Duke Raleigh Hospital

Abstract Background: Germline microRNA-disrupting variants (mirSNPs) predict late radiation toxicity, which generally presents as fibrosis, in several cancer types. mirSNP signatures of toxicity are radiation fractionation (size of delivered dose) dependent, meaning that identifying patients at risk of toxicity from one form of radiation treatment affords the opportunity to choose safer alternatives for their management. As radiation is an integral part of breast cancer management, with several fractionation approaches gaining acceptance, we tested the hypothesis that mirSNP signatures could predict late radiation toxicity in these patients. Methods: DNA was isolated from buccal swabs from 121 breast cancer patients treated with conventionally fractionated radiation (CFRT, 38%) or moderately hypofractionated radiation (16-20 fractions, 62%) and tested for over 120 mirSNPs. Acute, chronic and late radiation toxicity as well as clinical factors were collected, including post-mastectomy radiation or implant, chemotherapy treatment, alcohol and smoking history, autoimmunity, and DNA repair mutant status. Most of the cohort was White and non-Hispanic (81.8%), with 11.5% of women White and Hispanic, and 6.6% of women non-White and non-Hispanic. We applied a previously developed mirSNP signature of late grade > 2 CFRT radiation toxicity defined in prostate cancer patients [1]. We then explored the addition of clinical factors to this signature to see if any improved predictive accuracy. Finally, we incorporated germline mirSNPs marginally associated with late toxicity (Fisher or Jonckheere-Terpstra p < 0.1) in our breast cohort alongside the CFRT prediction in elastic net and boosted tree models. Results: The late CFRT radiation toxicity signature achieved robust predictive performance for late grade > 2 toxicity in our breast patient cohort, with a specificity of 0.957, a positive predictive value (PPV) of 0.79, and an overall AUC of 0.734. Notably, all patients with grade 0 late toxicity were accurately identified as low risk, and the model predicted grade 3 late toxicity more accurately than grade 2 (60% vs. 30%, p=0.317 for difference in proportions). As expected, the late CFRT radiation toxicity signature showed no predictive power for predicting acute or chronic toxicity in our cohort, adding to our recent research demonstrating different biological pathways involved in radiation induced acute, chronic, and late toxicity [2]. We found that none of the clinical factors improved the performance of the late CFRT radiation toxicity signature in our cohort, and in fact, the LOOCV AUC slightly decreased to 0.710. In contrast, adding just 6 additional mirSNPs, including MAT1A and KRAS, boosted the AUC to 0.810-0.837 and increased the sensitivity from 0.52 (CFRT alone) to 0.79 (CFRT + 6 SNPs). Interestingly, only 2 of these mirSNPs overlapped with the original CFRT model, and both MAT1A and KRAS variants appeared protective: the rate of late toxicity dropped from 38% to 4% (wild type to mutant MAT1A) and from 27% to 5% (wild type to heterozygous KRAS). Conclusions: These findings further highlight the power and generalizability of germline mirSNP signatures to meaningfully predict late radiation-induced toxicity, including in breast cancer patients. These are important steps towards meaningful biological insights into late radiation toxicity, as well as indicate the possibility of truly personalizing radiation recommendations in breast cancer.1.Kishan, A.U., et al., Germline variants disrupting microRNAs predict long-term genitourinary toxicity after prostate cancer radiation. Radiother Oncol, 2022. 167: p. 226-232.2.Kishan, A.U., et al., Validation and Derivation of miRNA-Based Germline Signatures Predicting Radiation Toxicity in Prostate Cancer. Clin Cancer Res, 2025. 31(12): p. 2530-2538. Citation Format: J. Weidhaas, K. McGreevy, S. McCloskey, J. Hegde, M. Steinberg, J. Baker, M. Dinome, A. Kusske, J. Glaspy, R. Callahan, K. McCann, M. Teshome, N. Mcandrew, A. Bardia, D. Telesca. Germline microRNA-based variants predicting late radiation toxicity in breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-07-09.

Abstract Background Treatment options for Carbapenem-resistant (CR) Gram-negative infections due to metallo-beta-lactamase (MBL) enzymes are limited. The clinical impact of MBLs vs. other mechanisms of carbapenem resistance in Enterobacterales and non-fermenting bacteria remains unclear.Table 1.Demographics, isolate characteristics, and outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusFigure 1.30-day desirability of outcome ranking (DOOR) outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusCRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. DOOR events assessed at 30 days include: unsuccessful discharge, lack of clinical response, and C. difficile infection and/or renal failure. Not all rows total to 100 due to rounding. P-value calculated using Wilcoxon test. Methods We conducted a matched cohort study of patients enrolled in one of three MDRO Network studies, POP (CR Pseudomonas aeruginosa [CRPA]), SNAP (CR Acinetobacter baumannii [CRAb]), or CRACKLE-2 (CR-Enterobacterales [CRE]) with isolates that met infection criteria. Patients with MBL-producing isolates (blaVIM, blaIMP, or blaNDM present) were matched 1:2 to patients with non-MBL CR isolates (a different carbapenemase or CR without a carbapenemase) based on study, region, and anatomical source. We compared baseline characteristics, 30- and 90-day mortality, and 30-day desirability of outcome ranking (DOOR) scores.30-day Desirability of Outcome Ranking (DOOR) Probability by MBL StatusLegend: CI – confidence interval, CRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. The DOOR probability was calculated as the probability of a more desirable result in the presence of MBL as compared to non-MBL isolate. Confidence intervals were calculated using the method in Halperin et al (Biometric 1989; 45:500-521), and CI’s that do not include 50% are considered statistically significant. Estimates less than 50% signify a less favorable outcome for the MBL group, while estimates greater than 50% signify more favorable outcomes for the MBL group. Results In total, 170 MBL isolates were matched to 340 non-MBL isolates from 10 countries (Table 1). The cohort included 42% CRPA (216/510), 5% CRAb (24/510), and 53% CRE (270/510). Demographics were balanced between groups; median age at culture was 61 (Q1, 44, Q3 73) years. Common infection sources were respiratory (151/510, 30%), urine (141/510, 28%), and blood (105/510, 21%). Of the MBL isolates, 92/170 harbored blaNDM (54%), 62/170 harbored blaVIM (36%), and 20/170 harbored blaIMP (12%); four isolates co-harbored two distinct MBL enzymes. All-cause 30-day mortality was 19% (33/170) for MBL vs 18% (61/340) for non-MBL (p=0.69); MBL presence was not associated with 30- or 90-day mortality. DOOR outcomes at 30-days (Figure 1) did not differ by MBL status in the full cohort or the CRE subgroup, but did differ in the CRPA/CRAb subgroup (p=0.037). Among CRPA/CRAb infections, MBL presence was associated with less desirable outcomes (DOOR probability 42.1%; 95% Halperin confidence interval: 35.0%-49.5%, Figure 2). Conclusion MBL presence was not associated with increased 30- or 90-day mortality compared to matched non-MBL isolates. However, in non-fermenter infections (CRPA/CRAb), MBL presence was linked to less desirable outcomes, an association not seen in CRE. These findings may inform prioritization of anti-MBL agents in future drug development. Disclosures Angelique E. Boutzoukas, MD, MPH, Elion Therapeutics: Advisor/Consultant|Innoviva Speciality Therapeutics: DSMB Participant Souha S. Kanj, MD, Menarini: Honoraria|pfizer: Honoraria Vance G. Fowler, MD, MHS, Affinergy, Janssen, Contrafect: Advisor/Consultant|AstraZeneca; EDE; Basilea: Grant/Research Support|Debiopharm, GSK; Affinium, Basilea,: Advisor/Consultant|Destiny, Amphliphi, Armata, Akagera: Advisor/Consultant|Merck; Contrafect; Karius; Janssen: Grant/Research Support|UpToDate: Royalties|Valanbio: Stock options Yohei Doi, MD, PHD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Michael Satlin, MD, MS, AbbVie: DSMB Participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|SNIPRBiome: Grant/Research Support Robert A. Bonomo, MD, Merck: Grant/Research Support|Shinogi: Grant/Research Support|VenatoRx: Grant/Research Support David van Duin, MD, PhD, British Society for Antimicrobial Chemotherapy: Editor stipend|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant

CYP2C9 and CYP2C19 are major CYP450 enzymes that heavily influence the hepatic metabolism and bioactivation of many medications, including over-the-counter and narrow therapeutic index drugs. Compared to the wild-type alleles, genetic variants in either gene could potentially alter the pharmacokinetics of widely used medications, affect the desired therapeutic outcomes of a drug therapy, or increase the risk of undesired adverse events. The frequency of genetic polymorphisms associated with CYP450 enzymes can widely differ across and between racial and ethnic groups. This narrative review highlights the differences in CYP2C9 and CYP2C19 allele frequencies among European and Asian population subgroups, using published literature. Identifying the substantial differences across European and Asian populations, as well as within Asian subgroups, indicates the need to further scrutinize general population data. Clinical scientists and healthcare providers should advocate for more inclusive clinical pharmacogenomic data and racially and ethnically diverse pharmacogenomic databases. Clinical trials of limited racial and geographical diversity may not necessarily have strong external generalizability for all populations. Furthermore, clinical trials that designate an all-inclusive Asian population consisting of multiple ethnicities may not be adequate due to the perceived genetic differences among Asian subgroups. Gravitating towards a more comprehensive approach to utilizing pharmacogenomic data necessitates granular population-level genetic information which can be leveraged to improve how drug therapies are prescribed, achieve health equity, and advance the future of precision medicine.

To evaluate the impact of a lay health worker support role in the inpatient setting. Healthcare systems are facing critical nursing and nurse assistant staffing shortages. These disciplines can be challenging to recruit and retain, leading healthcare leaders to identify innovative staffing models. Whereas lay health workers have been used in the community and low-income setting, there is scant evidence of their use in the inpatient setting. We implemented a lay health worker role, called Patient Attendant Service Aides (PASAs), on two medical/surgical units at a community hospital. A pre/post-implementation design was used for this study. An online survey was provided to nurses, nursing assistants, and PASAs on the two medical/surgical units to assess their satisfaction and perceptions of the role. Nursing quality metrics, patient satisfaction, and nursing and nursing assistant turnover were evaluated before and after implementing the role. The online survey showed that nurses and nursing assistants felt that PASAs helped offload their workload, allowing them to focus on nursing-related tasks. PASAs felt supported by the team and believed they were making a meaningful contribution to the unit. There were slight improvements in patient satisfaction, although not significant. There was a significant improvement in nursing turnover on Unit A, from 71.1% to 21.6% (p = 0.009). This is one of the first studies to evaluate the use of lay health workers in the inpatient setting; we found this role to be a feasible way to offload tasks from clinical staff. This role may serve as a pathway for workforce development, as several PASAs are now enrolled in nursing assistant training. Nurse managers may consider using lay health workers in the inpatient setting as they face severe clinical staff shortages.

We report Tensorial tomographic Fourier Ptychography (ToFu), a new non-scanning label-free tomographic microscopy method for simultaneous imaging of quantitative phase and anisotropic specimen information in 3D. Built upon Fourier Ptychography, a quantitative phase imaging technique, ToFu additionally highlights the vectorial nature of light. The imaging setup consists of a standard microscope equipped with an LED matrix, a polarization generator, and a polarization-sensitive camera. Permittivity tensors of anisotropic samples are computationally recovered from polarized intensity measurements across three dimensions. We demonstrate ToFu's efficiency through volumetric reconstructions of refractive index, birefringence, and orientation for various validation samples, as well as tissue samples from muscle fibers and diseased heart tissue. Our reconstructions of muscle fibers resolve their 3D fine-filament structure and yield consistent morphological measurements compared to gold-standard second harmonic generation scanning confocal microscope images found in the literature. Additionally, we demonstrate reconstructions of a heart tissue sample that carries important polarization information for detecting cardiac amyloidosis.