THE IMPACT OF ROUTINE CARDIAC TROPONIN I-BASED CARDIOTOXICITY SCREENING ON CLINICAL OUTCOMES IN PATIENTS ON CANCER IMMUNOTHERAPY.

Purpose: Immune checkpoint inhibitors (ICI) used as cancer therapy have been associated with a range of cardiac immune-related adverse events (irAEs), including fulminant myocarditis with a high case fatality rate. Early detection through cardiotoxicity screening by biomarker monitoring can lead to prompt intervention and improved patient outcomes. In this study, we investigate the association between cardiotoxicity screening with routine serial troponin I monitoring in asymptomatic patients receiving ICI, cardiovascular adverse event (CV AE) detection, and overall survival (OS). Methods: We instituted a standardized troponin I screening protocol at baseline and with each ICI dose (every 2-4 weeks) in all patients receiving ICI at our center starting Jan 2019. We subsequently collected data in 825 patients receiving ICI at our institution from January 2018 to October 2021. Of these patients, 428 underwent cardiotoxicity screening with serial troponin I monitoring during ICI administration (Jan 2019-Oct 2021) and 397 patients were unmonitored (Jan 2018-Dec 2018). We followed patients for nine months following their first dose of ICI and compared outcomes of CV AEs and OS between monitored and unmonitored patients. Additionally, we investigated rates of CV AEs, all-cause mortality, and oncologic time-to-treatment failure (TTF) between patients with an elevated troponin I value during the monitoring period versus patients without elevated troponin I. Results: We found a lower rate of severe (grades 4-5) CV AEs, resulting in critical illness or death, in patients who underwent troponin monitoring (0.5%) compared to patients who did not undergo monitoring (1.8%), (HR 0.17, 95% CI 0.02-0.79, p = 0.04). There was no difference in overall CV AEs (grades 3-5) or OS between monitored and unmonitored patients. In the entire cohort, patients with at least one elevated troponin I during the follow up period, during routine monitoring or unmonitored, had a higher risk of overall CV AEs (HR 10.96, 95% CI 4.65-25.85, p<0.001) as well as overall mortality (HR 2.67, 95% CI 1.69 - 4.10, p<0.001) compared to those without elevated troponin. Oncologic time-to-treatment failure (TTF) was not significantly different in a sub-cohort of monitored vs. unmonitored patients. Conclusions: Patients undergoing cardiotoxicity screening with troponin I monitoring during ICI therapy had a lower rate of severe (grade 4-5) CV AEs compared patients who were not screened. Troponin I elevation in screened and unscreened patients was significantly associated with increased CV AEs as well as increased mortality. Troponin I monitoring did not impact oncologic time-to-treatment-failure in a sub-cohort analysis of patients treated with ICI. These results provide preliminary evidence for clinical utility of cardiotoxicity screening with troponin I monitoring in patients receiving ICI therapy.

Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research.

Purpose of the Review: Even as immune checkpoint inhibitors (ICIs) have transformed the lifespan of many patients, they may also trigger acceleration of long-term cardiovascular disease. Our review aims to examine the current landscape of research on ICI-mediated atherosclerosis and address key questions regarding its pathogenesis and impact on patient management. Recent Findings: Preclinical mouse models suggest that T cell dysregulation and proatherogenic cytokine production are key contributors to plaque development after checkpoint inhibition. Clinical data also highlight the significant burden of atherosclerotic cardiovascular disease (ASCVD) in patients on immunotherapy, although the value of proactively preventing and treating ASCVD in this population remains an open area of inquiry. Current treatment options include dietary/lifestyle modification and traditional medications to manage hypertension, hyperlipidemia, and diabetes risk factors; no current targeted therapies exist. Summary: Early identification of high-risk patients is crucial for effective preventive strategies and timely intervention. Future research should focus on refining screening tools, elucidating targetable mechanisms driving ICI atherosclerosis, and evaluating long-term cardiovascular outcomes in cancer survivors who received immunotherapy. Moreover, close collaboration between oncologists and cardiologists is essential to optimize patient outcomes.

Using deep learning-based natural language processing to identify reasons for statin nonuse in patients with atherosclerotic cardiovascular disease.

Background: Statins conclusively decrease mortality in atherosclerotic cardiovascular disease (ASCVD), the leading cause of death worldwide, and are strongly recommended by guidelines. However, real-world statin utilization and persistence are low, resulting in excess mortality. Identifying reasons for statin nonuse at scale across health systems is crucial to developing targeted interventions to improve statin use. Methods: We developed and validated deep learning-based natural language processing (NLP) approaches (Clinical Bidirectional Encoder Representations from Transformers [BERT]) to classify statin nonuse and reasons for statin nonuse using unstructured electronic health records (EHRs) from a diverse healthcare system. Results: We present data from a cohort of 56,530 ASCVD patients, among whom 21,508 (38%) lack guideline-directed statin prescriptions and statins listed as allergies in structured EHR portions. Of these 21,508 patients without prescriptions, only 3,929 (18%) have any discussion of statin use or nonuse in EHR documentation. The NLP classifiers identify statin nonuse with an area under the curve (AUC) of 0.94 (95% CI 0.93-0.96) and reasons for nonuse with a weighted-average AUC of 0.88 (95% CI 0.86-0.91) when evaluated against manual expert chart review in a held-out test set. Clinical BERT identifies key patient-level reasons (side-effects, patient preference) and clinician-level reasons (guideline-discordant practices) for statin nonuse, including differences by type of ASCVD and patient race/ethnicity. Conclusions: Our deep learning NLP classifiers can identify crucial gaps in statin nonuse and reasons for nonuse in high-risk populations to support education, clinical decision support, and potential pathways for health systems to address ASCVD treatment gaps.

Changes in Medicaid enrollment during the COVID-19 pandemic across 6 states.

The coronavirus disease 2019 public health emergency (PHE) caused extensive job loss and loss of employer-sponsored insurance. State Medicaid programs experienced a related increase in enrollment during the PHE. However, the composition of enrollment and enrollee changes during the pandemic is unknown. This study examined changes in Medicaid enrollment and population characteristics during the PHE. A retrospective study documenting changes in Medicaid new enrollment and disenrollment, and enrollee characteristics between March and October 2020 compared to the same time in 2019 using full-state Medicaid populations from 6 states of a wide geographical region. The primary outcomes were Medicaid enrollment and disenrollment during the PHE. New enrollment included persons enrolled in Medicaid between March and October 2020 who were not enrolled in January or February, 2020. Disenrollment included persons who were enrolled in March of 2020 but not enrolled in October 2020. The study included 8.50 million Medicaid enrollees in 2020 and 8.46 million in 2019. Overall, enrollment increased by 13.0% (1.19 million) in the selected states during the PHE compared to 2019. New enrollment accounted for 24.9% of the relative increase, while the remaining 75.1% was due to disenrollment. A larger proportion of new enrollment in 2020 was among adults aged 27 to 44 (28.3% vs 23.6%), Hispanics (34.3% vs 32.5%) and in the financial needy (44.0% vs 39.0%) category compared to 2019. Disenrollment included a larger proportion of older adults (26.1% vs 8.1%) and non-Hispanics (70.3% vs 66.4%) than in 2019. Medicaid enrollment grew considerably during the PHE, and most enrollment growth was attributed to decreases in disenrollment rather than increases in new enrollment. Our results highlight the impact of coronavirus disease 2019 on state health programs and can guide federal and state budgetary planning once the PHE ends.

Breed predispositions, clinical findings, and prognostic factors for death in dogs with nonregenerative immune-mediated anemia.

BACKGROUND: Breed predispositions, survival, and prognostic factors have not been evaluated in dogs with nonregenerative immune-mediated anemia (nrIMA). HYPOTHESIS/OBJECTIVES: To describe clinicopathologic variables, evaluate their associations with survival, and determine breed predispositions for dogs with nrIMA. ANIMALS: Fifty-nine client-owned dogs with nrIMA. METHODS: Referral hospital records were reviewed retrospectively for dogs with primary nrIMA (PCV ≤30%, corrected reticulocyte percentage (CR%) ≤1.0, bone marrow sampling with evidence of immune-mediated destruction, and underlying causes excluded). Breed predispositions were evaluated by calculation of odds ratios in a case control study; prognostic factors by logistic regression in a cohort study. RESULTS: Fifty-nine dogs with nrIMA had a median PCV of 12% (interquartile range [IQR]: 10%-17%) and CR% 0.1 (0%-0.2%). At least ≥1 ACVIM IMHA diagnostic criteria were met by 35 dogs (59%). Whippets, Lurchers, and miniature Dachshunds were predisposed to nrIMA. Median survival time was 277 days (IQR: 37-1925), with 3- and 12-month survival rates 61% and 43%, respectively. Erythroid regeneration and remission were achieved by 88% and 62% of dogs, respectively. Corrected reticulocyte percentage >0.2 was associated with improved survival. CONCLUSION AND CLINICAL IMPORTANCE: Although there is overlap of clinical features between dogs with IMHA and nrIMA, the prognosis for those with nrIMA depends predominantly on the severity of reticulocytopenia.

Medical Student Values Inform Career Plans in Service & Surgery-A Qualitative Focus Group Analysis.

BACKGROUND: Diversifying the surgical workforce is a critical component of improving care for underserved patients. To recruit surgeons from diverse backgrounds, we must understand how medical students choose their specialty. We investigate how preclinical students contemplate entering a surgical field. MATERIALS AND METHODS: We conducted semistructured focus groups during two iterations of a seminar class called Service Through Surgery. Discussion goals included identifying student values and assessing how they inform early career decisions. We used a systematic, collaborative, and iterative process for transcript analysis, including developing a codebook, assessing inter-rater reliability, and analyzing themes. RESULTS: Twenty-four preclinical medical students from diverse backgrounds participated in seven focus groups; most were women (16; 67%), in their first year of medical school (19; 79%), and interested in surgery (17; 71%). Participants ranked professional fulfillment, spending time with family, and serving their communities and/or underserved populations among their most important values and agreed that conducting groundbreaking research, working long hours, and finding time for leisure activities were the least important. We constructed a framework to describe student responses surrounding their diverse visions for service in future surgical careers through individual doctoring interactions, roles in academia, and broader public service. CONCLUSIONS: Our framework provides a basis for greater understanding and study of the ways in which preclinical medical students think about their personal values and visions for service in potential future surgical careers. This research can guide early interventions in medical education to promote diversity and care for the underserved in surgery.

Improved enrichment strategies for phosphorylated peptides on titanium dioxide using methyl esterification and pH gradient elution.

Improvements to phosphopeptide enrichment protocols employing titanium dioxide (TiO2) are described and applied to identification of phosphorylation sites on recombinant human cyclin-dependent kinase 2 (CDK2). Titanium dioxide binds phosphopeptides under acidic conditions, and they can be eluted under basic conditions. However, some nonphosphorylated peptides, particularly acidic peptides, bind and elute under these conditions as well. These nonphosphorylated peptides contribute significantly to ion suppression of phosphopeptides and also increase sample complexity. We show here that the conversion of peptide carboxylates to their corresponding methyl esters sharply reduces nonspecific binding, improving the selectivity for phosphopeptides, just as has been reported for immobilized metal affinity chromatography (IMAC) columns. We also present evidence that monophosphorylated peptides can be effectively fractionated from multiply phosphorylated peptides, as well as acidic peptides, via stepwise elution from TiO2 using pH step gradients from pH 8.5 to pH 11.5. These approaches were applied to human CDK2 phosphorylated in vitro by yeast CAK1p in the absence of cyclin. We confirmed phosphorylation at T160, a site previously documented and shown to be necessary for CDK2 activity. However, we also discovered several novel sites of partial phosphorylation at S46, T47, T165, and Y168 when ion-suppressing nonphosphorylated peptides were eliminated using the new protocols.