Citations

ABSTRACT Premature physeal closure occurs following trauma, cancer, or infection. Current treatments have poor success rates. With recent pediatric donor tissue availability, physeal allograft transfer (PAT) can now be considered. The purpose of this study was to study the safety and feasibility of PAT in a large animal model. The aim of this study is to gather foundational data to inform future studies into the efficacy of PAT. Physeal defects were created in the distal femur of nine female domestic swine and treated with PAT from two male donor pigs, cementation, or bone autograft. Viability was assessed. After 3 months, physes were visualized using CT and MRI. Integration, tissue composition, donor DNA presence, and microscopic appearance were evaluated. Physeal allografts demonstrated 93% viability after procurement and preservation. All animals reached the 3‐months study endpoint without gross deformations. No physeal bars formed in any group. Cystic changes were seen in experimental and control femurs. All groups showed disorganized tissue architecture without growth plate recapitulation. High allografts viability and structural integrity after procurement support the potential of this treatment. Although no gross deformities were found, transferred physes demonstrate poor integration and incomplete repair. The lack of physeal bar formation in the control group limits the reliability of the animal model for studying physeal allograft transfer. Lastly, this study was designed as a feasibility study and lacks power to compare treatment effects statistically. The efficacy of PAT for preventing growth arrest remains undetermined.

Abstract Inpatient boarding (holding patients in the emergency department [ED] while awaiting an inpatient bed) is associated with increased risk of delirium, medication safety events, and hospital mortality in older adults. We investigated boarding trends across age strata to determine if older patients had elevated rates compared to younger patients. Administrative data for ED encounters resulting in admission from 3 healthcare systems (2 Midwest, 1 Northeast) from 1/1/19 to 12/31/24 were reviewed. Age was categorized by strata: < 21, 21-64, 65-74, 75-84, and ≥ 85. Based on the CMS Age Friendly Hospital Measures, the proportion of patients boarding for 3+ hours was calculated within each year and age strata. Boarding rates varied substantially by system and age group. At Systems 1 (S1) and 3 (S3), ≥ 85 patients had the highest rates (S1: 54.9%, S3: 70.9% in 2024) and, at System 2 (S2), all adult patients (21+) had similar rates (20.5-22.4% in 2024). Boarding rates increased in all systems over the study period. At S1 and S3, < 21 patients had the highest average yearly increase in boarding (S1: 7.4%, S3: 3.9%). At S2, boarding increased most in ≥ 85 (23.9%). In this multisystem evaluation, approximately one in two older adults experience ED boarding, with the oldest patients (≥ 85) facing the greatest exposure to boarding in recent years. These findings taken alongside known delays and safety risks associated with boarding and patient care complexity amongst the oldest adults may result in disproportionate harm to some of the most vulnerable patients.

Abstract Background Aortic valve calcification (AVC), as measured by gold-standard computed tomography (CT) Agatston score, provides an anatomic assessment of aortic stenosis (AS) severity and is a key predictor of AS progression and need for valve replacement. AVC detection and quantification from transthoracic echocardiography (TTE) could expand AS early diagnosis and risk stratification, currently limited by CT availability and radiation exposure. Methods A multi-view video-based deep learning framework was developed using 1166 TTE aortic valve videos from 187 TTE studies acquired in 110 patients with available AVC score by CT. EchoAVC architecture includes a feature extraction model followed by a quality-aware model that aggregates video-level information to obtain patient-level predictions for AVC detection and quantification (score). The framework was validated internally with 173 TTE studies from 86 patients across seven centres, and externally using 430 TTE studies from 280 patients across four different centres. The associations between EchoAVC estimations and AS severity, progression, and need for aortic valve replacement were examined. Results EchoAVC demonstrated excellent performance in AVC detection (AUROC 0.98, accuracy 94.4%), and quantification (R = 0.64) in the external multi-centre testing set. EchoAVC score was correlated with echocardiographic AS severity descriptors, including aortic valve mean pressure gradient (ρ = 0.749) and peak velocity (ρ = 0.757), and predicted future increase in mean pressure gradient (ρ = 0.382), peak velocity (ρ = 0.433) and calcium score by CT (ρ = 0.650). In 361 patients followed for a median of 3.8 years, 139 underwent aortic valve replacement. Baseline presence and extent of AVC as predicted by EchoAVC showed strong risk-stratification power for aortic valve replacement, remarkably in line with those obtained by CT, and incremental over TTE AS descriptors. EchoAVC was further tested in routine clinical practice images, confirming strong associations with AS severity and progression, including stratification for incident AS in previously unaffected individuals (p<0.001). Conclusions EchoAVC enables accurate and non-invasive detection and quantification of AVC, offering substantial diagnostic and prognostic value for aortic stenosis progression and need for valve replacement. This technique holds promise as a scalable tool for early detection and clinical management of aortic valve stenosis. Clinical Perspective What Is New? * Aortic valve calcification can be detected and quantified on standard, two-dimensional transthoracic echocardiography * EchoAVC score is associated with echocardiographic metrics of aortic stenosis severity * EchoAVC predicts progressive increase in aortic stenosis severity and need for aortic valve replacement What Are the Clinical Implications? * This openly available deep learning framework can be used to estimate aortic valve calcium in patients at risk of or presenting aortic stenosis to predict aortic stenosis progression * EchoAVC may help identify patients likely to have high aortic valve calcium and prioritize them for confirmatory CT assessment, thereby supporting earlier identification of calcific aortic valve disease in clinical pathways.

Aims Total elbow arthroplasty (TEA) has shown favourable outcomes in the management of severely comminuted distal humeral fractures in low-demand elderly patients, leading to its increased use in recent years. Less is known about the outcomes of TEA when used for the failure of either internal fixation or conservative management, particularly whether not performing TEA acutely influences the options for further management if fixation fails. This systematic review aimed to assess the clinical and functional outcomes following TEA when used for the post-traumatic sequelae of a distal humeral fracture, and to compare these outcomes with those in patients with a distal humeral fracture who undergo TEA acutely. Methods MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus databases were searched from January 2000 to September 2024 for studies reporting complications, reoperations, the range of motion of the elbow, or functional outcomes following the use of TEA in the management of the post-traumatic sequelae of distal humeral fractures, including those due to failed fixation, nonunion, and post-traumatic arthritis. Demographic and clinical data were collected, descriptive statistics were summarized, and meta-analyses were undertaken to compare the outcomes between salvage and acute TEA. Results A total of 16 studies were included, with a total of 380 patients who underwent salvage TEA and 251 who underwent TEA as the initial management. Salvage TEA was associated with a significantly higher overall risk of complications (odds ratio (OR) 2.5 (95% CI 1.0 to 5.9)), though the rate of reoperations did not differ from those who underwent TEA acutely (OR 1.4 (95% CI 0.8 to 2.4)). Pooled analyses revealed a similar postoperative range of flexion (mean difference (MD) -2.4° (95% CI -9.1 to 4.3)) and extension of the elbow (MD 1.1° (95% CI -2.3 to 4.5)) and pronation (MD 0.0° (95% CI -1.1 to 1.1)) and supination (MD -0.0° (95% CI -1.0 to 0.9)) of the forearm. However, salvage TEA showed significantly inferior functional outcomes, as assessed by the Mayo Elbow Performance Score (MD 9.7 (95% CI -18.8 to -0.6)). Conclusion These findings indicate that salvage TEA represents a viable option for the management of post-traumatic sequelae following the teatment of a distal humeral fracture, although patients who underwent salvage TEA had a significantly increased rate of complications and significantly inferior functional outcomes compared with those who underwent TEA acutely. Cite this article: Bone Joint J 2026;108-B(1):21–29.

ABSTRACT Introduction Positron emission tomography (PET) myocardial flow reserve (MFR) is a robust indicator of coronary vascular health and a strong predictor of cardiovascular risk. Clinical guidelines typically use fixed MFR thresholds (e.g., <2.0) to stratify risk, yet this approach overlooks individual variation, particularly by age and sex. We aimed to establish age- and sex-adjusted MFR percentiles and to evaluate their prognostic and predictive performance for cardiovascular risk assessment, in comparison with conventional fixed-threshold MFR approach. Methods Using data from the REFINE PET registry (24,820 patients from 12 sites), we measured PET MFR and derived age- and sex-adjusted MFR reference percentiles using quantile regression in patients without known coronary artery disease. All patients were categorized into percentile-based quartile groups. The primary outcome for prognostic and prediction analyses was major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, or heart-failure hospitalization. Time-to-event associations were evaluated using covariate-adjusted survival models, with cumulative incidence and hazard ratios (HR) estimated at 1 and 5 years in the derivation dataset, an independent but similar validation dataset A, and a high-risk validation dataset B. Predictive performance for MACE was assessed using discrimination, calibration, and reclassification metrics, comparing percentile-based models with models using a fixed MFR threshold (<2.0). Results Among participants (mean age 66.5 years; median follow-up 3.6 years), age- and sex-adjusted MFR quartile groups were strong independent predictors of MACE, with adjusted HR increasing stepwise across quartile groups at both early and later follow-up. At 1 year, HR (95% CI) comparing the lowest to the highest quartile group were 4.06 (3.41–4.82) in the derivation cohort, 3.31 (2.32–4.71) in validation cohort A, and 2.35 (2.05–2.70) in validation cohort B. At 5 years, the corresponding HR were 2.18 (1.86–2.56), 1.77 (1.31–2.40), and 1.59 (1.36–1.86). Percentile-based models demonstrated consistently higher discrimination, better calibration, and greater net reclassification for MACE at both time points compared with fixed-threshold MFR models. Although 67.2% of patients had preserved MFR (>2.0), cardiovascular risk increased steadily across MFR percentiles even within this range. Conclusion Age- and sex-adjusted MFR percentiles provide a reliable, clinically actionable measure of vascular health, improving cardiovascular risk stratification by better capturing age- and sex-related heterogeneity in vascular risk. Compared with traditional fixed-threshold approaches, MFR percentiles demonstrate improved predictive performance for cardiovascular risk assessment across diverse patient populations. CLINICAL PERSPECTIVE What is new? In a large, multinational real-world registry of more than 24,000 patients undergoing PET MPI, we derived age- and sex-adjusted myocardial flow reserve (MFR) percentiles, establishing a lifespan-based reference framework with age-specific reference values. Age- and sex-adjusted MFR percentiles showed a strong, graded association with 1- and 5-year cardiovascular risk and demonstrated improved prognostic and predictive performance compared with fixed MFR thresholds and models without MFR across independent derivation and validation datasets, including a higher-risk cohort. Lower adjusted MFR percentiles were consistently associated with higher risk of major adverse cardiovascular events, including all-cause mortality, myocardial infarction, and heart-failure hospitalization. What are the clinical implications? Age- and sex-adjusted MFR percentiles provide a personalized, dynamic measure of coronary vascular health that improves cardiovascular risk stratification by accounting for age- and sex-related heterogeneity. A percentile-based approach may help clinicians better identify patients at elevated cardiovascular risk who may warrant closer monitoring or intensified preventive strategies, while avoiding unnecessary intervention in lower-risk individuals. By integrating macrovascular and microvascular dysfunction, age- and sex-adjusted MFR percentiles offer a clinically interpretable marker of vascular aging that may inform future research on aging biomarkers, novel therapeutics and cardiovascular risk assessment across the spectrum of atherosclerotic and microvascular disease.

Abstract INTRODUCTION Plasma phosphorylated tau at threonine 217 (p‐tau217) has emerged as one of the most promising blood‐based biomarkers for Alzheimer's disease (AD). While rare, heterophilic antibodies (HAb) are a persistent potential confounding factor in immunoassays. METHODS Potential HAb interference in the Lumipulse G pTau217 assay in samples exhibiting concentrations > 10 pg/mL were investigated. Samples were subjected to HAb blocking reagent (HBT), and in some cases, polyethylene glycol (PEG) precipitation and serial dilutions. RESULTS In 14 of the 15 suspected HAb cases, HBT treatment greatly reduced measured p‐tau217 concentrations. and in one of three specimens selected for further investigation, reduced Aβ42 concentrations PEG precipitation in the three selected samples also reduced p‐tau217 concentrations, while serial dilution yielded mixed effects. Control specimens were unaffected by sample treatment or dilutions. DISCUSSION HAb may result in falsely elevated p‐tau217 and p‐tau217/Aβ42 ratio. HAb interference should be considered in cases of unusually high p‐tau217 concentrations prior to clinical interpretation. Highlights Potential heterophile antibody (HAb) interference in the Lumipulse p‐tau217 immunoassay was investigated. Investigation was performed using HAb blocking reagent, and in some cases also using PEG precipitation . Patients with p‐tau217 concentrations > 10 pg/mL exhibited positive HAb interference in 14 of 15 cases. HAb interference can lead to falsely positive p‐tau217/Aβ42 ratios.

ABSTRACT Cytotoxic T lymphocytes (CTLs) are known to eliminate target cells through perforin-mediated, contact-dependent killing - a process limited by the number of effector T cells despite its serial nature. CTLs likely also possess a mass killing mechanism that can eliminate target cells more efficiently. Using CAR-T cells against B7H3 present on B16 tumor targets, we demonstrate that activated T cells can also kill targets in a perforin-independent manner by releasing diffusible TNF and IFNγ capable of killing nearby targets in a paracrine fashion even if they bear no antigen. Against an unperturbed target, paracrine killing is inefficient but is enhanced by the deletion of TNFR1 signaling molecules such as TAK1, HOIP, or TBK1/IKKε. Notably, these molecules are inhibited naturally by pathogen-encoded antagonists. Expression of a microbial-encoded antagonist, such as the Yersinia -encoded YopJ that antagonizes TAK1 or Ebola-encoded VP35 that antagonizes TBK1/IKKε, alters the target cell response to these cytokines from non-lethal to lethal. We propose that target cells are inherently resistant to killing by TNF and IFNγ, but the presence of a microbial factor alters this sensitivity, providing for the selective elimination of the infected cell while minimizing harm to uninfected bystander cells. We propose the term ‘pathogen-restriction’ to describe this discriminatory mechanism. Potentially, any microbial-derived factor that crosstalks with the TNF and IFNγ signaling pathways can function as a pathogen-restriction element. GRAPHICAL ABSTRACT Short Summary T cells use TNF and IFNγ to kill target cells in a paracrine manner where target elimination is restricted by the presence of pathogen-derived factors.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

Abstract Background Agitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD‐related syndromes and its relationship to various neuropsychiatric symptoms (NPS). Method We analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD‐related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non‐fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants’ symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex. Result Males were more likely to experience anxiety (bvFTD: p <0.001, CBS: p <0.01, PSP: p <0.0001), apathy (nfvPPA: p <0.01, PSP: p <0.01), depression (bvFTD: p <0.0001, PSP<0.01), disinhibition (nfvPPA: p <0.0001), PSP: p <0.001), and motor symptoms (bvFTD: p <0.01, CBS: p <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA ( p <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP. Conclusion This study reveals significant sex differences in NPS in FTLD‐related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD‐related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD‐related syndromes.

Abstract Background The polymorphic APOE gene is a susceptibility gene for Alzheimer's disease (AD). The ε4 allele is associated with increased risk for AD, particularly late‐onset disease, in a dose‐dependent manner. Additionally, homozygous ε4/ε4 individuals have increased risk of adverse events when undergoing amyloid lowering treatments. APOE genotyping is considered the gold standard for determination of ApoE4 zygosity. Recently, proteotype assays for ApoE4 have become available for high‐throughput immunoassay analyzers. These assays utilize the same specimen type as AD blood biomarkers and can potentially offer improved turnaround times compared to genotyping. In this study, we compare the performance of two automated ApoE4 proteotype research use only (RUO) immunoassays against APOE genotyping. Method EDTA‐plasma samples ( n = 65) from individuals undergoing ApoE PCR‐based genotyping for clinical purposes were evaluated. Samples were tested with the Beckman Coulter APOE ε4 RUO assay on the Access 2 and DXI 9000 instruments (Beckman Coulter, Inc), which provides algorithm calculated results for determining ApoE4 zygosity. Manufacturer generated data from 300 genotyped samples was used to calculate estimated cut‐points for ApoE4 zygosity for this study with results <0.55 classified as no E4, ≥0.55 to <4.55 as heterozygous E4, and ≥4.55 as homozygous E4. Samples were also tested with the Lumipulse G ApoE4 and Pan‐ApoE RUO assays on the Fujirebio Lumipulse G1200 analyzer. The ratio of ApoE4/Pan‐ApoE was utilized for determining zygosity with results <5% classified as no E4, ≥5% to <75% as heterozygous E4, and ≥75% as homozygous E4, as listed in the manufacturer IFU. Result APOE genotype distributions were (n, %): ε3ε4 (30, 46%), ε3ε3 (18, 28%), ε4ε4 (12, 18%), ε2ε3 (3, 5%), ε2ε4 (2, 3%). ApoE4 zygosity was categorized as no ε4 (21, 32%), heterozygous ε4 (32, 49%), or homozygous ε4 (12, 19%). The Beckman Coulter APOE ε4 RUO assay classified 65/65 (100%) patients correctly using manufacturer generated cut‐points on both instruments. The Lumipulse G ApoE4 and Pan‐ApoE RUO assays classified 61/65 (94%) patients correctly using the manufacturer listed cut‐points. Conclusion ApoE4 proteotype immunoassays may represent simplified and more accessible testing alternatives to genotyping for the assessment of ApoE4 zygosity in individuals being considered for amyloid lowering treatments.