Multicenter Trial Research Articles

ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma.

Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults. ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

LX9211, a rising star for relieving of diabetic peripheral neuropathic pain.

In a multicenter trial, LX9211 significantly reduced pain in diabetic peripheral neuropathy (DPN) patients, with the 10 mg dose showing notable relief by the first week. Although the higher dose was less effective, side effects like dizziness and nausea were generally mild. These findings highlight the importance of exploring both pharmaceutical and natural treatments, such as flavonoids, for managing DPN.

Primary Open-Angle Glaucoma Polygenic Risk Score and Risk of Disease Onset

Primary open-angle glaucoma (POAG) is a heritable disease. A polygenic risk score (PRS) threshold may be used to identify individuals at low risk of disease onset. To assess the utility of a POAG PRS to identify ocular hypertensive individuals at low risk of disease onset. This is a post hoc analysis of the Ocular Hypertension Treatment Study (OHTS), a multicenter randomized clinical trial across 22 centers in the US conducted among 1636 participants with ocular hypertension from February 1994 to April 2019 with available genetic data. Of the 1636 original participants, 1077 had available genetic data; after excluding 67 for missing data, data quality concerns, or ancestry other than European or African, 1010 were included in the present analysis. Data for this report were analyzed from November 2023 to June 2024. From 1994-2002, participants were randomized to receive topical intraocular pressure (IOP)-lowering medications. From 2002 onwards, all participants were given topical IOP-lowering medications. Twenty-year conversion rates by POAG PRS threshold, baseline randomization status, and OHTS clinical risk tertile. Among the 1010 participants in this study, 563 (65.8%) were female, and the mean (SD) age was 55.9 (9.4) years. In a mixed-effects logistic regression model adjusted for OHTS risk factors for conversion to POAG and randomization status, a PRS under the 48th percentile was associated with a 1.49 times higher likelihood of disease-free status after 20 years of follow-up (95% CI, 1.04-2.15; P = .03; unadjusted hazard ratio [HR], 1.64; 95% CI, 1.13-2.38; P = .009), compared with high polygenic risk. When we stratified the trial cohort into nongenetic OHTS clinical risk tertiles, the largest differences in survival probability at 20 years based on PRS threshold was observed in eyes in the highest tertile, initial observation group (20-year conversion rate: 61.1% in the high polygenic risk group vs 23.8% in the low polygenic risk group; 95% CI, -63.0 to -11.6; P = .01), with randomization to early treatment partially mitigating the effect of high genetic risk (20-year conversion rate: 37.3% in the high polygenic risk group vs 24.1% in the low polygenic risk group; 95% CI, -35.6 to 9.3%; P = .32). These findings support considering use of a POAG PRS threshold to identify individuals at low risk of disease onset, with those below the PRS threshold more likely to have lower conversion rates over 20 years. Among those considered at highest risk based on the OHTS clinical risk model, early treatment may partially offset the association with high genetic risk but provide limited benefit for those with low genetic risk. ClinicalTrials.gov Identifier: NCT00000125.

Development of the continuous ambulatory vestibular assessment (CAVA) system to provide an automatic diagnosis for vestibular conditions: protocol for a multicentre, single-arm, non-randomised clinical trial

IntroductionDizziness is a common symptom that can occur in an unpredictable and episodic manner leading to the imprecise reporting of symptoms. Patients will often see many specialists before receiving a...

Acute Promyelocytic Leukemia: Long-Term Outcomes from the HARMONY Project

Treatment outcomes for acute promyelocytic leukemia (APL) have improved with the widespread use of targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Our study aimed to validate these data in a large patient cohort, and to redefine prognostic factors.Leveraging the HARMONY Platform, we analyzed 1438 newly-diagnosed APL patients, diagnosed between 1999 to 2022. Patient data derived from the 2 international multicenter GIMEMA-APL0406 and NCRI-AML17 trials, and 4 European registries (HOVON, AMLSG, Swedish AML Registry and SAL). The study cohort included 721 males and 717 females, with a median age of 50.5 years (range 16-94 years). Of 1309 patients starting therapy, 562 received ATRA-ATO, and 747 AIDA-like chemotherapy. Early death (ED) occurred in 85 of 1438 patients (5.9%) at a median of 9 days after APL diagnosis and was independently associated with increasing age and high Sanz risk score (OR:1.06, 95% C.I: 1.04-1.08, and OR:4.65, 95% C.I.:2.55-8.51, respectively). The median follow-up was 5.5 years (IQR=3.2-7.5). ATRA-ATO regimen was associated with the best outcome, reaching 91% 7-year overall survival (vs 81% for AIDA-like, HR:2.14, 95%C.I.:1.51-3.05), 89% event-free survival (vs 71% for AIDA-like, HR:2.72 95%CI: 2.01–3.69) and 3% relapse (vs 13% for AIDA-like, HR:4.19, 95%CI:2.38–7.39, p<0.001 for all outcomes). The survival advantage of ATRA/ATO was independent of patients’ age, Sanz-risk score, and treatment scenario.Our study confirms the superiority of ATRA-ATO over ATRA-chemotherapy in APL patients. ED still represents an unmet medical need, in particular in older patients and in high-risk APL.

Efficacy and Safety of Weekly Calcifediol Formulations (75 and 100 µg) in Subjects with Vitamin D Deficiency: A Phase II/III Randomised Trial

Background/Objective: Optimal vitamin D levels are required for bone health and proper functionality of the nervous, musculoskeletal and immune systems. The objective of this study was to assess the efficacy and safety profiles of new weekly calcifediol formulations with the potential to improve adherence and outcome. Methods: A Phase II-III, double-blind, randomized, multicentre trial (EudraCT 2020-001099-14 and NCT04735926). Subjects were randomized 2:2:1 to calcifediol 75 µg, 100 µg and placebo. 25(OH)D levels were measured at 4, 16, 24, 32 and 52 weeks. The main outcome was the percentage of subjects who achieved a response defined as 25(OH)D levels ≥20 ng/mL and/or ≥30 ng/mL at week 16. Results: 398 subjects (51.1 ± 15.96 years, 74.2% females, 98.7% Caucasian) with plasma 25(OH)D levels between 10 and 20 ng/mL were randomized. A total of 376 subjects completed 16 weeks of treatment, and 355 subjects completed the study. Six patients withdrew due to an adverse event, all unrelated to treatment. At week 16, 93.6% and 74.4% of subjects receiving calcifediol 75 µg achieved response levels of ≥20 ng/mL and ≥30 ng/mL, respectively. The calcifediol 100 µg group showed 98.7% and 89.9% of responders for ≥20 ng/mL and ≥30 ng/mL, respectively. Both calcifediol groups showed superiority over placebo at each response level at all time points analyzed (p &lt; 0.0001). Calcifediol treatments increased 25(OH)D levels from baseline to week 24 and remained stable thereafter. The frequency of treatment-emergent adverse events was balanced between groups. Conclusions: New weekly calcifediol 75 and 100 µg formulations showed an effective and sustained response with a good long-term safety profile.

Pressure-Mediated Biofeedback With Pelvic Floor Muscle Training for Urinary Incontinence

Supervised pelvic floor muscle training (PFMT) has been recommended as the first-line treatment for women with stress urinary incontinence (SUI), but more evidence on whether adjunctive methods would provide additional benefits is needed. To compare the efficacy of PFMT with or without a home-based pressure-mediated biofeedback (BF) device. This multicenter assessor-blinded randomized clinical trial was conducted in the obstetric clinics of 5 participating tertiary hospitals in China. Participants included eligible women with new-onset postpartum SUI who were enrolled from March 28, 2022, to October 13, 2023. All participants received 3 months of supervised PFMT and were randomized to either the intervention (PFMT with a home-based pressure-mediated BF device) or the control group (home-based PFMT). The primary outcome was the severity of urinary incontinence evaluated by the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form after 3 months of supervised PFMT. The secondary outcomes included the cure and improvement rates, PFM strength, quality of life, self-efficacy, and adherence. A total of 452 participants (median age, 34 [IQR, 31-36] years; median body mass index [calculated as the weight in kilograms divided by the height in square meters], 23.71 [IQR, 21.37-25.97]; median time since delivery, 50 [IQR, 43-61] days) were included in the analysis, with 223 in the intervention group and 229 in the control group. Compared with the control group, the intervention group achieved a significantly greater reduction in incontinence severity (median, 3.00 [IQR, 1.00-6.00] vs 2.00 [IQR, 0-4.00] points; z = -3.05; P = .002), significantly increased cure rate (45 of 223 [20.2%] vs 20 of 229 [8.7%]; z = 12.02; P = .001) and improvement (132 of 223 [59.2%] vs 102 of 229 [44.5%]; z = 9.71; P = .002), significantly greater pelvic floor muscle strength (median, 26.00 [IQR, 17.00-38.00] vs 21.00 [IQR, 13.50-33.50] cm H2O; z = -2.28; P = .02), and a significantly greater correlation between subjective and objective adherence (r = 0.825 vs r = 0.627). In this randomized clinical trial, the efficacy of pressure-mediated BF combined with PFMT was superior to that of PFMT alone. These findings support the use of pressure-mediated BF devices for improving treatment outcomes for patients with SUI. ClinicalTrials.gov Identifier: NCT05115864.

Clinical and economic benefits of patients undergoing lobectomy with the use of powered vascular staplers—based on China’s real-world data

Background Endoscopic surgery is widely performed with an increasing use of powered vascular staplers (PVS). However, few studies have examined PVS use in China, most of which have focused on clinical effects; fewer studies have examined the economic benefits of PVS. This study evaluated the clinical and economic benefits of the PVS compared to standard-of-care (SOC) staplers in lobectomy using results from a single-arm, multicenter clinical trial conducted in China and actual clinical use in a hospital collected in a real healthcare setting. Methods Patients with lung cancer undergoing thoracoscopic lobectomy were included in the study. The clinical and economic benefits of powered vascular stapler have been evaluated from a hospital’s perspective based on parameters such as bleeding occurrence, hospitalization time, secondary thoracotomy, and hospitalization costs. To compare the bleeding associated with use of PVS and SOC stapler in clinical use, PVS single-arm multi-center clinical trial data is used for the intervention group, and sampling data from hospitals is used for the control group. To ensure the outcome indicators between the two groups are comparable, we set the same inclusion criteria for the two groups of data and then used propensity score matching (PSM) to match two groups of patients according to the baseline characteristics. Results The results show that bleeding incidence in patients with SOC stapler group is 17.33% from hospital sampling data. In contrast, in the PVS group, it is 4.00%, and these rates are statistically different (P = 0.0167). Considering converted to open thoracic surgery, the rate of the SOC stapler group is 5.78% and that of the PVS group is 4.00%. These rates are not statistically different (P = 0.6166). Regarding hospitalization days, the length of the SOC stapler group is 18.97 days, while that in the PVS group is 12.38 days, and these data are statistically different (P = 0.0002). As patients in the PVS group have reduced bleeding, they will require less resource use from blood transfusion, drug services and surgical services. If PVS is used for transection of vessel, it can reduce the bleeding incidence by 13.33% and save 75.47 CNY in blood transfusion costs, 571.36 CNY in drug costs, and 183.38 CNY in surgical service costs per patient. From these three aspects, the hospital saves per patient 830.21 CNY. Conclusions Compared with the SOC stapler group, the PVS group has a lower bleeding incidence and shorter hospital days for lobectomy. In terms of blood transfusion costs, drug costs and surgical service costs, the hospital saves per patient 830.21 CNY.

Comparison of BiliCocoon phototherapy with overhead phototherapy in hyperbilirubinemic neonates. A randomized clinical trial.

Around 2-6% of term or late preterm neonates receive phototherapy for hyperbilirubinemia. Standard treatment today is overhead phototherapy. A new device has been developed, the BiliCocoon, where the neonates are "wrapped" presumably making them more comfortable. The aim was to compare the efficacy and performance of the BiliCocoon with overhead LED phototherapy. A randomized open-label multicenter trial in three Danish neonatal units. Healthy hyperbilirubinemic neonates, gestational age ≥33 weeks and postnatal age 24 h to 14 days were randomized to 24 hours' of treatment with BiliCocoon or overhead blue LED phototherapy with an equal level of irradiance. A mixed effect model with random effect by center was used to compare the percentage decrease in total serum bilirubin (TSB) between the treatments. Totally 83 neonates were included. Mean TSB reduction in the BiliCocoon group (N = 42), adjusted for baseline TSB, was significantly lower than in the overhead LED group (N = 41), 29% vs. 38% (p-value < 0.01). Overall difference in temperature by treatment (BiliCocoon vs overhead) was 0.70 [0.37; 1.02] °C, p-value < 0.01. Bilirubin reducing efficacy of BiliCocoon was lower than that of overhead phototherapy, but it was sufficient for nearly all neonates during 24 hours of treatment. The BiliCocoon has a bilirubin reducing efficacy, sufficient for almost all neonates during 24 hours of phototherapy. The BiliCocoon does not have an equal bilirubin reducing efficacy as overhead phototherapy. The duration of light exposure was longer for the neonates treated in the BiliCocoon. A few neonates can be exclusively breastfed in the BiliCocoon throughout the treatment. The reason for stopping breastfeeding in the BiliCocoon was most often, that the neonates developed hyperthermia.

Effect of perioperative rehabilitation exercise on postoperative outcomes in patients aged ≥65 years undergoing gastrointestinal surgery: A multicenter randomized controlled trial

Study objectivesThis study aimed to assess the effect of perioperative rehabilitation exercise, initiated shortly after hospital admission, on postoperative outcomes in elderly patients. DesignA prospective, multicenter, randomized, controlled, open-label, and assessor-blinded clinical trial. SettingHospital wards. PatientsElderly patients (≥65 years, n = 160) scheduled for gastrointestinal surgery between June 2021 and November 2022 were enrolled and randomly assigned to the intervention or control group. InterventionsPatients were divided into two groups base on whether they had received a specific type of exercise program initiated after hospital admission and continued until 30 days after surgery. MeasurementsThe primary outcome was the Comprehensive Complications Index (CCI) measured at 30 days after surgery. Secondary outcomes were the rate of complications, number of complications, patient satisfaction, hospital readmission, postoperative length of stay, gastrointestinal function recovery, postoperative quality of life and psychological status. Intention-to-treat (ITT) and per-protocol (PP) analyses were conducted. Main resultsITT analysis showed a significantly lower 30-day CCI in the intervention group (β: -6.31; 95 % Confidence Interval [CI], −11.26 to −1.37, P = 0.013). Compared to controls, the intervention group had a decreased rate of hospital readmission (Odds Ratio: 0.00; 95 % CI, 0.00 to 0.32, P = 0.022), less number of complications (β: -0.57; 95 % CI, −1.03 to −0.11, P = 0.016), as well as lower rate of postoperative anxiety (β: -0.74; 95 % CI, −1.42 to −0.06, P = 0.033) and depression scores (β: -1.13; 95 % CI, −0.97 to −1.30, P = 0.008). Additionally, the intervention group reported higher satisfaction (β: 0.98; 95 % CI, 0.33 to 1.64, P = 0.004) and Euro quality of life-Visual Analogue Scale scores (β: 8.88; 95 % CI, 2.48 to 15.28, P = 0.007). Similar results were found in the PP analysis. ConclusionPerioperative rehabilitation exercise has a positive impact on postoperative complications, quality of life and psychological well-being in elderly patients undergoing gastrointestinal surgery, even when implemented after hospital admission.

Determining the Optimal Short-Term Storage Duration for T Cells Extracted from Peripheral Blood Prior Flow Cytometry Analysis.

Researching medical sample storage is crucial for maintaining the integrity of biological specimens and ensuring the accuracy of research investigations and diagnostic tests. Improper storage conditions can lead to sample degradation, compromising the reliability of results. Standardized storage procedures are essential for quality control, particularly in multicenter trials where samples are collected and processed at various locations. Moreover, ethical considerations dictate careful handling of patient samples to uphold privacy and rights. This study focuses on the surface phenotype of T cells, which is vital for diagnosing immunodeficiency disorders and autoimmune diseases and for monitoring disease activity and treatment efficacy. The effect of storage duration on T cell surface proteins is multifactorial, influenced by factors like protein degradation, cellular metabolism, and cytokine release. Long-term storage can lead to the gradual loss of T cell function, necessitating techniques to preserve cell activity. Changes in surface markers can affect disease diagnosis, emphasizing the importance of accurate sample processing. Findings from this study reveal time-dependent changes in T cell surface markers during storage. CD3 levels declined significantly after the fourth day, with FITC labeling proving superior to APC. CD4 levels remained consistent until the fourth day, contrasting with previous findings on foreskin tissue. HLA-DR levels declined rapidly, indicating unsuitability for storage, consistent with other studies on cryopreserved cells. CD16 and CD8 levels decreased gradually, while CD56 declined rapidly after the third day, consistent with recent research. There were detectable and significant differences after the samples were stored for an improper period, which may have affected the integrity of the results, suggesting that understanding the factors influencing T cell surface protein changes during storage is crucial for maintaining result integrity.

Usefulness of a dedicated laser-cut metal stent with an anchoring hook and thin delivery system for endoscopic ultrasound-guided hepaticogastrostomy in malignant biliary obstruction: a prospective multicenter trial (with video).

Background and AimsEUS-guided hepaticogastrostomy (EUS-HGS) carries a risk of serious adverse events (AEs). A newly designed, partially covered laser-cut stent with antimigration anchoring hooks and a thin tapered tip (7.2F), called a Hook stent, has been developed to prevent serious AEs associated with EUS-HGS. The present prospective multicenter clinical trial evaluated the efficacy and safety of the Hook stent for EUS-HGS after failure of ERCP in patients with unresectable malignant biliary obstruction. MethodsThe primary endpoint was the rate of clinical success, and the secondary endpoints were the rates of technical success, AEs, recurrent biliary obstruction (RBO), procedure success without using a tract dilation device, re-intervention for RBO, time to RBO (TRBO) and overall survival (OS). ResultsA total of 38 patients underwent EUS-HGS using the Hook stent. Its technical and clinical success rates in patients undergoing EUS-HGS were 100% and 92.1%, respectively. The procedure success rate without using a tract dilation device was 94.7%. Four (10.5%) patients developed early AEs, but there were no severe AEs such as stent migration. RBO developed in 26.3% of patients. Re-intervention for RBO had a 100% success rate. The median TRBO was not reached, and the median OS was 191 days. ConclusionsEUS-HGS using the Hook stent demonstrated a high clinical success rate, a low rate of early AEs, and an acceptable stent patency. The Hook stent is safe and feasible for use in patients undergoing EUS-HGS.

Frailty screening with comprehensive geriatrician-led multidisciplinary assessment for older adults during emergency hospital attendance in Ireland (SOLAR): arandomised controlled trial.

Multidisciplinary comprehensive geriatric assessment (CGA) improves outcomes in hospitalised older adults but there is limited evidence on its effectiveness in the emergency department. We aimed to assess the benefits of CGA in the emergency department for older adults living with frailty. In this randomised controlled trial, we enrolled older adults (≥75years) who presented to the emergency department with medical complaints at University Hospital Limerick (Limerick, Ireland). Participants screened positive for frailty on the Identification of Seniors at Risk screening tool (score ≥2). Patients requiring resuscitation as well as those with COVID-19, psychiatric, surgical, or trauma complaints were excluded. Participants were randomly allocated 1:1 to geriatrician-led multidisciplinary CGA and management or usual care. Outcome assessors were masked to treatment allocation. The primary efficacy outcome was time spent in the emergency department, defined as the time from registration on the computer database until time of discharge or admission to an inpatient ward in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT04629690. Between Nov 9, 2020, and May 13, 2021, we recruited 228patients. 113participants were included in theintervention group (mean age 82·4years [SD 4·9]; 63 [56%] women; 113 [100%] White Irish) and 115in the control group (83·1[5·6]; 61 [53%]; 112 [97%]). Median time in the emergency department was 11·5h (IQR 5-27) in the intervention group and 20h (7-29) in the control group (median difference [Hodges-Lehmann estimator] 3·1 h [95%CI 0·6-7·5]; p=0·013). There were no adverse events related to the intervention. Geriatrician-led multidisciplinary assessment of older adults living with frailty was associated with reduced time spent in the emergency department setting at index visit and lower rates of nursing home admission, greater increases in quality of life, and lower decreases in function at both 30days and 180days. Multicentre trials are needed to confirm the external validity of the findings. This study provides an evidence base for similar teams in an emergency department setting. Health Research Board (ILP-HSR-2017-014).

Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial.

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2-5 years with POMC or LEPR deficiency or BBS. This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2-5 years who had hyperphagia and obesity due to biallelic POMC (including PCSK1) or LEPR variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at ClinicalTrials.gov (NCT04966741) and is complete. Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] vs five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7-99·8). The mean percent change in BMI from baseline at week 52 was -18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was -26% (SD 11) in patients with POMC or LEPR deficiency and -10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) were seen at Week 52. 91% of caregivers reported that patients were less hungry than at baseline. All adverse events were mild or moderate; skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions were most common. No serious adverse events or adverse events leading to study discontinuation or death were reported. To our knowledge this is the first trial of setmelanotide in patients younger than 6 years old. These results support the benefit of the drug as an early intervention to manage obesity in this population. Rhythm Pharmaceuticals.

Triggering oocyte maturation in IVF treatment in normal responders: a systematic review and network meta-analysis.

To compare efficacy and safety of hCG, GnRH agonist, dual, and double triggers in predicted normal responders undergoing ovarian stimulation and IVF DESIGN: A systematic review and network meta-analysis of randomized controlled trials (RCTs). RCTs indexed in PubMed, MEDLINE, EMBASE, clinical trial registries and Cochrane Database of Systematic Reviews up to December 2023. Twelve high-integrity RCTs comprising 1,931 women were included, which compared hCG trigger to GnRH agonist trigger, dual trigger, and double trigger. Statistical analysis was performed using STATA version 16. Key outcomes included clinical pregnancy rates (CPR), live birth rates (LBR), number of oocytes, number of mature oocytes, miscarriage rate and rates of ovarian hyperstimulation syndrome (OHSS). The network meta-analysis for CPR were relative risk (RR) 1.13 (95% Confidence Interval (CI):0.80-1.60) for hCG versus GnRH agonist trigger, RR 1.23 (95% CI:0.92-1.65) for hCG versus dual trigger, RR 0.38 (95% CI:0.21-0.69) for hCG versus double trigger, RR 1.09 (95% CI:0.70-1.70) for GnRH agonist versus dual trigger and 0.34 (95% CI:0.17-0.67) for GnRH agonist versus double trigger and RR 0.31 (95%CI:0.16-0.60) for double versus dual trigger. Dual trigger demonstrated the highest SUCRA (85.1%), indicating superior efficacy for clinical pregnancy rates. For LBR, while connectivity was limited, the RR was 1.31 (95% CI: 1.00-1.70) for dual versus hCG trigger, and RR 1.60 (95% CI: 1.05-2.43) for dual versus GnRH agonist trigger. OHSS rates were significantly lower with the GnRH agonist compared to hCG trigger (RR 0.56, 95% CI: 0.19-1.75). There were no randomized controlled trials reporting OHSS rates with the use of dual or double trigger. No significant differences were observed in the number of oocytes retrieved, mature oocytes, or miscarriage rates among the trigger protocols. The findings indicate that there is no evidence to suggest that using GnRH agonist, dual, or double protocols is superior to hCG trigger in improving clinical pregnancy rates. While live birth rates may benefit from dual trigger, results are limited by available RCTs. Larger, multicentre trials are needed for further evaluation of live birth rates and understanding of long-term outcomes.

Sexual function and menopausal symptoms among patients at high risk of ovarian carcinoma undergoing interval salpingectomy or risk-reducing salpingo-oophorectomy in the prospective multicenter WISP trial

Sexual function and menopausal symptoms among patients at high risk of ovarian carcinoma undergoing interval salpingectomy or risk-reducing salpingo-oophorectomy in the prospective multicenter WISP trial

Anemia Acuity Effect on Transfusion Strategies in Acute Myocardial Infarction

In patients with acute myocardial infarction (MI), limited physiologic adaptation to acute anemia might lead to greater benefit from a liberal red blood cell (RBC) transfusion strategy. Data on such a possible benefit are lacking. To compare acute anemia with chronic anemia and post-MI outcomes and estimate the differential effect of a restrictive RBC transfusion strategy compared with a liberal strategy on post-MI outcomes according to anemia acuity. A prespecified subgroup analysis of the Myocardial Ischemia and Transfusion (MINT) multicenter randomized clinical trial was conducted in 126 hospitals in 6 countries between April 26, 2017, and April 14, 2023, with 30-day follow-up and blinded adjudication of the primary outcome. The analysis included 3144 of 3504 MINT participants (89.7%) with acute MI, a hemoglobin (Hb) level less than 10 g/dL at randomization, and a first Hb measurement available on the day of or the day following hospital admission. The MINT trial randomized participants to a restrictive (Hb <7-8 g/dL) or liberal (Hb <10 g/dL) RBC transfusion strategy. Acute anemia was defined as having a first Hb value greater than 13 g/dL (men) or 12 g/dL (women), or as having a decrease greater than or equal to 2 g/dL between the first Hb measurement and measurement at randomization. Other Hb levels were categorized as chronic anemia. The primary outcome was a composite of death or recurrent MI up to 30 days after randomization. Secondary outcomes were death, recurrent MI, cardiac death, heart failure, pulmonary complications, and major bleeding events. Intention-to-treat analysis was performed. Among 3144 included participants (mean [SD] age, 72.3 [11.6] years; 1715 [54.5%] male; 1307 [41.6%] with type 1 MI), 1078 [34.3%]) had acute anemia. Acute anemia was associated with an increased risk of death or recurrent MI (adjusted risk ratio, 1.25; 95% CI, 1.05-1.48). The effect of a restrictive RBC transfusion strategy compared with a liberal strategy was similar for participants with either acute or chronic anemia for all outcomes. In this secondary analysis of the MINT trial, acute anemia was associated with less favorable post-MI outcomes than chronic anemia but did not modify the effects of the randomized transfusion strategy. In patients with anemia and MI, the acuity of anemia should not influence the choice of transfusion trigger. ClinicalTrials.gov Identifier: NCT02981407.

Comparing the Neurocognitive Effects of Right-Unilateral Ultra-Brief Pulse Electroconvulsive Therapy and Magnetic Seizure Therapy for the Treatment of Major Depressive Episode

Magnetic seizure therapy (MST) is under investigation as a treatment for adults with major depression. Prior research suggested that MST has comparable antidepressant efficacy with electroconvulsive therapy (ECT), but with greater cognitive safety. The objective of the study was to compare the neurocognitive outcomes of patients receiving an acute course of MST with those receiving ECT for the treatment of major depressive episode. This was a between-subject, double-masked, randomized, multi-center clinical trial. Seventy-three participants with a severe major depressive episode were enrolled and randomly assigned to treatment with MST (N = 38) or ultra-brief pulse right unilateral ECT (N = 35). The main outcomes were change in performance from baseline to end of acute treatment on multiple neurocognitive measures. Patients receiving MST, relative to those receiving ECT, had superior cognitive outcomes up to 72-hours post-treatment. Specifically, following MST treatment, there was significant improvement in fine motor dexterity (p=0.017) and no significant change in cognitive domains of attention, verbal fluency, executive function, and verbal learning and memory. In contrast, following treatment with ECT, patients demonstrated significantly worsened performance on measures of verbal fluency (p<0.001), executive function (p=0.038), and verbal memory retention (p<0.001). Autobiographical memory consistency significantly decreased following treatment with both ECT (p<0.001) and MST, though the magnitude of change was greater for ECT. The study findings confirm prior work and provide new evidence supporting the enhanced cognitive safety of MST relative to ECT. Future research is warranted on MST to optimize its application in individuals across the lifespan with neuropsychiatric illnesses. ClinicalTrials.gov identifier: NCT00488748.

Influence of the Olfatín Project on the reduction of pain related to intranasal influenza vaccination, as part of a school influenza vaccination program

PurposeTo evaluate the influence of viewing the Olfatín Project video on the assessment of school LAIV-associated pain in three and four-year-old children through the Wong Baker Faces® pain classification scale. Design and methodsA three-arm randomized multicenter clinical trial with a placebo control group was carried out. The main variable measured was pain, assessed through the score on the Wong Baker Faces® Pain Rating Scale. There were a total population of 4591 children three and four-year-olds (born in 2019 and 2020) and who attended the 1st and 2nd year of early childhood education. Before the school vaccination, researchers randomly assigned participant schools corresponding to each of the basic health areas to each of the three study groups: Olfatín's video viewing, a control video viewing not related to influenza and no video viewing. ResultsNo significant differences according to sex, age or the minor's grade according to the assigned intervention were detected. 72.3% of those vaccinated assigned a 0 from the Wong Baker Faces® scale: 75.4% of those who watched Olfatín's video, 68.3% for those in Drilo's group and 72.8% for those who didn't watch any video, but without significant differences (p = 0.08). There were no significant differences either stratifying by sex. ConclusionLAIV is a painless vaccine for children, which has to be taken into account by the health authorities when planning the pediatric influenza vaccination campaign. Practice implicationsOlfatín's cartoon video can be used by professionals to create a greater experience for children and therefore a better acceptance.

Targeted Therapy in Salivary Gland Cancer: Prevalence of a Selected Panel of Actionable Molecular Alterations in a German Tertiary Referral Center Patient Cohort.

Salivary gland carcinomas (SGC) are a heterogeneous group of malignancies, with 24 subtypes defined by the World Health Organization (WHO). The standard of therapy is surgical resection, with adjuvant radiotherapy in most cases. However, disease recurrence (R) or metastasis (M) is common and no active systemic therapies are currently available for RM-SGC resulting in a 5-year survival rate of only 20%. Overall, 55 SGC patients with seven different histological tumor subtypes were included in this study. formalin-fixed paraffin-embedded (FFPE) tissue samples were used for immunohistochemical (IHC) staining targeting HER2/neu, androgen receptor (AR), PD-L1, EGFR, panTRK, and TROP2. Fluorescence in situ hybridization (FISH) was performed for detecting HER2/neu amplifications and NTRK1/2/3 translocations in selected cases with relevant HER2/neu and panTRK protein expression, respectively. IHC and FISH results were correlated with patients' clinical and histopathological data. The overall prevalence of druggable molecular alterations, defined as an immunoreactive score ≥ 9 in at least one of the analyzed targets, was 54.4% with the highest percentage in oncocytic carcinomas (100%) and lowest percentage in acinic cell carcinomas (10%). EGFR overexpression proved to be the most common alteration (32.7% of cases) followed by overexpression of TROP2 (27.3%), AR (10.9%), HER2/neu (7.3%), PD-L1 (1.8%), and panTRK (1.8%). HER2/neu amplifications were found in 50% and NTRK translocations were found in 100% of all cases with elevated Her2/neu and panTRK protein expression, respectively. Our data indicate that targeted therapy using e.g., trastuzumab deruxtecan, bicalutamide, pembrolizumab, cetuximab, entrectinib or sacituzumab govitecan might be a promising option especially for a relevant subset of patients with RM-SGC not suitable for salvage surgery. However, evidence from clinical studies regarding response rates to these therapies remains sparse, which underlines the need of multicenter clinical trials.