The power of genetic diversity in genome-wide association studies of lipids.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Diagnostic metabolomic profiling of Parkinson's disease biospecimens.

BACKGROUND: Reliable and sensitive biomarkers are needed for enhancing and predicting Parkinson's disease (PD) diagnosis. OBJECTIVE: To investigate comprehensive metabolomic profiling of biochemicals in CSF and serum for determining diagnostic biomarkers of PD. METHODS: Fifty subjects, symptomatic with PD for ≥5 years, were matched to 50 healthy controls (HCs). We used ultrahigh-performance liquid chromatography linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring relative concentrations of ≤1.5 kDalton biochemicals. A reference library created from authentic standards facilitated chemical identifications. Analytes underwent univariate analysis for PD association, with false discovery rate-adjusted p-value (≤0.05) determinations. Multivariate analysis (for identifying a panel of biochemicals discriminating PD from HCs) used several biostatistical methods, including logistic LASSO regression. RESULTS: Comparing PD and HCs, strong differentiation was achieved from CSF but not serum specimens. With univariate analysis, 21 CSF compounds exhibited significant differential concentrations. Logistic LASSO regression led to selection of 23 biochemicals (11 shared with those determined by the univariate analysis). The selected compounds, as a group, distinguished PD from HCs, with Area-Under-the-Receiver-Operating-Characteristic (ROC) curve of 0.897. With optimal cutoff, logistic LASSO achieved 100% sensitivity and 96% specificity (and positive and negative predictive values of 96% and 100%). Ten-fold cross-validation gave 84% sensitivity and 82% specificity (and 82% positive and 84% negative predictive values). From the logistic LASSO-chosen regression model, 2 polyamine metabolites (N-acetylcadaverine and N-acetylputrescine) were chosen and had the highest fold-changes in comparing PD to HCs. Another chosen biochemical, acisoga (N-(3-acetamidopropyl)pyrrolidine-2-one), also is a polyamine metabolism derivative. CONCLUSIONS: UHPLC-MS/MS assays provided a metabolomic signature highly predictive of PD. These findings provide further evidence for involvement of polyamine pathways in the neurodegeneration of PD.

Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA.

BACKGROUND: Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. METHODS: Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. RESULTS: Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. CONCLUSIONS: Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.

Ursodeoxycholic Acid Treatment Preferentially Improves Overall Survival Among African Americans With Primary Biliary Cholangitis.

BACKGROUND: We used data from the Fibrotic Liver Disease Consortium to evaluate the impact of ursodeoxycholic acid (UDCA) treatment across race/ethnicity, gender, and clinical status among patients with primary biliary cholangitis. METHODS: Data were collected from "index date" (baseline) through December 31, 2016. Inverse Probability of Treatment Weighting was used to adjust for UDCA treatment selection bias. Cox regression, focusing on UDCA-by-risk factor interactions, was used to assess the association between treatment and mortality and liver transplant/death. RESULTS: Among 4,238 patients with primary biliary cholangitis (13% men; 8% African American, 7% Asian American/American Indian/Pacific Island [ASINPI]; 21% Hispanic), 78% had ever received UDCA. The final multivariable model for mortality retained age, household income, comorbidity score, total bilirubin, albumin, alkaline phosphatase, and interactions of UDCA with race, gender, and aspartate aminotransferase/alanine aminotransferase ≥1.1. Among untreated patients, African Americans and ASINPIs had higher mortality than whites (adjusted hazard ratio [aHR] = 1.34, 95% confidence interval [CI] 1.08-1.67 and aHR = 1.40, 95% CI 1.11-1.76, respectively). Among treated patients, this relationship was reversed (aHR = 0.67, 95% CI 0.51-0.86 and aHR = 0.88, 95% CI 0.67-1.16). Patterns were similar for liver transplant/death. UDCA reduced the risk of liver transplant/death in all patient groups and mortality across all groups except white women with aspartate aminotransferase/alanine aminotransferase ≥1.1. As compared to patients with low-normal bilirubin at baseline (≤0.4 mg/dL), those with high-normal (1.0 > 0.7) and mid-normal bilirubin (0.7 > 0.4) had significantly higher liver transplant/death and all-cause mortality. DISCUSSION: African American and ASINPI patients who did not receive UDCA had significantly higher mortality than white patients. Among African Americans, treatment was associated with significantly lower mortality. Regardless of UDCA treatment, higher baseline bilirubin, even within the normal range, was associated with increased mortality and liver transplant/death compared with low-normal levels.

The Ottawa subarachnoid hemorrhage clinical decision rule for classifying emergency department headache patients.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a serious cause of headaches. The Ottawa subarachnoid hemorrhage (OSAH) rule helps identify SAH in patients with acute nontraumatic headache with high sensitivity, but provides limited information for identifying other intracranial pathology (ICP). OBJECTIVES: To assess the performance of the OSAH rule in emergency department (ED) headache patients and evaluate its impact on the diagnosis of intracranial hemorrhage (ICH) and other ICP. METHOD: We conducted a retrospective cohort study from January 2016 to March 2017. Patients with acute headache with onset within 14 days of the ED visit, were included. We excluded patients with head trauma that occurred in the previous 7 days, new onset of abnormal neurologic findings, or consciousness disturbance. According to the OSAH rule, patients with any included predictors required further investigation. RESULTS: Of 913 patients were included, 15 of them were diagnosed with SAH. The OSAH rule had 100% (95% CI, 78.2%-100%) sensitivity and 37.0% (95% CI, 33.8-40.2%) specificity for identifying SAH. Twenty-two cases were identified as SAH or ICH with 100% sensitivity (95% CI, 84.6%-100%) and 37.3% (95% CI, 34.1%-40.5%) specificity. As for non-hemorrhagic ICP, both the sensitivity and negative predictive values (NPV) decreased to 75.0% (95% CI, 53.3%-90.2%) and 98.2% (95% CI, 96.1%-99.3%), respectively. CONCLUSIONS: The OSAH rule had 100% sensitivity and NPV for diagnosing SAH and ICH with acute headache. The sensitivity and specificity were lower for non-hemorrhagic ICP. The OSAH rule may be an effective tool to exclude acute ICH and SAH in our setting.

Adjuvant ribavirin and longer direct-acting antiviral treatment duration improve sustained virological response among hepatitis C patients at risk of treatment failure.

The role of ribavirin (RBV) in the era of direct-acting antivirals (DAA) is not clear, and DAA studies have been largely genotype- and regimen-specific. Using data from the Chronic Hepatitis Cohort Study, we evaluated the role of RBV and increased DAA treatment duration among patients with chronic hepatitis C (HCV) in routine clinical care. We performed multivariable analysis of data from 4133 patients receiving any of the following: sofosbuvir (SOF); daclatasvir + SOF; grazoprevir + elbasvir; paritaprevir/ritonavir + ombitasvir; simeprevir + SOF; and SOF + ledipasvir; SOF + velpatasvir ± voxilaprevir; and glecaprevir + pibrentasvir-all with/ without RBV. Inverse probability treatment weighting was used to adjust for treatment selection bias. Sustained virological response (SVR) was defined by undetectable HCV RNA 12 weeks after end of therapy. The overall SVR rate was 95%. Mean treatment duration was 12 ± 4.5 weeks. The final model included treatment duration and diabetes, as well as the interaction of RBV with previous treatment status (treatment naïve, interferon treatment failure [TF] or previous DAA TF), cirrhosis status, and HCV genotype (GT). Each one-month increment of treatment duration increased odds of SVR by 99% (aOR = 1.99). Diabetes, previous DAA TF, and decompensated cirrhosis significantly reduced odds of SVR. RBV significantly increased the likelihood of SVR among patients with decompensated cirrhosis (aOR = 5.05), previous DAA treatment failure (aOR = 5.43), and GT3 (aOR = 13.28). Among RBV-free regimens, patients with GT3 were less likely to achieve SVR than those with GT1 or 2 (aOR 0.07). Diabetes, decompensated cirrhosis, and prior DAA TF independently reduced the likelihood of SVR. Longer treatment duration increased likelihood of SVR. Conclusion: RBV increased likelihood of SVR among patients with GT3, previous DAA TF, or decompensated cirrhosis.

Three-dimensional spherical gelatin bubble-based scaffold improves the myotube formation of H9c2 myoblasts.

Microenvironmental factors including physical and chemical cues can regulate stem cells as well as terminally differentiated cells to modulate their biological function and differentiation. However, one of the physical cues, the substrate's dimensionality, has not been studied extensively. In this study, the flow-focusing method with a microfluidic device was used to generate gelatin bubbles to fabricate highly ordered three-dimensional (3D) scaffolds. Rat H9c2 myoblasts were seeded into the 3D gelatin bubble-based scaffolds and compared to those grown on 2D gelatin-coating substrates to demonstrate the influences of spatial cues on cell behaviors. Relative to cells on the 2D substrates, the H9c2 myoblasts were featured by a good survival and normal mitochondrial activity but slower cell proliferation within the 3D scaffolds. The cortical actin filaments of H9c2 cells were localized close to the cell membrane when cultured on the 2D substrates, while the F-actins distributed uniformly and occupied most of the cell cytoplasm within the 3D scaffolds. H9c2 myoblasts fused as multinuclear myotubes within the 3D scaffolds without any induction but cells cultured on the 2D substrates had a relatively lower fusion index even differentiation medium was provided. Although there was no difference in actin α 1 and myosin heavy chain 1, H9c2 cells had a higher myogenin messenger RNA level in the 3D scaffolds than those of on the 2D substrates. This study reveals that the dimensionality influences differentiation and fusion of myoblasts.

In utero metal exposures measured in deciduous teeth and birth outcomes in a racially-diverse urban cohort.

A growing number of studies have examined associations of metal exposures with birth outcomes, however, results from these studies have been inconsistent, and hampered by methodological limitations. We measured direct fetal exposure to three metals (lead, manganese and zinc) during the second and third trimester and examined its association with birth weight and gestational age at delivery. Participants in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS), a population-based birth cohort established between September 2003 and December 2007, were invited to donate teeth to the study. Lead, manganese and zinc during the second and third trimesters were measured via high-resolution microspatial mapping of dentin growth rings, a validated biomarker for prenatal metal exposure. Gestational age at delivery and infant birth weight were obtained from the delivery medical record. A total of 145 children had tooth metal measurements and birth outcome data. Mean birth weight was 3431 ±â€¯472 g and mean gestational age at delivery was 39.0 ±â€¯1.3 weeks. Overall, there was a positive association between second (ß = 0.21, 95% CI: 0.05, 0.37, P = 0.01) and third trimester (ß = 0.21, 95% CI: 0.05, 0.37, P = 0.01) tooth manganese and birth weight Z-score; this remained statistically significant after covariate adjustment. There was also a negative association between second trimester tooth lead level and birth weight Z-score (ß = -0.20, 95% CI: -0.38, -0.02, P = 0.02), however, this was attenuated after adjusting for covariates. Mixture analysis revealed similar findings. There was evidence for a sex-specific effect of manganese with birth weight Z-score, with the association stronger in female compared to male infants. Overall, we found evidence suggesting that higher in utero manganese is associated with larger birth weight Z-scores and that these associations may vary by infant sex.

Ambient air pollution is associated with pediatric pneumonia: a time-stratified case-crossover study in an urban area.

BACKGROUND: Pneumonia, the leading reason underlying childhood deaths, may be triggered or exacerbated by air pollution. To date, only a few studies have examined the association of air pollution with emergency department (ED) visits for pediatric pneumonia, with inconsistent results. Therefore, we aimed to elucidate the impact of short-term exposure to particulate matter (PM) and other air pollutants on the incidence of ED visits for pediatric pneumonia. METHODS: PM2.5, PM10, and other air pollutant levels were measured at 11 air quality-monitoring stations in Kaohsiung City, Taiwan, between 2008 and 2014. Further, we extracted the medical records of non-trauma patients aged ≤17 years and who had visited an ED with the principal diagnosis of pneumonia. A time-stratified case-crossover study design was employed to determine the hazard effect of air pollution in a total of 4024 patients. RESULTS: The single-pollutant model suggested that per interquartile range increment in PM2.5, PM10, nitrogen dioxide (NO2), and sulfur dioxide (SO2) on 3 days before the event increased the odds of pediatric pneumonia by 14.0% [95% confidence interval (CI), 5.1-23.8%], 10.9% (95% CI, 2.4-20.0%), 14.1% (95% CI, 5.0-24.1%), and 4.5% (95% CI, 0.8-8.4%), respectively. In two-pollutant models, PM2.5 and NO2 were significant after adjusting for PM10 and SO2. Subgroup analyses showed that older children (aged ≥4 years) were more susceptible to PM2.5 (interaction p = 0.024) and children were more susceptible to NO2 during warm days (≥26.5 °C, interaction p = 0.011). CONCLUSIONS: Short-term exposure to PM2.5 and NO2 possibly plays an important role in pediatric pneumonia in Kaohsiung, Taiwan. Older children are more susceptible to PM2.5, and all children are more susceptible to NO2 during warm days.

ICU admission following an unscheduled return visit to the pediatric emergency department within 72 hours.

INTRODUCTION: The purpose of this study was to describe the demographic characteristics and prognosis of children admitted to the intensive care unit (ICU) after a pediatric emergency department (PED) return visit within 72 h. METHOD: We conducted this retrospective study from 2010 to 2016 in the PED of a tertiary medical center in Taiwan and included patients under the age of 18 years old admitted to the ICU after a PED return visit within 72 h. Clinical characteristics were collected to perform demographic analysis. Pediatric patients who were admitted to the ICU on an initial visit were also enrolled as a comparison group for outcome analysis, including mortality, ventilator use, and length of hospital stay. RESULTS: We included a total of 136 patients in this study. Their mean age was 3.3 years old, 65.4% were male, and 36.0% had Chronic Health Condition (CHC). Disease-related return (73.5%) was by far the most common reason for return. Compared to those admitted on an initial PED visit, clinical characteristics, including vital signs at triage and laboratory tests on return visit with ICU admission, demonstrated no significant differences. Regarding prognosis, ICU admission on return visit has a higher likelihood of ventilator use (aOR:2.117, 95%CI 1.021~4.387), but was not associated with increased mortality (aOR:0.658, 95%CI 0.150~2.882) or LOHS (OR:-1.853, 95%CI -4.045~0.339). CONCLUSION: Patients who were admitted to the ICU on return PED visits were associated with an increased risk of ventilator use but not mortality or LOHS compared to those admitted on an initial visit.

Clinical learning in the context of uncertainty: a multi-center survey of emergency department residents' and attending physicians' perceptions of clinical feedback.

BACKGROUND: Feedback is an essential part of clinical teaching and learning, yet it is often perceived as unsatisfactory in busy clinical settings. Clinical teachers need to balance the competing demands of clinical duty and feedback provision. The influence of the clinical environment and the mutual relationship between feedback giving and seeking has been inadequately investigated. This study therefore aimed to quantify the adequacy, perceptions, and influential factors of feedback provision during resident training in emergency departments (EDs). METHODS: A multicenter online questionnaire study was undertaken. The respondents comprised ED residents and clinical teachers from four teaching hospitals in Taiwan. The questionnaire was developed via an expert panel, and a pilot study ensured validity. Ninety clinical teachers and 54 residents participated. RESULTS: The respondents reported that the majority of feedback, which usually lasted 1-5 min, was initiated by the clinical teachers. Feedback satisfaction was significantly lower for the clinical teachers than for the residents (clinical teachers M = 13.8, SD = 1.83; residents M = 15.3, SD = 2.14; p < 0.0001), and positive feedback was provided infrequently in clinical settings (31.1%). Both groups of participants admitted hesitating between providing/seeking feedback and completing clinical work. Being busy, the teachers' clinical abilities, the learners' attitudes, and the relationship between both parties were reported as the most influential factors in feedback provision. CONCLUSION: ED clinical feedback provision is often short, circumstantial, and initiated by clinical teachers. Providing or seeking feedback appears to be an important part of clinical learning in the context of uncertainty. The importance of the relationship between the feedback seeker and the provider highlights the interactive, reciprocal nature of clinical feedback provision.

The influence of crowding on clinical practice in the emergency department.

BACKGROUND: This study aimed to clarify the association between the crowding and clinical practice in the emergency department (ED). METHODS: This 1-year retrospective cohort study conducted in two EDs in Taiwan included 70,222 adult non-trauma visits during the day shift between July 1, 2011, and June 30, 2012. The ED occupancy status, determined by the number of patients staying during their time of visit, was used to measure crowding, grouped into four quartiles, and analyzed in reference to the clinical practice. The clinical practices included decision-making time, patient length of stay, patient disposition, and use of laboratory examinations and computed tomography (CT). RESULT: The four quartiles of occupancy statuses determined by the number of patients staying during their time of visit were <24, 24-39, 39-62, and >62. Comparing >62 and <24 ED occupancy statuses, the physicians' decision-making time and patients' length of stay increased by 0.3h and 1.1h, respectively. The percentage of patients discharged from the ED decreased by 15.5% as the ED observation, general ward, and intensive care unit admissions increased by 10.9%, 4%, and 0.7%, respectively. CT and laboratory examination slightly increased in the fourth quartile of ED occupancy. CONCLUSION: Overcrowding in the ED might increase physicians' decision-making time and patients' length of stay, and more patients could be admitted to observation units or an inpatient department. The use of CT and laboratory examinations would also increase. All of these could lead more patients to stay in the ED.

Can different physicians providing urgent and non-urgent treatment improve patient flow in emergency department?

BACKGROUND: Emergency Department (ED) overcrowding is a worldwide problem, and it might be caused by prolonged patient stay in the ED. This study tried to analyze if different practice models influence patient flow in the ED. MATERIALS AND METHODS: A retrospective, 1-year cohort study was conducted across two EDs in the largest healthcare system in Taiwan. A total of 37,580 adult non-trauma patients were involved in the study. The clinical practice between two ED practice models was compared. In one model, urgent and non-urgent patients were treated by different emergency physicians (EPs) separately (separated model). In the other, EPs treated all patients assigned randomly (merged model). The ED length of stay (LOS), diagnostic tool use (including laboratory examinations and computed tomography scans), and patient dispositions (including discharge, general ward admission, intensive care unit (ICU) admissions, and ED mortality) were selected as outcome indicators. RESULT: Patients discharged from ED had 0.4h shorter ED LOS in the separated model than in merged model. After adjusting for the potential confounding factors through regression model, there was no difference of patient disposition of the two practice models. However, the separated model showed a slight decrease in laboratory examination use (adjusted odds ratio, 0.9; 95% confidence interval, 0.83-0.96) compared with the merged model. CONCLUSION: The separated model had better patient flow than the merged model did. It decreased the ED LOS in ED discharge patients and laboratory examination use.

Traffic Intensity of Patients and Physicians in the Emergency Department: A Queueing Approach for Physician Utilization.

BACKGROUND: The unpredictable nature of patient visits poses considerable challenges to the staffing of emergency department (ED) medical personnel. There is a lack of common physician usage parameters at present. OBJECTIVE: The aim of this study was to quantify the ED traffic intensity of patients and physicians using a queueing model approach. METHODS: A retrospective administrative electronic data analysis was conducted in a tertiary medical center. All patients who registered at the ED in 2013 were included. Precisely recorded patient waiting time, service time, and disposition time were obtained. An M/M/s (Markovian patient arrival, Markovian patient service, s servers) queueing model was used, while taking account of the actual physician number and number of patients managed simultaneously. Physician utilization and performance indicators were measured. RESULTS: A total of 148,581 patients were analyzed after exclusion. The overall mean waiting time, service time, and disposition time were 0.23 (standard deviation [SD] = 0.24), 2.31 (SD = 3.89), and 2.54 (SD = 3.90) hours, respectively. Hourly physician utilization (ρ), stratified by different patient entities, was ρ = 0.75 ± 0.17 for adult non-trauma, ρ = 0.75 ± 0.28 for pediatric, and ρ = 0.53 ± 0.18 for trauma (p = 0.0004). There was a surge of utility for pediatric non-trauma patients in the late evening (ρ = 1.4 at 11 pm). The distribution of number of patients in the system was derived and compared by different patient entities and time points. CONCLUSIONS: A queueing model was built to model traffic intensity of physicians and patients, the physician utility trend disclosed the fluctuation of manpower utility. The estimated parameters serve as important factors for developing tailored staffing policies for minimizing ED waiting and improving ED crowding.

Administration of Downstream ApoE Attenuates the Adverse Effect of Brain ABCA1 Deficiency on Stroke.

The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1-B/-B) reduced brain grey matter (GM) and white matter (WM) density in the ischemic brain and decreased functional outcomes after stroke. However, the downstream molecular mechanism underlying brain ABCA1-deficiency-induced deficits after stroke is not fully understood. Adult male ABCA1-B/-B and ABCA1-floxed control mice were subjected to distal middle-cerebral artery occlusion and were intraventricularly infused with artificial mouse cerebrospinal fluid as vehicle control or recombinant human ApoE2 into the ischemic brain starting 24 h after stroke for 14 days. The ApoE/apolipoprotein E receptor 2 (ApoER2)/high-density lipoprotein (HDL) levels and GM/WM remodeling and functional outcome were measured. Although ApoE2 increased brain ApoE/HDL levels and GM/WM density, negligible functional improvement was observed in ABCA1-floxed-stroke mice. ApoE2-administered ABCA1-B/-B stroke mice exhibited elevated levels of brain ApoE/ApoER2/HDL, increased GM/WM density, and neurogenesis in both the ischemic ipsilateral and contralateral brain, as well as improved neurological function compared with the vehicle-control ABCA1-B/-B stroke mice 14 days after stroke. Ischemic lesion volume was not significantly different between the two groups. In vitro supplementation of ApoE2 into primary cortical neurons and primary oligodendrocyte-progenitor cells (OPCs) significantly increased ApoER2 expression and enhanced cholesterol uptake. ApoE2 promoted neurite outgrowth after oxygen-glucose deprivation and axonal outgrowth of neurons, and increased proliferation/survival of OPCs derived from ABCA1-B/-B mice. Our data indicate that administration of ApoE2 minimizes the adverse effects of ABCA1 deficiency after stroke, at least partially by promoting cholesterol traffic/redistribution and GM/WM remodeling via increasing the ApoE/HDL/ApoER2 signaling pathway.

The impact of prolonged waiting time for coronary care unit admission on patients with non ST-elevation acute coronary syndrome.

BACKGROUND: The boarding of patients in the emergency department consumes nursing and physician resources, and may delay the evaluation of new patients. It may also contribute to poor cardiovascular outcomes in patients with acute coronary syndrome (ACS). This study analyzed the relationship between the delay in coronary care unit (CCU) admission and the clinical outcomes of patients with ACS with non-ST-segment elevation (NSTE-ACS). METHODS: Patients were divided into 2 groups according to the CCU waiting time (<12h and >12h). Outcome variables including in-hospital mortality, gastrointestinal bleeding and stroke during hospitalization, and duration of hospital stay were compared between the 2 study groups. We used the GRACE risk scores to classify disease severity of the study patients for stratifying analysis. RESULT: A difference was found in the outcome of gastrointestinal bleeding. Among those with GRACE risk scores of <3 (low mortality risk) and 3 (high mortality risk), 5% and 3.1% of patients developed gastrointestinal bleeding, respectively, with CCU waiting time of >12h compared to CCU waiting time of <12h. However, there was no significant statistical difference (P=0.065 and 0.547). In addition, there were no significant differences in the in-hospital mortality rate, incidence of stoke, and duration of hospital stay between the 2 groups. CONCLUSION: There was no significant difference in the clinical outcomes of NSTE-ACS patients without profound shock between those with CCU waiting times of <12 and >12h. If necessary, CCU admission should be prioritized for patients whose hemodynamic instability or respiratory failure.

Do-not-resuscitate orders and related factors among family surrogates of patients in the emergency department.

PURPOSE: The purpose of this study was to investigate the prevalence of do-not-resuscitate (DNR) orders and to identify relevant factors influencing the DNR decision-making process by patients' surrogates in the emergency department (ED). METHODS: A prospective, descriptive, and correlational research design was adopted. A total of 200 surrogates of cancer or non-cancer terminal patients, regardless of whether they signed a DNR order, were recruited as subjects after physicians of the emergency department explained the patient's conditions, advised on withholding medical treatment, and provided information on palliative care to all surrogates. RESULTS: Of the 200 surrogates, 23 % signed a DNR order for the patients. The demographic characteristics of patients and surrogates, the level of understanding of DNR orders, and factors of the DNR decision had no significant influence on the DNR decision. However, greater severity of disease (odds ratio (OR) = 1.38; 95 % confidence interval (CI) = 0.95-1.74), physician's initiative in discussing with the families (OR = 1.42; 95 % CI = 1.21-1.84), and longer length of hospital stay (OR = 1.06; 95 % CI = 1.03-1.08) were contributing factors affecting patient surrogates' DNR decisions. CONCLUSIONS: The findings of this study indicated that surrogates of patients who were more severe in disease condition, whose physicians initiated the discussion of palliative care, and who stayed longer in hospital were important factors affecting the surrogates' DNR decision-making. Therefore, early initiation of DNR discussions is suggested to improve end-of-life care.

The influence of emergency department crowding on the efficiency of care for acute stroke patients.

OBJECTIVE: To investigate the impact of emergency department (ED) crowding (number of ED patients) and number of ED staff on the efficiency of the ED care process for acute stroke patients. DESIGN: Retrospective cohort study conducted from 1 May 2008 to 31 December 2013. SETTING: Largest primary stroke center (3000-bed tertiary academic hospital) in southern Taiwan. PARTICIPANTS: Patients aged 18-80 years presenting to the ED with acute stroke symptoms ≤3 h from symptom onset (n = 1142). MAIN OUTCOME MEASURES: Door-to-assessment time (DTA), door-to-computed tomography completion time (DTCT) and door-to-needle time (DTN). RESULTS: Of the 785 patients with ischemic stroke, 90 (11.46%) received thrombolysis. In the multivariate regression analysis, the number of ED patients and the number of attending physicians were significantly associated with delayed DTA and DTCT but not DTN. Initial assessment by a resident was also associated with delayed DTA and DTCT. The number of nurses was associated with delayed DTCT and DTN. CONCLUSIONS: Although ED crowding was not associated with delayed DTN, it predicted delayed DTA and DTCT in thrombolysis-eligible stroke patients. The number of attending physicians affected initial assessment and DTCTs, whereas the number of nurses impacted thrombolytic administration times.