile score was 63±13.6 in the PCB group and 49.5±4.7 in the control group (p<0.001). Median time to free ambulation at home was significantly lower in the PCB group (9 h [8.2-11.8]) than in the control group (33.5 h [24-47]; p<0.001). Postoperative pain did not differ between the groups (β=-0.41 [-1.78 to 0.95]; p=0.548). The number of steps at day 3, the time of first rescue analgesic, the number of patients using rescue analgesia, consumption of morphine, and patient's experience did not differ between the groups. PCB decreased the time to return to unaided walking, with improved gait, compared with PSNB, improving effective analgesia and low consumption of rescue analgesics. This innovative regional anesthesia strategy enhanced recovery after surgery.

Nicotine reduces discrimination between threat and safety in the hippocampus, nucleus accumbens and amygdala

Nicotine intake is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in rodents and humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n = 88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to enhanced physiological arousal to learned threats and overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

Tranexamic Acid in Preventing Postpartum Blood Loss in Vaginal Delivery- a Double Blinded, Randomized Controlled Trial

To assess the effect of prophylactic tranexamic acid (1 g) in reducing postpartum blood loss and the incidence of PPH after vaginal delivery, in addition to active management of third stage of labour. In this randomized controlled trial, 650 women with singleton pregnancies of ≥ 34 weeks gestation who were undergoing vaginal delivery were included. Eligible women were randomly assigned to receive either 1 g of tranexamic acid or placebo intravenously in addition to active management of third stage of labour. Calibrated blood collection bags were used to measure postpartum blood loss during the third and fourth stage of labour. Out of 886 women who were approached for the study, 650 who met the inclusion criteria were enrolled, and 320 in group A and 321 in group B were analysed. Maternal characteristics were similar in both groups. Mean blood loss did not differ significantly among the intervention and placebo groups (378.5±261.2 ml vs. 383±258.9 ml; p = 0.93). The incidence of primary postpartum hemorrhage was comparable in both groups (Group A: 15.9%, Group B: 15.3%, p = 0.814). The median (interquartile) quantitative fall in haemoglobin within 12-24 hours following delivery in group A was 0.60 g% (0.40-0.90) and group B was 0.60 g% (0.40-0.80) which were comparable in both groups (p=0.95). The most common adverse effect reported was dizziness and there were no thromboembolic events at three months follow-up in both groups. The use of tranexamic acid as a prophylactic measure along with active management of third stage of labour does not provide additional benefit in reducing the postpartum blood loss as well as incidence of PPH after vaginal delivery.

Clinical efficacy of a multilamellar cream on skin physiology and microbiome in an epidermal stress model: A controlled double-blinded study.

Stratum corneum (SC) is essential for skin barrier function, mitigating water loss and shielding against potentially harmful substances and allergens. The SC's lipid matrix, arranged in a lamellar structure, is integral to its protective role. Our study explores the restoration effects of a multilamellar cream with an acidic pH compared to a basic placebo cream on skin physiology and its interaction with the skin microbiome after stress induction via tape stripping (TS). In this double-blind study, 14 healthy participants aged 21-58 years were assessed pre- and post-tape stripping, followed by a 14 days application of a multilamellar test cream and a placebo cream with evaluations on days 7, 14 and 17 for sustained effects. Skin physiology was analysed in terms of epidermal barrier function, SC hydration and surface pH. The microbiome was analysed by 16S rRNA amplicon sequencing the 16S rRNA gene using Illumina MiSeq, with subsequent species identification. Our study showed significant improvements in skin barrier repair and SC hydration with verum, particularly after 14 days of application, while both creams initially enhanced stratum corneum hydration. No significant changes in surface-pH were detected. The skin microbiome analysis revealed that TS slightly decreased alpha diversity, a trend that verum significantly reversed, enhancing diversity beyond baseline levels after 14 days. Overall, while both creams contributed to a broader microbial phyla diversity over time, no significant changes in the abundance of specific genera or species were noted between treatments. Our study delineates the efficacy of a pH-optimized multilamellar cream in enhancing epidermal barrier recovery and SC hydration post-sequential TS, in contrast to an unstructured basic placebo. Verum cream significantly improved skin barrier function and SC hydration at day 14, with sustained effects evident beyond the treatment period. Furthermore, the multilamellar formulation facilitated the restitution of cutaneous microbiome diversity, a key indicator of healthy skin ecology, underscoring the symbiotic relationship between barrier integrity and microbial composition. These findings underscore the importance of multilamellar emollient structures in dermatological therapeutics, with potential implications for the design of advanced skincare interventions that holistically support cutaneous resilience and homeostasis.

Microbiota in Mild Inflammatory Bowel Disease (IBD) Can Be Modulated by Beta-Glucans and Mannanoligosaccharides: A Randomized, Double-Blinded Study in Dogs

Microbiota in Mild Inflammatory Bowel Disease (IBD) Can Be Modulated by Beta-Glucans and Mannanoligosaccharides: A Randomized, Double-Blinded Study in Dogs

Palmitoylethanolamide Does Not Affect Recovery from Exercise-Induced Muscle Damage in Healthy Males.

Strenuous eccentric exercise (EE) induces microstructural muscle damage, which decreases muscle performance. Palmitoylethanolamide (PEA) exerts analgesic and anti-inflammatory effects in clinical pain conditions and preclinical models of experimentally induced-inflammation. This might hold clues for improved recovery from EE. Therefore, the current study evaluates the effect of PEA supplementation on functional and molecular responses to a single EE bout. Eleven healthy male participants were included in a double-blind crossover study in which they received PEA (350 mg Levagen+) or placebo (maltodextrin) supplements, in a randomized order. In each experimental condition participants performed an acute bout of EE (24x10 eccentric contractions of the knee extensors on an isokinetic dynamometer). At baseline, 24 (D1), 48 (D2), 72 (D3) and 120 h (D5) following EE, maximal voluntary contraction and jump height were measured. Blood samples were collected at baseline and on D1-D5, and muscle biopsies were collected at baseline and on D2. Perceived muscle soreness, sleep quality and food intake were recorded daily. Muscle strength and jump height decreased following EE (up to ~40 and ~ 17% respectively; Ptime < 0.05) in both conditions. This drop was accompanied by an increase in plasma creatine kinase and perceived muscle soreness (Ptime < 0.05). Furthermore, EE, but not PEA, increased the expression of the myogenic marker Pax7 and of the catabolic markers p-FoxO1-3a, p62 and LC3BII/I (Ptime < 0.05). PEA supplementation does not improve muscle soreness, muscle strength and jump performance following a single EE bout. Additionally, PEA supplementation had no effect on local or systemic markers of muscle damage, catabolism or regeneration.

Comparative Study of Diluted Hydrogen Peroxide and Sulfur Hexafluoride in the Contrast-Enhanced Ultrasound Assessment of Anal Fistulas.

Endoanal ultrasound for the diagnosis of anal fistulas requires the injection of hydrogen peroxide, but it is often uncomfortable for the patient and possesses potential complications. Novel ultrasound contrast is currently available. We aimed to assess the efficacy and safety of sulfur hexafluoride as an ultrasound contrast agent for the diagnosis of perianal fistula by comparing it with those of 50% diluted hydrogen peroxide. Double-blind superiority study with 4 consecutive visits to perform an ultrasound without contrast, a hydrogen peroxide-enhanced ultrasound, a sulfur hexafluoride-enhanced ultrasound and a rectal exploration in the operating room (the gold standard). The ultrasound images were independently reviewed by three expert surgeon sonographers. This study was conducted at a single university hospital. Data from 176 patients were evaluated. Demographic and exploratory data and the ultrasound findings related to the location of the internal fistula orifice, description of the primary and secondary tracts, and presence of cavities and sphincter defects were analyzed. The complications occurring before and after the contrast agent administration and the presence of pain measured using a score were considered. Eighty-eight patients were included (men: 71.5%; mean age: 48.3 years).62.5% had a complex type and 83.7% had a transsphincteric type. Sulfur hexafluoride-enhanced ultrasounds demonstrated a higher interobserver agreement in determining the secondary tracts (κ= 0.604) and anal fistula height (κ=0.604) compared with other methods. Both hydrogen peroxide-enhanced ultrasound (90.91%) and sulfur hexafluoride-enhanced ultrasound (89.77%) detected the internal orifice more frequently than ultrasounds without contrast (62.5%) (p < 0.001),with no differences between contrast agents (p = 0.810). Sulfur hexafluoride-enhanced ultrasound were less painful than peroxide-enhanced ultrasound (p < 0.001). Most of the patients had transsphincteric anal fistulas. Sulfur hexafluoride proved comparable to hydrogen peroxide in evaluating fistulous tracts and identifying the internal orifice and additionally reduced significantly pain and discomfort. Furthermore, demonstrated a higher interobserver agreement in determining the secondary tracts and anal fistula height compared with other methods. See Video Abstract.

Cardiac Cine MRI Using a Commercially Available 0.55-T Scanner.

Purpose To compare parameters of left ventricular (LV) and right ventricular (RV) volume and function between a commercially available 0.55-T low-field-strength cardiac cine MRI scanner and a 1.5-T scanner. Materials and Methods In this prospective study, healthy volunteers (May 2022 to July 2022) underwent same-day cine imaging using both scanners (0.55 T, 1.5 T). Volumetric and functional parameters were assessed by two experts. After analyzing the results of a blinded crossover reader study of the healthy volunteers, 20 participants with clinically indicated cardiac MRI were prospectively included (November 2022 to February 2023). In a second blinded expert reading, parameters from clinical 1.5-T scans in these participants were compared with those same-day 0.55-T scans. Results are displayed as Bland-Altman plots. Results Eleven healthy volunteers (mean age: 33 years [95% CI: 27, 40]; four of 11 [36%] female, seven of 11 [64%] male) were included. Very strong mean correlation was observed (r = 0.98 [95% CI: 0.97, 0.98]). Average deviation between MRI systems was 1.6% (95% CI: 0.3, 2.9) for both readers. Twenty participants with clinically indicated cardiac MRI were included (mean age: 55 years [95% CI: 48, 62], six of 20 [30%] female, 14 of 20 [70%] male). Mean correlation was very strong (r = 0.98 [95% CI: 0.97, 0.98]). LV and RV parameters demonstrated an average deviation of 1.1% (95% CI: 0.1, 2.1) between MRI systems. Conclusion Cardiac cine MRI at 0.55 T yielded comparable results for quantitative biventricular volumetric and functional parameters compared with routine imaging at 1.5 T, if acquisition time is doubled. Keywords: Cardiac, Comparative Studies, Heart, Cardiovascular MRI, Cine, Myocardium Supplemental material is available for this article. ©RSNA, 2024.

A phase 2a study investigating the effects of ritlecitinib on brainstem auditory evoked potentials and intraepidermal nerve fiber histology in adults with alopecia areata.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Current Treatments for Generalized Pustular Psoriasis: A Narrative Summary of a Systematic Literature Search.

Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules, with or without systemic inflammation. GPP can significantly reduce patients' quality of life (QoL). Several therapeutic approaches have been described in the literature, but there is no consensus on optimal treatment. In this review, we summarize published literature on efficacy, safety and QoL outcomes associated with current treatment of GPP with both approved and non-approved products. Embase and MEDLINE databases were searched (1980-September 2023). A search protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on the PROSPERO database (CRD42021215437). Details on publication, population, intervention, efficacy, safety and QoL were captured and checked by independent reviewers. In total, 118 publications were included, with only 19% of publications reporting on the results of clinical trials. Treatment modalities reported for GPP included non-biologic systemic therapies such as retinoids, cyclosporine and methotrexate, topical agents, biologics and small molecules, among others. Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials; based on this, spesolimab is now approved for GPP treatment in regions including the USA, Japan, China, the EU and several other countries. Some other biologics are approved exclusively in Japan and Taiwan for the treatment of GPP based on open-label studies with small patient numbers in lieu of double-blind studies. Non-standardization of clinical outcomes across studies remains a major hurdle in reaching a consensus on optimal treatment. However, recently trials have been conducted using well-defined, disease-specific endpoints to evaluate GPP-targeted treatments, which will hopefully advance patient care. In conclusion, this review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.

Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75min mid-LAD balloon occlusion followed by reperfusion. After 4w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45µg/kg/day rhPlGF-2 or PBS (CON) for 2w using osmotic pumps. We evaluated the treatment effect at 8w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.

Efficacy of Leflunomide Compared to Methotrexate in the Treatment of Moderate to Severe Plaques Psoriasis: A Randomized Controlled Clinical Trial

Introduction: Psoriasis is a chronic inflammatory autoimmune skin disease. Several treatment options are available including topical and systemic options. Methotrexate was the main systemic medication in treating severe psoriasis, yet adverse events can limit its use. Leflunomide is an isoxazole derivative that inhibits the synthesis of pyrimidines, and subsequently inhibits RNA and DNA synthesis. Objective: As available data directly comparing MTX to leflunomide in psoriasis are lacking, this double blinded study was designed to compare the efficacy of methotrexate versus leflunomide in the treatment of moderate to severe psoriasis. Methods: The study included 40 patients (25 males and 15 females) with chronic plaque psoriasis, s. Patients were randomly assigned to one of two equal groups, group A for subcutaneous methotrexate injections and group B for leflunomide (loading dose 100mg daily for the first 3 days then 20 mg daily for 3 months. Disease severity was determined by psoriasis area and severity index (PASI) score before and at the end of treatment The treatment response was evaluated at the baseline and weeks 4, 8 and 12 PASI score. Results: Both groups were matching at the baseline in aspects of gender, age, disease duration and PASI scores Both medications yielded comparable results with no significant difference between both groups in PASI score neither in side effects.. Conclusion: Leflunomide can be as effective as methotrexate in treatment of moderate to severe psoriasis.

Protocol for a randomised controlled unblinded feasibility trial of HD-DRUM: a rhythmic movement training application for cognitive and motor symptoms in people with Huntington’s disease

IntroductionHuntington’s disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated...