National Trends in Transfer of Patients with Primary Intracerebral Hemorrhage: An Analysis of 12-Year Nationwide Data.

OBJECTIVES: The guidelines of the American Hospital Association encourage transferring intracerebral hemorrhage patients from community hospitals to centers with stroke expertise. However, research on the differences in outcomes between transferred intracerebral hemorrhage hospitalizations and directly admitted hospitalizations have been largely limited to small single-center studies. In this study, we explored the national trends in transferred intracerebral hemorrhage hospitalizations, as well as evaluated the differences, in terms of demographic characteristics, co-morbidity, resource utilization, and outcomes, between transferred intracerebral hemorrhage hospitalizations and directly admitted hospitalizations. MATERIALS AND METHODS: From the National Inpatient Sample (2004 - 2016), we assessed the linear trends in the proportion of interhospital transfers for intracerebral hemorrhage hospitalizations. We constructed a series of multivariate logistic regression models to explore the association of transfer status with inpatient mortality and discharge disposition, controlling for demographic, clinical, and hospital characteristics. We used survey design variables to report nationally weighted estimates. RESULTS: Among 786,999 hospitalizations, 137,340 (17.5%, 95% CI: 16.4-18.6) were transferred. Overall, interhospital transfers for intracerebral hemorrhage has been increasing over the 12-year period of this study. Patients in transferred hospitalizations were younger, more likely to be white, and more likely to have private insurance. Transferred hospitalizations were associated with significantly lower adjusted odds of inpatient mortality, compared to directly admitted hospitalizations. CONCLUSIONS: As the US healthcare system continues shifting towards value-based care, evidence on the short- and long-term outcomes of transfer of intracerebral hemorrhage patients will inform optimal management of intracerebral hemorrhage patients.

Risk of intracranial hemorrhage associated with pregnancy in women with cerebral arteriovenous malformations.

BACKGROUND: Prior studies on rupture risk of brain arteriovenous malformations (AVMs) in women undergoing pregnancy and delivery have reported conflicting findings, but also have not accounted for AVM morphology and heterogeneity. Here, we assess the association between pregnancy and the risk of intracranial hemorrhage (ICH) in women with AVMs using a cohort-crossover design in which each woman serves as her own control. METHODS: Women who underwent pregnancy and delivery were identified using DRG codes from the Healthcare Cost and Utilization Project State Inpatient Databases for California (2005-2011), Florida (2005-2014), and New York (2005-2014). The presence of AVM and ICH was determined using ICD 9 codes. Pregnancy was defined as the 40 weeks prior to delivery, and postpartum as 12 weeks after. We defined a non-exposure control period as a 52-week period prior to pregnancy. The relative risks of ICH during pregnancy were compared against the non-exposure period using conditional Poisson regression. RESULTS: Among 4 022 811 women identified with an eligible delivery hospitalization (median age, 28 years; 7.3% with gestational diabetes; 4.5% with preeclampsia/eclampsia), 568 (0.014%) had an AVM. The rates of ICH during pregnancy and puerperium were 6355.4 (95% CI 4279.4 to 8431.5) and 14.4 (95% CI 13.3 to 15.6) per 100 000 person-years for women with and without AVM, respectively. In cohort-crossover analysis, in women with AVMs the risk of ICH increased 3.27-fold (RR, 95% CI 1.67 to 6.43) during pregnancy and puerperium compared with a non-pregnant period. CONCLUSIONS: Among women with AVM, pregnancy and puerperium were associated with a greater than 3-fold risk of ICH.

Long-Term Cognitive Impairment Associated With Delirium in Acute Neurological Injury.

OBJECTIVES: To characterize the risk of long-term cognitive impairment associated with delirium in acute neurologic injury patients. DESIGN: We analyzed a 10-year cohort of adult acute neurologic injury patients (stroke and traumatic brain injury) without preexisting mild cognitive impairment or dementia, utilizing administrative databases. Patients were followed for in-hospital delirium and mild cognitive impairment or dementia. We report incidence and adjusted hazard ratios for mild cognitive impairment or dementia associated with delirium. Subgroups analyzed include acute neurologic injury categories, dementia subtypes, repeated delirium exposure, and age strata. SETTING: We used state emergency department and state inpatient databases for New York, Florida, and California. All visits are included in the databases regardless of payer status. PATIENTS: We included adult patients with diagnosis of stroke and traumatic brain injury as acute neurologic injury. Patients with preexisting mild cognitive impairment or dementia were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 911,380 acute neurologic injury patients, 5.2% were diagnosed with delirium. Mild cognitive impairment or dementia incidence among delirium patients was approximately twice that of nondelirium patients. In adjusted models, risk of mild cognitive impairment or dementia was higher among patients with delirium (adjusted hazard ratio, 1.58). Increased risk was observed across all subgroups including patients less than or equal to 55 years old. CONCLUSIONS: Identification, management, and prevention of in-hospital delirium could potentially improve long-term cognitive outcomes in acute neurologic injury patients.

Association of Primary Intracerebral Hemorrhage With Pregnancy and the Postpartum Period.

Importance: Intracerebral hemorrhage (ICH) during pregnancy and the postpartum period results in catastrophic maternal outcomes. There is a paucity of population-based estimates of pregnancy-related ICH risk, including risk during the extended postpartum period. Objective: To evaluate ICH risk during pregnancy and an extended 24-week postpartum period in a population-level cohort and to determine fetal and maternal outcomes as well as demographic and comorbidity factors associated with ICH during pregnancy and post partum. Design, Setting, and Participants: This study used a cohort-crossover design in which patients serve as their own controls when no longer exposed (pregnant or post partum). Administrative data were obtained from all hospital admissions for New York, California, and Florida for a 7- to 10-year period. Participants included all women admitted for labor and delivery who were older than 12 years and did not have a prior diagnosis of ICH. Conditional Poisson regression models were used to evaluate ICH risk, and data were reported as rate ratios and 95% CIs. Data analysis was performed from August 2018 to February 2020. Exposures: Women were tracked using hospitalization records for the duration of pregnancy (40 weeks), for 24 weeks post partum, and for an additional 64 weeks when no longer exposed. Main Outcomes and Measures: Diagnosis of ICH during both 64-week observation periods was determined using validated International Classification of Diseases, Ninth Revision codes. Results: A total of 3 314 945 pregnant women were included (mean [SD] age, 28.17 [6.47] years; 1 451 780 white [43.79%], 474 808 black [14.32%], 246 789 Asian [7.44%], and 835 917 Hispanic [25.22%]). The risk of ICH was significantly higher during the third trimester (2.9 vs 0.7 cases per 100 000 pregnancies; rate ratio, 4.16; 95% CI, 2.52-6.86) and remained elevated during the first 12 weeks post partum (4.4 vs 0.5 cases per 100 000 pregnancies; rate ratio, 9.15; 95% CI, 5.16-16.23). Advanced maternal age (adjusted odds ratio [OR], 1.08; 95% CI, 1.05-1.10), nonwhite race (adjusted ORs, 2.44 [95% CI, 1.73-3.44] for black patients, 2.12 [95% CI, 1.34-3.35] for Asian patients, and 1.59 [95% CI, 1.12-2.26] for Hispanic patients), hypertension (adjusted OR, 2.02; 95% CI, 1.19-3.42), coagulopathy (adjusted OR, 14.17; 95% CI, 9.17-21.89), preeclampsia or eclampsia (adjusted OR, 9.23; 95% CI, 6.99-12.19), and tobacco use (adjusted OR, 2.83; 95% CI, 1.53-5.23) were independently associated with ICH during pregnancy and the postpartum period. Pregnancy-related ICH was associated with a higher risk of maternal (relative risk difference, 792.6; absolute risk difference, 0.18) and fetal (relative risk difference, 5.3; absolute risk difference, 0.03) death, compared with pregnancies without ICH. Conclusions and Relevance: These findings suggest that the risk of ICH is significantly higher during the third trimester of pregnancy and the first 12 weeks post partum. There are age and race disparities in ICH risk that are associated with devastating maternal and fetal outcomes. These data illustrate the critical need for continuous monitoring and aggressive management of ICH-associated risk factors. These findings suggest that extended postpartum monitoring of high-risk women may be warranted.

In-hospital outcomes and 30-day readmission rates among ischemic and hemorrhagic stroke patients with delirium.

OBJECTIVE: Delirium is associated with poor outcomes among critically ill patients. However, it is not well characterized among patients with ischemic or hemorrhagic stroke (IS and HS). We provide the population-level frequency of in-hospital delirium and assess its association with in-hospital outcomes and with 30-day readmission among IS and HS patients. METHODS: We analyzed Nationwide in-hospital and readmission data for years 2010-2015 and identified stroke patients using ICD-9 codes. Delirium was identified using validated algorithms. Outcomes were in-hospital mortality, length of stay, unfavorable discharge disposition, and 30-day readmission. We used survey design logistic regression methods to provide national estimates of proportions and 95% confidence intervals (CI) for delirium, and odds ratios (OR) for association between delirium and poor outcomes. RESULTS: We identified 3,107,437 stroke discharges of whom 7.45% were coded to have delirium. This proportion significantly increased between 2010 (6.3%) and 2015 (8.7%) (aOR, 95% CI: 1.04, 1.03-1.05). Delirium proportion was higher among HS patients (ICH: 10.0%, SAH: 9.8%) as compared to IS patients (7.0%). Delirious stroke patients had higher in-hospital mortality (12.3% vs. 7.8%), longer in-hospital stay (11.6 days vs. 7.3 days) and a significantly greater adjusted risk of 30-day-readmission (16.7%) as compared to those without delirium (12.2%) (aRR, 95% CI: 1.13, 1.11-1.15). Upon readmission, patients with delirium at initial admission continued to have a longer length of stay (7.7 days vs. 6.6 days) and a higher in-hospital mortality (9.3% vs. 6.4%). CONCLUSION: Delirium identified through claims data in stroke patients is independently associated with poor in-hospital outcomes both at index admission and readmission. Identification and management of delirium among stroke patients provides an opportunity to improve outcomes.

Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial.

Cellular therapy is a promising investigational modality to enhance poststroke recovery. We conducted a single-arm, phase I clinical trial to determine the safety and feasibility of intravenous (IV) administration of autologous bone marrow mononuclear cells (MNCs) after acute ischemic stroke (AIS). Patients with moderate severity of AIS underwent bone marrow harvest followed by IV reinfusion of MNCs within 24-72 hours of onset. A target dose of 10 million cells per kilogram was chosen based on preclinical data. Patients were followed up daily during hospitalization and at 1, 3, 6, 12, and 24 months for incidence of adverse events using laboratory, clinical (12 months), and radiological (24 months) parameters. The trial was powered to detect severe adverse events (SAEs) with incidences of at least 10% and planned to enroll 30 patients. Primary outcomes were study-related SAEs and the proportion of patients successfully completing study intervention. A propensity score-based matched control group was used for the estimation of effect size (ES) for day-90 modified Rankin score (mRS). There were no study-related SAEs and, based on a futility analysis, enrolment was stopped after 25 patients. All patients successfully completed study intervention and most received the target dose. Secondary analysis estimated the ES to be a reduction of 1 point (95% confidence interval: 0.33-1.67) in median day-90 mRS for treated patients as compared with the matched control group. Bone marrow harvest and infusion of MNCs is safe and feasible in patients with AIS. The estimated ES is helpful in designing future randomized controlled trials. Stem Cells 2019;37:1481-1491.

Direct Assessment of Health Utilities Using the Standard Gamble Among Patients With Primary Intracerebral Hemorrhage.

BACKGROUND: Standard gamble (SG) directly measures patients' valuation of their health state. We compare in-hospital and day-90 SG utilities (SGU) among intracerebral hemorrhage patients and report a 3-way association between SGU, EuroQoL-5 dimension, and modified Rankin Scale at day 90. METHODS AND RESULTS: Patients with intracerebral hemorrhage underwent in-hospital and day-90 assessments for the modified Rankin Scale, EuroQoL-5 dimension, and SG. SG provides patients a choice between their current health state and a hypothetical treatment with varying chances of either perfect health or a painless death. Higher SGU (scale, 0-1) indicates lower risk tolerance and thus higher valuation of the current health state. Logistic regression was used to estimate the likelihood of low SGU (≤0.6), and Wilcoxon paired signed-rank test compared in-hospital and day-90 SGU. In-hospital and day-90 SG was obtained from 381 and 280 patients, respectively, including 236 paired observations. Median (interquartile range) in-hospital and day-90 SGUs were 0.85 (0.40-0.98) and 0.98 (0.75-1.00; P<0.001). In-hospital SGUs were lower with advancing age (P=0.007), higher National Institutes of Health Stroke Scale, and intracerebral hemorrhage scores (P<0.001). Proxy-based assessments resulted in lower SGUs; median difference (95% CI), -0.2 (-0.33 to -0.07). After adjustment, higher National Institutes of Health Stroke Scale and proxy assessments were independently associated with lower SGU, along with an effect modification of age by race. Day-90 SGU and modified Rankin Scale were significantly correlated; however, SGUs were higher than the EuroQoL-5 dimension utilities at higher modified Rankin Scale levels. CONCLUSIONS: Divergence between directly (SGU) and indirectly (EuroQoL-5 dimension) assessed utilities at high levels of functional disability warrant careful prognostication of intracerebral hemorrhage outcomes and should be considered in designing early end-of-life care discussions with families and patients.

Rationale and design of a statewide telestroke registry: Lone Star Stroke Consortium Telestroke Registry (LeSteR).

INTRODUCTION: The Lone Star Stroke Consortium Telestroke Registry (LeSteR) currently consisting of 3 academic hub centres and 27 partner spokes is a statewide initiative organised by leading academic health centres in the State of Texas to understand practice patterns of acute stroke management via telestroke (TS) in Texas, a state with one of the largest rural populations in the USA. METHODS AND ANALYSIS: All patients who had presumed stroke for whom a TS consultation has been obtained in the network are entered into a web-based, Health Insurance Portability and Accountability Act-compliant database from September 2013 to present. Spokes were enrolled into LeSteR in a staggered approach in two data collection phases: a retrospective phase and a prospective phase. Basic clinical, demographic data and relevant time metrics are collected in the retrospective phase. Starting 1 September 2015, additional outcome data including 90-day modified Rankin score, readmission and 90-day disposition are obtained by a standard phone interview. From the registry initiation to 31 December 2017, there are 8089 patients who had suspected stroke in the registry. Over 60% of patients enrolled after 1 September 2015 have reported outcome data. Enrolment is still active for this registry. ETHICS AND DISSEMINATION: LeSteR is a statewide TS registry organised by academic health centres that will provide significant insight regarding the impact of TS in the State of Texas. Findings from LeSteR will provide data that can be analysed to improve the allocation of healthcare resources using TS to treat stroke in a state with one of the largest rural populations.

Variability and Delay in Telestroke Physician Alert among Spokes in a Telestroke Network: A Need for Metric Benchmarks.

INTRODUCTION: Telestroke has increased access to acute management of ischemic stroke in areas that lack stroke care expertise, yet delays persist in evaluation and treatment. We describe variation in time to alert a telestroke physician of suspected acute ischemic stroke patients potentially eligible for acute stroke therapies among community hospitals in our telestroke network, and explore demographic and spoke-related characteristics associated with delays. METHODS: From our telestroke registry, we identified suspected acute ischemic stroke patients who arrived within 6 hours of symptom onset and underwent video consultation at 1 of 17 community hospitals in our hub-and-spoke network. We compared time between patient arrival to telestroke alert (door-to-page-time) and to tissue plasminogen activator (tPA) administration for eligible patients (door-to-needle-time). We identified factors associated with prolonged metrics. RESULTS: Of 1020 cases between 9/2015 and 3/2017, 47% received tPA. Sixty percent had door-to-page-time more than 15 minutes (median 19.5; IQR, 11-34). Door-to-page-time more than 15 minutes was associated with an 8-fold increase in likelihood of door-to-needle-time more than 60 minutes. Patients with severe stroke experienced faster door-to-page-times. Hospitals with more beds had prolonged door-to-page-time. Full time in-house neurology presence, even when not covering emergent consultations, was associated with faster door-to-page-time over telestroke. Seventy-one percent of patients underwent CT brain prior to the telestroke physician alert; this scenario delayed door-to-page and door-to-needle times. CONCLUSIONS: Door-to-page-time varied considerably among spokes. Awaiting CT scan prior to alerting the telestroke consultant of a stroke code delayed metrics. Telestroke physician alert standards are needed, as are educational initiatives on acute ischemic stroke management and workflow.

Outcomes Among Patients With Ischemic Stroke Treated With Intravenous tPA (Tissue-Type Plasminogen Activator) via Telemedicine.

Background and Purpose- Telemedicine is increasingly utilized for intravenous tPA (tissue-type plasminogen activator) delivery. The comparative safety of leaving tPA-treated patients at a presenting (spoke) hospital (drip-and-stay) or transferring patients to a central treating (hub) hospital (drip-and-ship) is not established. We sought to compare outcomes between drip-and-ship and drip-and-stay patients treated with tPA via telemedicine. We hypothesized that there would be no differences in short-term outcomes of in-hospital mortality, length of stay, or discharge disposition or in 90-day outcomes between groups. Methods- We retrospectively identified patients treated with tPA at 17 spoke hospitals between September 2015 and December 2016. Demographic, clinical, and outcome data were obtained from a prospective telemedicine registry. We used negative binomial, multinomial, and logistic regression analyses to evaluate length of stay, discharge disposition, and inpatient mortality, respectively. We compared the proportion of patients with 90-day modified Rankin Scale score <2 by group. Results- Among 430 tPA-treated patients, 232 (53.9%) were transferred to the hub after treatment. The median arrival National Institutes of Health Stroke Scale score was higher for drip-and-ship (10; interquartile range, 5-18) compared with drip-and-stay patients (6; interquartile range, 4-10; P<0.001). Unadjusted length of stay was longer in drip-and-stay patients (incidence rate ratio, 0.82; 95% CI, 0.71-0.95). There were no significant differences in adjusted length of stay, hospital mortality, or discharge disposition. Among the 64% of patients with complete 90-day modified Rankin Scale score, the proportion with good outcomes (modified Rankin Scale score <2) did not differ between groups. Conclusions- We found no differences in measured outcomes between drip-and-ship and drip-and-stay patients treated in our network, although our study may be underpowered to detect small differences.

Demographic, clinical, and geographical factors associated with lack of receipt of physician recommended chemotherapy in women with breast cancer in Texas.

PURPOSE: Identifying demographic, clinical, and geographical factors that contribute to disparities in the receipt of physician recommended chemotherapy in breast cancer patients. METHODS: The Texas Cancer Registry was used to identify women aged ≥ 18 years with invasive breast cancer diagnosed from 2007 to 2011 who received a recommendation for chemotherapy. Multivariable logistic regression was performed to determine associations between demographic and clinical factors and the receipt of chemotherapy. Cox proportional regression was used to estimate the hazard ratio (HR) for overall survival. Spatial analysis was conducted using Poisson models for breast cancer mortality and receipt of chemotherapy. RESULTS: Age ≥ 65 years, residence in areas with > 20% poverty index, and early disease stage were associated with lack of receipt of chemotherapy (all p < 0.001). Lack of receipt of chemotherapy was associated with decreased overall survival (HR 1.33, 95% CI 1.12-1.59, p = 0.001). A 38-county cluster in West Texas had lower receipt of chemotherapy (relative risk 0.88, p = 0.02) and increased breast cancer mortality (p = 0.03) compared to the rest of Texas. CONCLUSION: Older age, increased poverty and rural geographical location are barriers to the receipt of chemotherapy. Interventions that target these barriers may reduce health disparities and improve breast cancer survival.

Real-World Treatment Trends in Endovascular Stroke Therapy.

Background and Purpose- Recent landmark trials provided overwhelming evidence for effectiveness of endovascular stroke therapy (EST). Yet, the impact of these trials on clinical practice and effectiveness of EST among lower volume centers remains poorly characterized. Here, we determine population-level patterns in EST performance in US hospitals and compare EST outcomes from higher versus lower volume centers. Methods- Using validated diagnosis codes from data on all discharges from hospitals and Emergency Rooms in Florida (2006-2016) and the National Inpatient Sample (2012-2016) we identified patients with acute ischemic stroke treated with EST. The primary end point was good discharge outcome defined as discharge to home or acute rehabilitation facility. Multivariate regressions adjusted for medical comorbidities, intravenous tPA (tissue-type plasminogen activator) usage and annual hospital stroke volume were used to evaluate the likelihood of good outcome over time and by annual hospital EST volume. Results- A total of 3890 patients (median age, 73 [61-82] years, 51% female) with EST were identified in the Florida cohort and 42 505 (median age, 69 [58-79], 50% female) in the National Inpatient Sample. In both Florida and the National Inpatient Sample, the number of hospitals performing EST increased continuously. Increasing numbers of EST procedures were performed at lower annual EST volume hospitals over the studied time period. In adjusted multivariate regression, there was a continuous increase in the likelihood of good outcomes among patients treated in hospitals with increasing annual EST procedures per year (odds ratio, 1.1; 95% CI, 1.1-1.2 in Florida and odds ratio, 1.3; 95% CI, 1.2-1.4 in National Inpatient Sample). Conclusions- Analysis of population-level datasets of patients treated with EST from 2006 to 2016 demonstrated an increase in the number of centers performing EST, resulting in a greater number of procedures performed at lower volume centers. There was a positive association between EST volume and favorable discharge outcomes in EST-performing hospitals.

High in-hospital blood pressure variability and severe disability or death in primary intracerebral hemorrhage patients.

OBJECTIVE: To quantify in-hospital systolic blood pressure variability among patients with intracerebral hemorrhage, determine the association between high systolic blood pressure variability (HSBPV) and 90-day severe disability or death, and examine the association between pre-hospital factors and HSBPV. METHODS: Adult, radiologically confirmed, intracerebral hemorrhage patients enrolled in a multi-site cohort were included. Using a semi-automated algorithm, systolic blood pressure values recorded from routine non-invasive systolic blood pressure monitoring in critical and acute care settings were extracted for the duration of hospitalization. Inter and intra-patient systolic blood pressure variability was quantified using generalized estimating equation methods. Modified Poisson and logistic regression models were fit to determine the association between HSBPV and 90-day severe disability or death and between pre-hospital characteristics and HSBPV, respectively. RESULTS: A total of 566 patients managed at four certified stroke centers were included. Over 120,000 systolic blood pressure readings were analyzed, and a standard deviation (SD) of 13.0 was parameterized as a cut-off point to categorize HSBPV. Patients with HSBPV had a greater risk of 90-day severe disability or death (relative risk: 1.20, 95% confidence interval: 1.04-1.39), after controlling for age, pre-morbid functional status, and other disease severity measures. Greater likelihood of in-hospital HSBPV was independently observed in elderly, female patients, and in patients with high admission systolic blood pressure. CONCLUSION: Quantification of HSBPV is feasible utilizing routinely collected systolic blood pressure readings, and a singular cut-off parameter for systolic blood pressure variability demonstrated association with 90-day severe disability or death. Elderly, female, and patients with high admission systolic blood pressure may be more likely to demonstrate HSBPV during hospitalization.

No Weekend or After-Hours Effect in Acute Ischemic Stroke Patients Treated by Telemedicine.

BACKGROUND: Stroke outcomes have been shown to be worse for patients presenting overnight and on weekends (after-hours) to stroke centers compared with those presenting during business hours (on-hours). Telemedicine (TM) helps provide evaluation and safe management of stroke patients. We compared time metrics and outcomes of stroke patients who were assessed and received intravenous recombinant tissue plasminogen activator (IV-tPA) via TM during after-hours with those during on-hours. METHODS: Analysis of our TM registry from September 2015 to December 2016, identified 424 stroke patients who were assessed via TM and received IV-tPA. We compared baseline characteristics, clinical variables, time metrics, and outcomes between the after-hours (5 pm-7:59 am, weekends) and on-hours (weekdays 8 am-4:59 pm) patients. RESULTS: Of the 424 patients, 268 were managed via TM during after-hours, and 156 during on-hours. Baseline characteristics and clinical variables were similar between the groups. Importantly, there were no differences in all relevant time metrics including door to IV-tPA bolus time. IV-tPA complications (including all intracerebral hemorrhage (ICH), any systemic bleeding, and angioedema), discharge disposition, and 90-day modified Rankin Scale were also similar in the groups. CONCLUSIONS: There was no difference in IV-tPA treatment times, acute stroke evaluation times, or mortality between the patients treated after-hours versus on-hours. Unlike in-person neurology coverage at many centers, the coverage provided by TM does not differ depending on the hour or day. Access to stroke specialists 24/7 via TM can ensure dependable and timely clinical care for acute stroke patients regardless of the time of day or day of the week.

Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

INTRODUCTION: We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. MATERIALS AND METHODS: Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. RESULTS: 8 of 8 IBC samples expressed isolated CD44+CD49f+CD133/2+ stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p < 0.001). CONCLUSIONS: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages and has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

Gene set analysis of post-lactational mammary gland involution gene signatures in inflammatory and triple-negative breast cancer.

BACKGROUND: Epidemiological studies have found that triple-negative breast cancer (TNBC) and TN inflammatory breast cancer (IBC) are associated with lower frequency and duration of breast-feeding compared to non-TNBC and non-TN IBC, respectively. Limited breast-feeding could reflect abrupt or premature involution and contribute to a "primed" stroma that is permissive to the migration of cancer cells typical of IBC. We hypothesized that gene expression related to abrupt mammary gland involution after forced weaning may be enriched in the tissues of IBC patients and, if so, provide a potential correlation between limited breast-feeding and the development of aggressive breast cancer. METHODS: We utilized the Short Time-series Expression Miner (STEM) program to cluster significant signatures from two independent studies that analyzed gene expression at multiple time-points of mouse mammary gland involution. Using 10 significant signatures, we performed gene ontology analysis and gene set enrichment analysis (GSEA) on training and validation sets from human breast cancer gene expression data to identify specific genes that are enriched in IBC compared to non-IBC and in TN compared to non-TN in IBC and non-IBC groups. RESULTS: Examining the combined data, we identified 10 involution gene clusters (Inv1-10) that share time-dependent regulation after forced weaning. Inv5 was the only cluster significantly enriched in IBC in the training and validation set (nominal p-values <0.05) and only by unadjusted p-values (FDR q-values 0.26 and 0.46 respectively). Eight genes in Inv5 are upregulated in both the training and validation sets in IBC. Combining the training and validation sets, both Inv5 and Inv6 have nominal p-values <0.05 and q-values 0.39 and 0.20, respectively. The time course for both clusters includes genes that change within 12 hours after forced weaning. CONCLUSIONS: Results from this in silico study suggest correlation between molecular events during abrupt involution and aggressive breast cancer. Specifically, candidate genes from Inv5 merit functional investigation regarding the role of limited breast-feeding in IBC development.

Rationale and Design of a Statewide Cohort to examine efficient resource utilization for patients with Intracerebral hemorrhage (EnRICH).

BACKGROUND: Intracerebral hemorrhage is a devastating disease with no specific treatment modalities. A significant proportion of patients with intracerebral hemorrhage are transferred to large stroke treatment centers, such as Comprehensive Stroke Centers, because of perceived need for higher level of care. However, evidence of improvement in patient-centered outcomes for these patients treated at larger stroke treatment centers as compared to community hospitals is lacking. METHODS / DESIGN: "Efficient Resource Utilization for Patients with Intracerebral Hemorrhage (EnRICH)" is a prospective, multisite, state-wide, cohort study designed to assess the impact of level of care on long-term patient-centered outcomes for patients with primary / non-traumatic intracerebral hemorrhage. The study is funded by the Texas state legislature via the Lone Star Stroke Research Consortium. It is being implemented via major hub hospitals in large metropolitan cities across the state of Texas. Each hub has an extensive network of "spoke" hospitals, which are connected to the hub via traditional clinical and administrative arrangements, or by telemedicine technologies. This infrastructure provides a unique opportunity to track outcomes for intracerebral hemorrhage patients managed across a health system at various levels of care. Eligible patients are enrolled during hospitalization and are followed for functional, quality of life, cognitive, resource utilization, and dependency outcomes at 30 and 90 days post discharge. As a secondary aim, an economic analysis of the incremental cost-effectiveness of treating intracerebral hemorrhage patients at higher levels of care will be conducted. DISCUSSION: Findings from EnRICH will provide much needed evidence of the effectiveness and efficiency of regionalized care for intracerebral hemorrhage patients. Such evidence is required to inform policy and streamline clinical decision-making.

Estimates and Temporal Trend for US Nationwide 30-Day Hospital Readmission Among Patients With Ischemic and Hemorrhagic Stroke.

Importance: Readmission reduction is linked to improved quality of care, saves cost, and is a desirable patient-centered outcome. Nationally representative readmission metrics for patients with stroke are unavailable to date. Such estimates are necessary for benchmarking performance. Objectives: To provide US nationwide estimates and a temporal trend for overall, planned, and potentially preventable 30-day hospital readmission among patients with ischemic and hemorrhagic stroke; to investigate the association between hospitals' stroke discharge volume, teaching status, and 30-day readmission; and to highlight reasons for 30-day readmission and explore the association of 30-day readmission in terms of mortality, length of stay, and cost of care among patients with stroke. Design, Setting, and Participants: Cohort, year-wise analysis of the Nationwide Readmissions Database between January 1, 2010, and September 30, 2015. The setting was a population-based cohort study providing national estimates of 30-day readmission. The database represents 50% of all US hospitalizations from 22 geographically dispersed states. Participants were adult (≥18 years) patients with a primary discharge diagnosis of intracerebral hemorrhage, acute ischemic stroke, or subarachnoid hemorrhage. Hospitals were categorized by their annual stroke discharge volume and were classified as teaching hospitals if they had an American Medical Association-approved residency program or had a ratio of full-time equivalent interns and residents to beds of 0.25 or higher. Main Outcomes and Measures: Readmission was defined as any admission within 30 days of index hospitalization discharge. Using Centers for Medicare & Medicaid Services-defined algorithms, events were classified as planned or unplanned and as potentially preventable. Results: Based on study criteria, 2 078 854 eligible patients were included (mean [SE] age, 70.02 [0.07] years; 51.9% female). Thirty-day readmission was highest for patients with intracerebral hemorrhage (13.70%; 95% CI, 13.40%-13.99%), followed by patients with acute ischemic stroke (12.44%; 95% CI, 12.33%-12.55%) and patients with subarachnoid hemorrhage (11.48%; 95% CI, 11.01%-11.96%). On average, there was a 3.3% annual decline in readmission between 2010 and 2014, which was statistically significant for the period of investigation (odds ratio, 0.96; 95% CI, 0.95-0.97). Patients discharged from nonteaching hospitals with high stroke discharge volume were at a significantly higher risk of 30-day readmission, and the top 2 reasons for readmission were acute cerebrovascular disease and septicemia. Conclusions and Relevance: This study suggests that nationally representative readmission metrics can be used to benchmark hospitals' performance, and a temporal trend of 3.3% may be used to evaluate the effectiveness of readmission reduction strategies.

Benchmarking Telestroke Proficiency: Page-to-Needle Time Among Neurovascular Fellows and Attendings.

BACKGROUND AND PURPOSE: Formal telestroke training for neurovascular fellows (NVFs) is necessary because of growing use of telestroke technologies in the management of acute ischemic stroke; yet, educational approaches and training benchmarks are not formalized. Time between telestroke consultant page and tissue-type plasminogen activator administration (page-to-needle time, PTNT) can provide an objective measure of proficiency. We compared PTNT between NVFs and neurovascular attendings (NVAs) and evaluated changes in PTNT with experience. METHODS: We identified suspected acute ischemic stroke patients in our telestroke registry from July 2013 to December 2015 who received tissue-type plasminogen activator. Using multivariable quantile regression, we estimated the difference and 95% confidence interval in median PTNT between NVFs and NVAs. We also report the coefficient of change in PTNT over increasing number of telestroke consults. RESULTS: NVFs evaluated 53.7% of 618 tissue-type plasminogen activator cases over telestroke. NVAs had significantly shorter PTNT compared with NVFs, with a difference in median PTNT of -9 minutes (95% confidence interval, -12.3 to -5.7). This difference persisted when adjusted for relative tissue-type plasminogen activator contraindications. For each additional telestroke consult, PTNT decreased by 0.07 minutes for NVFs or NVAs (P=0.02 and <0.01, respectively). CONCLUSIONS: PTNT improves by ≈1 minute for every 14 consults for both NVFs and NVAs. Our findings support the importance of integrating telestroke training into supervised neurovascular fellowships to increase proficiency prior to independent practice and suggest that PTNT can be a benchmark for tracking proficiency.

Systematic Review and Meta-Analysis of Bone Marrow-Derived Mononuclear Cells in Animal Models of Ischemic Stroke.

BACKGROUND AND PURPOSE: Bone marrow-derived mononuclear cells (BMMNCs) offer the promise of augmenting poststroke recovery. There is mounting evidence of safety and efficacy of BMMNCs from preclinical studies of ischemic stroke; however, their pooled effects have not been described. METHODS: Using Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, we conducted a systematic review of preclinical literature for intravenous use of BMMNCs followed by meta-analyses of histological and behavioral outcomes. Studies were selected based on predefined criteria. Data were abstracted by 2 independent investigators. After quality assessment, the pooled effects were generated using mixed-effect models. Impact of possible biases on estimated effect size was evaluated. RESULTS: Standardized mean difference and 95% confidence interval for reduction in lesion volume was significantly beneficial for BMMNC treatment (standardized mean difference: -3.3; 95% confidence interval, -4.3 to -2.3). n=113 each for BMMNC and controls. BMMNC-treated animals (n=161) also had improved function measured by cylinder test (standardized mean difference: -2.4; 95% confidence interval, -3.1 to -1.6), as compared with controls (n=205). A trend for benefit was observed for adhesive removal test and neurological deficit score. Study quality score (median: 6; Q1-Q3: 5-7) was correlated with year of publication. There was funnel plot asymmetry; however, the pooled effects were robust to the correction of this bias and remained significant in favor of BMMNC treatment. CONCLUSIONS: BMMNCs demonstrate beneficial effects across histological and behavioral outcomes in animal ischemic stroke models. Although study quality has improved over time, considerable degree of heterogeneity calls for standardization in the conduct and reporting of experimentation.