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Background: Sepsis is a leading cause of hospital mortality and there is evidence that outcomes vary by patient demographics including race and gender. Our objectives were to determine whether the introduction of a standardized sepsis order set was associated with (1) changes in overall mortality or early antibiotic administration or (2) changes in outcome disparities based on race or gender., Methods: Patients seen in the emergency department and admitted to the hospital with a diagnosis code of sepsis were identified and divided into a preintervention cohort seen during the 18 months prior to the initiation of a new sepsis order set and an intervention cohort seen during the 18 months after a quality initiative driven by introducing the order set. Associations between time period, race, gender, and mortality were assessed using univariate and multivariate logistic regression models. Other outcomes included early antibiotic administration (<3 h from arrival)., Results: Overall mortality was unchanged during the intervention period (7.8% vs. 7.2%) in both univariate (relative risk [RR] 1.08, 95% confidence interval [CI] 0.93-1.26) and multivariate logistic regression (RR 1.11, 95% CI 0.93-1.28) models. Although male gender tended to have higher mortality, there was no statistically significant association between gender and mortality in either cohort. In the multivariable model, Black race was associated with increased risk of death in the preintervention period (RR 1.41, 95% CI 1.02-1.94), but this association was not present in the intervention period. Patients of color also saw significantly more improvement in early antibiotic administration during the intervention period than White patients., Conclusions: An order set-driven sepsis initiative was not associated with overall improved mortality but was associated with decreased racial disparities in sepsis mortality and early antibiotics., (© 2025 The Author(s). Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Fluid resuscitation choices in prehospital trauma care are limited, with most Emergency Medical Services (EMS) agencies only having access to crystalloids. Which solution to use, how much to administer, and judging the individual risks and benefits of giving or withholding fluids remains an area of uncertainty. To address the role of crystalloid fluids in prehospital trauma care, we reviewed the available relevant literature and developed recommendations to guide clinical care. The topic of prehospital blood product administration is covered elsewhere.NAEMSP recommendsIsotonic crystalloid solutions should be the preferred fluids for use in prehospital trauma management. Specific choice of isotonic crystalloid solutions may be driven by medication compatibility and other operational issues.Permissive hypotension is reasonable in patients without traumatic brain injury (TBI).Avoiding or correcting hypotension in polytrauma patients with TBI may be a higher priority than restricting fluid use.Large volume crystalloid resuscitation should be generally avoided.Developing processes to administer warmed intravenous (IV) fluids is reasonable.Risks of IV fluid use, or restriction, in trauma resuscitation should be weighed against possible benefits.Strategies to reduce the need for IV fluids should be considered.A standard trauma resuscitation curriculum for prehospital providers should be developed to improve evidence-based delivery of IV fluids in trauma.

Background Pregnant laboring patients sometimes require interfacility transfer to a higher level of care. There is a paucity of evidence to inform when it is safe to transfer a laboring patient and when delivery may be too imminent to transfer. Methods This is a retrospective study of pregnant patients undergoing interfacility transfer with a specialized obstetric transport team deployed from a large Midwest regional healthcare system. The primary outcome was delivery prior to or within one hour of arrival at the receiving institution due to progression of labor. Data collected included basic demographics, vital signs, gravidity, parity, gestational age, contraction frequency if contractions were present, and cervical dilation. We sought to define the association between these variables and the primary outcome to inform risk assessment for precipitous delivery among patients being considered for interfacility transfer. Results Of the 370 pregnant patients for whom the specialized transfer team was requested, 11 (3%) met the primary outcome. Those with more advanced cervical dilation and those who did not receive regular prenatal care were more likely to meet the criteria for the primary outcome. For every centimeter of cervical dilation, the odds of meeting the primary outcome increased 2.3-fold (95% CI: 1.5-3.4). Conclusions We identified risk factors for early delivery among pregnant patients for whom an interfacility transfer was requested and described patients who were high-risk for obstetric interfacility transport due to the progression of labor. Our results can help inform risk assessments for transferring potentially high-risk laboring patients., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Indiana University Institutional Review Board issued approval 20146. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Lardaro et al.)

Background and Objectives: Hospitals and clinicians increasingly are reimbursed based on quality of care through financial incentives tied to value-based purchasing. Patient-centered care, measured through patient experience surveys, is a key component of many quality incentive programs. We hypothesize that operational aspects such as wait times are an important element of emergency department (ED) patient experience. The objectives of this paper are to determine (1) the association between ED wait times and patient experience and (2) whether patient comments show awareness of wait times., Methods: This is a cross-sectional observational study from January 1, 2019, to December 31, 2020, across 16 EDs within a regional health care system. Patient and operations data were obtained as secondary data through internal sources and merged with primary patient experience data from our data analytics team. Dependent variables are (1) the association between ED wait times in minutes and patient experience ratings and (2) the association between wait times in minutes and patient comments including the term wait (yes/no). Patients rated their "likelihood to recommend (LTR) an ED" on a 0 to 10 scale (categories: "Promoter" = 9-10, "Neutral" = 7-8, or "Detractor" = 0-6). Our aggregate experience rating, or Net Promoter Score (NPS), is calculated by the following formula for each distinct wait time (rounded to the nearest minute): NPS = 100* (# promoters - # detractors)/(# promoters + # neutrals + # detractors). Independent variables for patient age and gender and triage acuity, were included as potential confounders. We performed a mixed-effect multivariate ordinal logistic regression for the rating category as a function of 30 minutes waited. We also performed a logistic regression for the percentage of patients commenting on the wait as a function of 30 minutes waited. Standard errors are adjusted for clustering between the 16 ED sites., Results: A total of 50 833 unique participants completed an experience survey, representing a response rate of 8.1%. Of these respondents, 28.1% included comments, with 10.9% using the term "wait." The odds ratio for association of a 30-minute wait with LTR category is 0.83 [0.81, 0.84]. As wait times increase, the odds of commenting on the wait increase by 1.49 [1.46, 1.53]. We show policy-relevant bubble plot visualizations of these two relationships., Conclusions: Patients were less likely to give a positive patient experience rating as wait times increased, and this was reflected in their comments. Improving on the factors contributing to ED wait times is essential to meeting health care systems' quality initiatives., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study describes the local Emergency Medical Services (EMS) response and patient encounters corresponding to the civil unrest occurring over a four-day period in Spring 2020 in Indianapolis, Indiana (USA)., Methods: This study describes the non-conventional EMS response to civil unrest. The study included patients encountered by EMS in the area of the civil unrest occurring in Indianapolis, Indiana from May 29 through June 1, 2020. The area of civil unrest defined by Indianapolis Metropolitan Police Department covered 15 blocks by 12 blocks (roughly 4.0 square miles) and included central Indianapolis. The study analyzed records and collected demographics, scene times, interventions, dispositions, EMS clinician narratives, transport destinations, and hospital course with outcomes from receiving hospitals for patients extracted from the area of civil unrest by EMS., Results: Twenty-nine patients were included with ages ranging from two to sixty-eight years. In total, EMS transported 72.4% (21 of 29) of the patients, with the remainder declining transport. Ballistic injuries from gun violence accounted for 10.3% (3 of 29) of injuries. Two additional fatalities from penetrating trauma occurred among patients without EMS contact within and during the civil unrest. Conditions not involving trauma occurred in 37.9% (11 of 29). Among transported patients, 33.3% (7 of 21) were admitted to the hospital and there was one fatality., Conclusions: While most EMS transports did not result in hospitalization, it is important to note that the majority of EMS calls did result in a transport. There was a substantial amount of non-traumatic patient encounters. Trauma in many of the encounters was relatively severe, and the findings imply the need for rapid extraction methods from dangerous areas to facilitate timely in-hospital stabilization.

Introduction: Documentation of patient care is essential for both out-of-hospital and in-hospital clinical management. Secondarily, documentation is key for monitoring and improving quality; however, in some EMS systems initial care is often provided by non-transporting agencies whose personnel may not routinely complete patient care reports. Limited data exist describing effective methods for increasing complete patient care documentation among non-transporting agencies. The aim of this quality improvement project was to increase electronic health record (EHR) documentation compliance in a large urban fire-based non-transporting EMS agency., Methods: The improvement project began in May 2020. Our primary outcome was the proportion of completed EHR records for EMS responses. Primary drivers were determined from informal interviews with front-line firefighters. Interventions were implemented following a Plan-Do-Study-Act (PDSA) approach first at a single station, then battalion, and ultimately at the entire department. Interventions included performance reports, modifications of chart requirements, localized directive requiring EHR completion for all EMS runs, directive to officers that EHRs are required, documentation training, and a department-wide directive. We used statistical process control charts (p-chart) to identify special cause variation following interventions., Results: The baseline of EHR completion for the entire fire department was 5% (373/7423 records) for the month of January 2020. Front-line interviews with 58 firefighters revealed drivers including lack of accountability and unfamiliarity with the software. After implementing a station performance report at one fire station, the station's EHR rate climbed from 0.9% (3/337 records) to 26.7% (179/671) after 9 weeks. This test was expanded to a battalion of six stations with similar results. After multiple PDSA cycles focused on agency policy and training, overall department wide EHR compliance per month improved to 89% (4,816/5,439 records) for the month of February 2021 and sustained in following months., Conclusions: Within this large urban fire department, EHR documentation compliance improved significantly through a series of tests of change. Informal interviews with front-line personnel were instrumental in determining primary drivers to develop change ideas. Performance reports, training and facilitation of the reporting process, and department-wide directives led to acceptance and improvement with EHR compliance.

Objective: To describe interfacility transfer (IFT) intervals, transfer vehicle type, and levels of care in patients with large vessel occlusion (LVO) strokes transferred for emergent endovascular therapy (EVT)., Methods: We included all patients transferred by a single IFT agency in the state of Indiana from July 1, 2018 to December 1, 2020 to a comprehensive stroke center in Indianapolis for emergent EVT. Data were collected from the transfer center electronic medical records and matched to IFT and receiving hospital data., Results: Two hundred eighty-eight patients were included, of which 150 (52.0%) received EVT. The median call-to-needle interval (from call to the transfer center to EVT needle puncture) was 155.5 minutes (IQR 135.8-195.3). The median resource activation interval (call to the transfer center to IFT deployment) was 16 minutes (IQR 10-27 minutes); the median IFT response interval (call to IFT to arrival of the transferring unit) was 34 minutes (IQR 25-43 minutes); the median pre-transfer interval (call to the transfer center until departure from the sending hospital) was 60.4 minutes (IQR 47.1-72.6); and the median sending hospital interval at bedside was 25 minutes (IQR 20-30 minutes). Most patients (197, 68.4%) were sent via critical care rotor. Only 61 (21.2%) required interventions other than tissue plasminogen administration, such as titration of actively transfusing medications (e.g., nicardipine, propofol) (37 of 61, 59.7%), or intubation or ventilator management (25 of 61, 40.3%). Patients sent via critical care rotor had longer sending hospital intervals (26 minutes, IQR 22-32, vs 19 minutes, IQR 16-25; p < 0.001) but shorter transfer intervals than those sent via critical care ground., Conclusions: At longer distances, rotor transport saved significant time specifically in the total IFT interval of patients with LVO strokes. Emphasizing processes to reduce the resource activation interval and the sending hospital interval may help reduce the overall time-to-EVT.

Source Citation: Gray AJ, Roobottom C, Smith JE, et al. Early computed tomography coronary angiography in patients with suspected acute coronary syndrome: randomised controlled trial. BMJ. 2021;374:n2106. 34588162.

Background: Coronavirus disease 2019 (COVID-19) is associated with respiratory symptoms and renal effects. Data regarding fluid resuscitation and kidney injury in COVID-19 are lacking, and understanding this relationship is critical., Objectives: To determine if there is an association between fluid volume administered in 24 h and development of renal failure in COVID-19 patients., Methods: Retrospective chart review; 14 hospitals in Indiana. Included patients were adults admitted between March 11, 2020 and April 13, 2020 with a positive test for severe acute respiratory syndrome coronavirus 2 within 3 days of admission. Patients requiring renal replacement therapy prior to admission were excluded. Volumes and types of resuscitative intravenous fluids in the first 24 h were obtained with demographics, medical history, and other objective data. The primary outcome was initiation of renal replacement therapy. Logistic regression modeling was utilized in creating multivariate models for determining factors associated with the primary outcome., Results: The fluid volume received in the first 24 h after hospital admission was associated with initiation of renal replacement therapy in two different multivariate logistic regression models. An odds ratio of 1.42 (95% confidence interval 1.01-1.99) was observed when adjusting for age, heart failure, obesity, creatinine, bicarbonate, and total fluid volume. An odds ratio of 1.45 (95% confidence interval 1.02-2.05) was observed when variables significant in univariate analysis were adjusted for., Conclusions: Each liter of intravenous fluid administered to patients with COVID-19 in the first 24 h of presentation was independently associated with an increased risk for initiation of renal replacement therapy, supporting judicious fluid administration in patients with this disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: The COVID-19 pandemic has significantly impacted Emergency Medical Services (EMS) operations throughout the country. Some studies described variation in total volume of out-of-hospital cardiac arrests (OHCA) during the pandemic. We aimed to describe the changes in volume and characteristics of OHCA patients and resuscitations in one urban EMS system., Methods: We performed a retrospective cohort analysis of all recorded atraumatic OHCA in Marion County, Indiana, from January 1, 2019 to June 30, 2019 and from January 1, 2020 to June 30, 2020. We described patient, arrest, EMS response, and survival characteristics. We performed paired and unpaired t-tests to evaluate the changes in those characteristics during COVID-19 as compared to the prior year. Data were matched by month to control for seasonal variation., Results: The total number of arrests increased from 884 in 2019 to 1034 in 2020 (p = 0.016). Comparing 2019 to 2020, there was little difference in age [median 62 (IQR 59-73) and 60 (IQR 47-72), p = 0.086], gender (38.5% and 39.8% female, p = 0.7466, witness to arrest (44.3% and 39.6%, p = 0.092), bystander AED use (10.1% and 11.4% p = 0.379), bystander CPR (48.7% and 51.4%, p = 0.242). Patients with a shockable initial rhythm (19.2% and 15.4%, p = 0.044) both decreased in 2020, and response time increased by 18 s [6.0 min (IQR 4.5-7.7) and 6.3 min (IQR 4.7-8.0), p = 0.008]. 47.7% and 54.8% (p = 0.001) of OHCA patients died in the field, 19.7% and 19.3% (p = 0.809) died in the Emergency Department, 21.8% and 18.5% (p = 0.044) died in the hospital, 10.8% and 7.4% (p = 0.012) were discharged from the hospital, and 9.3% and 5.9% (p = 0.005) were discharged with Cerebral Performance Category score ≤ 2., Conclusion: Total OHCA increased during the COVID-19 pandemic when compared with the prior year. Although patient characteristics were similar, initial shockable rhythm, and proportion of patients who died in the hospital decreased during the pandemic. Further investigation will explore etiologies of those findings., Competing Interests: Declaration of Competing Interest None of the authors report any conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: We validated the NUE rule, using three criteria (Non-shockable initial rhythm, Unwitnessed arrest, Eighty years or older) to predict futile resuscitation of patients with out-of-hospital cardiac arrest (OHCA)., Methods: We performed a retrospective cohort analysis of all recorded OHCA in Marion County, Indiana, from January 1, 2014 to December 31, 2019. We described patient, arrest, and emergency medical services (EMS) response characteristics, and assessed the performance of the NUE rule in identifying patients unlikely to survive to hospital discharge., Results: From 2014 to 2019, EMS responded to 4370 patients who sustained OHCA. We excluded 329 (7.5%) patients with incomplete data. Median patient age was 62 years (IQR 49 - 73), 1599 (39.6%) patients were female, and 1728 (42.8%) arrests were witnessed. The NUE rule identified 290 (7.2%) arrests, of whom none survived to hospital discharge., Conclusion: In external validation, the NUE rule ( N on-shockable initial rhythm, U nwitnessed arrest, E ighty years or older) correctly identified 7.2% of OHCA patients unlikely to survive to hospital discharge. The NUE rule could be used in EMS protocols and policies to identify OHCA patients very unlikely to benefit from aggressive resuscitation.

Introduction: The rate of bacterial coinfection with SARS-CoV-2 is poorly defined. The decision to administer antibiotics early in the course of SARS-CoV-2 infection depends on the likelihood of bacterial coinfection., Methods: We performed a retrospective chart review of all patients admitted through the emergency department with confirmed SARS-CoV-2 infection over a 6-week period in a large healthcare system in the United States. Blood and respiratory culture results were abstracted and adjudicated by multiple authors. The primary outcome was the rate of bacteremia. We secondarily looked to define clinical or laboratory features associated with bacteremia., Results: There were 542 patients admitted with confirmed SARS-CoV-2 infection, with an average age of 62.8 years. Of these, 395 had blood cultures performed upon admission, with six true positive results (1.1% of the total population). An additional 14 patients had positive respiratory cultures treated as true pathogens in the first 72 h. Low blood pressure and elevated white blood cell count, neutrophil count, blood urea nitrogen, and lactate were statistically significantly associated with bacteremia. Clinical outcomes were not statistically significantly different between patients with and without bacteremia., Conclusions: We found a low rate of bacteremia in patients admitted with confirmed SARS-CoV-2 infection. In hemodynamically stable patients, routine antibiotics may not be warranted in this population., (© 2021 Wiley Periodicals LLC.)

Background: Patients with COVID-19 can present to the emergency department (ED) at any point during the spectrum of illness, making it difficult to predict what level of care the patient will ultimately require. Admission to a ward bed, which is subsequently upgraded within hours to an intensive care unit (ICU) bed, represents an inability to appropriately predict the patient's course of illness. Predicting which patients will require ICU care within 24 hours would allow admissions to be managed more appropriately., Methods: This was a retrospective study of adults admitted to a large health care system, including 14 hospitals across the state of Indiana. Included patients were aged ≥ 18 years, were admitted to the hospital from the ED, and had a positive polymerase chain reaction (PCR) test for COVID-19. Patients directly admitted to the ICU or in whom the PCR test was obtained > 3 days after hospital admission were excluded. Extracted data points included demographics, comorbidities, ED vital signs, laboratory values, chest imaging results, and level of care on admission. The primary outcome was a combination of either death or transfer to ICU within 24 hours of admission to the hospital. Data analysis was performed by logistic regression modeling to determine a multivariable model of variables that could predict the primary outcome., Results: Of the 542 included patients, 46 (10%) required transfer to ICU within 24 hours of admission. The final composite model, adjusted for age and admission location, included history of heart failure and initial oxygen saturation of <93% plus either white blood cell count > 6.4 or glomerular filtration rate < 46. The odds ratio (OR) for decompensation within 24 hours was 5.17 (95% confidence interval [CI] = 2.17 to 12.31) when all criteria were present. For patients without the above criteria, the OR for ICU transfer was 0.20 (95% CI = 0.09 to 0.45)., Conclusions: Although our model did not perform well enough to stand alone as a decision guide, it highlights certain clinical features that are associated with increased risk of decompensation., (© 2021 by the Society for Academic Emergency Medicine.)

Objectives: Studies suggest that inflammatory, autonomic, and coagulation alterations associated with cancer may increase incident atrial fibrillation (AF). New-onset AF is associated with increased mortality in other nonneoplastic disease processes. We investigated the association of active cancer with 30-day mortality in emergency department (ED) patients with new-onset AF., Methods: We conducted an analysis within an observational cohort study at a tertiary care hospital that included ED patients with new-onset AF. The exposure variable was presence of active cancer. We defined active cancer as the patient received chemotherapy, radiotherapy, or recent cancer-related surgery within 90 days of the ED visit. The primary outcome was 30-day mortality. Logistic regression was used to analyze the association between cancer status and 30-day mortality adjusting for patient age and sex., Results: During the 5.5-year study period, 420 patients with new-onset AF were included in our cohort, including 37 (8.8%) with active cancer. Patients with active cancer had no clinically relevant differences in their hemodynamic stability. Among the 37 patients with active cancer, 9 (24%) died within 30 days. Of the 383 patients without active cancer, 11 (3%) died within 30 days. After adjusting for age and sex, active cancer was an independent predictor of 30-day mortality, with an adjusted odds ratio of 10.8 (95% confidence interval, 3.8-31.1)., Conclusions: Among ED patients with new-onset AF, active cancer appears to be associated with 11-fold increased odds of 30-day mortality; new-onset AF may represent progressive organ dysfunction leading to an increased risk of short-term mortality in patients with cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Minimal access procedures have influenced surgical practice and patient expectations. Risk of laparoscopic conversion to open surgery is frequently cited but vaguely quantified. The present study examines three common procedures to identify risk factors for laparoscopic conversion to open (LCO) events. Cross-sectional analysis using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP; 2005 to 2009) identified cases with laparoscopic procedure codes for appendectomy, cholecystectomy, and bariatric procedures. The primary outcome was conversion of a laparoscopic procedure to its open equivalent. Summary statistics for laparoscopic and LCO groups were compared and logistic regression analysis was used to estimate patient and operative risk factors for conversion. Of 176,014 selected laparoscopic operations, 2,138 (1.2%) were converted. Most patients were female (68%) and white (71.2%); mean age was 45.1 years. LCO cholecystectomy was significantly more likely (n = 1526 [1.9%]) and LCO bariatric procedures were less likely (n = 121 [0.3%]); appendectomy was intermediate (n = 491 [1.0%], P < 0.001). Patient factors associated with LCO included male sex (P < 0.001), age 30 years or older (P < 0.025), American Society of Anesthesiologists Class 2 to 4 (P < 0.001), obesity (P < 0.01), history of bleeding disorder (P = 0.036), or preoperative systemic inflammatory response syndrome or sepsis (P < 0.001). LCO was associated with greater incidence of postoperative complications, including death, organ space surgical site infection, sepsis, wound dehiscence, and return to the operating room (P < 0.001). Overall LCO incidence is low in hospitals participating in ACS-NSQIP. Conversion risk factors include patient age, sex, obesity, and preoperative comorbidity as well as the procedure performed. This information should be valuable to clinicians in discussing conversion risk with patients.

Background: The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual., Objective: We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T)., Methods: The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved., Results: A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion., Limitations: The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses., Conclusions: The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: The number of uninsured children in the USA is increasing while the impact on children's health of being uninsured remains largely uncharacterized. We analyzed data from more than 23 million US children to evaluate the effect of insurance status on the outcome of US pediatric hospitalization., Methods: In our analysis of two well-known large inpatient databases, we classified patients less than 18 years old as uninsured (self-pay) or insured (including Medicaid or private insurance). We adjusted for gender, race, age, geographic region, hospital type, admission source using regression models. In-hospital death was the primary outcome and secondary outcomes were hospital length of stay and total hospital charges adjusted to 2007 dollars., Results: The crude in-hospital mortality was 0.75% for uninsured versus 0.47% for insured children, with adjusted mortality rates of 0.74 and 0.46%, respectively. On multivariate analysis, uninsured compared with insured patients had an increased mortality risk (odds ratio: 1.60, 95% CI: 1.45-1.76). The excess mortality in uninsured children in the US was 37.8%, or 16,787, of the 38,649 deaths over the 18 period of the study., Conclusion: Children who were hospitalized without insurance have significantly increased all-cause in-hospital mortality as compared with children who present with insurance.

AP-2 family transcription factors are essential for development and morphogenesis of diverse tissues and organs, but their precise roles in specification of neural crest stem cell (NCSC)-derived cell types have not been determined. Among three members known to be expressed in the NCSC (i.e. AP-2alpha, AP-2beta, and AP-2gamma), we found that only AP-2beta is predominantly expressed in the sympathetic ganglia of developing mouse embryos, supporting its role in sympathetic development. Indeed, AP-2beta null mice expressed significantly reduced levels of both noradrenaline (NA) and NA-synthesizing dopamine beta-hydroxylase in the peripheral nervous system. Strikingly, we also found that NA neuron development was significantly compromised in the locus coeruleus as well. Pharmacological treatment with an NA intermediate during pregnancy significantly rescues the neonatal lethality of AP-2beta(-/-) mice, indicating that NA deficiency is one of the main causes for lethality found in AP-2beta(-/-) mice. We also showed that forced expression of AP-2beta, but not other AP-2 factors, in NCSC favors their differentiation into NA neurons. In summary, we propose that AP-2beta plays critical and distinctive roles in the NA phenotype specification in both the peripheral and central nervous system during development.

Both fetal ventral mesencephalic (VM) and embryonic stem (ES) cell-derived dopamine neurons have been used successfully to correct behavioral responses in animal models of Parkinson's disease. However, grafts derived from fetal VM cells or from ES cells contain multiple cell types, and the majority of these cells are not dopamine neurons. Isolation of ES cell-derived dopamine neurons and subsequent transplantation would both elucidate the capacity of these neurons to provide functional input and also further explore an efficient and safer use of ES cells for the treatment of Parkinson's disease. Toward this goal, we used a Pitx3-enhanced green fluorescent protein (Pitx3-eGFP) knock-in mouse blastocyst-derived embryonic stem (mES) cell line and fluorescence-activated cell sorting (FACS) to select and purify midbrain dopamine neurons. Initially, the dopaminergic marker profile of intact Pitx3-eGFP mES cultures was evaluated after differentiation in vitro. eGFP expression overlapped closely with that of Pitx3, Nurr1, Engrailed-1, Lmx1a, tyrosine hydroxylase (TH), l-aromatic amino acid decarboxylase (AADC), and vesicular monoamine transporter 2 (VMAT2), demonstrating that these cells were of a midbrain dopamine neuron character. Furthermore, postmitotic Pitx3-eGFP(+) dopamine neurons, which constituted 2%-5% of all live cells in the culture after dissociation, could be highly enriched to >90% purity by FACS, and these isolated neurons were viable, extended neurites, and maintained a dopaminergic profile in vitro. Transplantation to 6-hydroxydopamine-lesioned rats showed that an enriched dopaminergic population could survive and restore both amphetamine- and apomorphine-induced functions, and the grafts contained large numbers of midbrain dopamine neurons, which innervated the host striatum. Disclosure of potential conflicts of interest is found at the end of this article.

The homeodomain transcription factor Phox2b is one of the key determinants involved in the development of noradrenergic (NA) neurons in both the central nervous system (CNS) and the peripheral nervous system (PNS). Using yeast two-hybrid screening, we isolated a Phox2b interacting protein, Trim11, which belongs to TRIM (Tripartite motif) or RBCC proteins family, and contains a RING domain, B-boxes, a coiled-coil domain, and the B30.2/SPRY domain. Protein-protein interaction assays showed that Phox2b was able to physically interact with Trim11. The B30.2/SPRY domain of Trim11 was required for the interaction with Phox2b. Expression of Phox2b and Trim11 was detected in the sympathetic ganglia (SG) of mouse embryos. Forced expression of Trim11 with Phox2b further increased mRNA levels of dopamine beta-hydroxylase (DBH) gene in primary avian neural crest stem cell (NCSC) culture. This study suggests a potential role for Trim11 in the specification of NA phenotype by interaction with Phox2b.

The MRL mouse is unique in its capacity for regenerative healing of wounds. This regenerative ability includes complete closure, with little scarring, of wounds to the ear pinna and repair of cardiac muscle, without fibrosis, following cryoinjury. Here, we examine whether neurogenic zones within the MRL brain show enhanced regenerative capacity. The largest neurogenic zone in the adult brain, the subventricular zone (SVZ), lies adjacent to the lateral wall of the lateral ventricle and is responsible for replacement of interneuron populations within the olfactory bulb. Initial gross observation of the anterior forebrain in MRL mice revealed enlarged lateral ventricles; however, little neurodegeneration was detected within the SVZ or surrounding tissues. Instead, increased proliferation within the SVZ was observed, based on incorporation of the thymidine analogue bromodeoxyuridine. Closer examination using electron microscopy revealed that a significant number of SVZ astrocytes interpolated within the ependyma and established contact with the ventricle. In addition, subependymal, protuberant nests of cells, consisting primarily of neuroblasts, were found along the anterior SVZ of MRL mice. Whole mounts of the lateral wall of the lateral ventricle stained for the neuroblast marker doublecortin revealed normal formation of chains of migratory neuroblasts along the entire wall and introduction of enhanced green fluorescent protein-tagged retrovirus into the lateral ventricles confirmed that newly generated neuroblasts were able to track into the olfactory bulb.

The zinc finger transcription factor GATA-3 is a master regulator of type 2 T-helper cell development. Interestingly, in GATA-3-/- mice, noradrenaline (NA) deficiency is a proximal cause of embryonic lethality. However, neither the role of GATA-3 nor its target gene(s) in the nervous system were known. Here, we report that forced expression of GATA-3 resulted in an increased number of tyrosine hydroxylase (TH) expressing neurons in primary neural crest stem cell (NCSC) culture. We also found that GATA-3 transactivates the promoter function of TH via specific upstream sequences, a domain of the TH promoter residing at -61 to -39 bp. Surprisingly, this domain does not contain GATA-3 binding sites but possesses a binding motif, a cAMP response element (CRE), for the transcription factor, CREB. In addition, we found that site-directed mutation of this CRE almost completely abolished transactivation of the TH promoter by GATA-3. Furthermore, protein-protein interaction assays showed that GATA-3 is able to physically interact with CREB in vitro as well as in vivo. Based on these results, we propose that GATA-3 may regulate TH gene transcription via a novel and distinct protein-protein interaction, and directly contributes to NA phenotype specification.

Neural precursors (NPs) derived from ventral mesencephalon (VM) normally generate dopaminergic (DA) neurons in vivo but lose their potential to differentiate into DA neurons during mitogenic expansion in vitro, hampering their efficient use as a transplantable and experimental cell source. Because embryonic stem (ES) cell-derived NPs (ES NP) do not go through the same maturation process during in vitro expansion, we hypothesized that expanded ES NPs may maintain their potential to differentiate into DA neurons. To address this, we expanded NPs derived from mouse embryonic day-12.5 (E12.5) VM or ES cells and compared their developmental properties. Interestingly, expanded ES NPs fully sustain their ability to differentiate to the neuronal as well as to the DA fate. In sharp contrast, VM NPs almost completely lost their ability to become neurons and tyrosine hydroxylase-positive (TH(+)) neurons after expansion. Expanded ES NP-derived TH(+) neurons coexpressed additional DA markers such as dopa decarboxylase and DAT (dopamine transporter). Furthermore, they also expressed other midbrain DA markers, including Nurr1 and Pitx3, and released significant amounts of DA. We also found that these ES NPs can be cryopreserved without losing their proliferative and developmental potential. Finally, we tested the in vivo characteristics of the expanded NPs derived from J1 ES cells with low passage number. When transplanted into the mouse striatum, the expanded NPs as well as control NPs efficiently generated DA neurons expressing mature DA markers, with approximately 10% tumor formation in both cases. We conclude that ES NPs maintain their developmental potential during in vitro expansion, whereas mouse E12.5 VM NPs do not.