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Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2 years) with NF1 who have symptomatic PN not amenable to complete resection. We report updated results from the LTFU phase of the pivotal, phase 2b ReNeu trial (NCT03962543) evaluating the efficacy and safety of mirdametinib. MATERIALS AND METHODS In ReNeu, mirdametinib capsules or tablets for oral suspension (2 mg/m2 BID, max 4 mg BID) are administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle (~2 years) treatment phase, patients could continue mirdametinib in an optional LTFU phase. These analyses are inclusive of the treatment and LTFU phases (data cutoff: June 12, 2024; an additional 9 months of cumulative data following the primary analysis). Exploratory analyses reported here included confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume from baseline on consecutive MRI scans within 2 to 6 months, assessed by blinded independent central review), duration of response (DoR), change from baseline in target PN volume, and safety. RESULTS Fifty-eight adults and 56 children were dosed with mirdametinib. Median (range) duration of mirdametinib treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered the LTFU. Confirmed ORR was 47% (27/58; 95% CI, 33%, 60%) in adults and 55% (31/56; 95% CI, 42%, 69%) in children. Of patients with a confirmed objective response, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of >50%). Median (range) best percentage change from baseline in target PN volume was -41% (-90%, 13%) in adults and -43% (-98%, 48%) in children. Median DoR was not reached. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhoea, nausea, and vomiting in adults, and diarrhoea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and in 14%, 14%, and 9%, respectively, of children. CONCLUSIONS An increase in confirmed ORR was observed with longer duration of mirdametinib treatment, with additional deep responses achieved in both adults and children with NF1-PN. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals identified in the LTFU phase. SUPPORTED BY SpringWorks Therapeutics, Inc.

Abstract Background To ensure the Pediatric Infectious Diseases (ID) Certifying Examination remains aligned with current clinical practice, the American Board of Pediatrics (ABP) conducted a comprehensive practice analysis to update the exam content outline. Methods A panel of 9 pediatric ID physicians identified 34 core tasks across 5 performance domains to guide revisions to the existing outline. The panel identified relevant, testable knowledge areas aligned with these tasks and organized them into 22 domains and 186 initial subdomains. A nationwide validation survey of board-certified pediatric ID physicians collected relevance ratings and feedback on missing or outdated topics and suggested exam weights, which were used to guide further revisions. Subsequently, the pediatric ID subboard conducted an item reclassification process, which resulted in additional refinement. Results The final content outline comprises 22 domains and 196 subdomains, with updated domain weights to better reflect the clinical landscape. Notably, domains such as cardiovascular, bone and joint, and urologic infections increased in weight, while antimicrobial principles decreased. Conclusions This rigorous, inclusive process strengthens the exam’s content validity and supports the ABP’s goal of certifying physicians who possess the knowledge needed to deliver safe and effective care.

Abstract Introduction This study investigated the impact of visual editing of sleep recordings for use in predicting neurodegenerative disorder (NDD) risk. Methods All participants underwent in-home Sleep Profiler studies. Forty-four were diagnosed with mild cognitive impartment (MCI = 40) or Alzheimer’s disease (AD = 4)(MCI/AD: 55% women, 72.6+/-8.6 years), 26 with REM sleep behavior disorder (RBD: women = 27%, age = 67+/-9.8), and 29 were controls (NC: women = 69%, age = 63+/-11.5). A 4-class machine learning algorithm used age plus eight sleep biomarkers to assign NDD risk probabilities. Records with CG-assigned probabilities >70% were labeled Probably-Normal, and from 45-70% Likely-Normal. Similar thresholds were used to assign Likely- or Probably-Abnormal. NDD risk characterizations were generated based on auto-scoring (“auto”), and again after the recordings were visually edited for accuracy (“edited”). Results Comparing the auto- vs. edited-NDD classifications in the MCI/AD group, the same NDD risk classifications were observed in 91% (39/43), with 2 cases shifting from Likely-Normal to Probably-Normal, one shifted from Likely-AD to Likely-Normal with AD Indications, and one changed from Probably-AD to Likely-AD. The same NDD risk classifications were observed in 81% (21/26) of the RBD cases, 3 shifted from Probably-Abnormal to Likely-Abnormal, one shifted from Likely-Normal to Probably-Normal, and one changed from Likely-Abnormal to Likely-Normal. The same NDD risk classifications were observed in 86% of the NC group, with 4 cases shifting from Likely-Normal to Probably-Normal. Conclusions These findings suggest that the likelihood of a gross misclassification of NDD risk resulting from auto-detected sleep biomarkers is relatively low with inconsistencies directed toward slightly increased NDD risk classifications.

Abstract Introduction This study investigated differences in opinions about neurodegenerative disorders (NDD) in countries with large populations and expanded access to healthcare. Methods A 5-point Likert scale survey assessed opinions of 30–59-year-olds, pertaining to their parents and NDD conditions. 100 surveys, translated into native languages, were acquired in eight developed countries. Positive (somewhat- or strongly-agree) vs. other responses, sex, and country were submitted to logistic regression and Chi-squared analyses. Results “It is important for me to know if my parent has a risk for developing a NDD condition in the future, even if nothing can be currently done to prevent or cure those diseases” had higher positive responses in Australia (92%) compared to Germany (74%) and the USA (78%). “I believe that knowing about my parent’s risk for developing a NDD condition will help me assist in the planning of their future” had higher number of positive responses in Australia (91%) versus Japan (70%), Germany (76%), Italy (80%) and UK (80%). “If my parent(s) was found to be at risk for a NDD condition, I would want to learn more about medications and adaptive therapies that could delay onset” was responded to more positively in Australia (92%), Canada (78%), France (87%), Germany (78%), Italy (88%), UK (88%), and USA (81%) versus Japan (60%). Conclusions Australians responded more positively to questions related to care of a parent with a NDD disorder. These findings suggest cultural differences that could influence education and support systems requirements for sleep medicine providers and NDD patients.

Abstract Perioperative low cardiac output syndrome (LCOS) remains a significant complication in adult cardiac surgery, contributing to substantial morbidity, prolonged intensive care, and increased mortality. Its incidence is expected to rise further due to the evolving complexity of referred surgical patients, often characterised by advanced age, multiple comorbidities, challenging anatomy, and impaired haemodynamics. Despite advances in pharmacological and perioperative care, outcomes for high-risk patients have not shown significant improvement, prompting interest in temporary mechanical circulatory support (tMCS) as a proactive strategy. This Expert Consensus Document from the European Association for Cardio-Thoracic Surgery (EACTS) presents the first dedicated guidance on the pre-emptive use of tMCS in high-risk adult cardiac surgical patients. Developed by a multidisciplinary task force, it emphasises structured risk stratification, early initiation, and individualised device management informed by interdisciplinary Heart Team discussions. The document proposes clinical pathways for patient selection, defines criteria for tMCS initiation, and provides practical algorithms for various scenarios, including advanced heart failure, cardiogenic shock, and post-cardiotomy LCOS. It reviews the current evidence on available tMCS devices, such as intra-aortic balloon pumps, microaxial flow pumps, veno-arterial extracorporeal life support and hybrid strategies, and addresses perioperative care, intensive care unit protocols, ethical considerations, as well as informed consent and support withdrawal. Despite promising results, substantial knowledge gaps remain, including long-term outcome data, device selection criteria, and cost-effectiveness analyses. This consensus aims to support clinical decision-making, standardise practice, and stimulate research to improve outcomes in a growing population of high-risk surgical patients.

Background. The spirometric response to standard-of-care (SOC) immunosuppressive therapy for the management of bronchiolitis obliterans syndrome (BOS) has been sparsely reported in the literature. Data from a Medicare-approved Registry were analyzed to characterize the effectiveness/durability of a wide range of SOC interventions to manage the decline of lung function and to validate the study spirometric criteria for initiation of rescue therapy. Methods. Lung transplant recipients with refractory BOS at 21 US collaborating centers were enrolled in the Registry. Data included both nonspirometric (eg, demographic, Immunosuppressive Regimens for management of BOS) and spirometric parameters (ie, forced expiratory volume in 1 s [FEV 1 ] measurements and derived indices). The utility of study FEV 1 criteria for treatment (ie, statistically significant rate of FEV 1 decline >30 mL/mo) was evaluated by comparing the spirometric course between participants who met or did not meet this criterion. Results. Only 21% of participants treated with SOC therapy had >50% decrease (76 ± 25% decrease) in the rate of FEV 1 decline. Although 51% of participants had a partial response (rate of FEV 1 decline decreased on average 71%), 49% of participants had a substantial increase (mean increase 224%). The FEV 1 criterion for treatment was able to identify 19% of participants (48/258) who achieved durable stabilization (ie, nonsignificant rate of FEV 1 <30 mL/mo) with SOC therapy. Conclusions. Patients with BOS have a widely variable response to SOC therapy. Our findings support the use of FEV 1 rate of decline to assess response to SOC therapy and to ensure appropriate assignment of participants with refractory BOS to rescue therapy treatment cohorts.

Abstract The acetabular labrum is a fibrocartilaginous structure that deepens the acetabular socket and helps maintain a suction seal. In patients with hip dysplasia, a distinct labral tear pattern called an inside‐out labral tear is often seen. This tear pattern is particularly challenging to correct via conventional techniques since the labrum can potentially remain everted and insufficiently restore the native hip labral suction seal after repair. An inverted hip labral repair technique is performed for this pathology at our institution and focuses on achieving optimal labral orientation to enhance the suction seal and joint stability, particularly in dysplastic hips. This Technical Note aims to describe the key surgical principles and clinical considerations of inverted hip labral repair. Technique Video video See video under supplementary data.

Abstract INTRODUCTION In multicenter Alzheimer's disease studies, amyloid positron emission tomography (PET) visual reads are typically performed centrally by a few experts. Incorporating a broader reader network enhances scalability and generalizability. METHODS Ten neuroimaging experts from eight Alzheimer's Disease Research Centers (ADRCs) visually read 180 amyloid PET scans (30 scans and 15 duplicate scans for each of four tracers, imaged across a wide variety of scanners), using preferred reading software without anatomical imaging or quantitation. Scans were classified as elevated or non‐elevated per tracer‐specific criteria. Inter‐ and intra‐rater agreement was assessed. RESULTS Inter‐rater agreement was substantial (Fleiss’ κ = 0.78), with full consensus on 69% of scans. Inter‐rater reliability was substantial to perfect across tracers (Fleiss’ κ = 0.70–0.87). Intra‐rater agreement was substantial to perfect (Cohen's κ = 0.79‐1). Scans with intermediate (10–40 Centiloid) quantitation had lower reader agreement. DISCUSSION A multicenter expert network achieved substantial agreement classifying amyloid PET scans. These scans provide a standard for reader training and reliability assurance in future studies. Highlights Calibration methods ensure reliable amyloid positron emission tomography (PET) visual reads across multiple raters. Substantial agreement is possible across readers using their preferred tools. Agreement is also substantial regardless of the amyloid PET tracer used. Scans with intermediate (10–40 Centiloid) quantitation have lower reader agreement. The calibration set will become a training tool for amyloid PET visual read studies.

AimsThe aim of this study was to compare the early clinical outcomes of robotically-assisted total knee arthroplasty (RA-TKA) and manual total knee arthroplasty (M-TKA), using daily remote patient monitoring.MethodsWe prospectively enrolled and compared patients who underwent 95 RA-TKAs with those who underwent 114 M-TKAs. All patients used an activity monitor and a patient engagement platform for two weeks preoperatively and 90 days postoperatively to collect daily visual analogue scale (VAS) pain scores, opioid consumption (in morphine milligram equivalents (MMEs)), step counts, weekly Oxford Knee Scores (OKSs), and monthly Forgotten Joint Scores (FJS). There were no significant differences between groups in sex or BMI. Patients in the RA-TKA group were significantly younger (mean age 63 vs 65 years; p = 0.006). Independent-samples t-tests, chi-squared tests, and Fisher’s exact tests were used for statistical analysis.ResultsRA-TKA led to significantly decreased pain (mean VAS 3.6 vs 4.2; p = 0.011) and significantly reduced opioid consumption in the first seven days postoperatively (a mean of 10 less MMEs per day; p < 0.001) compared with M-TKA. The RA-TKA group stopped taking opioids six days sooner (mean 24 days vs 30 days; p = 0.041). There were no significant differences in the number of days before stopping the use of walking aids (mean 31 days vs 35 days; p = 0.091). Patients in the RA-TKA group had significantly increased OKSs for the first five weeks (p = 0.013). There were no significant differences in the FJSs at all times or in OKSs beyond five weeks. There were no significant differences in the operating times (p = 0.405), step counts (p = 0.642), or complications (p = 0.222) between the groups.ConclusionThe use of robotic assistance in TKA led to significant improvements in pain, opioid consumption, and OKSs compared with manual instrumentation in the early recovery after primary TKA.Cite this article: Bone Joint J 2025;107-B(10):1054–1063.