Gender Differences in Takotsubo Cardiomyopathy as a Secondary Diagnosis: Higher Hospital Charges, More Procedures, and Longer Length of Stays

Background The incidence of Takotsubo Cardiomyopathy (TC) has risen steadily over the past decade, with current estimates of 15-30 cases per 100,000 per year. Historically, men diagnosed with TC have worse outcomes compared to women. The relationship between total hospital charges, number of procedures performed, and length of stay (LOS) between genders has not been previously reported with TC as a secondary diagnosis. Methods National Inpatient Sample (NIS) data from 2009-2015 was used to identify encounters of adult patients (≥18 years) undergoing coronary angiography that were ultimately given a secondary diagnosis of TC (International Classification of Diseases – 9 code 429.83). Demographics, comorbidities and outcomes including hospital mortality, total charges, and LOS were assessed and stratified by gender. Continuous variables were described using means and compared using independent two-sample t-tests. Total charges and LOS were described using medians and compared using Wilcoxon rank sum test. TC encounters were propensity matched by age, number of chronic conditions, number of procedures performed, and severity of illness. A discharge weight was included in all analyses to account for the complex sample design of the NIS. Results During 2009-2015, 1,448 men and 9,404 women with secondary TC were identified in the dataset, corresponding to a national estimate of 7,124 men and 46,163 women. The median hospital charges were $54,655 for men and$45,455 for women (p Conclusion Compared to women, men with a secondary diagnosis of TC are more likely to have a greater number of procedures, leading to a longer LOS and ∼$10,000 more in hospital charges. Greater awareness of TC as a potential secondary diagnosis is warranted among men

Abstract 219: Use of Machine Learning Models to Identify Atherosclerotic Cardiovascular Disease Patients at Very High Risk for Future Events in a Multi-state Health Care System

Background: In the 2018 AHA/ACC Blood Cholesterol Guideline, it is recommended that ASCVD patients be classified as very high-risk (VHR) vs not-VHR (NVHR) to guide treatment decisions. This has important implications for ezetimibe and PCSK9 inhibitor eligibility. We aimed to develop a tool that could assist in more easily identifying VHR patients based on machine learning (ML) techniques. This approach offers a powerful, assumption-free alternative to conventional methods, such as logistic regression, to identify potential interactions among risk factors while incorporating the hierarchy of interaction among variables. Method: We used EHR-derived ICD-10 codes to identify patients within our health system with ASCVD. VHR was defined by ≥2 major ASCVD events (ACS ≤12 months, history of MI \u3e12 months, ischemic stroke, or symptomatic PAD) or 1 major ASCVD event and ≥2 high-risk conditions (age ≥65, diabetes, hypertension, smoking, heterozygous familial hypercholesterolemia, CKD, CHF, persistently elevated LDL-C ≥100 mg/dl, or prior CABG/PCI). Patients not meeting these criteria were classified as NVHR. We randomly assigned patients into a training set and a testing set. Classification and regression tree (CART) modeling was performed on the training set and validated on the testing set. The results were compared with a random forest model. Variables in both models included age, sex, race, ethnicity, and each of the VHR criteria above. The primary outcome for both models was VHR classification. Performance of the two models were compared using area under the curve (AUC). Result: A total of 180,669 ASCVD patients were identified in 2018: 104,123 (58%) were VHR and 76,546 (42%) were NVHR. Mean age and sex were 73.1±11.9 years, 55% male and 70.1±13.4 years, 54% male for the VHR and NVHR groups, respectively. Half the population was randomly selected as the training dataset (n=90,334) and the other half was used as the testing dataset (n=90,335). Both CART and random forest models identified recent ACS, ischemic stroke, hypertension, PAD, and history of MI as the top five predictors of VHR status. Ninety-six percent of patients with recent ACS were classified as VHR. Among patients with no recent ACS, 95% were classified as VHR if they had a stroke and hypertension. Among patients with no ACS or stroke, 89% were classified as VHR if they had PAD. Finally, among patients with no ACS, stroke or PAD, 90% were classified as VHR if they had a history of MI. The misclassification rate of the CART model on the testing set was 4.3%. The AUC for the CART and random forest models was 0.949 and 0.968, respectively. Conclusion: Both ML methods were highly predictive of VHR status among those with ASCVD. Use of this approach affords a simplified means to drive clinical decision making at the point of care

Clinical Characteristics of Patients Classified as Very High Risk and Not Very High Risk Based on the 2018 AHA/ACC Multi-Society Cholesterol Guideline

Background The 2018 AHA/ACC Cholesterol Guideline recommendation to classify ASCVD patients as very high-risk (VHR) vs not-VHR (NVHR) has important implications for ezetimibe and PCSK9 inhibitor eligibility. We aimed to define the clinical characteristics of these two groups within a large multi-state healthcare system in the Western U.S. Methods We performed a retrospective cohort analysis of patients defined as having ASCVD in 2018 using EHR ICD-10 codes. VHR was defined by ≥2 major ASCVD events (ACS ≤12 months, history of MI \u3e12 months, ischemic stroke, or symptomatic PAD) or 1 major ASCVD event and ≥2 high-risk conditions (age ≥65, DM, HTN, smoking, HeFH, CKD, CHF, persistently elevated LDL-C, or prior CABG/PCI). Patients not meeting these criteria were classified as NVHR. Results A total of 180,669 ASCVD patients were identified: 104,123 (58%) were VHR and 76,546 (42%) were NVHR. Mean age and gender was 70.1±13.4 years, 54% male and 73.1±11.9 years, 55% male for the NVHR and VHR groups, respectively. Among patients with a history of MI or recent ACS, 99% and 96% were classified as VHR, respectively (Table). Age ≥65, HTN and DM were the most prevalent high-risk conditions. Conclusion Criteria used to predict future CV risk largely divide ASCVD patients into groups of similar prevalence. Nearly all ACS/MI patients were VHR. With growing emphasis on individualized risk assessment and intense LDL-C reduction, opportunity exists to further refine risk prediction within these two at-risk groups

Trends in Diagnosis Related Groups for inpatient admissions and associated changes in payment from 2012 to 2016

Importance: Hospitals are reimbursed based on Diagnosis Related Groups (DRGs), which are defined, in part, by patients having 1 or more complications or comorbidities within a given DRG family. Hospitals have made substantial investment in efforts to document these complications and comorbidities. Objective: To examine temporal trends in DRGs with a major complication or comorbidity, compare these findings with 2 alternative measures of disease severity, and estimate associated changes in payment. Design, Setting, and Participants: This retrospective cohort study used data from the all-payer National Inpatient Sample for admissions assigned to 1 of the top 20 reimbursed DRG families at US acute care hospitals from January 1, 2012, to December 31, 2016. Data were analyzed from July 10, 2018, to May 29, 2019. Exposures: Quarter year of hospitalization. Main Outcomes and Measures: The primary outcome was the proportion of DRGs with a major complication or comorbidity. Secondary outcomes were comorbidity scores, risk-adjusted mortality rates, and estimated payment. Changes in assigned DRGs, comorbidity scores, and risk-adjusted mortality rates were analyzed by linear regression. Payment changes were estimated for each DRG by calculating the Centers for Medicare & Medicaid Services weighted payment using 2012 and 2016 case mix and hospitalization counts. Results: Between 2012 and 2016, there were 62 167 976 hospitalizations for the 20 highest-reimbursed DRG families; the sample was 32.9% male and 66.8% White, with a median age of 57 years (interquartile range, 31-73 years). Within 15 of these DRG families (75%), the proportion of DRGs with a major complication or comorbidity increased significantly over time. Over the same period, comorbidity scores were largely stable, with a decrease in 6 DRG families (30%), no change in 10 (50%), and an increase in 4 (20%). Among 19 DRG families with a calculable mortality rate, the risk-adjusted mortality rate significantly decreased in 8 (42%), did not change in 9 (47%), and increased in 2 (11%). The observed DRG shifts were associated with at least $1.2 billion in increased payment. Conclusions and Relevance: In this cohort study, between 2012 and 2016, the proportion of admissions assigned to a DRG with major complication or comorbidity increased for 15 of the top 20 reimbursed DRG families. This change was not accompanied by commensurate increases in disease severity but was associated with increased payment

Molecular Remodeling of Tip Links Underlies Mechanosensory Regeneration in Auditory Hair Cells

Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism\u27s life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca(2+)-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery

Brain radiotherapy, tremelimumab-mediated CTLA-4-directed blockade +/- trastuzumab in patients with breast cancer brain metastases

Breast cancer brain metastases (BCBM) are a common and devastating complication of metastatic breast cancer with conventional systemic therapies demonstrating limited effectiveness. Consequently, radiotherapy (RT) ± surgery remains the cornerstone of BCBM management. Because preclinical and clinical evidence indicate that immune checkpoint blockade (ICB) may synergize with RT to promote systemic tumor regression, we explored the safety and efficacy of RT and concurrent tremelimumab-mediated cytotoxic T-lymphocyte associated protein 4 (CTLA-4) ICB with tremelimumab ± HER2-directed therapy with trastuzumab for BCBM. Eligible patients had BCBM indicated for brain RT. A Simon two-stage design was adopted to evaluate the efficacy of tremelimumab and RT in 20 patients with human epidermal growth factor receptor normal (HER2-) BCBM. The safety of concurrent RT, tremelimumab, and trastuzumab was evaluated in a cohort of 6 HER2+ patients. The primary endpoint was 12-week non-central nervous system (CNS) disease control rate (DCR). Secondary endpoints included safety, survival, and CNS response. Exploratory correlatives included characterization of peripheral blood immune responses among exceptional responders. Tremelimumab plus RT ± trastuzumab was tolerated with no treatment-related grade 4 adverse events reported. The 12-week non-CNS DCR was 10% (2/20) in the HER2- cohort and 33% (2/6) in the HER2+ cohort. One patient with HER2+ disease experienced a durable partial response with evidence of peripheral T-cell activation. Thus, tremelimumab and RT ± trastuzumab was tolerated. Although modest clinical activity was observed in the HER2- efficacy cohort, encouraging responses were observed in the HER2+ safety cohort. Consequently, a trial to determine efficacy in HER2+ BCBM is planned.Clinical Trial Registration Number: NCT02563925

Monitoring intracellular calcium ion dynamics in hair cell populations with Fluo-4 AM.

We optimized Fluo-4 AM loading of chicken cochlea to report hair-bundle Ca(2+) signals in populations of hair cells. The bundle Ca(2+) signal reported the physiological state of the bundle and cell; extruding cells had very high bundle Fluo-4 fluorescence, cells with intact bundles and tip links had intermediate fluorescence, and damaged cells with broken tip links had low fluorescence. Moreover, Fluo-4 fluorescence in the bundle correlated with Ca(2+) entry through transduction channels; mechanically activating transduction channels increased the Fluo-4 signal, while breaking tip links with Ca(2+) chelators or blocking Ca(2+) entry through transduction channels each caused bundle and cell-body Fluo-4 fluorescence to decrease. These results show that when tip links break, bundle and soma Ca(2+) decrease, which could serve to stimulate the hair cell's tip-link regeneration process. Measurement of bundle Ca(2+) with Fluo-4 AM is therefore a simple method for assessing mechanotransduction in hair cells and permits an increased understanding of the interplay of tip links, transduction channels, and Ca(2+) signaling in the hair cell

Blocking the transduction channel decreases hair-bundle and cell body Ca²⁺.

<p>(a–d) Control hair cells have Fluo-4 signal in the bundle (b) and cell body (d). (e–h) Hair cells incubated with 100 µM tubocurarine to block the transduction channel have decreased Fluo-4 signal in the bundle (f) and cell body (h). (i–j) To quantify Fluo-4 fluorescence, individual bundle and cell body ROIs were selected and integrated density of Fluo-4 channel was calculated (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051874#pone-0051874-g006" target="_blank">Figure 6</a>), then normalized to the control mean for each group. (a, c, e, g) Corresponding DIC images. (au = arbitrary units; control bundles n = 63, tubocurarine bundles n = 73, control cell bodies n = 72, tubocurarine cell bodies n = 77; **** p<0.0001).</p