Faculty Bibliography

Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.

BACKGROUND:Over the past 2 decades, guidelines for digoxin use have changed significantly. However, little is known about the national-level trends of digoxin use, hospitalizations for toxicity, and subsequent outcomes over this time period. METHODS:To describe digoxin prescription trends, we conducted a population-level, cohort study using data from IQVIA, Inc.'s National Prescription Audit (2007-2014) for patients aged ≥65 years. Further, in a national cohort of Medicare fee-for-service beneficiaries aged ≥65 years in the United States, we assessed temporal trends of hospitalizations associated with digoxin toxicity and the outcomes of these hospitalizations between 1999 and 2013. RESULTS:From 2007 through 2014, the number of digoxin prescriptions dispensed decreased by 46.4%; from 8,099,856 to 4,343,735. From 1999 through 2013, the rate of hospitalizations with a principal or secondary diagnosis of digoxin toxicity decreased from 15 to 2 per 100,000 person-years among Medicare fee-for-service beneficiaries. In-hospital and 30-day mortality rates associated with hospitalization for digoxin toxicity decreased significantly among Medicare fee-for-service beneficiaries; from 6.0% (95% confidence interval [CI], 5.2-6.8) to 3.7% (95% CI, 2.2-5.7) and from 14.0% (95% CI, 13.0-15.2) to 10.1% (95% CI, 7.6-13.0), respectively. Rates of 30-day readmission for digoxin toxicity decreased from 23.5% (95% CI, 22.1-24.9) in 1999 to 21.7% (95% CI, 18.0-25.4) in 2013 (P < .05). CONCLUSION:While digoxin prescriptions have decreased, it is still widely prescribed. However, the rate of hospitalizations for digoxin toxicity and adverse outcomes associated with these hospitalizations have decreased. These findings reflect the changing clinical practice of digoxin use, aligned with the changes in clinical guidelines.

BACKGROUND:Efforts to decrease hospitalization costs could increase post-acute care costs. This effect could undermine initiatives to reduce overall episode costs and have implications for the design of health care under alternative payment models. METHODS:Among Medicare fee-for-service beneficiaries aged ≥65 years hospitalized with acute myocardial infarction (AMI) between July 2010 and June 2013 in the Premier Healthcare Database, we studied the association of in-hospital and post-acute care resource utilization and outcomes by in-hospital cost tertiles. RESULTS:Among patients with AMI at 326 hospitals, the median (range) of each hospital's mean per-patient in-hospital risk-standardized cost (RSC) for the low, medium, and high cost tertiles were $16,257 ($13,097-$17,648), $18,544 ($17,663-$19,875), and $21,831 ($19,923-$31,296), respectively. There was no difference in the median (IQR) of risk-standardized post-acute payments across cost-tertiles: $5014 (4295-6051), $4980 (4349-5931) and $4922 (4056-5457) for the low (n = 90), medium (n = 98), and high (n = 86) in-hospital RSC tertiles (p = 0.21), respectively. In-hospital and 30-day mortality rates did not differ significantly across the in-hospital RSC tertiles; however, 30-day readmission rates were higher at hospitals with higher in-hospital RSCs: median = 17.5, 17.8, and 18.0% at low, medium, and high in-hospital RSC tertiles, respectively (p = 0.005 for test of trend across tertiles). CONCLUSIONS:In our study of patients hospitalized with AMI, greater resource utilization during the hospitalization was not associated with meaningful differences in costs or mortality during the post-acute period. These findings suggest that it may be possible for higher cost hospitals to improve efficiency in care without increasing post-acute care utilization or worsening outcomes.

IMPORTANCE:Payers and policy makers have advocated for transitioning toward value-based payment models. However, little is known about what is the extent of hospital variation in the value of care and whether there are any hospital characteristics associated with high-value care. OBJECTIVES:To investigate the association between hospital-level 30-day risk-standardized mortality rates (RSMRs) and 30-day risk-standardized payments (RSPs) for acute myocardial infarction (AMI), heart failure (HF), and pneumonia (PNA); to characterize patterns of value in care; and to identify hospital characteristics associated with high-value care (defined by having lower than median RSMRs and RSPs). DESIGN, SETTING, AND PARTICIPANTS:This national cross-sectional study applied weighted linear correlation to investigate the association between hospital RSMRs and RSPs for AMI, HF, and PNA between July 1, 2011, and June 30, 2014, among all hospitals; examined correlations in subgroups of hospitals based on key characteristics; and assessed the proportion and characteristics of hospitals delivering high-value care. The data analysis was completed in October 2017. The setting was acute care hospitals. Participants were Medicare fee-for-service beneficiaries discharged with AMI, HF, or PNA. MAIN OUTCOMES AND MEASURES:Hospital-level 30-day RSMRs and RSPs for AMI, HF, and PNA. RESULTS:The AMI sample consisted of 4339 hospitals with 487 141 hospitalizations for mortality and 462 905 hospitalizations for payment. The HF sample included 4641 hospitals with 960 960 hospitalizations for mortality and 903 721 hospitalizations for payment. The PNA sample contained 4685 hospitals with 952 022 hospitalizations for mortality and 901 764 hospitalizations for payment. The median (interquartile range [IQR]) RSMRs and RSPs, respectively, was 14.3% (IQR, 13.8%-14.8%) and $21 620 (IQR, $20 966-$22 567) for AMI, 11.7% (IQR, 11.0%-12.5%) and $15 139 (IQR, $14 310-$16 118) for HF, and 11.5% (IQR, 10.6%-12.6%) and $14 220 (IQR, $13 342-$15 097) for PNA. There were statistically significant but weak inverse correlations between the RSMRs and RSPs of -0.08 (95% CI, -0.11 to -0.05) for AMI, -0.21 (95% CI, -0.24 to -0.18) for HF, and -0.07 (95% CI, -0.09 to -0.04) for PNA. The largest shared variance between the RSMRs and RSPs was only 4.4% (for HF). The correlations between the RSMRs and RSPs did not differ significantly across teaching status, safety-net status, urban/rural status, or the proportion of patients with low socioeconomic status. Approximately 1 in 4 hospitals (20.9% for AMI, 23.0% for HF, and 23.9% for PNA) had both lower than median RSMRs and RSPs. CONCLUSIONS AND RELEVANCE:These findings suggest that there is significant potential for improvement in the value of AMI, HF, and PNA care and also suggest that high-value care for these conditions is attainable across most hospital types.

IMPORTANCE:Although studies have described differences in hospital outcomes by patient race and socioeconomic status, it is not clear whether such disparities are driven by hospitals themselves or by broader systemic effects. OBJECTIVE:To determine patterns of racial and socioeconomic disparities in outcomes within and between hospitals for patients with acute myocardial infarction, heart failure, and pneumonia. DESIGN, SETTING, AND PARTICIPANTS:Retrospective cohort study initiated before February 2013, with additional analyses conducted during the peer-review process. Hospitals in the United States treating at least 25 Medicare fee-for-service beneficiaries aged 65 years or older in each race (ie, black and white) and neighborhood income level (ie, higher income and lower income) for acute myocardial infarction, heart failure, and pneumonia between 2009 and 2011 were included. MAIN OUTCOMES AND MEASURES:For within-hospital analyses, risk-standardized mortality rates and risk-standardized readmission rates for race and neighborhood income subgroups were calculated at each hospital. The corresponding ratios using intraclass correlation coefficients were then compared. For between-hospital analyses, risk-standardized rates were assessed according to hospitals' proportion of patients in each subgroup. These analyses were performed for each of the 12 analysis cohorts reflecting the unique combinations of outcomes (mortality and readmission), demographics (race and neighborhood income), and conditions (acute myocardial infarction, heart failure, and pneumonia). RESULTS:Between 74% (3545 of 4810) and 91% (4136 of 4554) of US hospitals lacked sufficient racial and socioeconomic diversity to be included in this analysis, with the number of hospitals eligible for analysis varying among cohorts. The 12 analysis cohorts ranged in size from 418 to 1265 hospitals and from 144 417 to 703 324 patients. Within included hospitals, risk-standardized mortality rates tended to be lower among black patients (mean [SD] difference between risk-standardized mortality rates in black patients compared with white patients for acute myocardial infarction, -0.57 [1.1] [P = .47]; for heart failure, -4.7 [1.3] [P < .001]; and for pneumonia, -1.0 [2.0] [P = .05]). However, risk-standardized readmission rates among black patients were higher (mean [SD] difference between risk-standardized readmission rates in black patients compared with white patients for acute myocardial infarction, 4.3 [1.4] [P < .001]; for heart failure, 2.8 [1.8] [P < .001], and for pneumonia, 3.7 [1.3] [P < .001]). Intraclass correlation coefficients ranged from 0.68 to 0.79, indicating that hospitals generally delivered consistent quality to patients of differing races. While the coefficients in the neighborhood income analysis were slightly lower (0.46-0.60), indicating some heterogeneity in within-hospital performance, differences in mortality rates and readmission rates between the 2 neighborhood income groups were small. There were no strong, consistent associations between risk-standardized outcomes for white or higher-income neighborhood patients and hospitals' proportion of black or lower-income neighborhood patients. CONCLUSIONS AND RELEVANCE:Hospital performance according to race and socioeconomic status was generally consistent within and between hospitals, even as there were overall differences in outcomes by race and neighborhood income. This finding indicates that disparities are likely to be systemic, rather than localized to particular hospitals.

AIMS:ST-segment elevation myocardial infarctions (STEMI) in China and other low- and middle-income countries outnumber non-ST-segment elevation myocardial infarctions (NSTEMI). We hypothesized that the STEMI predominance was associated with lower biomarker use and would vary with hospital characteristics. METHODS AND RESULTS:We hypothesized that the STEMI predominance was associated with lower biomarker use and would vary with hospital characteristics. Using data from the nationally representative China PEACE-Retrospective AMI Study during 2001, 2006, and 2011, we compared hospital NSTEMI proportion across categories of use of any cardiac biomarker (CK, CK-MB, or troponin) and troponin, as well as across region, location, level, and teaching status. Among 15 416 acute myocardial infarction (AMI) patients, 14% had NSTEMI. NSTEMI patients were older, more likely female, and to have comorbidities. Median hospital NSTEMI proportion in each study year was similar across categories of any cardiac biomarker use, troponin, region, location, level, and teaching status. For instance, in 2011 the NSTEMI proportion at hospitals without troponin testing was 11.2% [inter quartile range (IQR) 4.4-16.7%], similar to those with ≥ 75% troponin use (13.0% [IQR 8.7-23.7%]) (P-value for difference 0.77). Analysed as continuous variables there was no relationship between hospital NSTEMI proportion and proportion biomarker use. With troponin use there was no relationship in 2001 and 2006, but a modest correlation in 2011 (R = 0.16, P = 0.043). Admissions for NSTEMI increased from 0.3/100 000 people in 2001 to 3.3/100 000 people in 2011 (P-value for trend < 0.001). CONCLUSION:STEMI is the dominant presentation of AMI in China, but the proportion of NSTEMI is increasing. Biomarker use and hospital characteristics did not account for the low NSTEMI rate. CLINICAL TRIAL REGISTRATION:www.clinicaltrials.gov (NCT01624883).

BACKGROUND:Millions of Americans live in the US territories, but health outcomes and payments among Medicare beneficiaries in these territories are not well characterized. METHODS:Among Fee-for-Service Medicare beneficiaries aged 65 years and older hospitalized between 1999 and 2012 for acute myocardial infarction (AMI), heart failure (HF), and pneumonia, we compared hospitalization rates, patient outcomes, and inpatient payments in the territories and states. RESULTS:Over 14 years, there were 4,350,813 unique beneficiaries in the territories and 402,902,615 in the states. Hospitalization rates for AMI, HF, and pneumonia declined overall and did not differ significantly. However, 30-day mortality rates were higher in the territories for all 3 conditions: in the most recent time period (2008-2012), the adjusted odds of 30-day mortality were 1.34 [95% confidence interval (CI), 1.21-1.48], 1.24 (95% CI, 1.12-1.37), and 1.85 (95% CI, 1.71-2.00) for AMI, HF, and pneumonia, respectively; adjusted odds of 1-year mortality were also higher. In the most recent study period, inflation-adjusted Medicare in-patient payments, in 2012 dollars, were lower in the territories than the states, at $9234 less (61% lower than states), $4479 less (50% lower), and $4403 less (39% lower) for AMI, HF, and pneumonia hospitalizations, respectively (P<0.001 for all). CONCLUSIONS AND RELEVANCE:Among Medicare Fee-for-Service beneficiaries, in 2008-2012 mortality rates were higher, or not significantly different, and hospital reimbursements were lower for patients hospitalized with AMI, HF, and pneumonia in the territories. Improvement of health care and policies in the territories is critical to ensure health equity for all Americans.