Citations

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive disease caused by the deposition of transthyretin (TTR) as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis. METHODS: This phase 2, double-blind, placebo-controlled trial randomized participants with transthyretin amyloidosis with cardiomyopathy to receive infusions every 4 weeks of either coramitug at 2 dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary end points were the change from baseline to week 52 in the 6-minute walk test and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular events (comprising hospitalization caused by cardiovascular events or urgent heart failure visits). RESULTS: In total, 104 participants (median age, 77 years; 93% men; 84% New York Heart Association class II; 13% with variant transthyretin amyloidosis with cardiomyopathy) were randomized and dosed: 34 to 10 mg/kg of coramitug, 35 to 60 mg/kg of coramitug, and 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range, 1224, 3406). In total, 90% of participants were receiving disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with transthyretin silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, 60 mg/kg of coramitug significantly reduced NT-proBNP levels compared with placebo (–48% [95% CI, –65% to –22%]; P =0.0017). The change in 6-minute walk test from baseline to week 52 was not statistically different from placebo with either dose. Coramitug (60 mg/kg) was associated with improved functional echocardiographic parameters and was well tolerated. CONCLUSIONS: This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in transthyretin amyloidosis with cardiomyopathy, was well tolerated and, at a dose of 60 mg/kg, resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6-minute walk test within 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05442047.

Introduction Many clinical practice guidelines (CPGs) claim to use Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, but its implementation varies. This suggests that CPG developers, methodologists and users would benefit from an instrument to evaluate the extent to which CPGs adhere to GRADE approach. Such a structured instrument is currently unavailable. Accordingly, this study will develop an evaluation instrument for assessing guideline adherence to the GRADE approach, which we have named ‘GRADE-Check’. The goal is to target items to which CPGs fail to adhere and that potentially have serious consequences resulting in inaccuracies in certainty of evidence and inappropriate direction or strength of recommendations, thereby discriminating across CPGs in issues of importance. Methods and analysis The panel will include up to 25 individuals with specific knowledge and expertise, including experienced authors, educators and methodologists on CPGs methodology and GRADE approach from relevant organisations. The instrument will focus on the key elements of GRADE, aiming for clarity for GRADE experts and non-GRADE experts to apply. The development process for GRADE-Check will consist of the following five phases: (1) recruitment of a panel of GRADE experts; (2) development of objectives and scope for the development of GRADE-Check and criteria for item selection; (3) generation of candidate items through a literature review and panel consultation; (4) panellist discussion to construct the initial draft and extended explanation manual and (5) user testing. Ethics and dissemination This study has been approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (no. (2025047K)). Our research findings will be published in peer-reviewed journal articles and presented at academic conferences. Additionally, the dissemination plan will include considerations for the development of implementation manuals, a dedicated project website and training tools.

Background: Orthopaedic sports medicine fellowships are highly competitive, yet objective data defining characteristics of successful applicants remain limited. Hypothesis: It was hypothesized that greater academic productivity, top-tier residency training, and certain demographic factors would be associated with matching into a top-ranked orthopaedic sports medicine fellowship. Study Design: Cross-sectional study. Methods: We retrospectively reviewed applicants who matched into one of the top 10 orthopaedic sports medicine fellowships from 2020 to 2025, as identified by previous applicant preference rankings. Applicant data were obtained from publicly available sources and verified by 2 independent reviewers. Variables included sex, degree type, residency program ranking, geographic region, and research productivity (total publications, primary publication count, H-index, and sports-related publications). Multivariate logistic regression assessed predictors of matching into top 5 versus 6th- to 10th-ranked programs. Results: Among 226 matched applicants, 87.7% were male and 99.1% held a doctorate in medicine degree. The mean total publication count was 12.4, mean H-index was 8.2, and 30.5% trained at a top 20 orthopaedic residency. Applicants matching into top 5 programs had significantly higher research metrics than those in the 6th- to 10th-ranked programs: total publications (20.1 vs 4.7), primary publication count (6.2 vs 1.6), and sports-related publications (11.4 vs 1.9). On regression analysis, total publications, H-index, and residency ranking were independent predictors of matching into a top 5 program. Conclusion: Matching into a top orthopaedic sports medicine fellowship is associated with higher academic productivity and training at a top-tier residency program.

Background/Objectives: Immortality and anti-aging research is accelerating, with implications across medicine. This narrative review explores the biological principles, translational innovations, and ethical considerations at the intersection of aging and plastic surgery, reframed for a broad clinical audience. Methods: A narrative review of the literature from PubMed, clinical trials, and translational studies was conducted, with emphasis on regenerative medicine, stem cells, tissue engineering, gene editing, and longevity pharmacologics within the field of plastic and reconstructive surgery. Results: Key themes include (1) the biology of aging and epigenetic reprogramming, (2) esthetic and regenerative innovations with broader clinical significance, (3) emerging genetic and pharmacologic longevity strategies, (4) ethical and regulatory challenges, and (5) future directions such as nanotechnology, artificial intelligence, and digital immortality. Conclusions: Immortality remains an aspirational frontier, but innovations in regenerative science and longevity research offer opportunities for improving healthspans. Medicine as a whole must balance innovation with ethics, equity, and safety in translating these discoveries to patient care.

Objective This study aimed to identify specific causes, clinical features, and contributing factors associated with early childhood mortality in a vulnerable subset of patients with cleft lip and/or palate (CL/P) who did not survive to undergo surgical repair. Design This was a retrospective chart review study. Setting The study was conducted at a single tertiary medical center. Patients/Participants We identified 26 liveborn CL/P patients who died without cleft repair from 1970 to 2024. Their data was compared to a control group of 2070 surgically repaired CL/P patients from the same institution. Main Outcome Measures Our primary goal was to characterize the clinical profile of patients experiencing prerepair mortality. Secondary outcomes included identifying causes of death, maternal and prenatal risk factors, and comparing these findings with the surgically repaired patients. Results All 26 unrepaired patients (100%) had genetic syndromes or isolated severe congenital anomalies, a significant difference compared to 24% in the surgically repaired group ( P < .0001). Trisomy 13 (30.8%), holoprosencephaly (23.1%), congenital cardiac defects (11.5%), and trisomy 18 (11.5%) were the leading causes of death. The median age at death for unrepaired patients was 25 days (interquartile range 4-125 days), significantly lower than the 61.9 years in the control group ( P < .0001). Multivariable logistic regression showed that genetic syndromes or severe congenital anomalies were strongly associated with early mortality ( P < .0001). Notably, all unrepaired patients who were born in the United States after 2005 had accurate prenatal diagnoses, which allowed clinical planning before the patients were born. Conclusions Prerepair mortality in CL/P is significantly driven by underlying genetic syndromes or congenital anomalies. For surgeons, this highlights the importance of genetic testing and prenatal care to guide appropriate surgical management. Considering a wait in surgical intervention until patients are approximately 4 months old may allow for better survival assessment and informed decisions for these high-risk individuals.

Obstructive sleep disordered breathing (oSDB), including obstructive sleep apnea (OSA), frequently coexists with cleft lip and palate, velopharyngeal insufficiency (VPI), and other craniofacial conditions. Moreover, oSDB is often a key factor in decisions for primary or revision cleft palate or velpharyngeal surgery. Due to the frequency with which cleft and craniofacial team members care for patients with oSDB, this article provides a primer for OSA evaluation and management for team members. oSDB can have a significant impact on quality of life, health outcomes, surgical planning, and global development for all children, especially those with cleft and craniofacial conditions. In this review, oSDB screening and testing methods are discussed, including interpretation of OSA testing. Considerations for specific craniofacial populations are included, such as those with 22q11.2 deletion syndrome and Pierre-Robin sequence. The impact of VPI surgery on OSA is discussed. Finally, approaches to OSA management are reviewed, with attention to how standard management approaches may shift in children with cleft and craniofacial conditions. As awareness of oSDB in children has increased, including increased access to diagnostic testing, studies have shown certain patient populations are more likely to have OSA and would benefit from screening. Children with craniofacial conditions, including cleft palate and velopharyngeal insufficiency, have altered risk profiles which impact management considerations for OSA. This article provides an introduction to key concepts in oSDB screening, diagnositics, and management, which can be valuable for any professional assisting in the care of children with a cleft or craniofacial condition.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a leading cause of kidney failure worldwide. Disease progression is driven by cyst expansion, tubular injury, and maladaptive metabolic and hemodynamic changes. Tolvaptan remains the only US Food and Drug Administration–approved disease-modifying therapy, however its tolerability and safety profile highlight the need for additional strategies. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for glycemic control, have demonstrated robust kidney-protective and cardioprotective effects across diverse patient populations, including those without diabetes. By lowering intraglomerular pressure, metabolic reprogramming, and attenuating hypoxic microenvironment and inflammation, SGLT2is target mechanisms that are relevant to ADPKD. However, concerns that SGLT2i may provoke osmotic diuresis and activate vasopressin led to systematic exclusion of patients with ADPKD from pivotal outcome trials. The 2025 Kidney Disease Improving Global Outcomes ADPKD guidelines explicitly advise against the use of SGLT2i for slowing kidney function decline in ADPKD. In this review, we examine mechanistic intersections between SGLT2i and ADPKD pathophysiology, summarize available preclinical and early clinical data, and discuss ongoing large trials designed to address safety and efficacy of SGLT2i in patients with ADPKD. We also highlight the importance of genetic heterogeneity, as most ongoing trials are enriched for rapid progressors carrying PKD1 or PKD2 pathogenic variants, while other genotypes such as DNAJB11 , ALG8 , and ALG9 , often associated with greater interstitial fibrosis, are underrepresented. Substratification of patients by genotype, risk of progression, and comorbidities will be essential to guide precision application of SGLT2i. Whether SGLT2i can ultimately be positioned as an adjunctive or standalone therapy for ADPKD remains unresolved.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .