bluuebunny/crossref_metadata_2025 huggingface dataset:
THE ACCURACY OF EXISTING PRE-HOSPITAL TRIAGE TOOLS FOR INJURED CHILDREN IN ENGLAND–AN ANALYSIS USING TRAUMA REGISTRY AND EMERGENCY DEPARTMENT DATA
Authors: Cheung R , Ardolino A , Lawrence T , Bouamra O , Lecky F E , Berry K , Chaudhury A , Issa S , Koralage N , Lyttle M D , Maconochie I K
Published: September 2013

Objectives & Background

Pre-hospital triage is becoming increasingly important as Regional Trauma Networks for children are implemented in England. The low incidence of trauma in children makes pre-hospital assessment of injury severity and where to send an injured child challenging. Currently there are few validated pre-hospital triage tools for children's trauma and no consensus on which to use. We investigate performance characteristics of pre-hospital paediatric triage tools currently in use in England for identifying injured children.

Methods

We identified a total of eight pre-hospital paediatric triage tools (six in current usage in England). Each tool was interrogated using 701 retrospective clinical episodes from the Trauma Audit and Research Network (TARN–representing severely injured children) and from 2934 patient records in four English Emergency Departments (representing moderate to minor injuries). Target rates for under– and over-triage were set as <5% and <25–50% respectively.

Results

From TARN data, two triage tools demonstrated acceptable under-triage rates (3% and 4%) for severe injuries but unacceptable over-triage of moderate injuries (83% and 72%). Two tools demonstrated acceptable over-triage (7% and 16%) with unacceptable under-triage (61% and 63%). Four tools demonstrated unacceptable under- and over-triage.

For moderate and minor injuries, three tools demonstrated acceptable under- and over-triage rates (all 0%). The other five tools had unacceptable under-triage rates (25–100%). All eight tools had acceptable over-triage rates (1%–21%). (See tables 1 and 2)

Abstract 004 Table 1

Performance characteristics of pre-hospital paediatric trauma triage tools–TARN/severe injuries

ToolnISS>15Undertriage rate (%)Overtriage rate (%)East Midlands701230383London472North West780Northern977South West London; Surrey1259Wessex3923Paediatric Trauma Score617Paediatric Triage Tape283946316Abstract 004 Table 2

Performance characteristics of pre-hospital paediatric trauma triage tools–Moderate/minor injuries

ToolnISS>15Undertriage (%)Overtriage (%)East Midlands29344018London2511North West021Northern019South West London; Surrey509Wessex507Paediatric Trauma Score1001Paediatric Triage Tape18114753

Conclusion

For severe injuries, none of the pre-hospital triage tools for injured children currently used in England meet recommended criteria for over- and under-triage rates. For moderate to minor injuries, all tools achieved acceptable over-triage rates but tended to under-triage. There is an urgent need for development of triage tools to accurately risk-stratify injured children in the pre-hospital setting.
REDUCING ADVERSE EFFECTS FROM INTRAVENOUS N-ACETYLECYSTEINE TREATMENT OF PARACETOMOL POISONING: PRINCIPAL RESULTS OF THE SCOTTISH AND NEWCASTLE ANTEMETIC ORE_TREATMENT FOR PARACETAMOL POISONING (SNAP) RANDOMISED CONTROLLED TRIAL
Authors: Gray A , Dear J , Thanacoody R , Thomas S , Eddleston M , Sandilands E , Coyle J , Cooper J , Rodriguez A , Butcher I , Lewis S , Vliegenthart A , Veiraiah A , Webb D , Bateman N
Published: September 2013

Objectives & Background

Paracetamol poisoning is common worldwide. Standard intravenous N-acetylcysteine (NAC) therapy is complex, and commonly associated with concentration-related adverse effects and the potential for administration errors. We aimed to determine whether adverse effect incidence could be reduced by antiemetic pre-treatment and/or a simpler and shorter intravenous N-acetylcysteine regimen.

Methods

We delivered, in 3 centres, a randomised factorial trial comparing a modified 12 h (100 mg/kg over 2 h, 200 mg/kg over 10 h) with a standard 20.25 h NAC regimen (150 mg/kg 15 min, 50 mg/kg 4 h, 100 mg/kg 16 h) with and without pre-treatment with ondansetron (4 mg IV). The primary endpoint was absence of retching, vomiting or need for rescue antiemetic at 2 h; secondary endpoints included the incidence of anaphylactoid reactions, the need for medication or treatment interruption, and hepatic toxicity (ALT, INR).

Results

In 217 participants, retching and vomiting were less common with ondansetron than placebo (OR 0.406, 97.5% CI 0.205–0.803, p=0.0031) and with the modified compared to the conventional acetylcysteine regimen (OR 0.260, 97.5% CI 0.130–0.518, p<0.0001). Frequency of anaphylactoid reactions was not affected by ondansetron, but less common with modified acetylcysteine; severe reactions 5/108 (4.6%) vs. 31/100 (31%) (p<0.0001). The proportion of patients with a 50% increase in ALT was not significantly different comparing conventional with modified regimens (OR 0.603, 97.5% CI 0.199–1.831), but more common with ondansetron than placebo (OR 3.295, 97.5% CI 1.013–10.723, p=0.0235).

Conclusion

In patients with paracetamol poisoning requiring acetylcysteine, adverse effects were substantially reduced by ondansetron pre-treatment and by using a modified, shorter treatment regimen. Ondansetron, but not the modified regimen, increased the frequency of liver function abnormalities. If large effectiveness studies confirm the modified regimen is non-inferior to conventional then shorter and safer treatment would be possible for this common poisoning.
TOPICAL LIGNOCAINE TO IMPROVE ORAL INTAKE IN CHILDREN WITH PAINFUL INFECTIOUS MOUTH ULCERS: A BLINDED RANDOMISED PLACEBO-CONTROLLED TRIAL
Authors: Hopper S , Tancharoen C , McCarthy M , Lee K J , Davidson A , Babl F
Published: September 2013

Objectives & Background

To establish the efficacy of 2% viscous lignocaine in increasing oral intake in children with painful infectious mouth conditions compared with placebo.

Methods

Randomised placebo–controlled trial of viscous lignocaine versus placebo at a single paediatric emergency department. Study staff, clinicians, nurses, care givers, and participants were blinded to the group assignment. Children with acute infectious ulcerative mouth conditions (gingivostomatitis, ulcerative pharyngitis or hand foot and mouth disease), and poor oral fluid intake were randomised to receive 0.15 ml/kg of either 2% viscous lignocaine or placebo with identical appearance and flavor. The primary outcome was the amount of fluid ingested in the 60 minutes following administration of the intervention. Secondary outcomes were specific ml/kg fluid targets and the incidence of adverse events.

Results

100 participants were recruited (50 per treatment group) all of whom completed the 60 minute fluid trial period. Oral intake one hour after drug administration was similar in both groups: lignocaine–mean (standard deviation) 9.48 ml/kg (7.02 ml/kg) vs. placebo 9.32 ml/kg (7.39 ml/kg); mean difference 0.15 ml/kg (95% confidence interval –2.7 ml/kg to 3.0 ml/kg; p=0.9). No evidence for difference between groups was found in secondary outcomes and there were no adverse events in either group.

Conclusion

Viscous lignocaine is no better than a flavoured gel placebo in improving oral intake in children with painful infectious mouth ulcers.
Mental health status and gender as risk factors for onset of physical illness over 10 years
Authors: Matheson Flora I , Smith Katherine L W , Moineddin Rahim , Dunn James R , Glazier Richard H
Published: September 2013

Background

There is a growing interest in understanding the connection between mental illness (MI) and the onset of new physical illnesses among previously physically healthy individuals. Yet the role of gender is often forgotten in research focused on comorbidity of health problems. The objective of this study was to examine gender differences in the onset of physical illness in a cohort of respondents who met criteria for MI compared with a control cohort without mental health problems.

Methods

This cohort study, conducted in Ontario, Canada, used a unique linked dataset with information from the 2000–2001 Canadian Community Health Survey and medical records (n=15 902). We used adjusted Cox proportional survival analysis to examine risk of onset of four physical health problems (chronic obstructive pulmonary disorder, asthma, hypertension and diabetes) for those with and without baseline MI across a 10-year period (2002–2011) among respondents aged 18–74 years. We controlled for socioeconomic and health indicators associated with health.

Results

The incidence of physical illness in the MI cohort was 28.5% among women and 29.9% among men (p=0.85) relative to controls (23.8% and 24%, respectively; p=0.48). Women in the MI cohort developed secondary physical health problems a year earlier than their male counterparts (p=0.002). Findings from the Cox proportional survival regression showed that women were at 14% reduced risk of developing physical illness, meaning that men were more disadvantaged (HR=0.89, CI 0.80 to 0.98). Those in the MI cohort were at 10 times greater risk of developing a secondary physical illness over the 10-year period (HR=1.10, CI 0.98 to 1.21). There was no significant interaction between gender and MI cohort (HR=1.05, CI 0.85 to 1.27).

Conclusions

Policy and clinical practice have to be sensitive to these complex-needs patients. Gender-specific treatment and prevention practices can be developed to target those at higher risk of multiple health conditions.
THE REGRESSION DISCONTINUITY DESIGN: A NOVEL APPROACH TO ASSESSING THE REAL-WORLD EFFECTIVENESS OF HUMAN PAPILLOMAVIRUS (HPV) VACCINATION ON ANOGENITAL WARTS
Authors: Smith Leah , Strumpf Erin , Levesque Linda , Kaufman Jay
Published: September 2013

Background

The human papillomavirus (HPV) vaccine and corresponding vaccination programs have been in Canada for over six years, yet there is no information on their effectiveness in reducing anogenital warts.

Objectives

To assess the effect of the HPV vaccine (vaccine impact) and Ontario's Grade 8 HPV vaccination program (program impact) on anogenital warts using the Regression Discontinuity Design (RDD; a quasi-experimental, instrumental variable-based technique used to assess the causal effects of policy interventions).

Methods

By linking Ontario's 36 immunization databases with provincial health records, we will identify a population-based cohort of all girls in Grade 8 in 2003/04-2008/09. Girls will be followed from September 1 of Grade 8 until August 31 of Grade 11. Exposure will be categorized based on HPV vaccine program eligibility (2003/04-2006/07 vs. 2007/08-2008/09) and actual vaccine receipt (0-2 vs. 3 doses). Outcomes will be identified based on a new diagnosis of and treatment for anogenital warts. For the RDD analysis, a continuous instrument will be created using birth month and year, where December 1993 (end of ineligible birth cohort) and January 1994 (start of eligible birth cohort) define the program eligibility cut-off. To estimate the program impact, local linear regression will be employed at the cut-off; here, exposure will be based on program eligibility (intention-to-treat). To estimate vaccine impact, we will use two-stage local linear regression, which will account for actual vaccination status. Several strategies will be used to test and minimize potential confounding bias – e.g., comparison of baseline characteristics, use of triangular kernel, optimal bandwidth selection.

Results

Based on preliminary data (21 immunization databases), we identified a cohort of 155,999 ineligible and 75,508 eligible girls (N=231,507). Eligibility cohorts were similar across factors like age, urban/rural status, and vaccination history, suggesting they are balanced on factors other than program exposure. A graph of the probability of vaccination by instrument confirmed two additional RDD assumptions – there was discontinuity in exposure at the cut-off (4.6% vs. 45.8%) and no discontinuities at locations other than the cut-off.

Conclusions

Preliminary results confirm the RDD is appropriate for use in this context. Complete, provincial-level results will be available by June 2013.
VALIDATION OF STANDARDIZATION METHODOLOGY TO MINIMIZE MEASUREMENT BIAS DUE TO SYSTEMATIC ACCELEROMETER WEAR-TIME VARIATION IN PRESCHOOLERS, ADOLESCENTS, AND ADULTS
Authors: Katapally Tarun , Froehlich-Chow Amanda , Leis Anne , Humbert Louise , Muhajarine Nazeem
Published: September 2013

Introduction

Increasingly, physical activity (PA) and sedentary behaviour (SED) are independently being associated with physical, mental and emotional well-being. The heightened research interest in this area has resulted in an upsurge of accelerometer usage to objectively quantify PA and SED. However, these epidemiological investigations consistently ignore systematic variation in the number of hours participants wear accelerometers each day (i.e., systematic accelerometer wear-time variation), and this has a direct impact on measured activity.

Objectives

Using three different cohorts (3–5 years ─ N=83; 10-14years ─ N=455; and 18 years and older ─ N=21), this study aims to validate a standardization methodology to minimize measurement bias due to accelerometer wear-time variation.

Methods

In epidemiological studies, accelerometry is generally conducted over seven consecutive days, and participants' data are considered 'valid' only if wear-time is at least 10 hours/day. However, there could be systematic wear-time variation even within 'valid' data. To explore this variation, accelerometer data from two studies set in Saskatoon, Saskatchewan were analyzed: Smart Cities, Healthy Kids (smartcitieshealthykids.com) and Healthy Start (http://www.canadainmotion.ca/healthy_start/). Subsequently, a standardization method was developed where case-specific observed wear-time was controlled for using an ‘analyst specified’ time period. Next, case-specific accelerometer data were interpolated to this controlled wear-time to produce standardized variables. To understand discrepancies owing to wear-time variation, identical analyses were conducted with data from all three cohorts both pre- and post-standardization. The results of these identical analyses were compared to objectively validate the standardization methodology.

Results

In all three cohorts, descriptive analyses revealed systematic wear-time variation between participants. Again, in all three cohorts, pre- and post-standardized analyses of the three outcome variables (SED, light physical activity and moderate vigorous physical activity) that cover the whole range of human activities revealed an identical and often significant trend of wear-time's influence on activity. For instance, SED which was consistently higher during weekdays pre-standardization, proved to be higher during weekends post-standardization.

Conclusions

Analyzing accelerometer data without standardizing wear-time will cause biased results and erroneous conclusions. Standardizing accelerometer data using the above mentioned methodology produces stable variables and a uniform platform to compare results between studies, irrespective of the studies' sample size or age characteristics.
LIFECOURSE ANALYSIS OF MANUAL OCCUPATIONS AND RISK OF PROSTATE CANCER IN MONTREAL, CANADA: A CASE-CONTROL STUDY
Authors: Blaser Christine , Nicolau Belinda , Parent Marie-Élise
Published: September 2013

Introduction

Cancer risk factors accumulate over time or affect the body at specific moments of development. Our lifecourse approach identified occupational exposures and social determinants of health associated with the risk of prostate cancer across a lifetime.

Objectives

To assess the risk of prostate cancer among men employed in manual occupations compared to the risk of those in non-manual occupations. Using three time points of exposure, we tested the accumulation, critical period and trajectory models.

Methods

Histologically-confirmed prostate cancer cases (n=1229), aged 40 to 75, were identified across 11 French hospitals in Montreal. Population controls (n=1307) were identified from the French provincial electoral list in the same areas of residence as the cases, and frequency-matched to cases by age (± 5 years). Information on socio-demographic, lifestyle characteristics, and detailed occupational history, was collected through face-to-face interviews. Using the British Registrar General's classification of occupations, jobs held at age 25 and 55, and father's occupation at birth, were categorised as manual or non-manual. Logistic regression models were applied.

Results

Men with exposure to manual occupations at the three time points were more likely to have had an unfavourable financial situation during childhood, a lower education level and a lower family income at diagnosis or interview. Based on the accumulation model, men who held only manual occupations were at 23% excess risk of prostate cancer [OR=1.23, 95%CI 1.00–1.51] compared to those who did not after controlling for other socioeconomic factors. Using the trajectory model, a decreased risk of prostate cancer [OR=0.79, 95%CI 0.59–1.05] was observed among men moving from manual to non-manual occupations during adulthood. The critical period model did not identify any risk differences when exposures occurred specifically at one of the three time points.

Conclusion

Although life-course models are difficult to disentangle, the observed associations between manual occupations and prostate cancer risk are consistent with both accumulation and trajectory models. Highest risks were observed with prolonged exposure to manual occupations. Conversely, moving from manual to non-manual occupations appeared to be protective against prostate cancer.
PREDICTING THE OCCURRENCE OF MAJOR ADVERSE CARDIAC EVENTS WITHIN 30 DAYS AFTER A PATIENT'S VASCULAR SURGERY: AN INDIVIDUAL PATIENT-DATA META-ANALYSIS
Authors: Vanniyasingam Thuvaraha , Thabane Lehana , Rodseth Reitze , Buse Giovana A. Lurati , Bolliger Daniel , Daniel Christoph S. , Cuthbertson Brian H. , Gibson Simon C. , Mahla Elisabeth , Leibowitz David W. , Biccard Bruce
Published: September 2013

Introduction

Major adverse cardiac events (MACE) – which include cardiac death and non-fatal myocardial infarction – are severe harmful outcomes that commonly arise after elective non-cardiac vascular surgeries. Current preoperative risk prediction models are not as effective in predicting post-operative outcomes. This talk will discuss the key results of an individual patient-data meta-analysis, based on data from six cohort studies of patients undergoing vascular surgery.

Objectives

We aimed to determine a prediction model that dichotomizes patients into high and low risk categories of MACE within 30 days after noncardiac vascular surgery.

Approach

This is an application of the minimum p-value method (MPM) to determine the optimal cut-off points for: (i) B-type naturietic peptide (BNP) and (ii) N-terminal pro B-type natriuretic peptide (NTproBNP) in predicting MACE within 30 days after non-cardiac vascular surgery. Elevated concentrations of these hormones are secreted into the blood in response to heart failure. We compare results from MPM with those based on the receiver operating characteristic (ROC) curve approach using logistic regression; develop and validate the prediction rule for MACE; and assess the robustness of the results under different statistical models.

Results

The ROC curve approach (applied by Rodseth and colleagues) identified 116pg/mL and 277.5pg/mL as the optimal thresholds for BNP and NTproBNP, respectively. The minimum p-value method dichotomized these covariates as BNP: 115.57pg/mL (p<0.0001) and NTproBNP: 241.7pg/mL (p=0.0001). Our logistic regression analysis identified MINP_thrshld, the indicator variable of our MPM results for BNP and NTproBNP, as a stronger covariate than our ROC curve results. Our final prediction model contained variables MINP_thrshld, the type of surgery, and diabetes mellitus. Internal validation was performed using bootstrapping while mixed effects logistic regression and generalized estimating equations were performed for sensitivity analysis. Although our model was validated using 1000 samples, it was not robust against methods that accounted for clustering effects.

Conclusion

As current preoperative risk stratification models are not as effective in predicting post-operative outcomes for vascular surgery patients, clinicians are at an advantage in using this model for the ease and accuracy that it provides. Further exploration into clustering effects is needed for determining the best model.
ASSOCIATION OF C-REACTIVE PROTEIN WITH METABOLIC SYNDROME AND DEPRESSIVE SYMPTOMS IN THE ENGLISH LONGITUDINAL STUDY OF AGEING
Authors: Au Bonnie , Schmitz Norbert
Published: September 2013

Introduction

The metabolic syndrome is a cluster of risk factors comprised of elevated fasting plasma glucose and insulin resistance, central obesity, low levels of high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension. Depression is a common co-morbidity in individuals with metabolic syndrome. Inflammatory mechanisms have been suggested to be involved in depression and metabolic syndrome. C-reactive protein (CRP), an acute-phase reactant of systemic inflammation, has been found to be independently associated with metabolic syndrome and depression.

Objectives

To assess the association between C-reactive protein with metabolic syndrome and depressive symptoms in a representative sample of British people aged 50 years and above.

Methods

Participants were 8398 men and women from the English Longitudinal Study of Ageing(ELSA), a prospective study of community-dwelling older adults. Associations between CRP with metabolic syndrome and depressive symptoms were examined using stratified multivariate logistic regression adjusted for age, smoking, physical activity, and alcohol consumption. Metabolic syndrome was based on the new worldwide definition by the International Diabetes Federation (IDF). Elevated depressive symptoms was based on a score >=4 using the 8-item Center for Epidemiologic Studies Depression Scale (CES-D) scale.

Results

The prevalence of having both metabolic syndrome and elevated depressive symptom was 27.5%. Preliminary results indicate that high CRP levels is associated with elevated depressive symptoms in individuals without metabolic syndrome (adjusted OR: 2.23, 95% CI: 1.65-3.02), but not in individuals with metabolic syndrome. High CRP levels is associated with metabolic syndrome in individuals with elevated depressive symptoms (adjusted OR: 3.41, 95% CI: 2.48-4.69) as well as in individuals without elevated depressive symptoms (adjusted OR: 3.46, 95% CI: 2.37-5.05).

Conclusions

Metabolic syndrome and depressive symptoms are independently related to CRP. A better understanding using longitudinal data will help assess whether inflammation is a determinant of depressive symptoms in individuals with metabolic syndrome.
ANTIBIOTIC STEWARDSHIP PROGRAM; CONTEXTUAL ENVIRONMENT AND FRAMEWORK
Authors: Al-Khatib Naser , Cholin Brenda , Moraros John
Published: September 2013

Introduction

Antibiotic Stewardship is currently an important topic in Public Health, Hospital Epidemiology and Infectious Disease Epidemiology. Designing, implementing and evaluating an Antibiotic Stewardship Program (ASP) is mandates by accreditation agencies. Prairie North Regional Health Authority (PNRHA)- Saskatchewan assigned me to collect and analyse quantitatively and qualitatively - data related to antibiotic prescription habits of physicians in three hospitals and community clinics.

Objectives

1- to review the literature on antibiotic Stewardship and its programs 2- to understand the local antibiotics prescribing environment (using one 2010 data) 3- to design an Antibiotic Stewardship Program for the PNRHA

Methods

Data collection by direct key stakeholders interviews, using hospital pharmacy, the lab and admission information systems. Community data were sourced from Saskatchewan Drug Plan administration - Using Excel and SPSS for data management, and biostatistics (parametric, non-parametric and variance analysis) - Using results for evidence based design of an Antibiotic Stewardship Program

Results

The detailed descriptive statistics were very helpful to draw a baseline. These descriptive statistics shed the light on usage of 33 antibiotics in three different hospitals. These results were categorized based on specialty, main groups of antibiotics, per doctor, per antibiotic, per DOT (Duration of Therapy) and DOT per 1000 patient-day.

Conclusions

There were recommendations on how to adopt the Antibiotic Stewardship and the suggested framework, as well as recommendations about data collection, analysis and measurements for future implementation of the Program. Specific steps were encouraged based on the exact results of specific antibiotics such as flouroquinolones, clindamycin, vancomycin and IV administration and conversion to oral antibiotics
FETAL ALCOHOL SPECTRUM DISORDER: COST OF SCREENING AND DIAGNOSIS IN CANADA
Authors: Lange Shannon , Burd Larry , Chudley Albert E. , Clarren Sterling K. , Rehm Jürgen , Popova Svetlana
Published: September 2013

Introductions

Prenatal alcohol exposure can lead to a myriad of adverse health outcomes for the child, including Fetal Alcohol Spectrum Disorder (FASD). Unfortunately, for a number of reasons, FASD is underdiagnosed in many countries, including Canada. The diagnosis of FASD is not simple and is a time consuming process that should be done via a comprehensive, multidisciplinary assessment of the individual.

Objectives

To estimate the per person and the annual cost of FASD screening diagnostic services in Canada.

Methods

The breakdown of the diagnostic process was based on the Fetal Alcohol Spectrum Disorder: Canadian Guidelines for Diagnosis. In order to calculate the per person cost of diagnosis, the number of hours required by each specialist involved in the diagnostic process were estimated, and the average rate per hour for each specialist was applied to the respective number of hours needed. The existing clinical capacity of all FASD multidisciplinary clinics in Canada, obtained from the 2005 and 2011 surveys conducted by the Canada Northwest FASD Research Network, was used to estimate the number of FASD cases diagnosed per year in Canada. The per person cost of FASD diagnosis was applied to the total number of FASD cases diagnosed per year in order to calculate the annual cost of FASD diagnostic services in Canada.

Results

It was estimated that a comprehensive, multidisciplinary FASD assessment requires 32 to 47 hours, resulting in a total cost of $3,110 to $4,570 per person. Based on a clinical capacity of 2,288 in Canada per year, and assuming that 50% (lower estimate) to 70% (upper estimate) of all individuals evaluated are diagnosed with FASD, it was calculated that 1,602 to 1,144 cases of FASD are diagnosed per year in Canada. As such, it was estimated that the cost of all FASD screening and diagnostic services in Canada ranges from $3.6 to $5.2 million (lower estimate), up to $5.0 to $7.3 million (upper estimate) per year.

Conclusions

Cost of FASD screening and diagnostic services is high in Canada. However, this economic burden is largely avoidable given that FASD is preventable if effective policies are implemented.
Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload
Authors: Gladden James D. , Zelickson Blake R. , Guichard Jason L. , Ahmed Mustafa I. , Yancey Danielle M. , Ballinger Scott , Shanmugam Mayilvahanan , Babu Gopal J. , Johnson Michelle S. , Darley-Usmar Victor , Dell'Italia Louis J.
Published: September 2013

Xanthine oxidase (XO) is increased in human and rat left ventricular (LV) myocytes with volume overload (VO) of mitral regurgitation and aortocaval fistula (ACF). In the setting of increased ATP demand, XO-mediated ROS can decrease mitochondrial respiration and contractile function. Thus, we tested the hypothesis that XO inhibition improves cardiomyocyte bioenergetics and LV function in chronic ACF in the rat. Sprague-Dawley rats were randomized to either sham or ACF ± allopurinol (100 mg·kg−1·day−1, n ≥7 rats/group). Echocardiography at 8 wk demonstrated a similar 37% increase in LV end-diastolic dimension ( P < 0.001), a twofold increase in LV end-diastolic pressure/wall stress ( P < 0.05), and a twofold increase in lung weight ( P < 0.05) in treated and untreated ACF groups versus the sham group. LV ejection fraction, velocity of circumferential shortening, maximal systolic elastance, and contractile efficiency were significantly depressed in ACF and significantly improved in ACF + allopurinol rats, all of which occurred in the absence of changes in the maximum O2consumption rate measured in isolated cardiomyocytes using the extracellular flux analyzer. However, the improvement in contractile function is not paralleled by any attenuation in LV dilatation, LV end-diastolic pressure/wall stress, and lung weight. In conclusion, allopurinol improves LV contractile function and efficiency possibly by diminishing the known XO-mediated ROS effects on myofilament Ca2+sensitivity. However, LV remodeling and diastolic properties are not improved, which may explain the failure of XO inhibition to improve symptoms and hospitalizations in patients with severe heart failure.
Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias
Authors: McCully Belinda H. , Hasan Wohaib , Streiff Cole T. , Houle Jennifer C. , Woodward William R. , Giraud George D. , Brooks Virginia L. , Habecker Beth A.
Published: September 2013

Obesity increases the risk of arrhythmias and sudden cardiac death, but the mechanisms are unknown. This study tested the hypothesis that obesity-induced cardiac sympathetic outgrowth and hyperinnervation promotes the development of arrhythmic events. Male Sprague-Dawley rats (250–275 g), fed a high-fat diet (33% kcal/fat), diverged into obesity-resistant (OR) and obesity-prone (OP) groups and were compared with rats fed normal chow (13% kcal/fat; CON). In vitro experiments showed that both OR and OP rats exhibited hyperinnervation of the heart and high sympathetic outgrowth compared with CON rats, even though OR rats are not obese. Despite the hyperinnervation and outgrowth, we showed that, in vivo, OR rats were less susceptible to arrhythmic events after an intravenous epinephrine challenge compared with OP rats. On examining total and stimulus-evoked neurotransmitter levels in an ex vivo system, we demonstrate that atrial acetylcholine content and release were attenuated in OP compared with OR and CON groups. OP rats also expressed elevated atrial norepinephrine content, while norepinephrine release was suppressed. These findings suggest that the consumption of a high-fat diet, even in the absence of overt obesity, stimulates sympathetic outgrowth and hyperinnervation of the heart. However, normalized cardiac parasympathetic nervous system control may protect the heart from arrhythmic events.
COX-1-derived PGE2and PGE2type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca2+influx in the subfornical organ
Authors: Wang Gang , Sarkar Pallabi , Peterson Jeffrey R. , Anrather Josef , Pierce Joseph P. , Moore Jamie M. , Feng Ji , Zhou Ping , Milner Teresa A. , Pickel Virginia M. , Iadecola Costantino , Davisson Robin L.
Published: September 2013

Regulation of blood pressure by angiotensin II (ANG II) is a process that involves the reactive oxygen species (ROS) and calcium. We have shown that ANG-II type 1 receptor (AT1R) and prostaglandin E2(PGE2) type 1 receptors (EP1R) are required in the subfornical organ (SFO) for ROS-mediated hypertension induced by slow-pressor ANG-II infusion. However, the signaling pathway associated with this process remains unclear. We sought to determine mechanisms underlying the ANG II-induced ROS and calcium influx in mouse SFO cells. Ultrastructural studies showed that cyclooxygenase 1 (COX-1) codistributes with AT1R in the SFO, indicating spatial proximity. Functional studies using SFO cells revealed that ANG II potentiated PGE2release, an effect dependent on AT1R, phospholipase A2(PLA2) and COX-1. Furthermore, both ANG II and PGE2increased ROS formation. While the increase in ROS initiated by ANG II, but not PGE2, required the activation of the AT1R/PLA2/COX-1 pathway, both ANG II and PGE2were dependent on EP1R and Nox2 as downstream effectors. Finally, ANG II potentiated voltage-gated L-type Ca2+currents in SFO neurons via the same signaling pathway required for PGE2production. Blockade of EP1R and Nox2-derived ROS inhibited ANG II and PGE2-mediated Ca2+currents. We propose a mechanism whereby ANG II increases COX-1-derived PGE2through the AT1R/PLA2pathway, which promotes ROS production by EP1R/Nox2 signaling in the SFO. ANG II-induced ROS are coupled with Ca2+influx in SFO neurons, which may influence SFO-mediated sympathoexcitation. Our findings provide the first evidence of a spatial and functional framework that underlies ANG-II signaling in the SFO and reveal novel targets for antihypertensive therapies.
Attenuated muscle metaboreflex-induced increases in cardiac function in hypertension
Authors: Sala-Mercado Javier A. , Spranger Marty D. , Abu-Hamdah Rania , Kaur Jasdeep , Coutsos Matthew , Stayer Douglas , Augustyniak Robert A. , O'Leary Donal S.
Published: September 2013

Sympathoactivation may be excessive during exercise in subjects with hypertension, leading to increased susceptibility to adverse cardiovascular events, including arrhythmias, infarction, stroke, and sudden cardiac death. The muscle metaboreflex is a powerful cardiovascular reflex capable of eliciting marked increases in sympathetic activity during exercise. We used conscious, chronically instrumented dogs trained to run on a motor-driven treadmill to investigate the effects of hypertension on the mechanisms of the muscle metaboreflex. Experiments were performed before and 30.9 ± 4.2 days after induction of hypertension, which was induced via partial, unilateral renal artery occlusion. After induction of hypertension, resting mean arterial pressure was significantly elevated from 98.2 ± 2.6 to 141.9 ± 7.4 mmHg. The hypertension was caused by elevated total peripheral resistance. Although cardiac output was not significantly different at rest or during exercise after induction of hypertension, the rise in cardiac output with muscle metaboreflex activation was significantly reduced in hypertension. Metaboreflex-induced increases in left ventricular function were also depressed. These attenuated cardiac responses caused a smaller metaboreflex-induced rise in mean arterial pressure. We conclude that the ability of the muscle metaboreflex to elicit increases in cardiac function is impaired in hypertension, which may contribute to exercise intolerance.
Kir6.2 limits Ca2+ overload and mitochondrial oscillations of ventricular myocytes in response to metabolic stress
Authors: Storey Nina M. , Stratton Rebecca C. , Rainbow Richard D. , Standen Nicholas B. , Lodwick David
Published: September 2013

ATP-sensitive K+ (KATP) channels are abundant membrane proteins in cardiac myocytes that are directly gated by intracellular ATP and form a signaling complex with metabolic enzymes, such as creatine kinase. KATP channels are known to be essential for adaption to cardiac stress, such as ischemia; however, how all the molecular components of the stress response interact is not fully understood. We examined the effects of decreasing the KATP current density on Ca2+ and mitochondrial homeostasis and ischemic preconditioning. Acute knockdown of the pore-forming subunit, Kir6.2, was achieved using adenoviral delivery of short hairpin RNA targeted to Kir6.2. The acute nature of the knockdown of Kir6.2 accurately shows the effects of Kir6.2 depletion without any compensatory effects that may arise in transgenic studies. We also investigated the effect of reducing the KATP current while maintaining KATP channel protein in the sarcolemmal membrane using a nonconducting Kir6.2 construct. Only 50% KATP current remained after Kir6.2 knockdown, yet there were profound effects on myocyte responses to metabolic stress. Kir6.2 was essential for cardiac myocyte Ca2+ homeostasis under both baseline conditions before any metabolic stress and after metabolic stress. Expression of nonconducting Kir6.2 also resulted in increased Ca2+ overload, showing the importance of K+ conductance in the protective response. Both ischemic preconditioning and protection during ischemia were lost when Kir6.2 was knocked down. KATP current density was also important for the mitochondrial membrane potential at rest and prevented mitochondrial membrane potential oscillations during oxidative stress. KATP channel density is important for adaption to metabolic stress.
Circular RNA and miR-7 in Cancer
Authors: Hansen Thomas B. , Kjems Jørgen , Damgaard Christian K.
Published: September 2013

MicroRNAs (miRNA) play important roles in fine-tuning gene expression and are often deregulated in cancer. The identification of competing endogenous RNA and circular RNA (circRNA) as important regulators of miRNA activity underscores the increasing complexity of ncRNA-mediated regulatory networks. Particularly, the recently identified circular RNA, ciRS-7, which acts as a designated miR-7 inhibitor/sponge, has conceptually changed the mechanistic understanding of miRNA networks. As miR-7 modulates the expression of several oncogenes, disclosing the regulation of miR-7 activity will likely advance the understanding of various cancer etiologies. Here, we review the current knowledge about the ciRS-7/miR-7 axis in cancer-related pathways and discuss possible models explaining the relevance of coexpressing miR-7 along with a circRNA inhibitor. Cancer Res; 73(18); 5609–12. ©2013 AACR.
Antitumor Immunity: Easy as 1, 2, 3 with Monoclonal Bispecific Trifunctional Antibodies?
Authors: Maher John , Adami Antonella A.
Published: September 2013

Monoclonal antibodies occupy an increasing niche in the arsenal available to treat cancer. Several developments have rendered this the fastest growing sector in the pharmaceutical industry. Traditionally, antibodies were developed to block key signaling molecules implicated in tumor progression. However, antibodies also recruit additional immune effector mechanisms against tumors, a property that may be exploited for clinical benefit. Bispecific antibodies represent one such strategy in which elements derived from two monoclonal antibodies are incorporated into a single molecular species. Commonly, the bispecific approach is used to achieve simultaneous cross-linking of CD3 and a tumor antigen such as epithelial cell adhesion molecule (EpCAM), thereby recruiting T-cell activation to the tumor cell surface. A further sophistication involves the engineering of trifunctional derivatives such as the clinically approved agent, catumaxomab. Catumaxomab has antigen-binding arms that engage CD3 and EpCAM and a constant domain that recruits Fc receptor-bearing cells, notably monocytes, dendritic cells, and natural killer cells. Owing to this triangular binding capability, catumaxomab can activate both innate and adaptive immune effector mechanisms in addition to promoting immunologic memory. Recent data indicate that this agent can also promote immunogenic cell death, particularly when used in combination with selected chemotherapeutic agents such as oxaliplatin. Cancer Res; 73(18); 5613–7. ©2013 AACR.
miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4
Authors: Zhao Gang , Wang Bo , Liu Yang , Zhang Jun-gang , Deng Shi-chang , Qin Qi , Tian Kui , Li Xiang , Zhu Shuai , Niu Yi , Gong Qiong , Wang Chun-you
Published: September 2013

miRNAs are associated with various types of cancer due to their ability to affect expression of genes that modulate tumorigenesis. In this study, we explored the role of miR-141 in pancreatic cancer. The analysis of clinical characteristics showed that miR-141 was significantly downregulated in tissues and cell lines of pancreatic cancer. Moreover, the decreased miR-141 level was significantly associated with tumor size and TNM stage, as well as lymph node and distant metastasis. Meanwhile, both Kaplan–Meier and multivariate survival analysis showed decreased miR-141 were associated with overall survival. Overexpression of miR-141 in pancreatic cancer cells inhibited cell proliferation, clonogenicity, and invasion; induced G1 arrest and apoptosis; and enhanced chemosensitivity. To understand how miR-141 mediates the phenotype of pancreatic cancer cells, a bioinformatics tool was used to identify MAP4K4 as a potential target of miR-141. The Dual-Luciferase reporter gene assay showed that miR-141 binds directly to the 3′-untranslated region (3′UTR) of MAP4K4 to inhibit MAP4K4 expression. Western blot and quantitative real-time PCR (qRT-PCR) analyses revealed that MAP4K4 expression was inversely correlated with miR-141 expression both in pancreatic cancer samples and cell lines. Knockdown of MAP4K4 inhibited cell proliferation, clonogenicity, and invasion, induced G1 arrest and apoptosis, and enhanced chemosensitivity. In a nude mouse xenograft model, both overexpression of miR-141 and knockdown of MAP4K4 significantly repressed pancreatic cancer cell growth. Therefore, we conclude that miR-141 targets MAP4K4, acts as a tumor suppressor in pancreatic cancer cells, and may serve as a novel therapeutic agent for miRNA-based pancreatic cancer therapy. Mol Cancer Ther; 12(11); 2569–80. ©2013 AACR.
Impact of Ejection Fraction on the Clinical Response to Cardiac Resynchronization Therapy in Mild Heart Failure
Authors: Linde Cecilia , Daubert Claude , Abraham William T. , St John Sutton Martin , Ghio Stefano , Hassager Christian , Herre John M. , Bergemann Tracy L. , Gold Michael R.
Published: September 2013

Background—

Current guidelines recommend cardiac resynchronization therapy (CRT) in mild heart failure (HF) patients with QRS prolongation and ejection fraction (EF) ≤30%. To assess the effect of CRT in less severe systolic dysfunction, outcomes in the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study were evaluated in which patients with left ventricular (LV) ejection fraction (LVEF) >30% were included.

Methods and Results—

The results of patients with baseline EF >30% (n=177) and those with EF ≤30% (n=431), as determined by a blinded core laboratory, were compared. In the LVEF >30% subgroup, there was a trend for improvement in the clinical composite response with CRT ON versus CRT OFF (
P
=0.06) and significant reductions in LV end systolic volume index (−6.7±21.1 versus 2.1±17.6 mL/m
2
;
P
=0.01) and LV mass (−20.6±50.5 versus 5.0±42.4 g;
P
=0.04) after 12 months. The time to death or first HF hospitalization was significantly prolonged with CRT (hazard ratio, 0.26;
P
=0.012). In the LVEF <30% subgroup, significant improvements in clinical composite response (
P
=0.02), reverse remodeling parameters, and time to death or first HF hospitalization (hazard ratio, 0.58;
P
=0.047) were observed. After adjusting for important covariates, the CRT ON assignment remained independently associated with improved time to death or first HF hospitalization (hazard ratio, 0.54;
P
=0.035), whereas there was no significant interaction with LVEF.

Conclusions—

Among subjects with mild HF, QRS prolongation, and LVEF >30%, CRT produced reverse remodeling and similar clinical benefit compared with subjects with more severe LV systolic dysfunction.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00271154.
Do Outcomes for Patients With Heart Failure Vary by Emergency Department Volume?
Authors: Brar Sandeep , McAlister Finlay A. , Youngson Erik , Rowe Brian H.
Published: September 2013

Background—

Heart failure is a common Emergency Department (ED) presentation but whether ED volume influences patient outcomes is unknown.

Methods and Results—

Retrospective cohort of all adults presenting to 93 EDs between 1999 and 2009 with a most responsible diagnosis of heart failure (n=44 925 ED visits; mean age, 76.4 years). Cases seen in low-volume EDs had less comorbidities and were less likely to be hospitalized (54.5%) than those seen in medium (61.8%; adjusted odds ratio [aOR] 1.16, [95% confidence interval {CI} 1.10–1.23]) or high-volume EDs (73.6%; aOR, 1.95 [95% CI, 1.83–2.07]). Of patients treated and released, low-volume ED cases exhibited higher risk of death/hospitalization/ED visit in the subsequent 7 (22.0%) and 30 days (44.9%) than medium (16.3%; aOR, 0.81 [95% CI, 0.73–0.90], and 35.3%; aOR, 0.79 [95% CI, 0.73–0.86]) or high-volume ED cases (13.0%; aOR, 0.69 [95% CI, 0.61–0.78], and 30.2%; aOR, 0.67 [95% CI, 0.61–0.74]). Of patients hospitalized at the time of their index ED visit, low-volume ED cases exhibited a higher risk of 30-day death/all-cause readmission (24.3%) than those seen in medium (21.9%; aOR, 0.83 [95% CI, 0.76–0.91]) or high-volume EDs (18.1%; aOR, 0.77 [95% CI, 0.70–0.85]).

Conclusions—

Low-volume EDs were more likely to discharge patients with heart failure home, but low-volume ED cases exhibited worse outcomes (driven largely by readmissions or repeat ED visits). Interventions to improve management of acute heart failure are required at low-volume sites.
Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure With Preserved Ejection Fraction in a Rat Metabolic Risk Model
Authors: Hamdani Nazha , Franssen Constantijn , Lourenço André , Falcão-Pires Inês , Fontoura Dulce , Leite Sara , Plettig Luisa , López Begoña , Ottenheijm Coen A. , Becher Peter Moritz , González Arantxa , Tschöpe Carsten , Díez Javier , Linke Wolfgang A. , Leite-Moreira Adelino F. , Paulus Walter J.
Published: September 2013

Background—

Obesity and diabetes mellitus are important metabolic risk factors and frequent comorbidities in heart failure with preserved ejection fraction. They contribute to myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance for myocardial DD of collagen deposition and titin modification was investigated in obese, diabetic ZSF1 rats after heart failure with preserved ejection fraction development at 20 weeks.

Methods and Results—

Four groups of rats (Wistar-Kyoto, n=11; lean ZSF1, n=11; obese ZSF1, n=11, and obese ZSF1 with high-fat diet, n=11) were followed up for 20 weeks with repeat metabolic, renal, and echocardiographic evaluations and hemodynamically assessed at euthanization. Myocardial collagen, collagen cross-linking, titin isoforms, and phosphorylation were also determined. Resting tension (F
passive
)–sarcomere length relations were obtained in small muscle strips before and after KCl–KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to F
passive
to be discerned. At 20 weeks, the lean ZSF1 group was hypertensive, whereas both obese ZSF1 groups were hypertensive and diabetic. Only the obese ZSF1 groups had developed heart failure with preserved ejection fraction, which was evident from increased lung weight, preserved left ventricular ejection fraction, and left ventricular DD. The underlying myocardial DD was obvious from high muscle strip stiffness, which was largely (±80%) attributable to titin hypophosphorylation. The latter occurred specifically at the S3991 site of the elastic N2Bus segment and at the S12884 site of the PEVK segment.

Conclusions—

Obese ZSF1 rats developed heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.