Faculty Bibliography

Understanding the genetic regulation of RNA abundance is essential for defining disease mechanisms. Conventional expression quantitative trait locus (eQTL) studies measure steady-state RNA and capture effects across the entire transcript lifecycle. While most eQTL likely affect transcription by altering promoter or enhancer function within the nucleus, others may act post-transcriptionally through RNA modification or stability in the cytosol. To distinguish these mechanisms, we compare eQTL from mature cellular RNA and recently transcribed nuclear RNA in brain and kidney. We identify distinct causal variants underlying cellular and nuclear eQTL at the same eGenes. Cellular eQTL are enriched in transcribed regions (P = 3.3×10⁻¹²⁶), suggesting post-transcriptional regulation, whereas nuclear eQTL are enriched in distal regulatory elements (P = 7.0×10⁻³²), consistent with transcriptional control. For example, stop-gain variants likely acting through nonsense-mediated decay appear only in cellular eQTL. Conversely, nuclear eQTL variants (e.g., TUBGCP4) within enhancers sometimes uniquely colocalize with disease loci (schizophrenia), revealing distinct regulatory mechanisms.

IMPORTANCE/UNASSIGNED:Patients with obstructive hypertrophic cardiomyopathy (oHCM) endure life-altering exercise limitations. Current treatment guidelines recommend β-blockers as first-line therapy primarily based on expert opinion. The Metoprolol vs Aficamten in Patients with Left Ventricular Outflow Tract Obstruction on Exercise Capacity in HCM (MAPLE-HCM) trial characterizes comprehensive exercise response to aficamten monotherapy vs β-blockade (metoprolol). OBJECTIVE/UNASSIGNED:To determine the effect of aficamten compared with metoprolol across all stages of exercise using 16 quantitative measures in individuals with oHCM. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a prespecified secondary analysis of the MAPLE-HCM study, a phase 3, randomized, active-control trial conducted from June 2023 to March 2025 with data analyzed between May and July 2025 at 71 sites in North America, South America, Europe, Israel, and China. Patients with symptomatic oHCM with objective evidence of exercise intolerance (peak oxygen uptake [pVO2] <100% of predicted) were included. Those with a history of atrial fibrillation (paroxysmal or persistent), medical indication for β-blockers or calcium channel blockers prohibiting drug discontinuation, or intolerance or medical contraindication to β-blockers were excluded. INTERVENTION/UNASSIGNED:Randomized 1:1 to titrated aficamten (5-20 mg daily) or matching titrated metoprolol (50-200 mg daily) for 24 weeks. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The main outcomes were submaximal exercise minute ventilation (VE)/carbon dioxide output (VCO2) slope and anaerobic threshold; peak exercise duration, workload, heart rate and heart rate reserve; and postexercise oxygen recovery rates; and composite variables, such as circulatory power. RESULTS/UNASSIGNED:Of 175 randomized participants (mean [SD] age, 57.7 [13.2] years; 102 [58.3%] male), 165 (94%) had core laboratory-validated exercise tests at baseline and week 24. Compared with metoprolol, aficamten treatment improved multiple stages of exercise; including submaximal exercise VE/VCO2 slope (-2.8; 95% CI, -4.0 to -1.5; P < .001) and anaerobic threshold (76 mL/min; 95% CI, 41 to 111; P < .001); peak workload (8 watts; 95% CI, 3 to 13; P = .003); the time required for VO2 to recover by 12.5% postexercise (-11 seconds; 95% CI, -16 to -5; P < .001); and circulatory power (819 mm Hg × mL/min per kg; 95% CI, 569 to 1070; P < .001). Large improvements (≥3.0 mL/kg/min) in peak VO2 were more common with aficamten compared with metoprolol (17 [20.5%] vs 3 [3.7%], respectively; odds ratio, 6.8; 95% CI, 2.0 to 22.5; P < .001). In contrast, large reductions in peak VO2 (≥3.0 mL/kg/min) were significantly more common with metoprolol than aficamten (17 [20.7%] vs 2 [2.4%], respectively; odds ratio, 10.6; 95% CI, 2.6 to ∞; P < .001). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This prespecified analysis of MAPLE-HCM demonstrated monotherapy with aficamten was superior to metoprolol in promoting adaptation to multiple phases of exercise in patients with symptomatic oHCM and supports aficamten as first-line therapy for oHCM. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT05767346.

BACKGROUND:Anticancer treatments are associated with cutaneous adverse events (cAEs) that can severely impact patients' quality of life (QoL) and interfere with treatment outcomes. LACOM aims to support clinicians in preventing and managing cAEs to optimize patient outcomes. METHODS:A panel of dermatologists, clinical oncologists, and radiation oncologists developed an evidence-based algorithm for the prevention and treatment of cancer treatment-related cAEs using a skincare regimen that includes hygiene, moisturization, sun protection, and camouflage products. RESULTS:The LACOM II algorithm discusses patient education before cancer treatment, appropriate skincare, triage, and the importance of treating emerging cAEs with a multidisciplinary team. CONCLUSIONS:Integrating proactive education, safe and effective skincare, triage, and reaction-specific management of cAEs is essential to optimize the care of patients living with cancer. The LACOM II algorithm provides evidence- and opinion-based best-practice recommendations to support clinicians working with oncology patients throughout the continuum of care, achieving optimal outcomes and improving patients' QoL. &nbsp.

BACKGROUND & AIM/OBJECTIVE:Accurate extraction of clinical and methodological features from published literature is essential for supporting evidence-based cardiovascular rehabilitation. With the rapid expansion of research outputs, manual data extraction is time-consuming and prone to errors. Large language models (LLMs) may help automate evidence synthesis tasks, but their performance in document extraction for cardiovascular rehabilitation nursing research remains unclear. We aimed to evaluate the ability of LLMs to extract key literature features in the field of cardiovascular exercise rehabilitation nursing. METHOD/METHODS:A diagnostic accuracy study was conducted using a reference standard established by two independent experts in cardiovascular rehabilitation. A structured extraction framework covering study characteristics, participant profiles, intervention components, and outcome domains was applied. LLM outputs were compared with the reference standard, and sensitivity, specificity, and area under the curve (AUC) were calculated. RESULTS:LLMs demonstrated high sensitivity (0.96-0.98) in identifying essential study features, indicating a low risk of missed information. Specificity ranged from moderate to high (0.70-0.77) and improved notably after incorporating nursing-specific chain-of-thought prompting. Overall diagnostic performance was excellent, with a post-hoc analysis AUC reaching 0.98. Error patterns were primarily related to ambiguous intervention descriptions and multi-component rehabilitation programs. CONCLUSIONS:LLMs show strong potential as an efficient and accurate tools for automating literature feature extraction in cardiovascular exercise-based rehabilitation nursing. Their use may enhance the speed and reliability of evidence synthesis, and support clinical decision-making. Further optimisation of prompting strategies and domain-specific tuning is warranted before widespread clinical adoption.

Chronic psychological stress is increasingly recognized as an important host-related determinant of cancer progression, yet how stress-associated neuroendocrine signaling reshapes the metastatic immune microenvironment remains incompletely understood. Here, using male mouse models of chronic restraint stress and chronic unpredictable mild stress, together with transcriptomic profiling, flow cytometry, functional assays, and a prospective clinical cohort, we investigated whether chronic stress promotes gastric cancer liver metastasis through glucocorticoid-associated neutrophil reprogramming, neutrophil extracellular trap (NET) formation, and hepatic immune remodeling. Chronic stress induced robust behavioral stress phenotypes, elevated corticosterone levels, and increased hepatic metastatic burden. Immune profiling revealed a myeloid-skewed and immunosuppressive hepatic niche characterized by neutrophil accumulation, impaired CD8⁺ T-cell effector function, and enhanced T-cell exhaustion. Mechanistically, glucocorticoids activated neutrophils through glucocorticoid receptor signaling, increased reactive oxygen species, and promoted NET formation, whereas pharmacological inhibition of glucocorticoid receptor signaling, degradation of NETs, or antibody-mediated neutrophil depletion attenuated stress-associated metastatic progression in vivo. In parallel, glucocorticoid stimulation increased hepatic lipocalin 2 (LCN2) expression and secretion, and conditioned medium from glucocorticoid-treated hepatocytes enhanced neutrophil migration, an effect attenuated by pharmacological LCN2 inhibition. In vivo, LCN2 blockade reduced circulating LCN2 levels and alleviated hepatic metastatic burden. In patients with gastric cancer liver metastasis, higher stress burden was associated with elevated cortisol and circulating myeloperoxidase-DNA levels and with shorter progression-free survival. Multivariable Cox regression further supported an association between Perceived Stress Scale-defined stress burden and shorter progression-free survival. Together, these findings support a stress-associated glucocorticoid-neutrophil-hepatic niche axis linking chronic stress to metastatic progression.

Non-homologous end-joining (NHEJ) is a major double-stranded DNA (dsDNA) break repair pathway essential for V(D)J recombination during lymphocyte development. The Ku70/Ku80 heterodimer (Ku) initiates NHEJ by encircling dsDNA ends and recruiting DNA-PKcs. Ku70 in plants and mammals acquired a C-terminal SAP domain implicated in nucleic acid binding. Here, we show that in murine models, the SAP domain is dispensable for Ku stability and recruitment to DNA breaks. Unlike Ku70-/- mice, Ku70ΔSAP/ΔSAP mice exhibit normal lymphocyte development despite mild radiation sensitivity. Structural modeling places the SAP domain in adjacent DNA grooves, where it can restrict Ku's lateral movement along dsDNA. Correspondingly, in mice lacking DNA-PKcs that caps the ends, Ku70ΔSAP reduces T cell counts and deletion sizes, consistent with Ku translocating off DNA. Moreover, SAP deletion reduced DNA-end affinity, increased dissociation, and exchange of purified Ku at low concentrations, and increased multiple-loading at high concentrations, consistent with increased lateral movement. In DNA-PKcs-/- murine fibroblasts, deletion or lysine mutation (K593/4A, corresponding to K595/6A in human Ku70) in the SAP domain decreased the relative intensity of laser-induced Ku spots, revealing a role of the SAP domain in constraining Ku lateral movement on dsDNA in the absence of DNA-PKcs (or in the short-range complex).

In nonequilibrium quantum systems, the quantum Mpemba effect (QME) emerges as a counterintuitive phenomenon: Systems exhibiting greater initial symmetry breaking restore symmetry faster. It has been attracting broad interest in studying QME dynamics and potential applications in quantum information science. While theoretical exploration of QME has surged, experimental studies, specifically on its flexible modulation, remain limited. Here, we report the observation and modulation of QME using a superconducting processor featuring an all-to-all connected, tunable-coupling architecture that enables precise control from short- to long-range interactions. This platform allows independent manipulation of coupling regimes, on-site potentials, and initial states, enabling us to elucidate their roles in QME. To quantify symmetry restoration, we employ entanglement asymmetry (EA), derived from the reconstructed density matrix via quantum state tomography, as a sensitive probe. In strong short-range coupling regimes, EA crossovers during quenches from tilted Néel states confirm the presence of QME. In contrast, in intermediate-coupling regimes, synchronized EA and entanglement entropy dynamics reveal the suppression of QME. Remarkably, QME reemerges with the introduction of on-site linear potentials or quenches from tilted ferromagnetic states, the latter proving robust against on-site disorder. Our study demonstrates flexible QME modulation on a superconducting platform with multiple controllable parameters, shedding light on quantum many-body nonequilibrium dynamics and opening avenues for quantum information applications.

AIM/OBJECTIVE:The "2026 HRS Expert Consensus Statement Update on Cardiovascular Implantable Electronic Device Lead Management and Extraction" provides updated recommendations to guide clinicians in the management of cardiovascular implantable electronic device (CIED) leads. BACKGROUND:Since the publication of the "2017 HRS Expert Consensus Statement on Cardiovascular Implantable Electronic Device Lead Management and Extraction," the field has evolved quickly. New evidence on CIED lead management and the blooming development of new CIED technologies, including leadless pacing and implantable cardioverter-defibrillator leads implanted outside the vascular system and new lumenless pacing leads and lead extraction tools, have contributed to the field's rapid evolution. METHODS AND RESULTS/RESULTS:A comprehensive literature search was conducted in accordance with the Institute of Medicine standards. The writing committee reviewed evidence gathered through electronic literature searches encompassing clinical trials, original studies, and meta-analyses conducted on human subjects published in English from MEDLINE, PubMed, Embase, and the Cochrane Library up to December 2024. The comprehensive literature review supports each evidence-based recommendation and is compiled in the evidence tables. A predefined threshold of >70% approval for each recommendation was required, with a quorum of two-thirds of the writing committee. The final mean consensus of 108 recommendations was 93.61%. DISCUSSION/CONCLUSIONS:The recommendations from the "2017 Expert Consensus Statement on Cardiovascular Implantable Electronic Device Lead Management and Extraction" have been updated with new evidence to guide clinicians. The new recommendations address the latest CIED technologies with the advantages over transvenous leads; new evidence supporting diagnosis, treatment, and prevention for CIED infection; appropriate lead management in transcatheter tricuspid valve replacement for tricuspid regurgitation; and standardization of transvenous lead extraction approach, protocol, and facilities to improve the outcomes of CIED lead management and extraction.

INTRODUCTION/BACKGROUND:Patients with a suspected high-consequence infectious disease (HCID), such as Ebola virus disease, may require routine laboratory testing to guide management. We assessed the capabilities of frontline hospitals and the barriers they face performing laboratory testing for patients with a suspected HCID. METHODS:A one-time confidential REDCap survey querying capabilities to safely perform laboratory tests that the Centers for Disease Control and Prevention considers critical for patients with a suspected HCID was sent to 95 institutions in Baltimore, MD, Boston, MA, New York City, NY, and Washington, DC, from January to May 2025. RESULTS:Fifty (53%) institutions responded, mostly teaching hospitals (96%), with 24% reporting prior experience evaluating a patient with suspected Ebola virus disease. While many hospitals could perform on-site blood gas (70%), hemoglobin/hematocrit (68%), and lactate (68%) tests on a suspected HCID patient, fewer could safely perform a chemistry panel (64%), a urinalysis (60%), a complete blood count with differential (56%), and a malaria rapid diagnostic test (RDT) (48%) on a suspected HCID patient. The five tests respondents most often considered extremely or very important were hemoglobin/hematocrit (91%), chemistry panel (90%), CBC with differential and platelet count (89%), malaria RDT (88%), and blood gas (88%). Reported barriers to performing routine laboratory testing included issues related to patient and staff safety, infection control, lack of appropriate space, and funding. CONCLUSIONS:Our survey identified several barriers to implementing safe laboratory testing. The inability to conduct these laboratory tests may result in delays in care when an HCID is suspected.