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1.  Association of a NOD2 Gene Polymorphism and T-Helper 17 Cells With Presumed Ocular Toxoplasmosis 
The Journal of Infectious Diseases  2012;207(1):152-163.
Retinochoroiditis manifests in patients infected with Toxoplasma gondii. Here, we assessed 30 sibships and 89 parent/case trios of presumed ocular toxoplasmosis (POT) to evaluate associations with polymorphisms in the NOD2 gene. Three haplotype-tagging single-nucleotide polymorphisms (tag-SNPs) within the NOD2 gene were genotyped. The family-based association test showed that the tag-SNP rs3135499 is associated with retinochoroiditis (P = .039). We then characterized the cellular immune response of 59 cases of POT and 4 cases of active ocular toxoplasmosis (AOT). We found no differences in levels of interferon γ (IFN-γ) and interleukin 2 produced by T-helper 1 cells when comparing patients with AOT or POT to asymptomatic individuals. Unexpectedly, we found an increased interleukin 17A (IL-17A) production in patients with POT or OAT. In patients with POT or AOT, the main cellular source of IL-17A was CD4+CD45RO+T-bet−IFN-γ− T-helper 17 cells. Altogether, our results suggest that NOD2 influences the production of IL-17A by CD4+ T lymphocytes and might contribute to the development of ocular toxoplasmosis.
doi:10.1093/infdis/jis640
PMCID: PMC3523795  PMID: 23100559
NOD2; IL-17; Th17; T lymphocytes; ocular toxoplasmosis; Toxoplasma gondii
2.  Relation between Volume of Exercise and Clinical Outcomes in Patients with Heart Failure 
Background
The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial showed that among patients with heart failure (HF), regular exercise confers a modest reduction in the adjusted risk for all-cause mortality or hospitalization.
Objective
This study determined whether greater volumes of exercise were associated with greater reductions in clinical events.
Methods
Patients randomized to the exercise training arm of HF-ACTION who were event-free at 3 mo after randomization were included (n= 959). Median follow-up was 28.2 months. Clinical end points were all-cause mortality or hospitalization and cardiovascular mortality or HF hospitalization.
Results
A reverse J-shaped association was observed between exercise volume and adjusted clinical risk. Based on Cox regression, exercise volume was not a significant linear predictor but was a logarithmic predictor (p=0.03) for all-cause mortality or hospitalization. For cardiovascular mortality or HF hospitalization, exercise volume was a significant (p=0.001) linear and logarithmic predictor. Moderate exercise volumes of 3 to <5 and 5 to <7 MET-hr per week were associated with reductions in subsequent risk that exceeded 30%. Exercise volume was positively associated with the change in peak oxygen uptake at 3 months (r=0.10; p=0.005).
Conclusions
In patients with chronic systolic HF, volume of exercise is associated with the risk for clinical events, with only moderate levels (3–7 MET-hr per week) of exercise needed to observe a clinical benefit. Although further study is warranted to confirm the relationship between volume of exercise completed and clinical events, our findings support the use of regular exercise in the management of these patients.
Clinical Trial Registry: http://clinicaltrials.gov/ct2/show/NCT00047437
doi:10.1016/j.jacc.2012.08.958
PMCID: PMC3804919  PMID: 23062530
exercise training; dose response; cardiac rehabilitation
3.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
Objective
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
Study design
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
Results
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Conclusions
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
doi:10.1016/j.jpeds.2012.01.053
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
4.  Comparative clinical evaluation of the IsoAmp® HSV assay with ELVIS® HSV culture/ID/typing test system for the detection of herpes simplex virus in genital and oral lesions 
Journal of Clinical Virology  2012;54(4):355-358.
Background
The novel IsoAmp® HSV Assay employs isothermal helicase-dependent nucleic acid amplification and a user-friendly disposable test device to achieve rapid (<1.5 hours), on-demand qualitative detection of herpes simplex virus (HSV) types 1 and 2 in oral and genital lesions.
Objectives
To compare performance of the IsoAmp® HSV Assay with the ELVIS® HSV ID/typing (shell-vial culture and DFA) test system for clinical specimens collected from oral and genital lesions in symptomatic patients.
Study design
A total of 994 specimens from male and female genital and oral lesions were obtained and evaluated at five study sites in the United States. Results from the IsoAmp® HSV Assay were compared to those from the ELVIS® system. Separate reproducibility studies were performed at 3 sites using a blinded and randomized study panel. Discrepant specimens were resolved by bidirectional sequencing analysis.
Results
After discrepant analysis, overall agreement of IsoAmp® with ELVIS® was 98.8% with 37.0% overall prevalence (all study sites). Reproducibility rates were well within expectations.
Conclusion
The IsoAmp® HSV assay showed excellent performance for clinical use for detection of HSV in genital and oral specimens. In contrast to ELVIS®, IsoAmp® HSV offers excellent sensitivity plus rapid on-demand testing and simpler specimen preparation.
doi:10.1016/j.jcv.2012.04.004
PMCID: PMC3402216  PMID: 22613012
Herpes simplex virus; Isothermal helicase-dependent amplification; Disposable detection device
5.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
doi:10.1093/cid/cir800
PMCID: PMC3258271  PMID: 22144537
6.  Identification of Susceptibility Loci for Scoliosis in FIS Families With Triple Curves 
The triple curve pattern (three lateral curvatures of equal severity) has been recognized as a distinct and unique clinical subtype of scoliosis. As part of a large study of familial idiopathic scoliosis (FIS), a subset of five families with a triple curve pattern (at least one member of each family having a triple curve) was evaluated to determine if this curve pattern was linked to any of the markers previously genotyped as part of the STRP-based previous linkage screen. Model independent linkage analysis (SIBPAL, v4.5) of the initial genomic screen identified candidate regions on chromosomes 6 and 10 when FIS was analyzed both as qualitative and quantitative traits in single- and multipoint linkage analyses. Additional fine mapping analyses of this subgroup with SNPs corroborated the findings in these regions (P <0.001). These regions have been previously linked to FIS, however, this is the first time these regions have been implicated in a clinically well-defined subgroup and may suggest a unique genetic etiology for the formation of a triple curve.
doi:10.1002/ajmg.a.33222
PMCID: PMC3392017  PMID: 20358593
idiopathic scoliosis; triple curve; genomic; chromosomes; familial; loci; screen; identification; spine; genes
7.  A Rapid and Simple Isothermal Nucleic Acid Amplification Test for Detection of Herpes Simplex Virus Types 1 and 2 
Background
A simple and rapid IsoAmp® HSV assay has been developed for qualitative detection of herpes simplex virus (HSV) types 1 and 2 from genital lesions. Sample preparation involved a simple dilution step and the diluted specimens were directly add to the device and amplified by isothermal helicase-dependent amplification (HDA). Amplification products were then detected by a DNA strip embedded in a disposable cassette without any instrument. The total test turn-around time is less than 1.5 hours from specimen processing to result reporting.
Objectives
To evaluate the analytical and clinical performance of the IsoAmp® HSV assay as well as the robustness and reproducibility of the assay.
Study Design
The analytical sensitivity of the IsoAmp® HSV assay were determined using both HSV-1 and HSV-2. Clinical performance was evaluated using 135 frozen specimens collected from patients with suspected HSV infection in genital area.
Results
The analytical sensitivity of the assays was 5.5 and 34.1 copies/reaction for HSV-1 and HSV-2 respectively with a 95% confidence interval. When the herpes viral culture was used as the reference standard, the clinical sensitivity and specificity of the IsoAmp® HSV assay were 100.0% and 96.3% respectively. The inter-laboratory reproducibility achieved an overall 97.5% agreement by testing a total of 80 blinded HSV-1 samples among five laboratories.
Conclusion
Adequate analytical and clinical performance of the IsoAmp® HSV assay was demonstrated. This assay is simple to perform and has acceptable inter-laboratory reproducibility.
doi:10.1016/j.jcv.2010.09.006
PMCID: PMC3018672  PMID: 20947417
herpes simplex viruses; isothermal helicase-dependent amplification; disposable detection device
8.  The Entomopathogenic Bacterial Endosymbionts Xenorhabdus and Photorhabdus: Convergent Lifestyles from Divergent Genomes 
PLoS ONE  2011;6(11):e27909.
Members of the genus Xenorhabdus are entomopathogenic bacteria that associate with nematodes. The nematode-bacteria pair infects and kills insects, with both partners contributing to insect pathogenesis and the bacteria providing nutrition to the nematode from available insect-derived nutrients. The nematode provides the bacteria with protection from predators, access to nutrients, and a mechanism of dispersal. Members of the bacterial genus Photorhabdus also associate with nematodes to kill insects, and both genera of bacteria provide similar services to their different nematode hosts through unique physiological and metabolic mechanisms. We posited that these differences would be reflected in their respective genomes. To test this, we sequenced to completion the genomes of Xenorhabdus nematophila ATCC 19061 and Xenorhabdus bovienii SS-2004. As expected, both Xenorhabdus genomes encode many anti-insecticidal compounds, commensurate with their entomopathogenic lifestyle. Despite the similarities in lifestyle between Xenorhabdus and Photorhabdus bacteria, a comparative analysis of the Xenorhabdus, Photorhabdus luminescens, and P. asymbiotica genomes suggests genomic divergence. These findings indicate that evolutionary changes shaped by symbiotic interactions can follow different routes to achieve similar end points.
doi:10.1371/journal.pone.0027909
PMCID: PMC3220699  PMID: 22125637
9.  Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment 
Pediatrics  2010;126(4):e865-e873.
OBJECTIVE
Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low-birth-weight (<1000 g) infants. We quantify risk factors predicting infection in high-risk premature infants and compare clinical judgment with a prediction model of invasive candidiasis.
METHODS
The study involved a prospective observational cohort of infants <1000 g birth weight at 19 centers of the NICHD Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: 1) potentially modifiable risk factors and 2) a clinical model at time of blood culture to predict candidiasis.
RESULTS
Invasive candidiasis occurred in 137/1515 (9.0%) infants and was documented by positive culture from ≥ 1 of these sources: blood (n=96), cerebrospinal fluid (n=9), urine obtained by catheterization (n=52), or other sterile body fluid (n=10). Mortality was not different from infants who had positive blood culture compared to those with isolated positive urine culture. Incidence varied from 2–28% at the 13 centers enrolling ≥ 50 infants. Potentially modifiable risk factors (model 1) included central catheter, broad-spectrum antibiotics (e.g., third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model (model 2) had an area under the receiver operating characteristic curve of 0.79, and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. Performance of clinical judgment did not vary significantly with level of training.
CONCLUSION
Prior antibiotics, presence of a central catheter, endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.
doi:10.1542/peds.2009-3412
PMCID: PMC3045840  PMID: 20876174
Candidiasis; premature infant; risk factors
10.  Assessment of Impact of Peptide Nucleic Acid Fluorescence In Situ Hybridization for Rapid Identification of Coagulase-Negative Staphylococci in the Absence of Antimicrobial Stewardship Intervention▿ 
Journal of Clinical Microbiology  2011;49(4):1581-1582.
Peptide nucleic acid fluorescence in situ hybridization (PNA FISH) was instituted at Boston Medical Center for the rapid identification of coagulase-negative staphylococci (CoNS). Without active notification or antimicrobial stewardship intervention, a pre- and postimpact analysis showed no benefit of this assay with respect to the length of hospital stay or vancomycin use.
doi:10.1128/JCM.02461-10
PMCID: PMC3122789  PMID: 21270213
11.  Comparison of BD Bactec Plus Blood Culture Media to VersaTREK Redox Blood Culture Media for Detection of Bacterial Pathogens in Simulated Adult Blood Cultures Containing Therapeutic Concentrations of Antibiotics▿ 
Journal of Clinical Microbiology  2011;49(4):1624-1627.
Antibiotic neutralization in blood culture media from two automated systems was evaluated by measuring the recovery of organisms and times to detection in simulated cultures. Overall, BD Bactec Plus media (Bactec FX system) outperformed TREK 80 ml Redox media (VersaTREK system), although results suggest a relative rather than an absolute increased rate of recovery for the Bactec media.
doi:10.1128/JCM.01958-10
PMCID: PMC3122859  PMID: 21307220
12.  Evaluation of GPR50, hMel-1B, and ROR-Alpha Melatonin-Related Receptors and the Etiology of Adolescent Idiopathic Scoliosis 
Journal of pediatric orthopedics  2010;30(6):539-543.
Background
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity in children. Studies have shown low melatonin levels resulting from pinealectomy in chickens and mice result in the development scoliosis, while supplementation with melatonin after the pinealectomy prevented it. The mere characterization of low melatonin levels is not sufficient to explain the development of idiopathic scoliosis in primates and humans, but we hypothesize that a mutation in melatonin-related receptors may be involved with the development of scoliosis.
Methods
The coding, splice-site, and promoter regions of three melatonin-related receptors (hMel-1B, RORα, and GPR50) were evaluated by DNA sequencing for variants associated with the phenotype of adolescent idiopathic scoliosis. An initial screening of 50 scoliosis patients with adolescent idiopathic scoliosis was compared with 50 controls by DNA sequencing of the three receptors. Additional cases and controls were evaluated when genetic variants were observed (for a total of 885 individuals).
Results
No significant differences were found in the hMel-1B and RORα receptors. We found two cSNPs in GPR50 (rs561077 and rs13440581) in the initial 50 patients. To evaluate the significance of these cSNPs, an additional 356 patients and 429 controls were analyzed. When the combined groups were analyzed, no significant associations were observed.
Conclusions
Despite the observed relationship between melatonin and scoliosis, there is no significant association between mutations found in any known melatonin-related receptors with adolescent idiopathic scoliosis. The strong evidence of a melatonin-related cause for the development of idiopathic scoliosis still encourages research into undiscovered melatonin-related receptors, melatonin-related hormones, and the catalytic enzymes for the serotonin-melatonin pathway.
Clinical Relevance
This investigation is a genetic testing of the remaining currently known melatonin-related receptors that have not previously been analyzed for association with AIS. Given the support in the literature of a relationship between melatonin and AIS, we have shown no mutations in any of the known melatonin-related receptor in patients with AIS.
doi:10.1097/BPO.0b013e3181e7902c
PMCID: PMC2928583  PMID: 20733416
adolescent idiopathic scoliosis; melatonin; genetics
13.  Corynebacterium falsenii Bacteremia Occurring in an Infant on Vancomycin Therapy▿  
Journal of Clinical Microbiology  2010;48(9):3440-3442.
Corynebacterium falsenii was described in 1998 as a new Corynebacterium species. We give the first detailed description of a clinically significant Corynebacterium falsenii bacteremia occurring in an infant while on vancomycin therapy.
doi:10.1128/JCM.00990-10
PMCID: PMC2937743  PMID: 20610679
14.  Males with Familial Idiopathic Scoliosis: A Distinct Phenotypic Subgroup 
Spine  2010;35(2):162-168.
Study Design
Statistical analysis of genomic screening and fine mapping data.
Objective
The goals of this study were to analyze a region on chromosome 17 and to identify specific genetic determinants within this region linked to familial idiopathic scoliosis (FIS) in a subgroup of families in which affected males have undergone surgery.
Summary of Background Data
The high prevalence and variability of FIS is indicative of genetic heterogeneity. To localize genes related to scoliosis, identification of groups of families with common clinical characteristics is a strategy that reduces genetic heterogeneity. Two independent studies have implicated a region on chromosome 17 as related to FIS.
Methods
With approval of the Institutional Review Board, the initial study population consisted of 202 families (1198 individuals), each of which had 2 or more affected individuals; 17 of those families had an affected male who had surgery. Individuals underwent genomic screening and subsequent fine mapping. Results were obtained using model-independent linkage analysis, with scoliosis set as a qualitative and as a quantitative trait, as implemented in SIBPAL (S.A.G.E., v4.5). The level of significance was set at P ≤ 0.05.
Results
The initial study population had significant results at markers d17s975 and d17s2196. Analyses of a subgroup of families with males having undergone surgery using a customized single nucleotide polymorphism panel resulted in increased significance of this region.
Conclusion
The data confirm a previously reported genetic locus on chromosome 17 as statistically significant in the etiology of FIS within a subgroup of families in which an affected male had spinal surgery.
doi:10.1097/BRS.0b013e3181b7f1a7
PMCID: PMC2808704  PMID: 20081511
chromosome 17; genomic screen; linkage analysis; idiopathic scoliosis
15.  Call to Action on Use and Reimbursement for Home Blood Pressure Monitoring A Joint Scientific Statement From the American Heart Association, American Society of Hypertension, and the Preventive Cardiovascular Nurses’ Association 
Hypertension  2008;52(1):10-29.
The standard method for the measurement of blood pressure (BP) in clinical practice has traditionally been to use readings taken with the auscultatory technique by a physician or nurse in a clinic or office setting. While such measurements are likely to remain the cornerstone for the diagnosis and management of hypertension for the foreseeable future, it is becoming increasingly clear that they often give inadequate or even misleading information about a patient’s true BP status. All clinical measurements of BP may be regarded as surrogate estimates of the “True” BP, which may regarded as the average level over prolonged periods of time. In the past 30 years there has been an increasing trend to supplement office or clinic readings with out-of-office measurements of BP, taken either by the patient or a relative at home (home or self-monitoring- HBPM) or by an automated recorder for 24 hours (ambulatory blood pressure monitoring- ABPM).
Of the two methods HBPM has the greatest potential for being incorporated into the routine care of hypertensive patients, in the same way that home blood glucose monitoring performed by the patient has become a routine part of the management of diabetes. The currently available monitors are relatively reliable, easy to use, inexpensive, and accurate, and are already being purchased in large numbers by patients. Despite this, their use has only been cursorily endorsed in current guidelines for the management of hypertension, and there have been no detailed recommendations as to how they should be incorporated into routine clinical practice. And despite the fact that there is strong evidence that HBPM can predict clinical outcomes and improve clinical care, the cost of the monitors is not generally reimbursed. It is the purpose of this Call to Action paper to address the issues of the incorporation of HBPM into the routine management of hypertensive patients and its reimbursement.
doi:10.1161/HYPERTENSIONAHA.107.189010
PMCID: PMC2989415  PMID: 18497370
16.  PNA-based microbial pathogen identification and resistance marker detection: an accurate, isothermal rapid assay based on genome-specific features 
Artificial DNA, PNA & XNA  2010;1(2):1-7.
With the rapidly growing availability of the entire genome sequences of microbial pathogens, there is unmet need for increasingly sensitive systems to monitor the gene-specific markers for diagnosis of bacteremia that enables an earlier detection of causative agent and determination of drug resistance. To address these challenges, a novel FISH-type genomic sequence-based molecular technique is proposed that can identify bacteria and simultaneously detect antibiotic resistance markers for rapid and accurate testing of pathogens. The approach is based on a synergistic combination of advanced Peptide Nucleic Acid (PNA)-based technology and signal-enhancing Rolling Circle Amplification (RCA) reaction to achieve a highly specific and sensitive assay. A specific PNA-DNA construct serves as an exceedingly selective and very effective biomarker, while RCA enhances detection sensitivity and provide with a highly multiplexed assay system. Distinct-color fluorescent decorator probes are used to identify about 20-nucleotide-long signature sequences in bacterial genomic DNA and/or key genetic markers of drug resistance in order to identify and characterize various pathogens. The technique's potential and its utility for clinical diagnostics are illustrated by identification of S. aureus with simultaneous discrimination of methicillin-sensitive (MSSA) versus methicillin-resistant (MRSA) strains. Overall these promising results hint to the adoption of PNA-based rapid sensitive detection for diagnosis of other clinically relevant organisms. Thereby, new assay enables significantly earlier administration of appropriate antimicrobial therapy and may, thus have a positive impact on the outcome of the patient.
PMCID: PMC2953854  PMID: 20953307
17.  PNA-based microbial pathogen identification and resistance marker detection 
Artificial DNA, PNA & XNA  2010;1(2):76-82.
With the rapidly growing availability of the entire genome sequences of microbial pathogens, there is unmet need for increasingly sensitive systems to monitor the gene-specific markers for diagnosis of bacteremia that enables an earlier detection of causative agent and determination of drug resistance. To address these challenges, a novel FISH-type genomic sequence-based molecular technique is proposed that can identify bacteria and simultaneously detect antibiotic resistance markers for rapid and accurate testing of pathogens. The approach is based on a synergistic combination of advanced Peptide Nucleic Acid (PNA)-based technology and signal-enhancing Rolling Circle Amplification (RCA) reaction to achieve a highly specific and sensitive assay. A specific PNA-DNA construct serves as an exceedingly selective and very effective biomarker, while RCA enhances detection sensitivity and provide with a highly multiplexed assay system. Distinct-color fluorescent decorator probes are used to identify about 20-nucleotide-long signature sequences in bacterial genomic DNA and/or key genetic markers of drug resistance in order to identify and characterize various pathogens. The technique's potential and its utility for clinical diagnostics are illustrated by identification of S. aureus with simultaneous discrimination of methicillin-sensitive (MSSA) versus methicillin-resistant (MRSA) strains. Overall these promising results hint to the adoption of PNA-based rapid sensitive detection for diagnosis of other clinically relevant organisms. Thereby, new assay enables significantly earlier administration of appropriate antimicrobial therapy and may, thus have a positive impact on the outcome of the patient.
doi:10.4161/adna.1.2.13256
PMCID: PMC3116573  PMID: 21686242
PNA; bacteral detection; drug resistance; S. aureus; RCA
18.  Factors That Influence the Receipt of Eye Care 
Objectives
To better understand what factors influence the receipt of eye care so that screening and education programs can be designed to promote early detection and treatment.
Methods
Twenty focus groups were conducted. Analyses entailed debriefing sessions, coding, and interpreting transcribed data.
Results
Attitudes about eyesight and eye exams influence the receipt of preventive eye care. Limited knowledge about certain eye diseases and conditions was reported. Participants stated that their primary care providers did not communicate information with them about eyesight nor did they conduct basic eye screenings.
Conclusions
Improving provider-patient interactions and developing public health messages about eye diseases and preventive eye care can facilitate increased use of appropriate eye care services.
doi:10.5555/ajhb.2008.32.5.547
PMCID: PMC2941200  PMID: 18241139
health education; health professionals; vision; receipt of care; qualitative research
19.  Cardiovascular Risk Reduction with Renin-Angiotensin Aldosterone System Blockade 
Nursing Research and Practice  2010;2010:101749.
This paper examines the evidence supporting treatments within the renin-angiotensin aldosterone system (RAS), the role cardioprotection plays within the management of hypertension, considerations around medication adherence, and the role of the nurse or nurse practitioner in guiding patients to achieve higher hypertension control rates. A large body of data now exists to support the use of angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) which act on RAS, in the management of hypertension and their effect on cardiovascular risk reduction. Current evidence suggests that inhibition of the RAS is an important target for cardioprotection. RAS inhibition controls blood pressure and also reduces target-organ damage. This is especially important in populations at high-risk for damage including patients with diabetes and those with chronic kidney disease. Both ARBs and ACEIs target the RAS offering important reductions in both BP and target organ damage.
doi:10.1155/2010/101749
PMCID: PMC3169243  PMID: 21994809
20.  Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure: HF-ACTION Randomized Controlled Trial 
Context
Guidelines recommend that exercise training be considered for medically stable outpatients with heart failure. Previous studies have not had adequate statistical power to measure the effects of exercise training on clinical outcomes.
Objective
To test the efficacy and safety of exercise training among patients with heart failure.
Design, Setting, and Patients
Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure and reduced ejection fraction. Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) were randomized from April 2003 through February 2007 at 82 centers within the United States, Canada, and France; median follow-up was 30 months.
Interventions
Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, or usual care alone.
Main Outcome Measures
Composite primary end point of all-cause mortality or hospitalization and prespecified secondary end points of all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or heart failure hospitalization.
Results
The median age was 59 years, 28% were women, and 37% had New York Heart Association class III or IV symptoms. Etiology was ischemic in 51%. Median left ventricular ejection fraction was 25%. Exercise adherence decreased from a median of 95 minutes per week during months 4 through 6 of follow-up to 74 minutes per week during months 10 through 12. A total of 759 (65%) patients in the exercise group died or were hospitalized, compared with 796 (68%) in the usual care group (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.84–1.02; P = .13). There were nonsignificant reductions in the exercise training group for mortality (189 [16%] in the exercise group vs 198 [17%] in the usual care group; HR, 0.96; 95% CI, 0.79–1.17; P = .70), cardiovascular mortality or cardiovascular hospitalization (632 [55%] in the exercise group vs 677 [58%] in the usual care group; HR, 0.92; 95% CI, 0.83–1.03; P = .14), and cardiovascular mortality or heart failure hospitalization (344 [30%] in the exercise group vs 393 [34%] in the usual care group; HR, 0.87; 95% CI, 0.75–1.00; P = .06). In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81–0.99; P = .03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82–1.01; P = .09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74–0.99; P = .03) for cardiovascular mortality or heart failure hospitalization. Other adverse events were similar between the groups.
Conclusions
In the protocol-specified primary analysis, exercise training resulted in nonsignificant reductions in the primary end point of all-cause mortality or hospitalization and in key secondary clinical end points. After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modest significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization.
Trial Registration
clinicaltrials.gov Identifier: NCT00047437
doi:10.1001/jama.2009.454
PMCID: PMC2916661  PMID: 19351941
22.  Genome Sequence of Azotobacter vinelandii, an Obligate Aerobe Specialized To Support Diverse Anaerobic Metabolic Processes▿ †  
Journal of Bacteriology  2009;191(14):4534-4545.
Azotobacter vinelandii is a soil bacterium related to the Pseudomonas genus that fixes nitrogen under aerobic conditions while simultaneously protecting nitrogenase from oxygen damage. In response to carbon availability, this organism undergoes a simple differentiation process to form cysts that are resistant to drought and other physical and chemical agents. Here we report the complete genome sequence of A. vinelandii DJ, which has a single circular genome of 5,365,318 bp. In order to reconcile an obligate aerobic lifestyle with exquisitely oxygen-sensitive processes, A. vinelandii is specialized in terms of its complement of respiratory proteins. It is able to produce alginate, a polymer that further protects the organism from excess exogenous oxygen, and it has multiple duplications of alginate modification genes, which may alter alginate composition in response to oxygen availability. The genome analysis identified the chromosomal locations of the genes coding for the three known oxygen-sensitive nitrogenases, as well as genes coding for other oxygen-sensitive enzymes, such as carbon monoxide dehydrogenase and formate dehydrogenase. These findings offer new prospects for the wider application of A. vinelandii as a host for the production and characterization of oxygen-sensitive proteins.
doi:10.1128/JB.00504-09
PMCID: PMC2704721  PMID: 19429624
23.  Effects of Exercise Training on Health Status in Patients With Chronic Heart Failure: Findings From the HF-ACTION Randomized Controlled Trial 
Context
Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent.
Objective
To test the effects of exercise training on health status among patients with heart failure.
Design, Setting, and Patients
Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with ejection fraction ≤ 35%. Patients were randomized from April 2003 through February 2007.
Interventions
Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, vs usual care alone. Randomization was stratified by heart failure etiology, which was a covariate in all models.
Main Outcome Measures
Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle.
Results
Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.2; 95% confidence interval, 4.4–6.0) compared with usual care alone (3.3; 95% confidence interval, 2.5–4.1). The additional 1.9-point increase in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected.
Conclusions
Exercise training conferred modest but statistically significant improvements in health status compared with usual care without training. Improvements occurred early and persisted over time.
Trial Registration
clinicaltrials.gov Identifier: NCT00047437
doi:10.1001/jama.2009.457
PMCID: PMC2690699  PMID: 19351942
24.  Utilizing New Prescription Drugs: Disparities among Non-Hispanic Whites, Non-Hispanic Blacks, and Hispanic Whites 
Health Services Research  2007;42(4):1499-1519.
Objective
To examine racial and ethnic disparities in new prescription drug use.
Data Sources/Study Setting
Secondary data analyses of the Medical Expenditure Panel Survey (1996–2001), a national survey representative of U.S. noninstitutionalized civilian population. Drug approval dates were from the GenRx database of Mosby.
Study Design
A negative binomial model was used to compare annual number of times when new drugs were obtained across racial and ethnic groups. Covariates in the model were demographic, economic characteristics, and health status. Drugs were considered new if approved within the past 5 years. We compared non-Hispanic whites with non-Hispanic blacks, and non-Hispanic whites with Hispanic whites, respectively, to examine racial and ethnic disparities separately.
Principal Findings
Descriptive analyses found smaller racial disparities than ethnic disparities: the average annual number of times when new drugs were obtained was higher among non-Hispanic whites than non-Hispanic blacks (1.71 versus 1.36; p < 0.01) and Hispanic whites (1.71 versus 1.11; p < 0.01). Multivariate analyses found smaller ethnic than racial disparities: the number was 22–33 percent lower among non-Hispanic blacks than non-Hispanic whites (significant), and 5–16 percent lower among Hispanic whites than non-Hispanic whites (not always significant), respectively. While the absolute racial disparities decreased over the early years of the life cycles of the products, the reduction in disparities over time was not significant.
Conclusions
There are racial disparities in the use of new medications, which persist during the first 5 years of marketing. Socioeconomic and health characteristics account for a larger share of ethnic disparities than racial disparities.
doi:10.1111/j.1475-6773.2006.00682.x
PMCID: PMC1955281  PMID: 17610435
Race; ethnicity; disparities; utilization; new prescription drugs
25.  Randomised controlled trial of a secondary prevention program for myocardial infarction patients ('ProActive Heart'): study protocol. Secondary prevention program for myocardial infarction patients 
Background
Coronary heart disease (CHD) is a significant cause of health and economic burden. Secondary prevention programs play a pivotal role in the treatment and management of those affected by CHD although participation rates are poor due to patient, provider, health system and societal-level barriers. As such, there is a need to develop innovative secondary prevention programs to address the treatment gap. Telephone-delivered care is convenient, flexible and has been shown to improve behavioural and clinical outcomes following myocardial infarction (MI). This paper presents the design of a randomised controlled trial to evaluate the efficacy of a six-month telephone-delivered secondary prevention program for MI patients (ProActive Heart).
Methods
550 adult MI patients have been recruited over a 14 month period (December 2007 to January 2009) through two Brisbane metropolitan hospitals, and randomised to an intervention or control group (n = 225 per group). The intervention commences within two weeks of hospital discharge delivered by study-trained health professionals ('health coaches') during up to 10 × 30 minute scripted telephone health coaching sessions. Participants also receive a ProActive Heart handbook and an educational resource to use during the health coaching sessions. The intervention focuses on appropriate modification of CHD risk factors, compliance with pharmacological management, and management of psychosocial issues. Data collection occurs at baseline or prior to commencement of the intervention (Time 1), six months follow-up or the completion of the intervention (Time 2), and at 12 months follow-up for longer term outcomes (Time 3). Primary outcome measures include quality of life (Short Form-36) and physical activity (Active Australia Survey). A cost-effective analysis of the costs and outcomes for patients in the intervention and control groups is being conducted from the perspective of health care costs to the government.
Discussion
The results of this study will provide valuable new information about an innovative telephone-delivered cost-effective secondary prevention program for MI patients.
Trial Registration Number
ACTRN12607000595415
doi:10.1186/1471-2261-9-16
PMCID: PMC2689849  PMID: 19426524

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