Citations

Abstract Background Coronary flow augmentation occurs through the simultaneous interaction and regulation of both endothelium-dependent and endothelium-independent mechanisms. A decrease in coronary flow reserve (CFR) secondary to either mechanism is associated with poor prognosis. However, at the individual level, the integrated impact of these two mechanisms has not been thoroughly investigated. Purpose This study investigated the prognostic implications of an integrated metric, CFRsum, combining endothelium-dependent and -independent CFR. Methods A total of 1441 patients with angina with non-obstructive coronary artery (ANOCA) undergoing coronary reactivity testing were studied. Endothelium-independent CFR was measured during adenosine-induced hyperemia, and endothelium-dependent CFR during intracoronary acetylcholine infusion. CFRsum was calculated by summing these components. Cardiovascular event was defined as composite of cardiovascular death, myocardial infarction, heart failure, and cerebral infarction. Results Our patients had a median age of 51.7 years, 69.0% of whom were female, and their CFRsum was 4.57 [3.88, 5.37]. Patients were divided into three tertile-based groups, and Cox proportional hazards analysis demonstrated that all CFR classes were independent predictors of prognosis, with CFRsum providing the best model fit (Likelihood ratio: 54.62, degrees of freedom: 7, P < 0.001). The Kaplan-Meier curve (Figure) demonstrated a stepwise deterioration in prognosis across CFRsum tertile groups, with lower CFRsum being associated with progressively worse outcomes (p < 0.001). Stratification by follow-up duration (3 years) revealed that patients with middle-range CFRsum exhibited comparable outcomes to those with the highest CFRsum during the early phase (<3y) but significantly worse outcomes in the late phase (≥3y) (P = 0.459 and P < 0.001, respectively). Conclusion CFRsum showed superior prognostic value over traditional CFR metrics in patients with ANOCA, identifying a compensated group with time-varying outcomes. This novel metric improves the assessment of microvascular function and supports better clinical management.

Cancer health disparities represent profound inequalities in incidence, outcomes, and survivorship across populations. While traditionally examined through distinct lenses of either molecular biology or social epidemiology, these disparities arise from the complex interplay of genetic susceptibility, epigenetic dysregulation, and social determinants of health (SDoH). This review proposes that DNA damage and genomic instability serve as a critical mechanistic bridge, integrating exposures from the societal level to cellular dysfunction. We synthesize evidence demonstrating how SDoH—such as systemic inequities, environmental exposures, and chronic stress—converge with genetic and epigenetic factors to disproportionately increase DNA damage burden, impair repair mechanisms, and accelerate tumorigenesis in marginalized communities. Using the elevated gastrointestinal cancer rates among Native Hawaiians and Pacific Islanders (NH/PI) as a case study, we illustrate how historical, environmental, and socioeconomic factors interact with biological pathways to drive disparities. The review highlights key advances in DNA damage research—from somatic mutation theory to the modern understanding of chronic genomic stress—and explores how innovations in single-cell genomics, biomarker discovery, and computational modeling can unravel disparity etiologies. We argue that a translational framework linking social exposure data to molecular biomarkers of DNA damage is essential for moving beyond descriptive disparities to mechanistic understanding. Ultimately, addressing cancer equity requires interdisciplinary strategies that bridge molecular oncology, public health, and community-engaged research, targeting the root causes where social inequities become biologically embedded as genomic instability.

ABSTRACT Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) can reduce seizures in patients with drug-resistant epilepsy. However, seizure freedom is rare, and there is no early response biomarker to predict long-term seizure suppression. To evaluate a short-term biomarker of therapeutic response to DBS, we studied 18-minute trials of ANT stimulation in patients with drug-resistant epilepsy undergoing intracranial electroencephalography. We compared a standard high-frequency periodic versus a non-periodic pulse pattern. We found that short-term ANT stimulation within the clinically used amplitude range preferentially altered the first 150 ms of anterograde ANT to anterior cingulate and superior frontal connectivity. Non-periodic ANT stimulation selectively modified early cortico-cortical evoked potentials more than periodic stimulation, and these changes were driven by the response phase. These pattern-specific changes in connectivity between the ANT and spatially restricted cortical areas suggest differing mechanisms and are a promising biomarker for patients being treated with ANT-DBS.

OBJECTIVE Deep brain stimulation (DBS) is emerging as an additional surgical option for refractory, multifocal epilepsy. Four-lead DBS systems can be used when seizure onset is poorly localized, generalized, or involves multiple targetable circuits. The goal of this study was to assess preliminary outcomes and complication rates in 4-lead DBS systems for treating epilepsy. METHODS A consecutive series of 32 patients with 4-lead DBS implants who had at least 6 months of follow-up was reviewed, and demographics, outcomes, and complications were abstracted. RESULTS Thirty-two patients implanted with 4 DBS leads (including off-label use) were included. The median age at surgery was 28.5 years, the median age at epilepsy diagnosis was 7.5 years, and 18 patients (56%) were women. The median epilepsy duration prior to implantation was 21 years. The most common seizure localization was frontotemporal (53%), followed by generalized (28%) and parietoccipital (13%). Prior vagus nerve stimulation had been trialed in 20 patients (63%), and an invasive stereotactic EEG recording was performed in 17 patients (59%). Eight patients had prior epilepsy surgery (25%). DBS targets included the anterior thalamic nucleus in combination with the centromedian thalamic nucleus, hippocampus, pulvinar nucleus, cingulate, insula, and globus pallidus. The median surgical duration was 5 hours 22 minutes, with a median operating room time of 8 hours 21 minutes. The median postoperative follow-up was 27 (interquartile range 17–41) months. Three patients experienced transient neurological deficits and 2 patients required intraoperative lead repositioning. There were no infections or hemorrhages. Most patients benefited from stimulation (22% Engel class I, 22% class II, 28% class III, and 28% class IV). The median patient-reported seizure reduction rate was 70%, with a responder rate of 72%. One patient elected to have the system explanted. CONCLUSIONS Four-lead DBS is safe and can achieve meaningful improvement in challenging cases of multifocal epilepsy with a low complication rate.

ABSTRACT Background While immune checkpoint inhibitors (ICIs) have shown significant efficacy, a common side effect is cutaneous immune‐related adverse events (irAEs). This study focuses on exploring the association between specific human leukocyte antigen (HLA) alleles and the development of cutaneous irAEs in melanoma patients undergoing ICI monotherapy and combination therapy. As certain HLA types are indicative of susceptibility to autoimmune diseases, it was hypothesized that HLA typing could serve as a potential screening tool for identifying patients at increased risk for developing irAEs. Methods A retrospective chart review was performed of 515 patients with melanoma who underwent ICI therapy, either as monotherapy or in combination, and had HLA typing available. This analysis spans from 2003 to 2023 with a focus on cutaneous irAEs. Statistical analyses were conducted to assess the association between HLA alleles and irAEs. Results Our analysis revealed that the HLA‐B*51:01 allele was associated with a higher risk of cutaneous irAEs after adjusting for ICI regimen (hazard ratio: 1.71 [95% CI, 1.12–2.61], p = .013.) Conclusion This is the largest study to link an HLA allele with ICI‐induced cutaneous irAEs. The findings may support the use of HLA typing as an initial screen for developing irAEs, providing a simple, straightforward metric that can be rapidly performed on patients prior to initiation of ICIs. However, further research is needed across different cancer and toxicity types.

ABSTRACT Calcific tendinopathy is a common musculoskeletal disorder marked by calcium deposition within tendons, often accompanied by pain, impaired mobility, and in severe cases, ossification. However, the mechanisms underlying tendon mineralization remain poorly understood. In contrast to pathological human calcification, turkeys naturally develop tendon mineralization during growth without signs of inflammation or ossification. This study had two phases: an observational phase to assess onset and progression of calcification, and an interventional phase to evaluate the role of mechanical loading. In the observational phase, flexor tendons were collected from turkeys aged 1–16 weeks in a serial sacrifice study and analyzed by Von Kossa staining and biomechanical testing. Calcification began at 7 weeks, localized within organized collagen matrices, progressed through Weeks 8–14, and peaked by 16 weeks. In the interventional phase, nine female turkeys were randomized at 4 weeks into a transection group ( n = 3), sham group ( n = 3), and control group ( n = 3). Transection at the muscle–tendon junction eliminated mechanical loading. At 16 weeks, tendons were analyzed by histology, quantitative RT‐PCR, ICP‐MS, and biomechanical testing. Transected tendons showed a near‐complete absence of mineralization, reduced expression of osteogenic markers (osteopontin, osteocalcin, Runx‐2), and significantly lower calcium, magnesium, and phosphorus levels. Biomechanical testing indicated reduced stress relaxation, stiffness, and Young's modulus in the transected group. Tendon calcification in turkeys functioned as a mechanically regulated, nonpathological process. The study established a relevant model for early tendon mineralization and offered a basis for developing load‐dependent therapies for human tendon disease.

Abstract Background Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort. Methods Lithium-heparin plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 IFCC guidance. Uniform and sex-specific 99th percentile URLs and nonparametric 95% CIs were determined in plasma and serum separately and combined. Results The final study population comprised 4147 participants (52.5% female) with a median (25th–75th percentiles) age of 48.0 (33.0–59.0) years; 45.8%, 47.9%, 5.2%, and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n = 8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16–23) ng/L for females and 32 (28–35) ng/L for males; the uniform 99th percentile URL was 27 (24–31) ng/L. URLs were comparable in plasma and serum samples. Conclusions This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used in a large, global, healthy reference population.

BACKGROUND AND OBJECTIVES: Minimum clinically important differences (MCIDs) for patient-reported outcome metrics (PROMs) in patients with cervical spondylotic myelopathy (CSM) lack consensus on the most appropriate calculation method. This retrospective study aimed to identify the optimal MCIDs for commonly used PROMs in CSM. METHODS: The CSM database from the Quality Outcomes Database SpineCORe Study Group was analyzed. Baseline, 3-month, and 24-month PROM values for Neck Disability Index (NDI), 5-dimension Euro-quality of life (EQ-5D) in quality-adjusted life years, modified Japanese Orthopaedic Association (mJOA) score, and neck/arm pain numeric rating scale (NRS) were collected. MCIDs were calculated for each PROM using previously validated techniques. MCID values were compared using the area under the curve (AUC) with the North American Spine Society satisfaction scale as an anchor. RESULTS: A total of 1141 patients with CSM undergoing surgery were included in this analysis. Improvement of ≥30% from baseline was the optimal MCID for NDI and neck/arm NRS. At 24 months, the optimal percentage cutoff MCID for these instruments resulted in AUCs of 0.76, 0.72, and 0.67, similar to the 30% improvement method, with AUCs of 0.73, 0.71, and 0.67, respectively. Numeric cutoffs (0.065 at 3 months; 0.149 at 24 months) were the superior MCIDs for EQ-5D. For mJOA score, a severity-adjusted MCID outperformed other methods, yielding an AUC of 0.67 at 24 months. MCIDs were achieved in 63% of patients for NDI, 59% for neck pain NRS, 61% for arm pain NRS, 52% for EQ-5D, and 59% for mJOA score at 24 months. CONCLUSION: Using the Quality Outcomes Database SpineCORe data set, we defined optimal MCIDs for key PROMs in CSM. A ≥30% improvement from baseline was optimal in NDI and arm/neck NRS. An absolute numeric cutoff was superior for EQ-5D (0.149 at the 24-month follow-up). A severity-adjusted MCID performed best for mJOA score. These redefined benchmarks better capture the treatment impact and guide care decisions for patients with CSM.