National Heart Lung Blood Institute Research Articles

Aplastic anemia from past to the present: A bibliometric analysis with research trends and global productivity during 1980 to 2022.

There is no bibliometric study in the literature on Aplastic Anemia (AA). In the present study, the purpose was to summarize the intellectual structure of the subject, uncover the global productivity in this respect, and identify the latest research trends by performing a bibliometric analysis of the articles published on AA. For this purpose, outputs for different research components of scientific outputs (i.e., countries, institutions, journals, and authors) were analyzed. A total of 3221 articles on Aplastic Anemia published between 1980 and 2022 were analyzed by using various statistical methods and bibliometric approaches. The Spearman Correlation Coefficient was used for correlation analysis and bibliometric network visualization maps were used to identify trending topics, citation analysis, and international collaborations. The top 3 contributing countries to the literature were the USA in this respect (800, 24.8%), China (514, 15.9%), and Japan (442, 13.7%). The top 3 most active institutions were the National Institutes of Health USA (n = 177), National Heart Lung Blood Institute (n = 153), and Udice French Research Universities (n = 136). The top 3 most productive journals were the British Journal of Haematology (n = 239), Blood (n = 181), and Bone Marrow Transplantation (n = 137). The most prolific author was Neal Stuart Young (n = 130). Specific keywords that were most frequently used in articles were severe aplastic anemia, immunosuppressive therapy, pediatrics/children, anti-thymocyte globulin, cyclosporine, hematopoietic stem cell transplantation, myelodysplastic syndromes, Paroxysmal Nocturnal Hemoglobinuria, hepatitis-associated aplastic anemia, allogeneic stem cell transplantation, haploidentical hematopoietic stem cell transplantation, pancytopenia, eltrombopag, fludarabine, Graft-Versus-Host Disease, survival, apoptosis, cytokines, and cyclophosphamide. It was determined that the trend topics in recent years were eltrombopag, COVID-19, Treg, Th17, thrombopoietin receptor agonists, haploidentical hematopoietic stem cell transplantation, haploidentical donor/transplantation, and posttransplantation cyclophosphamide. In the formation of the AA literature, it was determined that the research leadership belonged to the USA, China, Japan, European countries (United Kingdom, Italy, Germany, France, Switzerland), India, and South Korea, which have large economies.

Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial

Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding. We aimed to compare recombinant VWF with tranexamic acid for reducing heavy menstrual bleeding in patients with von Willebrand disease. VWDMin, a phase 3, open-label, randomised crossover trial, was done in 13 haemophilia treatment centres in the USA. Female patients aged 13-45 years with mild or moderate von Willebrand disease, defined as VWF ristocetin cofactor less than 0·50 IU/mL, and heavy menstrual bleeding, defined as a pictorial blood assessment chart (PBAC) score more than 100 in one of the past two cycles were eligible for enrolment. Participants were randomly assigned (1:1) to two consecutive cycles each of intravenous recombinant VWF, 40 IU/kg over 5-10 min on day 1, and oral tranexamic acid 1300 mg three times daily on days 1-5, the order determined by randomisation. The primary outcome was a 40-point reduction in PBAC score by day 5 after two cycles of treatment. Efficacy and safety were analysed in all patients with any post-baseline PBAC scores. The trial was stopped early due to slow recruitment on Feb 15, 2022, by a data safety monitoring board request, and was registered at ClinicalTrials.gov, NCT02606045. Between Feb 12, 2019, and Nov 16, 2021, 39 patients were enrolled, 36 of whom completed the trial (17 received recombinant VWF then tranexamic acid and 19 received tranexamic acid then recombinant VWF). At the time of this unplanned interim analysis (data cutoff Jan 27, 2022), median follow-up was 23·97 weeks (IQR 21·81-28·14). The primary endpoint was not met, neither treatment corrected PBAC score to the normal range. Median PBAC score was significantly lower after two cycles with tranexamic acid than with recombinant VWF (146 [95% CI 117-199] vs 213 [152-298]; adjusted mean treatment difference 46 [95% CI 2-90]; p=0·039). There were no serious adverse events or treatment-related deaths and no grade 3-4 adverse events. The most common grade 1-2 adverse events were mucosal bleeding (four [6%] patients during tranexamic acid treatment vs zero during recombinant VWF treatment) and other bleeding (four [6%] vs two [3%]). These interim data suggest that recombinant VWF is not superior to tranexamic acid in reducing heavy menstrual bleeding in patients with mild or moderate von Willebrand disease. These findings support discussion of treatment options for heavy menstrual bleeding with patients based on their preferences and lived experience. National Heart Lung Blood Institute (National Institutes of Health).

320 Trends in Acute Care of Vaso-Occlusive Episodes in the Emergency Department Following the 2014 National Heart Lung Blood Institute Guidelines

Patients presenting to the Emergency Department (ED) with sickle cell disease (SCD) vaso-occlusive episodes (VOE) encounter variability in triage acuity level designation and pain management practices. Our study aims to describe national trends in Emergency Severity Index (ESI) level designation and the rate of narcotic administration for ED patients with SCD VOE. We additionally compare both of these variables before and after publication of the 2014 National Heart Lymph Blood Institute (NHLBI) guidelines for the management of patients with VOE.

0322 sleep disordered breathing and MRI makers of brain aging in the Hispanic Community Health Study/Study of Latinos

Abstract Introduction We aim to determine if white matter hyperintensities and decreased brain volumes are associated with sleep-disordered breathing (SDB), in a diverse sample of middle-aged and older Hispanic/Latino adults. Methods Our sample of 1,119 Hispanics/Latinos (ages older than 50-years; 70% female) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) underwent brain magnetic resonance imaging (MRI) as part of the Study of Latinos - Investigation of Neurocognitive Aging MRI (SOL-INCA MRI) ancillary study. MRI outcomes of interest included global (gray matter, total brain) and regional (lobar cortices, hippocampus) brain volumes, lateral ventricle volume, and total white matter hyperintensity (WMH) volume. All MRI measures were residualized for total cranial volume. Our main exposure was visit-1 sleep data (2008-2011), which includes information about SDB defined with the respiratory event index 3% (REI), ≥5 and ≥15 (moderate-severe SDB) identified by home-sleep apnea test. Survey linear regression models to assess the association between sleep measures and MRI outcomes adjusted for age, sex, education, Hispanic/Latino background, body mass index, tobacco use, alcohol consumption, and physical activity factors and accounted for HCHS/SOL complex study design. We tested for effect modifications by age, sex and Hispanic/Latino background. Results Mean age was 63.9±7.0 years. Adjusting for age, sex, and education, individuals with a REI ≥15 (vs. <5) had decrements in total brain volume (Btotal=-6.115[-10.19 ; -2.04]; p<0.01), total gray matter volume(B= -3.702 [-6.7 ; -0.7]; p<0.05), and frontal cortical gray matter volume (B= -1.844[-3.48; -0.21]; p<0.05), and increments in hippocampal volume β= 0.138[0.04; 0.23]; p<0.01). The associations persisted after adjustment for Hispanic/Latino background and behavioral risk factors. Older age modified associations between the REI and age and total brain volumes (Bage*REI=-0.019[-0.04 ;~0.00]; p<0.05). There was no consistent evidence for effect moderation by sex or Hispanic/Latino background. Conclusion In a diverse sample of Hispanic/Latinos, moderate-severe SDB was associated with decreased total brain volumes and increments in hippocampal volumes. Our findings suggest that SDB related neuroimaging markers of brain health could serve to identify Hispanic/Latino participants with sleep related Alzheimer’s disease and related dementia risk. Support (If Any) This work is supported by National Institute on Aging (R01AG048642, RF1AG054548, and R01AG063868) and by the National Heart Lung Blood Institute (R01HL098297). Dr. González also receives additional support from P30AG59299. The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-philip glass beck HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements.

0324 sleep duration and brain MRI biomarkers: results from SOL-INCA MRI study

Abstract Introduction Long and short sleep have been associated with stroke and dementia. Sleep patterns may differ by sex and Hispanic/Latino background. Within Hispanics/Latinos heterogeneity in sleep outcomes exists and is understudied. The purpose of this study was to examine associations between sleep duration and MRI biomarkers of brain health. Methods SOL-Investigation of Neurocognitive Aging (SOL-INCA) MRI study is an ongoing ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Our analytic sample consisted of 1,103 adults 50-years and older from diverse Hispanics/Latino backgrounds that completed baseline sleep assessments (2008-2011) and underwent neuroimaging (2018-ongoing; Mean age 64 ±6.9 years). The main exposures were baseline self-reported average nightly sleep duration. Outcomes included brain volume measures residualized for cranial volume (e.g. total brain, hippocampal, and white matter hyperintensities). Brain outcomes were modeled, using regression techniques, as a function of sleep duration and adjusting for age, sex, education, Hispanic/Latino background, language use, self-reported cardiovascular events, BMI, depressive symptoms, Apena/Hypopena index and self-reported sleep quality. Results Mean sleep duration was 7.7 ± 1.36 hours, and 13.2% reported sleeping >9 hours. Increasing sleep duration was associated with smaller total brain (Btotal_brain -1.32 [-2.33 ; -0.32], p<0.05) per hour increment and larger lateral ventricle volumes (Blateral_ventricle=0.02 [~0.00; 0.04], p<0.05) after adjusting for sociodemographic, behavioral, cardio-vascular and sleep quality characteristics. The associations were not modified by sex or Hispanic/Latino background. Conclusion We found that increments in sleep duration was associated with lower total brain volume and larger ventricle size, MRI measures that could associate with increased dementia-risk in diverse Hispanic/Latino adults. Support (If Any) This work is supported by National Institute on Aging (R01AG048642, RF1AG054548, and R01AG063868) and by the National Heart Lung Blood Institute (R01HL098297). Dr. González also receives additional support from P30AG59299. The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-philip glass beck HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements.

Effects of exercise training on cardiotoxicity in cancer survivors. A systematic review

Background: Cardiotoxicity is a major long-term complication of anti-cancer drugs such as anthracycline and androgen deprivation therapy (ADT). These drugs also impact the quality of life, reduced functional capacity, and life expectancy. Exercise attenuates the cardiotoxic effects of anticancer treatments, as indicated by a growing body of evidence. Methods: Studies for this review were retrieved from databases PubMed, SCOPUS, EMBASE, COCHRANE, and Web of Science and were restricted only to clinical trials. Study results were screened and synchronized to Mendeley. Studies that met the eligibility criteria were extracted into the spreadsheet, summarizing information regarding the site and cancer stages, adjuvant therapy, various exercise interventions, and outcome measures. Risk of bias quality analysis was done in accordance with the National Heart Lung Blood Institute. Results: In this systematic review, 9021 articles were screened. After the exclusion criteria, seven articles were included for qualitative analysis. Outcome measures analyzed were measures of cardiotoxicity such as left ventricular ejection fraction (LVEF), cardiac biomarkers, and global longitudinal strain. Conclusion: Although a structured exercise protocol including aerobic and resistance training has been found to improve, the functional capacity is an indirect measure of cardiotoxicity. There is a lack of data in terms of improvement seen in direct measurements of cardiotoxicity such as LVEF and cardiac biomarkers. A lack of evidence regarding the effects of exercise on the direct measurement of cardiotoxicity encourages the need for further research.

Patient-perceived and practitioner-perceived barriers to accessing foot care services for people with diabetes mellitus: a systematic literature review

BackgroundFoot-related complications are common in people with diabetes mellitus, however foot care services are underutilized by this population. This research aimed to systematically review the literature to identify patient and practitioner-perceived barriers to accessing foot care services for people with diabetes.MethodsPRISMA guidelines were used to inform the data collection and extraction methods. CINAHL, MEDLINE, and Scopus databases were searched in March 2022 to identify original research articles that reported on barriers to accessing diabetes foot care services from the patient and/or practitioner perspective. Both quantitative and qualitative studies were included. The methodological quality of included studies was assessed using the Critical Appraisal Skills Program (CASP) tool for qualitative/mixed methods studies or the National Heart, Lung & Blood Institute (NHLBI) tool for quantitative studies. Following data extraction, content analysis was used to identify reported barriers. Themes and subthemes were presented separately for patient-perspectives and practitioner-perspectives. A narrative summary was used to synthesize the findings from the included studies.ResultsA total of 20 studies were included. The majority of CASP and NHLBI criteria were met by most studies, indicating good overall methodological quality. Three predominant themes emerged from the patient perspective that represented barriers to accessing foot care services: lack of understanding, socioeconomic factors, and lack of service availability. Four themes emerged from the practitioner perspective: poor interprofessional communication, lack of resources, lack of practitioner knowledge, and perceived patient factors.ConclusionsThis study has identified a number of barriers to accessing foot care services from both the patient and practitioner perspectives. Although patients focused predominantly on patient-level factors, while practitioners focused on barriers related to the health care system, there was some overlap between them. This emphasizes the importance of recognising both perspectives for the future integration of policy changes and access facilitators that may help to overcome these barriers.

Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: A retrospective cohort study of patients with and without COVID-19.

BackgroundMost data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have been presented as case series without comparison to patients with other acute respiratory illnesses.MethodsWe examined emergency department patients between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. We determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). We compared clinical presentation, diagnostics, treatment, and outcomes.FindingsAmong 316 patients, 33 tested positive for SARS-CoV-2; 31 without COVID-19 tested positive for another respiratory virus. Among patients with additional viral testing (27/33), no SARS-CoV-2 co-infections were identified. Compared to those who tested negative, patients with COVID-19 reported longer symptoms duration (median 7d vs. 3d, p < 0.001). Patients with COVID-19 were more often hospitalized (79% vs. 56%, p = 0.014). When hospitalized, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d, p < 0.001) and more often developed ARDS (23% vs. 3%, p < 0.001). Most comorbidities, medications, symptoms, vital signs, laboratories, treatments, and outcomes did not differ by COVID-19 status.InterpretationWhile we found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections.FundingNational Center for Advancing Translational Sciences, National Heart Lung Blood Institute, National Institute of Allergy and Infectious Diseases, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative.

Associations between historical residential redlining and current age-adjusted rates of emergency department visits due to asthma across eight cities in California: an ecological study

Asthma disproportionately affects communities of colour in the USA, but the underlying factors for this remain poorly understood. In this study, we assess the role of historical redlining as outlined in security maps created by the Home Owners' Loan Corporation (HOLC), the discriminatory practice of categorising neighbourhoods on the basis of perceived mortgage investment risk, on the burden of asthma in these neighbourhoods. We did an ecological study of HOLC risk grades and asthma exacerbations in California using the security maps available for the following eight cities: Fresno, Los Angeles, Oakland, Sacramento, San Diego, San Jose, San Francisco, and Stockton. Each census tract was categorised into one of four risk levels (A, B, C, or D) on the basis of the location of population-weighted centroids on security maps, with the worst risk level (D) indicating historical redlining. We obtained census tract-level rates of emergency department visits due to asthma from CalEnviroScreen 3.0. We assessed the relationship between risk grade and log-transformed asthma visit rates between 2011 and 2013 using ordinary least squares regression. We included potential confounding variables from the 2010 Census and CalEnviroScreen 3.0: diesel exhaust particle emissions, PM2·5, and percent of the population living below 2 times the federal poverty level. We also built random intercept and slope models to assess city-level variation in the relationship between redlining and asthma. In the 1431 census tracts assessed (64 [4·5%] grade A, 241 [16·8%] grade B, 719 [50·2%] grade C, and 407 [28·4%] grade D), the proportion of the population that was non-Hispanic black and Hispanic, the percentage of the population living in poverty, and diesel exhaust particle emissions all significantly increased as security map risk grade worsened (p<0·0001). The median age-adjusted rates of emergency department visits due to asthma were 2·4 times higher in census tracts that were previously redlined (median 63·5 [IQR 34·3] visits per 10 000 residents per year [2011-13]) than in tracts at the lowest risk level (26·5 [18·4]). In adjusted models, redlined census tracts were associated with a relative risk of 1·39 (95% CI 1·21-1·57) in rates of emergency department visits due to asthma compared with that of lowest-risk census tracts. Historically redlined census tracts have significantly higher rates of emergency department visits due to asthma, suggesting that this discriminatory practice might be contributing to racial and ethnic asthma health disparities. National Heart Lung Blood Institute.

New Strategies and Challenges in Lung Proteomics and Metabolomics. An Official American Thoracic Society Workshop Report.

This document presents the proceedings from the workshop entitled, "New Strategies and Challenges in Lung Proteomics and Metabolomics" held February 4th-5th, 2016, in Denver, Colorado. It was sponsored by the National Heart Lung Blood Institute, the American Thoracic Society, the Colorado Biological Mass Spectrometry Society, and National Jewish Health. The goal of this workshop was to convene, for the first time, relevant experts in lung proteomics and metabolomics to discuss and overcome specific challenges in these fields that are unique to the lung. The main objectives of this workshop were to identify, review, and/or understand: (1) emerging technologies in metabolomics and proteomics as applied to the study of the lung; (2) the unique composition and challenges of lung-specific biological specimens for metabolomic and proteomic analysis; (3) the diverse informatics approaches and databases unique to metabolomics and proteomics, with special emphasis on the lung; (4) integrative platforms across genetic and genomic databases that can be applied to lung-related metabolomic and proteomic studies; and (5) the clinical applications of proteomics and metabolomics. The major findings and conclusions of this workshop are summarized at the end of the report, and outline the progress and challenges that face these rapidly advancing fields.

Acute respiratory distress syndrome: shifting the emphasis from treatment to prevention.

Although results from clinical trials have advanced the treatment of acute respiratory distress syndrome (ARDS), mortality remains high. More recently, focus has shifted from treatment of ARDS to early identification and prevention in at-risk populations. There have been 30 published and registered clinical trials with either the primary or secondary goal of reducing ARDS. With this change in paradigm, come additional challenges and consideration in study design that depends not only on the intervention but also whether the intervention aims for a primary, secondary, or tertiary prevention of ARDS that targets a patient population for universal, selective, or indicated prevention. These epidemiologic concepts of prevention in public health also apply to ARDS and are relevant to the study population to target, the timing of the intervention relative to critical illness, the study design and outcomes to measure in an ARDS prevention study. This shift in focus is reflected by the new National Heart Lung Blood Institute Prevention and Early Treatment of Acute Lung Injury network, and signifies an overall movement away from reacting to and supporting acute organ failure after it is established to early detection and prevention in acute critical illness wherever and whenever it may occur.

Opposite association between diabetes, dyslipidemia, and hepatocellular carcinoma mortality in the middle-aged and elderly

Limited data exist regarding metabolic risk factors for deaths from hepatocellular carcinoma (HCC) in aging individuals. We investigated the association between diabetes, dyslipidemia, and HCC mortality in those aged 40 years or more (middle-aged and elderly). In this prospective cohort study based on nationwide health screening units, we consecutively followed middle-aged and elderly participants who had no chronic hepatitis B or C virus infection and received health screening from January 1 1998 to December 31 2008. There were 235 deaths from HCC among 50,080 individuals, ascertained by validated death certificates and the national death registry. Diabetes (adjusted hazard ratio [HR], 3.38; 95% confidence interval [CI], 2.35 to 4.86) was positively associated with deaths from HCC. However, hypertriglyceridemia (HR, 0.38; 95% CI, 0.26 to 0.55) and hypercholesterolemia (HR, 0.50; 95% CI, 0.37 to 0.67) were inversely associated with HCC mortality. The above significant associations remained in the lag time analyses, applied to check for reverse causation. Metabolic syndrome, as defined by the American Heart Association / National Heart Lung Blood Institute criteria (HR, 0.63; 95% CI, 0.46 to 0.86) or by the International Diabetes Federation criteria (HR, 0.62; 95% CI, 0.43 to 0.89), was inversely associated with deaths from HCC, especially in men. Middle-aged and elderly individuals, once having diabetes, deserve HCC surveillance to reduce HCC mortality. More research is needed to elucidate why having baseline dyslipidemia relates to lower future HCC mortality.

Healthy Eating Index 2005 and selected macronutrients are correlated with improved lung function in humans

A number of dietary components have been associated with lung function. However, a comprehensive measure of a healthy diet has not been compared with lung function. Herein, we test the hypothesis that a healthy overall diet, as assessed by the Healthy Eating Index 2005 (HEI-2005), will be associated with increased lung function. This is an investigation using the Atherosclerosis Risk in Communities Research Materials obtained from the National Heart Lung Blood Institute. The study surveyed dietary habits of 15 567 American subjects from 4 communities in 1987 to 1990. Spirometric measures of lung function were also taken at entry to the study and a second time 3 years later. Based on food and nutritional data collected by food frequency questionnaire, an HEI-2005 score was calculated for each subject. This total score, together with its 12 components scores and associated macronutrient, was compared with lung function results by linear regression. Models were controlled for smoking behavior, demographics, and other important covariates. The HEI-2005 total scores were positively associated with forced expiratory volume in 1 second per forced vital capacity (FEV(1)/FVC) at visit 1 (β = .101 per increase in 1 quintile of HEI-2005) and visit 2 (β = .140), and FEV(1) as percentage of the predicted FEV(1) at visit 2 (β = .215) (P < .05). In addition, HEI-2005 component scores that represented high intakes of whole grains (β = .127 and .096); saturated fats (β = −.091); and solid fats, alcohol, and added sugar (β = −.109 and −.131) were significantly associated with FEV(1)/FVC at either visit 1 or visit 2. Intakes of total calories (β =−.082 at visit 1) and saturated fatty acids (β = −.085 at visit 2) were negatively associated with FEV(1)/FVC. Dietary polyunsaturated fatty acids (β = .085 and .116) and long-chain omega-3 fatty acids (β = .109 and .103), animal protein (β = .132 and .093), and dietary fiber (β = .129) were positively associated with lung health. An overall healthy diet is associated with higher lung function.

Rationale, timeline, study design, and protocol overview of the therapeutic hypothermia after pediatric cardiac arrest trials.

To describe the rationale, timeline, study design, and protocol overview of the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Multicenter randomized controlled trials. Pediatric intensive care and cardiac ICUs in the United States and Canada. Children from 48 hours to 18 years old, who have return of circulation after cardiac arrest, who meet trial eligibility criteria, and whose guardians provide written consent. Therapeutic hypothermia or therapeutic normothermia. From concept inception in 2002 until trial initiation in 2009, 7 years were required to plan and operationalize the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Two National Institute of Child Health and Human Development clinical trial planning grants (R21 and R34) supported feasibility assessment and protocol development. Two clinical research networks, Pediatric Emergency Care Applied Research Network and Collaborative Pediatric Critical Care Research Network, provided infrastructure resources. Two National Heart Lung Blood Institute U01 awards provided funding to conduct separate trials of in-hospital and out-of-hospital cardiac arrest. A pilot vanguard phase that included half the clinical sites began on March 9, 2009, and this was followed by full trial funding through 2015. Over a decade will have been required to plan, design, operationalize, and conduct the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Details described in this report, such as participation of clinical research networks and clinical trial planning grants utilization, may be of utility for individuals who are planning investigator-initiated, federally supported clinical trials.

The joint effect of cigarette smoking and polymorphisms on LRP5, LEPR, near MC4R and SH2B1 genes on metabolic syndrome susceptibility in Taiwan

Metabolic syndrome (MetS) is a combination of medical disorders, consisting of multiple, interrelated risk factors of metabolic origin. To investigate the associations of MetS with appetite-related genes (LEPR, near MC4R and SH2B1) and cholesterol metabolism-related gene (LRP5) polymorphism variants and the joint effect of cigarette smoking and these polymorphism variants on MetS in a community-based case-control study. Metabolic syndrome was defined according to the American Heart Association and National Heart Lung Blood Institute (AHA/NHLBI) criteria. A total of 237 MetS cases and 202 subjects without MetS aged 40 or over in Taiwan were analyzed. The genotypes of LRP5-rs3736228, LEPR-rs1137100, near MC4R-rs17782313 and SH2B1-rs4788102 were analyzed by the PCR-restriction fragment length polymorphism method. A strong association of the SNP rs17782313 near MC4R gene with MetS susceptibility was found. The data indicated that the C allele of near MC4R-rs17782313 is an obvious risk factor for MetS susceptibility. The joint effects of cigarette smoking and susceptible genotypes of LRP5, LEPR, near MC4R or SH2B1 genes led to a relatively higher risk of having MetS. Using subjects with the wild-type of LRP5, LEPR, near MC4R or SH2B1 genes and without a smoking habit as a reference group, those with cigarette smoking (current and former) and more than one variant type had a 4.1-fold (95 % CI = 1.6-10.2) risk of having MetS. The genotypes of the appetite-related genes (LEPR, near MC4R and SH2B1) and cholesterol metabolism-related gene (LRP5), together with a cigarette smoking habit, are important risk factors for MetS.

Metabolic syndrome and all‐cause mortality in older men and women

Prevalence of metabolic syndrome (MetS) increases with age, but its association with all-cause mortality in older persons remains uncertain. This study investigated the association of all-cause mortality with MetS and its individual components in older men and women. A total of 917 men and 1043 women aged 65 years and older from two Italian population-based cohorts were included in the study. MetS was defined according to four different definitions: National Cholesterol Education Program (NCEP), NCEP revised according to the American Heart Association and National Heart Lung Blood Institute (NCEP-R), International Diabetes Organization (IDF) and Joint Interim Statement (JIS). All of these definitions include abdominal obesity, hyperglycaemia, hypertriglyceridaemia, low high-density lipoprotein cholesterol and hypertension. Hazard Ratios (HR) and their corresponding 95% confidence interval (95%CI) estimated from multivariable-adjusted Cox regression models were used to investigate the associations of all-cause mortality with baseline MetS status and individual MetS components. After 6·5 ± 1·8 years of follow-up, there were 179 deaths among women and 193 among men. Mortality risk was increased in women with MetS by any definition, regardless of individual components, but limited to age 70-79 years (NCEP, HR = 2·02, 95%CI, 1·16-3·53; NCEP-R, HR = 2·51, 95%CI, 1·45-4·34; IDF, HR = 2·16, 95%CI, 1·26-3·72; JIS, HR = 2·16, 95%CI, 1·26-3·72). Mortality risk of men was associated with hypertriglyceridaemia below age 70 years (HR = 2·50, 95%CI, 1·19-5·25), but unrelated to MetS status. Metabolic Syndrome is associated with all-cause mortality in older women but not in men. The association, however, is limited to a narrow age range.

Approaches to investigating common bleeding disorders: An evaluation of North American coagulation laboratory practices

Bleeding disorders commonly result from deficiencies or defects in von Willebrand factor (VWF), platelets, coagulation factors, or fibrinolytic proteins. The primary goal of our study was to assess current North American coagulation laboratory practices for diagnosing bleeding disorders, using an on-line patterns-of-practice survey of diagnostic laboratory members of the North American Specialized Coagulation Laboratory Association. The survey examined laboratory approaches to evaluating bleeding disorders, with specific questions about the tests and test panels offered and compliance to recent guideline recommendations on diagnosing von Willebrand disease (VWD) and platelet function disorders. All laboratories responding to the survey performed a prothrombin time/international normalized ratio, an activated partial thromboplastin time, and coagulation factor assays, and many tested for VWD and platelet disorders. However, few laboratories had test panels that evaluated the more common bleeding disorders and few performed some assays, including VWF multimer assessments and assays for fibrinolytic disorders. Additionally, the cutoffs used by laboratories to diagnose type 1 VWD varied considerably, with only a minority following the National Heart Lung Blood Institute recommendations. In contrast, laboratories that tested for platelet function disorders mostly complied with aggregation testing recommendations, as published in the recent North American guidelines. Our results indicate that there are some gaps in the strategies used by laboratories to diagnose bleeding disorders that might be addressed by development of further guidelines and test algorithms that emphasize evaluations for common bleeding disorders. Laboratories may also benefit from guidelines on test interpretation, and external evaluation of their bleeding disorder testing strategies.

Shipping of therapeutic somatic cell products.

Shipment of therapeutic somatic cells between a current good manufacturing practice (cGMP) facility and a clinic or between different cGMP facilities requires validated standard operating procedures (SOP). Under National Heart Lung & Blood Institute (NHLBI) sponsorship, the Production Assistance for Cellular Therapies (PACT) group conducted a validation study for the shipping SOP it has created, including shipments of cryopreserved somatic cells, fresh peripheral blood specimens and apheresis products. Comparisons of pre- and post-shipped cells and cell products at the three participating facilities included measurements of viability, phenotypic profiles and cellular functions. The data were analyzed at the University of Pittsburgh Biostatistics Facility. No consistent shipping effects on cell viability, phenotype or functions were detected for cryopreserved and shipped peripheral blood mononuclear cells (PBMC), monocytes, immature dendritic cells (iDC), NK-92 or cytotoxic T cells (CTL). Cryopreserved mesenchymal stromal cells (MSC) had a significantly decreased viability after shipment, but this effect was in part because of inter-laboratory variability in the viable cell counts. Shipments of fresh peripheral blood and apheresis products for the generation of CTL and dendritic cells (DC), respectively, had no significant effects on cell product quality. MSC were successfully generated from fresh bone marrow samples shipped overnight. This validation study provides a useful set of data for guiding shipments of therapeutic somatic cells in multi-institutional clinical trials.

Emergency Room Utilization by California Sickle Cell Patients During Pediatric to Adult Care Transition

AbstractAbstract 254Clinical experience and research with sickle cell patients and those with other genetic diseases suggests that the period of “transition,” in which patients move from pediatric care to adult-centered clinical care, is a period of high health services utilization. Young adult patients may not have learned to effectively manage disease symptoms and may not be connected to a “medical home” or have established a relationship with a primary care physician or adult hematologist. Further, these patients may not have insurance coverage previously provided by parents or by public pediatric insurance programs.As part of a collaborative agreement through the Centers for Disease Control and Prevention (CDC) and the National Heart, Lung & Blood Institute (NHLBI), California and five other states are conducting epidemiologic surveillance to determine the prevalence of hemoglobinopathies as well as health services utilization. Such data are essential to inform allocation of resources to meet the medical and social service needs of patients. Within the state, this project is a collaborative effort among the CA Dept. of Public Health Genetic Disease Screening Program, Children's Hospital Los Angeles and Children's Hospital & Research Center Oakland. Using administrative data obtained as a part of this effort, we describe emergency room (ER) utilization patterns among young adults with sickle cell disease.The CA Office of Statewide Health Planning and Development has collected data on ER utilization for the years 2005 – 2008. Using ICD 9 codes beginning with 282.6 to identify sickle cell-related ER visits during those years, we report usage patterns by patient age, gender, and payer type. To calculate risk of repeat ER visits, we used a negative binomial regression model (with 1 visit as the baseline for analysis, rather than 0 visits, due to the limitations of the data set). The following means and counts are adjusted to account for this shift. Analyses were conducted using SAS 9.1.The mean number of ER visits among sickle cell patients in the data set was 3.36 per year and 54% of visits were made by women, but gender differences in average visits per year per patient (3.18 female, 3.60 male) were not statistically significant. Medi-Cal (Medicaid) was the primary payer for 47% of visits during this time frame, and patients with Medi-Cal averaged nearly one additional visit per year (3.82 visits) compared to patients with other forms of payment (3.04 visits). Among patients seen at any time during the four years and controlling for gender and payer type, we found a 78% increase (IRR 1.78, 95% CI 1.59, 2.00) in risk of visiting the ER a second or subsequent time in a given year among the 20 to 30 year old group compared to all other age groups, a four fold increase (IRR 4.22, 95% CI 3.61, 4.93) in risk of a second or subsequent visit in a year compared to the group aged 10 to 20 years, and a 30% increase (IRR 1.34, 95% CI 1.16, 1.55) compared to the group 30 to 40 years of age. Average number of visits in the transition age group was 4.53 per year, compared to 1.93 per year in the 10 to 20y group and 3.56 in the 30 to 40y age group. The number of individuals visiting the ER per year was higher in this age group compared to the two adjoining age groups (520 individuals on average per year for 20 – 30y, vs. 311 per year for 10 – 20y and 355 for 30 to 40y). The increase in visits per year of age can be seen (Figure 1) to begin at age 18 or 19 and continue to approximately age 30. The proportion of patients with no insurance coverage increased from 8% in the 10 to 20y age category to 19% of patients in the 20 to 30y age category, and remains high for the subsequent age categories (11 to 17%).The transition period from pediatric care to adult care in California sickle cell patients is marked by a dramatic increase in emergency room visits (both more patients visiting and more visits per patient) compared to other age groups. ERs are also visited significantly more often by uninsured sickle cell patients in this age group than other age groups. Patients in this age group would likely benefit from access to a medical home model of care. [Display omitted] Disclosures:Coates:Novartis: Research Funding, Speakers Bureau.

Characterization of Microrna Expression Profile In Platelets In Sickle Cell Disease

AbstractAbstract 2030Sickle cell disease (SCD) is associated with a high rate of thromboembolic complications, particularly in patients with advanced vasculopathy. Recent functional studies have revealed pathological platelet activation associated with intravascular hemolysis, the severity of pulmonary hypertension (PAH), and impaired NO-signaling in platelets mediated by NO scavenging by plasma hemoglobin (Villagra J et al, Blood 2007; Hu W et al, Blood 2010, prepublished online). In addition, our previous amplified platelet transcriptome studies in SCD patients have demonstrated dysregulated arginine and polyamine metabolism, potentially contributing to this dysfunction at the transcriptional level (Raghavachari N et al, Circulation 2007). New RNA technologies for purification of total RNA including small RNAs now allow for more refined study of transcriptional events in platelets from individual patients. We have undertaken the present study to demonstrate and validate the presence and differential expression of microRNAs (miRNAs) in platelets from patients with SCD compared with African American control subjects. We hypothesize that posttranscriptional regulation of the platelet function by miRNAs is an important contributor to SCD pathogenesis associated with pathological platelet activation. To date, there have been no studies undertaken to study the role of platelet miRNAs in SCD. Platelet rich plasma samples from 43 subjects were obtained from University of Pittsburgh Medical Center (UPMC) and National Heart, Lung, Blood Institute (NHLBI). Out of these there were 27 SCD patients and 17 were sex-, race- matched healthy controls. Out of the SCD patients, 18 were known to have PAH and 14 were on hydroxyurea (HU) at the time of study enrollment. Total platelet RNA including miRNAs were extracted using the miRNeasy Minikit (Qiagen, Valencia, CA) with yield in the range of 110–1875 ng from 16 ml of whole blood per donor. We hybridized these samples on a miRNA microarray platform (Agilent version 3) containing 866 human miRNAs. The array data was normalized using quantile normalization and were analyzed with GeneSpring GX 11 software. Differential expression profiles between sickle cell disease patients and controls were determined separately for the NHLBI and UPMC cohort to detect a greater than 2 fold difference change in miRNA expression at p-value of 0.05. Our final expression list included only common miRNAs identified in both cohorts, allowing for an additional level of validation. Final validation was performed by RT-PCR of a subset of the differentially expressed miRNAs. Our analysis identified 42 significantly differentially expressed miRNAs in platelets when comparing the SCD with the control groups, at a fold-change > 2 and p-value <0.05. Out of these there were 18 up- and 24 down-regulated miRNAs. Interestingly, within the SCD group, there were 14 differentially expressed miRNAs between the subjects on HU and those off HU and 23 differentially expressed miRNAs between subjects with and without PAH. Further confirmation of relative expression of downregulated miR-376a and miR409-3p along with upregulated 1225-3p was conducted by real-time PCR. Computational analysis revealed that predicted targets of these 3 miRNAs belong to the regulation of transcription, transcription factor activity and regulation of RNA metabolic process Gene Ontology (GO) annotations. These results are currently being directly tested by evaluating the effect of perturbing mir-376, mir 409-3pand mir-1225-3p on platelet activation, differentiation and budding. The results will be updated at the meeting. The present study confirms the existence of rplatelet miRNAs, their differential expression in SCD and lays down the foundations to study their role in the molecular pathogenesis of SCD. Future evaluation of miRNA-target mRNA interactions will provide an experimental framework for the study of disease-specific platelet biology and potentially identify biomarkers for predicting patients at high risk of developing vasculopathy. Disclosures:No relevant conflicts of interest to declare.