Citations

Abstract Objectives Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays. Methods To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS. Results Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL. Conclusions Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, usability, footprint, and intended use, should be considered.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P < 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Bone health is a key determinant of success in spine surgery, making preoperative assessment of bone quality essential to optimal surgical risk stratification. Magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score offers a novel approach to assess bone health in spine surgery candidates. The ability of MRI to assess bone quality without exposure to ionizing radiation makes it a potentially advantageous alternative to other traditional measures of bone density. VBQ has additionally shown potential to predict adverse outcomes, such as fragility fractures, instrumentation failure, subsidence and proximal junctional kyphosis. Variations of VBQ, such as endplate bone quality, S1 VBQ, and cervical VBQ, provide targeted insights at specific anatomical regions and potentially enhance the predictive accuracy of VBQ. However, clinical application of VBQ is limited by variability in MRI systems, patient-specific factors, and lack of standardized threshold values. This review aims to critically evaluate VBQ scores as an opportunistic, MRI-based assessment of bone health and its potential role in predicting surgical outcomes. While VBQ may provide some valuable insights into bone health, its role in preoperative risk assessment likely remains supplementary and requires further research to establish clinical validity and optimal cutoffs.

Background: Ischemic stroke remains a leading cause of morbidity and mortality worldwide. Cardioembolic sources account for a significant proportion of these events, necessitating accurate identification of underlying structural heart abnormalities. Traditionally, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) have been utilized for this purpose, although both have limitations. Cardiac computed tomography (CCTA) has emerged as a potential alternative, offering non-invasive imaging with high sensitivity and specificity for detecting intracardiac thrombi. Objective: This study aimed to evaluate the diagnostic yield of CCTA compared to TTE and TEE in detecting high-risk cardioaortic sources of embolism, including left ventricular (LV) thrombus, left atrial (LA) thrombus, valvular thrombus, and ulcerated aortic plaques, in patients with ischemic stroke. Methods: We conducted a retrospective, single-center cohort study at Mayo Clinic, Rochester, MN, including 426 ischemic stroke patients who underwent CCTA within 30 days of stroke onset between March 2019 and June 2023. We compared the diagnostic yields of CCTA, TTE, and TEE in detecting structural cardiac sources of embolism. Results: The overall diagnostic yield of CCTA for detecting high-risk cardioaortic sources was 15.5%. Specifically, CCTA identified LV thrombus in 2.3% of patients, LA thrombus in 4.0%, valvular thrombus in 2.8%, and ulcerated aortic plaques in 7.0%. In comparative analysis, CCTA demonstrated a higher yield than TTE (16.0% vs 3.5%, p < 0.001) and a comparable yield to TEE (25.3% vs 20.7%, p = 0.47) in detecting these sources. Conclusions: CCTA proved to be a viable option for identifying high-risk structural sources of cardioembolism in ischemic stroke patients. Its non-invasive nature, coupled with the ability to perform imaging soon after stroke onset, underscores its clinical utility. However, further prospective and blinded studies are required to validate these findings and fully establish the efficacy of CCTA in this context.

Abstract Background Dose‐driven continuous scanning (DDCS) enhances the efficiency and precision of proton pencil beam delivery by reducing beam pauses inherent in discrete spot scanning (DSS). However, current DDCS optimization studies using traveling salesman problem (TSP) formulations often rely on fixed beam intensity and computationally expensive interpolation for move spot generation, limiting efficiency and methodological robustness. Purpose This study introduces a Break Spot‐Guided (BSG) method, combined with two acceleration strategies—dose rate skipping and bounding—to optimize beam intensity while minimizing beam delivery time (BDT). In addition, a ‐method is proposed for efficient move spot generation, aiming to balance computational efficiency and dose calculation accuracy. Methods The BSG framework simplifies the original mixed‐integer nonlinear programming (MINLP) problem by transforming it into a series of TSP evaluations using break‐spot dose rates. The two acceleration strategies are integrated to reduce computational complexity. The ‐method is introduced to efficiently generate move spots without compromising dose fidelity. The performance of the BSG method, with and without the acceleration strategies, and the ‐method, was evaluated across multiple clinical cases. Results By jointly optimizing the scan path and dose rate, the proposed BSG‐S‐B method offered the most efficient delivery, achieving a 64% reduction in BDT compared to DSS and a 57% reduction compared to Liu's method in the prostate case. These gains were consistently observed across all cases. Utilizing acceleration strategies, BSG‐S‐B significantly reduced computation time from hours to minutes (e.g., from 10 525.7 to 108.5 s in the prostate case, and from 6202.4 to 129.8 s in the head‐and‐neck case). When combined with the ‐method, it reduced the number of move spots by more than 50%, while still ensuring dosimetric quality. Conclusions The proposed framework significantly improves computational efficiency, making scan path optimization with dose rate selection feasible for clinical DDCS delivery. The ‐method effectively reduces computational complexity while maintaining dose calculation accuracy, demonstrating strong potential for clinical adoption in proton therapy treatment planning.

Summary Among individuals of European Ancestry (EA), genome‐wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRSs) associated with non‐Hodgkin lymphoma (NHL) risk. We evaluated subtype‐specific PRSs, based on established EA‐SNPs, in Israeli Jews (IJ) and Palestinian Arabs (PA) and performed a GWAS in the combined ethnic groups to identify new loci. We included three common pathologically confirmed subtypes: diffuse large B‐cell (DLBCL), follicular (FL) and marginal zone (MZL) lymphomas. Controls were frequency matched to cases by age and sex. Among 752 IJ (201—DLBCL; 130—FL; 54—MZL/367—controls) and 593 PA (203—DLBCL; 41—FL/349‐controls), we computed PRSs weighted by EA‐derived effect estimates and used logistic regression models adjusted for confounders. In the combined ethnic groups of IJ and PA, subtype‐specific PRSs were significantly associated with the corresponding subtype, with a 1.69‐fold, 2.21‐fold and 2.26‐fold risk for DLBCL, FL and MZL, respectively; however, these effect sizes were attenuated compared to those reported in EA and varied by ethnicity. In the GWAS of the combined ethnic groups, two novel SNPs in the 6p21.32 locus were associated with DLBCL risk. Additional GWAS studies are needed among Jewish and Arab populations to improve genetic risk prediction for NHL in these ethnic groups.

Abstract Current discussion surrounding the clinical capabilities of generative language models (GLMs) predominantly center around multiple-choice question-answer (MCQA) benchmarks derived from clinical licensing examinations. While accepted for human examinees, characteristics unique to GLMs bring into question the validity of such benchmarks. Here, we validate four benchmarks using eight GLMs, ablating for parameter size and reasoning capabilities, validating via prompt permutation three key assumptions that underpin the generalizability of MCQA-based assessments: that knowledge is applied, not memorized, that semantic consistency will lead to consistent answers, and that situations with no answers can be recognized. While large models are more resilient to our perturbations compared to small models, we globally invalidate these assumptions, with implications for reasoning models. Additionally, despite retaining the knowledge, small models are prone to answer memorization. All models exhibit significant failure in null-answer scenarios. We then suggest several adaptations for more robust benchmark designs more reflective of real-world conditions.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the clonal proliferation of myeloid precursors and rapid progression. Historically consisting of intensive chemotherapy, AML management has evolved significantly due to advances in molecular diagnostics and risk stratification. This review discusses current therapeutic paradigms in AML, emphasizing the growing role of personalized medicine across age and risk groups. For younger, fit patients, intensive regimens such as the “7 + 3” protocol remain the standard, often enhanced by targeted agents like FMS-like tyrosine kinase 3 (FLT3) and IDH inhibitors. Older or unfit individuals benefit from low-intensity treatments such as hypomethylating agents combined with venetoclax, now considered a frontline standard of care. The use of liposomal chemotherapy (CPX-351), measurable residual disease (MRD) monitoring, and maintenance therapy further refine post-remission strategies. Emerging therapies, including menin inhibitors, antibody–drug conjugates, and immunotherapies like CAR-T cells and vaccines, offer additional options, especially in relapsed/refractory settings. This comprehensive review outlines the current landscape and future directions in AML therapy, emphasizing the transition toward individualized, mutation-driven treatment strategies.

Background: Ischemia–reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI). While the precise mechanisms of AKI are still incompletely defined, extensive evidence highlights tubular cell injury and death as key factors in its development. Necroptosis has recently emerged as a critical pathway in the pathogenesis of ischemia–reperfusion-induced AKI (IR-AKI). Although sex differences in susceptibility to IR-AKI have been reported, it remains unclear whether there are sex differences in necroptosis dynamics and whether these differences underlie the observed sexual dimorphism in kidney IRI. This study aimed to address these questions. Methods: male and female C57BL/6 J mice were subjected to AKI via ischemia induced by bilateral renal pedicle clamping for 18 min at 37 °C. Plasma, urine, and kidney samples were collected at 0 h, 3 h, 6 h, 12 h, 24 h, 48 h, and 72 h post-reperfusion. Kidney injury and function were assessed by measuring plasma creatinine (PCr), blood urea nitrogen (BUN) levels, and histological damage (PAS and cleaved caspase3 staining). Necroptosis activation was assessed by quantifying phosphorylated forms of key markers: p-RIPK1 and p-MLKL. To explore the role of sex hormones in regulating necroptosis dynamics, ovariectomized female mice were subjected to the same IR-AKI protocol, and their kidney injury and functional outcomes were compared with those of intact counterparts. Results: The PCr was 0.35 ± 0.04 and 0.32 ± 0.06 mg/dL for males and females, respectively, at 3 h of IR. The levels exponentially increased to 2.05 ± 0.18 at 48 h post-reperfusion in the males but only gradually to 0.94 ± 0.13 mg/dL in females. Necroptosis activation began as early as 3 h post-IR in males but was delayed until ~6 h in females. Males exhibited stronger and more sustained necroptosis activation than females, showing elevated phosphorylation levels of pRIPK1 and pMLKL in Western blot. Female sex hormone deficiency exacerbated the female response to IR-induced injury, which reduced the sex difference in the dynamic of the necroptotic activation and subsequent kidney injury. To our knowledge, this is the first study to characterize sex differences in the initiation and progression of necroptosis and subsequent injury in a mouse model of IR-AKI. Conclusions: Our findings reveal distinct temporal patterns of programmed cell death between sexes. Necroptosis-targeted therapies require early intervention in males, which can be delayed in females after IR-AKI, highlighting the need for sex-specific therapeutic windows.