Faculty Bibliography

The integrated stress response (ISR) coordinates cellular adaptation to diverse stress conditions. In Drosophila, two bZIP transcription factors, Xrp1 and crc (ATF4 homolog), are induced during ISR. Crc protein can dimerize with two CEBP factors in vitro, but the in vivo relevance of those interactions remained unknown. Here, we report that the CEBPG homolog, Irbp18, is an essential partner of crc during ISR. Specifically, Irbp18 is broadly required for the transcriptional induction of ISR target genes in the photoreceptors of ninaE^G69D, a Drosophila model of retinitis pigmentosa. Moreover, CUT&RUN analysis indicates that Irbp18 loss reduces or abolishes crc binding to target DNAs in photoreceptors and impairs crc's ability to induce target transcripts upon overexpression. Functionally, Irbp18 loss causes retinal degeneration and suppresses ISR signaling in parkin mutants, a model of Parkinson's disease. Together, these findings identify Irbp18 as a cofactor for crc, impacting pathological outcomes in Drosophila models of degeneration.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Circumferential minimally invasive surgery (cMIS) techniques in adult spinal deformity (ASD) surgery may reduce physiological burden compared with open technique, but their utility in octogenarians has not been previously assessed. METHODS:Operative ASD patients aged 80 years or older with complete baseline (BL) and 2-year postoperative radiographic and health-related quality of life data were assessed and compared by surgical technique: open vs cMIS. Propensity score matching aligned groups by BL Charlson Comorbidity Index (CCI), C7-S1 sagittal vertical axis, pelvic incidence minus lumbar lordosis mismatch, and C7 plumb line. BL and peri/postoperative factors were assessed using analysis of variance and Bonferroni-adjusted analysis of covariance while controlling for BL CCI and posterior fusion length. RESULTS:Thirty-four octogenarian ASD patients met inclusion criteria, of whom 29.4% underwent cMIS and 70.6% underwent open correction. cMIS patients were less likely to require surgical intensive care unit (10% vs 75%, P < .001) and had shorter hospital stays (4.6 vs 10.1 days, P = .013). Open patients reported higher Scoliosis Research Society-22 Appearance and Mental domain scores (both P < .005) and more frequently reached minimal clinically important difference in both domains by 2 years (P = .025, .024). cMIS patients more often required reoperation for radiographic sagittal imbalance by 2 years when controlling for CCI and levels fused (20.0% vs 8.3%, P < .001). No deaths occurred in either group by 2 years. CONCLUSION/CONCLUSIONS:In octogenarians undergoing ASD surgery, cMIS reduced physiological burden but had higher reoperation rates, whereas open surgery showed greater durability.

PURPOSE/OBJECTIVE:The goal of this work is to introduce an automated method to assess the quality of under-sampled MRI reconstructions. THEORY AND METHODS/METHODS:We propose a general framework for pixel-wise uncertainty quantification in accelerated MRI reconstructions, enabling automatic identification of unreliable regions without using ground-truth fully-sampled reference images. Our method integrates conformal quantile regression with learning-based image reconstruction methods to estimate statistically rigorous pixel-wise uncertainty intervals. We trained and evaluated our model on Cartesian undersampled brain and knee data obtained from the fastMRI dataset using acceleration factors ranging from 2 to 10. An end-to-end Variational Network was used for image reconstruction. RESULTS:Quantitative experiments demonstrate strong agreement between predicted uncertainty maps and true reconstruction error. Using our method, the corresponding Pearson correlation coefficient was higher than 90% at acceleration levels at and above four-fold; whereas it dropped to less than 70% when the uncertainty was computed using a simpler heuristic notion (magnitude of the residual). Qualitative examples further show the uncertainty maps based on quantile regression capture the magnitude and spatial distribution of reconstruction errors across acceleration factors, with regions of elevated uncertainty aligning with pathologies and artifacts. CONCLUSION/CONCLUSIONS:The proposed framework enables evaluation of reconstruction quality without access to fully-sampled ground-truth reference images. It represents a step toward adaptive MRI acquisition protocols that may be able to dynamically balance scan time and diagnostic reliability.

IMPORTANCE/UNASSIGNED:The decision to transfuse a patient with myocardial infarction (MI) and anemia at a higher vs lower hemoglobin threshold must consider the potential benefit of reduced risk of 30-day death or MI and the potential risk of heart failure. OBJECTIVES/UNASSIGNED:To estimate bayesian posterior risk differences and posterior probabilities that a liberal vs restrictive transfusion strategy is associated with reduced risk of 30-day death or MI and whether the probabilities exceed predefined thresholds. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The Myocardial Ischemia and Transfusion (MINT) trial recruited adults from April 26, 2017, to April 14, 2023, who were hospitalized with MI and anemia at 144 sites in 6 countries. Statistical analysis was performed from July 31, 2024, to February 18, 2026. INTERVENTION/UNASSIGNED:The MINT trial randomized participants to a restrictive (transfuse if hemoglobin is <7 to 8 g/dL) or liberal (maintain hemoglobin at >10 g/dL) transfusion strategy. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Bayesian posterior risk differences were estimated for 30-day death or MI and for heart failure using 3 prior beliefs regarding the treatment strategies: noninformative, liberal strategy superiority, or restrictive strategy superiority. RESULTS/UNASSIGNED:The mean (SD) age of the 3504 participants was 72.1 (11.6) years and 1911 (54.5%) were men. Compared with the restrictive strategy, the risk of 30-day death or MI with the liberal strategy was 1.4% (95% credible interval, -0.8% to 3.5%) to 2.4% (95% credible interval, 0.3%-4.6%) lower, depending on prior beliefs. The probability that the liberal strategy was associated with a lower risk of 30-day death or MI ranged from 89.1% to 98.8%, and the probability that a liberal strategy was associated with at least 1 less death or MI per 100 treated was between 62.7% and 90.4%. Conversely, the risk of heart failure with the liberal strategy was 0.2% (95% credible interval, -1.6% to 1.2%) to 0.6% (95% credible interval, -2.0% to 0.8%) higher compared with the restrictive strategy, depending on prior beliefs. The probability that the liberal strategy was associated with a higher risk of heart failure ranged from 60.6% to 80.0%, and the probability that a liberal strategy was associated with at least 1 more heart failure event per 100 treated was between 13.3% and 29.3%. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This post hoc analysis of a randomized clinical trial of patients with MI and anemia suggests that a liberal transfusion strategy was associated with a lower risk of 30-day death or MI, outweighing the increased risk of heart failure. Consistent with guideline recommendations and according to patients' values and clinician risk assessment, a liberal transfusion strategy may be reasonable. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02981407.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Cornerstone therapies for metastatic prostate cancer include androgen deprivation and androgen receptor pathway inhibition, but cognitive impairment is a recognized, life-altering potential adverse effect of this treatment. Abiraterone acetate (AA), an androgen receptor pathway and CYP17A1 inhibitor, suppresses androgen synthesis and may contribute to cognitive changes. This cell culture-based study uses the BE(2)M17 human male neuroblastoma model to investigate AA-induced alterations in gene and protein expression that may underlie cognitive decline, laying the foundation for a mechanistic investigation aimed at identifying molecular targets to mitigate cognitive impairment in men with prostate cancer receiving androgen-directed therapies. MATERIALS AND METHODS/METHODS:BE(2)M17 cells were pretreated for 12 h with dihydrotestosterone (DHT; 5 nM) or vehicle control, then exposed to AA (0, 5, 10 µM, 24 h). RNA and protein were analyzed by qRT-PCR and Western blot for markers of amyloid processing, neuronal health, and mitochondrial function. RESULTS:= 0.0003). CONCLUSIONS:AA, alone or combined with DHT, disrupts key pathways involved in neuronal health, amyloid processing, and mitochondrial function. These findings suggest a potential mechanistic link between AA treatment and cognitive impairment.

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.

OBJECTIVE:To assess the perceived clinical impact of radiologist staffing shortages across the U.S. and identify potential short- and long-term solutions. METHODS:A 26-question survey on breast imaging staffing shortages was distributed to active Society of Breast Imaging physician members from May 31, 2024, to June 28, 2024. Questions regarding the impact on patient care and radiologist wellbeing, as well as potential solutions, were included. Bivariable analysis (chi-squared) was performed between the survey demographics and survey response questions of interest. RESULTS:Of 226 respondents who felt understaffed in their practice due to an insufficient number of radiologists, the most frequently reported impact on patients was delayed diagnostic imaging (171/226, 75.7%) and procedures (155/226, 68.6%). The most frequently reported impacts on radiologists were increased stress (198/226, 87.6%), working hours (173/226, 76.6%), and burnout (173/226, 76.6%). As a perceived consequence, 56.2% (127/226) of respondents reported colleagues transitioning to part-time and 35.8% (81/226) reported colleagues switching practice types. To mitigate effects of understaffing, the most frequently reported short-term strategy was offering moonlighting (100/226, 44.2%), whereas offering part-time employment was the most frequently reported long-term strategy for retaining (86/226, 38.1%) and recruiting (120/226, 53.1%) radiologists. Over one-third (77/226, 34.1%) of respondents reported using advanced practice providers, most often for procedural support and patient navigation. CONCLUSION/CONCLUSIONS:Understaffed breast radiologists often perceived delays in patient care and increased levels of physician burnout. Moonlighting and part-time opportunities may mitigate these effects in the short and long-term, respectively.

Artificial Intelligence (AI) is rapidly being incorporated within healthcare, including medical education. Hematology-oncology (HO) is a complex field and AI is of great value in education and practice. We explored HO fellow's confidence and concerns with use of AI, AI training that HO fellows currently receive, and interest in future AI training. Multi-institutional survey administered to fellows in six adult HO programs. The survey was distributed electronically over one month with weekly reminders. Results were collected in RedCap and analyzed using R. 36 of 153 potential participants responded (23.5% response rate). Almost all (35, 97%) reported using AI. Fellows who reported using AI for work used it primarily for patient care (28, 82%) and/or research (29, 85%). Most were "somewhat confident" in the accuracy of AI-generated clinical information (25, 74%) and found AI "somewhat reliable" for clinical decision support (25, 74%). Respondents cited concerns about the use of AI in clinical practice, most often reliability of clinical data (32, 94%). Only one respondent (2.8%) received formal education on AI during fellowship and over who received informal training only reported its quality as "fair" or "poor" with 29 of these remaining 35 (83%) respondents interested in formal training. 31 fellows (86%) reported thinking AI would be important in their future career plans and 17 (49%) felt AI training should be required for HO fellows. While almost all HO fellows use AI, formal education in AI is rare in HO fellowship. Most fellows expressed interested in such training and believe that AI will be important in their careers, but also expressed concerns about use of AI, especially reliability of AI-generated clinical data. We plan to create formal curricula specific to HO training.