DNA Damage and Nuclear Morphological Changes in Cardiac Hypertrophy Are Mediated by SNRK Through Actin Depolymerization.

BACKGROUND: Proper nuclear organization is critical for cardiomyocyte function, because global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy; however, the mechanism for this process is not well delineated. AMPK (AMP-activated protein kinase) family of proteins regulates metabolism and DNA damage response (DDR). Here, we examine whether a member of this family, SNRK (SNF1-related kinase), which plays a role in cardiac metabolism, is also involved in hypertrophic remodeling through changes in DDR and structural properties of the nucleus. METHODS: We subjected cardiac-specific Snrk-/- mice to transaortic banding to assess the effect on cardiac function and DDR. In parallel, we modulated SNRK in vitro and assessed its effects on DDR and nuclear parameters. We also used phosphoproteomics to identify novel proteins that are phosphorylated by SNRK. Last, coimmunoprecipitation was used to verify Destrin (DSTN) as the binding partner of SNRK that modulates its effects on the nucleus and DDR. RESULTS: Cardiac-specific Snrk-/- mice display worse cardiac function and cardiac hypertrophy in response to transaortic banding, and an increase in DDR marker pH2AX (phospho-histone 2AX) in their hearts. In addition, in vitro Snrk knockdown results in increased DNA damage and chromatin compaction, along with alterations in nuclear flatness and 3-dimensional volume. Phosphoproteomic studies identified a novel SNRK target, DSTN, a member of F-actin depolymerizing factor proteins that directly bind to and depolymerize F-actin. SNRK binds to DSTN, and DSTN downregulation reverses excess DNA damage and changes in nuclear parameters, in addition to cellular hypertrophy, with SNRK knockdown. We also demonstrate that SNRK knockdown promotes excessive actin depolymerization, measured by the increased ratio of G-actin to F-actin. Last, jasplakinolide, a pharmacological stabilizer of F-actin, rescues the increased DNA damage and aberrant nuclear morphology in SNRK-downregulated cells. CONCLUSIONS: These results indicate that SNRK is a key player in cardiac hypertrophy and DNA damage through its interaction with DSTN. This interaction fine-tunes actin polymerization to reduce DDR and maintain proper cardiomyocyte nuclear shape and morphology.

Iron drives anabolic metabolism through active histone demethylation and mTORC1.

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

DNA damage and nuclear morphological changes in cardiac hypertrophy are mediated by SNRK through actin depolymerization.

BACKGROUND: Proper nuclear organization is critical for cardiomyocyte (CM) function, as global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy, however, the mechanism for this process is not well delineated. AMPK family of proteins regulate metabolism and DNA damage response (DDR). Here, we examine whether a member of this family, SNF1-related kinase (SNRK), which plays a role in cardiac metabolism, is also involved in hypertrophic remodeling through changes in DDR and structural properties of the nucleus. METHODS: We subjected cardiac specific (cs)- Snrk -/- mice to trans-aortic banding (TAC) to assess the effect on cardiac function and DDR. In parallel, we modulated SNRK in vitro and assessed its effects on DDR and nuclear parameters. We also used phospho-proteomics to identify novel proteins that are phosphorylated by SNRK. Finally, co-immunoprecipitation (co-IP) was used to verify Destrin (DSTN) as the binding partner of SNRK that modulates its effects on the nucleus and DDR. RESULTS: cs- Snrk -/- mice display worse cardiac function and cardiac hypertrophy in response to TAC, and an increase in DDR marker pH2AX in their hearts. Additionally, in vitro Snrk knockdown results in increased DNA damage and chromatin compaction, along with alterations in nuclear flatness and 3D volume. Phospho-proteomic studies identified a novel SNRK target, DSTN, a member of F-actin depolymerizing factor (ADF) proteins that directly binds to and depolymerize F-actin. SNRK binds to DSTN, and DSTN downregulation reverses excess DNA damage and changes in nuclear parameters, in addition to cellular hypertrophy, with SNRK knockdown. We also demonstrate that SNRK knockdown promotes excessive actin depolymerization, measured by the increased ratio of globular (G-) actin to F-actin. Finally, Jasplakinolide, a pharmacological stabilizer of F-actin, rescues the increased DNA damage and aberrant nuclear morphology in SNRK downregulated cells. CONCLUSIONS: These results indicate that SNRK is a key player in cardiac hypertrophy and DNA damage through its interaction with DSTN. This interaction fine-tunes actin polymerization to reduce DDR and maintain proper CM nuclear shape and morphology. Clinical Perspective: What is new? Animal hearts subjected to pressure overload display increased SNF1-related kinase (SNRK) protein expression levels and cardiomyocyte specific SNRK deletion leads to aggravated myocardial hypertrophy and heart failure.We have found that downregulation of SNRK impairs DSTN-mediated actin polymerization, leading to maladaptive changes in nuclear morphology, higher DNA damage response (DDR) and increased hypertrophy. What are the clinical implications? Our results suggest that disruption of DDR through genetic loss of SNRK results in an exaggerated pressure overload-induced cardiomyocyte hypertrophy.Targeting DDR, actin polymerization or SNRK/DSTN interaction represent promising therapeutic targets in pressure overload cardiac hypertrophy.

[WITHDRAWN] Hexokinase-1 mitochondrial dissociation and protein O-GlcNAcylation drive heart failure with preserved ejection fraction.

The authors have requested that this preprint be removed from Research Square.

ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice.

Pregnancy is associated with substantial physiological changes of the heart, and disruptions in these processes can lead to peripartum cardiomyopathy (PPCM). The molecular processes that cause physiological and pathological changes in the heart during pregnancy are not well characterized. Here, we show that mTORc1 was activated in pregnancy to facilitate cardiac enlargement that was reversed after delivery in mice. mTORc1 activation in pregnancy was negatively regulated by the mRNA-destabilizing protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocyte hypertrophy during pregnancy, and mice with cardiac-specific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved postpartum cardiac function. Collectively, these data provide what we believe to be a novel pathway for the regulation of mTORc1 through mRNA stabilization of a P53 ubiquitin ligase. This pathway was critical for normal cardiac growth during pregnancy, and its reduction led to PPCM-like adverse remodeling in mice.

Hexokinase 1 cellular localization regulates the metabolic fate of glucose.

The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.

Ironing out mechanisms of iron homeostasis and disorders of iron deficiency.

Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients' symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.

Physician Workflow in Two Distinctive Emergency Departments: An Observational Study.

OBJECTIVES: We characterize physician workflow in two distinctive emergency departments (ED). Physician practices mediated by electronic health records (EHR) are explored within the context of organizational complexity for the delivery of care. METHODS: Two urban clinical sites, including an academic teaching ED, were selected. Fourteen physicians were recruited. Overall, 62 hours of direct clinical observations were conducted characterizing clinical activities (EHR use, team communication, and patient care). Data were analyzed using qualitative open-coding techniques and descriptive statistics. Timeline belts were used to represent temporal events. RESULTS: At site 1, physicians, engaged in more team communication, followed by direct patient care. Although physicians spent 61% of their clinical time at workstations, only 25% was spent on the EHR, primarily for clinical documentation and review. Site 2 physicians engaged primarily in direct patient care spending 52% of their time at a workstation, and 31% dedicated to EHRs, focused on chart review. At site 1, physicians showed nonlinear complex workflow patterns with a greater frequency of multitasking and interruptions, resulting in workflow fragmentation. In comparison, at site 2, a less complex environment with a unique patient assignment system, resulting in a more linear workflow pattern. CONCLUSION: The nature of the clinical practice and EHR-mediated workflow reflects the ED work practices. Physicians in more complex organizations may be less efficient because of the fragmented workflow. However, these effects can be mitigated by effort distribution through team communication, which affords inherent safety checks.

Iron and Heart Failure: Diagnosis, Therapies, and Future Directions.

To date, 3 clinical trials have shown symptomatic benefit from the use of intravenous (IV) iron in patients with heart failure (HF) with low serum iron. This has led to recommendations in support of the use of IV iron in this population. However, the systemic and cellular mechanisms of iron homeostasis in cardiomyocyte health and disease are distinct, complex, and poorly understood. Iron metabolism in HF appears dysregulated, but it is still unclear whether the changes are maladaptive and pathologic or compensatory and protective for the cardiomyocytes. The serum markers of iron deficiency in HF do not accurately reflect cellular and mitochondrial iron levels, and the current definition based on the ferritin and transferrin saturation values is broad and inclusive of patients who do not need IV iron. This is particularly relevant in view of the potential risks that are associated with the use of IV iron. Reliable markers of cellular iron status may differentiate subgroups of HF patients who would benefit from cellular and mitochondrial iron chelation rather than IV iron.

The complementary nature of query-based and directed health information exchange in primary care practice.

OBJECTIVE: Many policymakers and advocates assume that directed and query-based health information exchange (HIE) work together to meet organizations' interoperability needs, but this is not grounded in a substantial evidence base. This study sought to clarify the relationship between the usage of these 2 approaches to HIE. MATERIALS AND METHODS: System user log files from a regional HIE organization and electronic health record system were combined to model the usage of HIE associated with a patient visit at 3 federally qualified health centers in New York. Regression models tested the hypothesis that directed HIE usage was associated with query-based usage and adjusted for factors reflective of the FITT (Fit between Individuals, Task & Technology) framework. Follow-up interviews with 8 key informants helped interpret findings. RESULTS: Usage of query-based HIE occurred in 3.1% of encounters and directed HIE in 23.5%. Query-based usage was 0.6 percentage points higher when directed HIE provided imaging information, and 4.8 percentage points higher when directed HIE provided clinical documents. The probability of query-based HIE was lower for specialist visits, higher for postdischarge visits, and higher for encounters with nurse practitioners. Informants used query-based HIE after directed HIE to obtain additional information, support transitions of care, or in cases of abnormal results. DISCUSSION: The complementary nature of directed and query-based HIE indicates that both HIE functionalities should be incorporated into EHR Certification Criteria. CONCLUSIONS: Quantitative and qualitative findings suggest that directed and query-based HIE exist in a complementary manner in ambulatory care settings.

Readministration of Platinum Agents in Recurrent Ovarian Cancer Patients Who Developed Hypersensitivity Reactions to Carboplatin.

BACKGROUND/AIM: Hypersensitivity reactions (HSRs) to carboplatin, a key drug for ovarian cancer patients, are problematic. The aim of this study was to evaluate the efficacy and safety of readministration of platinum agents (PTs) in recurrent ovarian cancer patients who developed HSRs to carboplatin. PATIENTS AND METHODS: Thirty-one patients with recurrent ovarian cancer who developed HSRs to carboplatin were divided into those who continued to receive PTs in the following cycle (continuation group, n=24) and those in whom either the drug was switched to non-platinum agents (non-PTs) or chemotherapy was ended (discontinuation group, n=7). Outcomes were evaluated based on patients' medical records. RESULTS: The median survival time following HSRs was 28.1 and 15.4 months in the continuation and discontinuation groups, respectively (p=0.018). In the continuation group, a total of 155 cycles of PTs were re-administrated, and 50 cycles (32%) led to recurrent HSRs. There were no recurrent HSRs with a severity of grade 3 or greater. CONCLUSION: Continuation of PTs in ovarian cancer patients may contribute to improvement in their overall survival without severe recurrent HSRs.

The associations between query-based and directed health information exchange with potentially avoidable use of health care services.

OBJECTIVE: To quantify the impact of two approaches (directed and query-based) to health information exchange (HIE) on potentially avoidable use of health care services. DATA SOURCES/STUDY SETTING: Data on ambulatory care providers' adoption of HIE were merged with Medicare fee-for-service claims from 2008 to 2014. Providers were from 13 counties in New York served by the Rochester Regional Health Information Organization (RHIO). STUDY DESIGN: Linear regression models with provider and year fixed effects were used to estimate changes in the probability of utilization outcomes for Medicare beneficiaries attributed to providers adopting directed and/or query-based HIE compared with beneficiaries attributed to providers who had not adopted HIE. DATA COLLECTION: Providers' HIE adoption status was determined through Rochester RHIO registration records. RHIO and claims data were linked via National Provider Identifiers. PRINCIPAL FINDINGS: Query-based HIE adoption was associated with a 0.2 percentage point reduction in the probability of an ambulatory care sensitive hospitalization and a 1.1 percentage point decrease in the likelihood of an unplanned readmission. Directed HIE adoption was not associated with any outcome. CONCLUSIONS: The Centers for Medicare & Medicaid Services' (CMS) EHR certification criteria includes requirements for directed HIE, but not query-based HIE. Pending further research, certification criteria should place equal weight on facilitating query-based and directed exchange.

Application of Artificial Intelligence for Preoperative Diagnostic and Prognostic Prediction in Epithelial Ovarian Cancer Based on Blood Biomarkers.

PURPOSE: We aimed to develop an ovarian cancer-specific predictive framework for clinical stage, histotype, residual tumor burden, and prognosis using machine learning methods based on multiple biomarkers. EXPERIMENTAL DESIGN: Overall, 334 patients with epithelial ovarian cancer (EOC) and 101 patients with benign ovarian tumors were randomly assigned to "training" and "test" cohorts. Seven supervised machine learning classifiers, including Gradient Boosting Machine (GBM), Support Vector Machine, Random Forest (RF), Conditional RF (CRF), Naïve Bayes, Neural Network, and Elastic Net, were used to derive diagnostic and prognostic information from 32 parameters commonly available from pretreatment peripheral blood tests and age. RESULTS: Machine learning techniques were superior to conventional regression-based analyses in predicting multiple clinical parameters pertaining to EOC. Ensemble methods combining weak decision trees, such as GBM, RF, and CRF, showed the best performance in EOC prediction. The values for the highest accuracy and area under the ROC curve (AUC) for segregating EOC from benign ovarian tumors with RF were 92.4% and 0.968, respectively. The highest accuracy and AUC for predicting clinical stages with RF were 69.0% and 0.760, respectively. High-grade serous and mucinous histotypes of EOC could be preoperatively predicted with RF. An ordinal RF classifier could distinguish complete resection from others. Unsupervised clustering analysis identified subgroups among early-stage EOC patients with significantly worse survival. CONCLUSIONS: Machine learning systems can provide critical diagnostic and prognostic prediction for patients with EOC before initial intervention, and the use of predictive algorithms may facilitate personalized treatment options through pretreatment stratification of patients.

Expanding Health Information Exchange Improves Identification of Frequent Emergency Department Users.

STUDY OBJECTIVE: Frequent emergency department (ED) users are of interest to policymakers and hospitals. The objective of this study is to examine the effect of health information exchange size on the identification of frequent ED users. METHODS: We retrospectively analyzed data from Healthix, a health information exchange in New York that previously included 10 hospitals and then grew to 31 hospitals. We divided patients into 3 cohorts: high-frequency ED users with 4 or more visits in any 30-day period, medium-frequency ED users with 4 or more visits in any year, and infrequent ED users with fewer than 4 visits in any year. For both the smaller (10-hospital) and larger (31-hospital) health information exchanges, we compared the identification rate of frequent ED users that was based on hospital-specific data with the corresponding rates that were based on health information exchange data. RESULTS: The smaller health information exchange (n=1,696,279 unique ED patients) identified 11.4% more high-frequency users (33,467 versus 30,057) and 9.5% more medium-frequency users (109,497 versus 100,014) than the hospital-specific data. The larger health information exchange (n=3,684,999) identified 19.6% more high-frequency patients (52,727 versus 44,079) and 18.2% more medium-frequency patients (222,574 versus 192,541) than the hospital-specific data. Expanding from the smaller health information exchange to the larger one, we found an absolute increase of 8.2% and 8.7% identified high- and medium-frequency users, respectively. CONCLUSION: Increasing health information exchange size more accurately reflects how patients access EDs and ultimately improves not only the total number of identified frequent ED users but also their identification rate.

Mapping of HIE CT terms to LOINC®: analysis of content-dependent coverage and coverage improvement through new term creation.

Objective: We describe and evaluate the mapping of computerized tomography (CT) terms from 40 hospitals participating in a health information exchange (HIE) to a standard terminology. Methods: Proprietary CT exam terms and corresponding exam frequency data were obtained from 40 participant HIE sites that transmitted radiology data to the HIE from January 2013 through October 2015. These terms were mapped to the Logical Observations Identifiers Names and Codes (LOINC®) terminology using the Regenstrief LOINC mapping assistant (RELMA) beginning in January 2016. Terms without initial LOINC match were submitted to LOINC as new term requests on an ongoing basis. After new LOINC terms were created, proprietary terms without an initial match were reviewed and mapped to these new LOINC terms where appropriate. Content type and token coverage were calculated for the LOINC version at the time of initial mapping (v2.54) and for the most recently released version at the time of our analysis (v2.63). Descriptive analysis was performed to assess for significant differences in content-dependent coverage between the 2 versions. Results: LOINC's content type and token coverages of HIE CT exam terms for version 2.54 were 83% and 95%, respectively. Two-hundred-fifteen new LOINC CT terms were created in the interval between the releases of version 2.54 and 2.63, and content type and token coverages, respectively, increased to 93% and 99% (P < .001). Conclusion: LOINC's content type coverage of proprietary CT terms across 40 HIE sites was 83% but improved significantly to 93% following new term creation.

Emergency Physicians' Perceived Influence of EHR Use on Clinical Workflow and Performance Metrics.

OBJECTIVE: Over the last decade, electronic health records (EHRs) have shaped clinical practice. In this article, we investigated the perceived effects of EHR use on clinical workflow and meaningful use (MU) performance metrics. MATERIALS AND METHODS: Semistructured interviews were conducted with 20 (n = 20) physicians at two urban emergency departments. Interview questions focused on time spent on EHR use, changes in clinical practices with EHR use, and the effect of MU performance metrics on clinical workflow. Qualitative coding using grounded theory and descriptive analyses were performed to provide descriptive insights. RESULTS: Physicians reported that EHRs improved their clinical workflow, especially on MU-related activities including door-to-doctor time and admit decision time. EHR use also affected physicians work efficiency, quality of care provided, and overall patient safety. CONCLUSION: Physicians' perception of EHRs is likely to influence their practices. With negative perceptions of EHR usability problems, positive aspects of EHR use, including the influence on MU performance metrics, may be overridden.

Efficiency of Emergency Physicians: Insights from an Observational Study using EHR Log Files.

OBJECTIVE: With federal mandates and incentives since the turn of this decade, electronic health records (EHR) have been widely adopted and used for clinical care. Over the last several years, we have seen both positive and negative perspectives on its use. Using an analysis of log files of EHR use, we investigated the nature of EHR use and their effect on an emergency department's (ED) throughput and efficiency. METHODS: EHR logs of time spent by attending physicians on EHR-based activities over a 6-week period (n = 2,304 patients) were collected. For each patient encounter, physician activities in the EHR were categorized into four activities: documentation, review, orders, and navigation. Four ED-based performance metrics were also captured: door-to-provider time, door-to-doctor time, door-to-disposition time, and length of stay (LOS). Association between the four EHR-based activities and corresponding ED performance metrics were evaluated. RESULTS: We found positive correlations between physician review of patient charts, and door-to-disposition time (r = 0.43, p < 0.05), and with LOS (r = 0.48, p < 0.05). There were no statistically significant associations between any of the other performance metrics and EHR activities. CONCLUSION: The results highlight that longer time spent on reviewing information on the EHR is potentially associated with decreased ED throughput efficiency. Balancing these competing goals is often a challenge of physicians, and its implications for patient safety is discussed.

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21.

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.

mRNA-binding protein tristetraprolin is essential for cardiac response to iron deficiency by regulating mitochondrial function.

Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically Ndufs1 in complex I and Uqcrfs1 in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, Uqcrfs1 levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of Ttp display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.

Bouncing Back Elsewhere: Multilevel Analysis of Return Visits to the Same or a Different Hospital After Initial Emergency Department Presentation.

STUDY OBJECTIVE: Analyses of 72-hour emergency department (ED) return visits are frequently used for quality assurance purposes and have been proposed as a means of measuring provider performance. These analyses have traditionally examined only patients returning to the same hospital as the initial visit. We use a health information exchange network to describe differences between ED visits resulting in 72-hour revisits to the same hospital and those resulting in revisits to a different site. METHODS: We examined data from a 31-hospital health information exchange of all ED visits during a 5-year period to identify 72-hour return visits and collected available encounter, patient, and hospital variables. Next, we used multilevel analysis of encounter-level, patient-level, and hospital-level data to describe differences between initial ED visits resulting in different-site and same-site return visits. RESULTS: We identified 12,621,159 patient visits to the 31 study EDs, including 841,259 same-site and 107,713 different-site return visits within 72 hours of initial ED presentation. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the initial-visit characteristics' predictive relationship that any return visit would be at a different site: daytime visit (OR 1.10; 95% CI 1.07 to 1.12), patient-hospital county concordance (OR 1.40; 95% CI 1.36 to 1.44), male sex (OR 1.27; 95% CI 1.24 to 1.30), aged 65 years or older (OR 0.55; 95% CI 0.53 to 0.57), sites with an ED residency (OR 0.41; 95% CI 0.40 to 0.43), sites at an academic hospital (OR 1.12; 95% CI 1.08 to 1.15), sites with high density of surrounding EDs (OR 1.73; 95% CI 1.68 to 1.77), and sites with a high frequency of same-site return visits (OR 0.10; 95% CI 0.10 to 0.11). CONCLUSION: This analysis describes how ED encounters with early revisits to the same hospital differ from those with revisits to a second hospital. These findings challenge the use of single-site return-visit frequency as a quality measure, and, more constructively, describe how hospitals can use health information exchange to more accurately identify early ED return visits and to support programs related to these revisits.