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1.  Cardiac Rehabilitation Exercise and Self Care for Chronic Heart Failure 
JACC. Heart failure  2013;1(6):540-547.
Chronic heart failure (CHF) is highly prevalent in older individuals and a major cause of morbidity, mortality, hospitalizations and disability. Cardiac rehabilitation (CR) exercise training and CHF self-care counseling have each been shown to improve clinical status and clinical outcomes in CHF. Systematic reviews and meta-analyses of CR exercise training alone (without counseling) have demonstrated consistent improvements in CHF symptoms in addition to reductions of cardiac mortality and hospitalizations, although individual trials have been less conclusive of the latter two findings. The largest single trial, HF-ACTION, showed a reduction in the adjusted risk for the combined end point of all-cause mortality or hospitalization (HR: 0.89, 95% CI: 0.81-0.99; P=0.03). Quality of life and mental depression also improved. CHF-related counseling whether provided in isolation or in combination with CR exercise training improves clinical outcomes and reduces CHF-related hospitalizations We review current evidence on the benefits and risks of CR and self-care counseling in patients with CHF, provide recommendations for patient selection for third party payers, and discuss the role of CR in promoting self-care and behavioral changes.
PMCID: PMC4271268  PMID: 24622007
Chronic Heart Failure; Cardiac Rehabilitation; Exercise Training; Self-Care; Counseling
2.  Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis 
G3: Genes|Genomes|Genetics  2014;5(2):167-174.
Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype.
PMCID: PMC4321025  PMID: 25504735
HSPG2; perlecan; idiopathic scoliosis; exome sequencing
3.  CHD7 Gene Polymorphisms and Familial Idiopathic Scoliosis 
Spine  2013;38(22):10.1097/BRS.0b013e3182a51781.
Study Design
Model-independent linkage analysis and tests of association were performed for 22 single nucleotide polymorphisms (SNPs) in the CHD7 gene in 244 families of European descent with familial idiopathic scoliosis (FIS).
To replicate an association between FIS and the CHD7 gene on 8q12.2 in an independent sample of families of European descent.
Summary of Background Data
The CHD7 gene on chromosome 8, responsible for the CHARGE syndrome, was previously associated with FIS in an independent study that included 52 families of European descent.
Model-independent linkage analysis and intra-familial tests of association were performed on the degree of lateral curvature considered as a qualitative trait (with thresholds of ≥10°, ≥15°, ≥20° and ≥30°) and as a quantitative trait (degree of lateral curvature). Results from the tests of associations from this study and the previous study were combined in a weighted meta-analysis.
No significant results (P< 0.01) were found for linkage analysis or tests of association between genetic variants of the CHD7 and FIS in this study sample, failing to replicate the findings from the previous study. Furthermore, no significant results (P< 0.01) were found from meta-analysis of the results from the tests of association from this sample and from the previous sample.
No association between the 22 genotyped SNPs in the CHD7 gene and FIS within this study sample was found, failing to replicate the earlier findings. Further investigation of the CHD7 gene and its potential association to FIS may be required.
PMCID: PMC3881965  PMID: 23883829
familial idiopathic scoliosis; genetic linkage; association analysis; meta-analysis; chromosome 8q12; CHARGE syndrome; CHD7
4.  Neurodevelopmental Outcome of Extremely Low Birth Weight Infants with Candida Infection 
The Journal of pediatrics  2013;163(4):961-967.e3.
Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birthweight (ELBW) infants enrolled in the Candida study was evaluated based on infection status.
Study design
ELBW infants born at NICHD Neonatal Research Network (NRN) centers between March 2004 and July 2007 screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317/1515 (90%) of the infants enrolled in the Candida study. The Bayley Scales of Infant Development (BSID)-II or the BSID-III was administered at 18 months adjusted age. A secondary comparison with 864 infants registered with NRN enrolled during the same cohort never screened for sepsis and therefore not eligible for the Candida study was performed.
Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83 (1.01,3.33, p=0.047).
In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.
PMCID: PMC3786056  PMID: 23726546
Candida; Neonatal sepsis; Neurodevelopmental and Prematurity
5.  Intra-familial tests of association between Familial Idiopathic Scoliosis and markers on 9q31.3-q34.3 and 16p12.3-q22.2 
Human heredity  2012;74(1):36-44.
Custom genotyping of markers in families with Familial Idiopathic Scoliosis (FIS) were used to fine-map candidate regions on chromosomes 9 and 16 in order to identify candidate genes that contribute to this disorder and prioritize them for next generation sequence analysis.
Candidate regions on 9q and 16p–16q, previously identified as linked to FIS in a study of 202 families, were genotyped with a high-density map of single nucleotide polymorphisms (SNPs). Tests of linkage for fine-mapping and intra-familial tests of association, including tiled regression, were performed on scoliosis as both a qualitative and quantitative trait.
Results and Conclusions
Nominally significant linkage results were found for markers in both candidate regions. Results from intra-familial tests of association and tiled regression corroborated the linkage findings and identified possible candidate genes suitable for follow-up with next generation sequencing in these same families. Candidate genes that met our prioritization criteria included FAM129B and CERCAM on chromosome 9 and SYT1, GNAO1, and CDH3 on chromosome 16.
PMCID: PMC4123546  PMID: 23154503
idiopathic scoliosis; chromosome 9q; chromosome 16; genetic heterogeneity; genetics; association; family-based association study; complex disease
6.  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.
PMCID: PMC3523795  PMID: 23100559
NOD2; IL-17; Th17; T lymphocytes; ocular toxoplasmosis; Toxoplasma gondii
7.  Relation between Volume of Exercise and Clinical Outcomes in Patients with Heart Failure 
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.
This study determined whether greater volumes of exercise were associated with greater reductions in clinical events.
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.
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).
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:
PMCID: PMC3804919  PMID: 23062530
exercise training; dose response; cardiac rehabilitation
8.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
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).
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.
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
9.  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.
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.
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.
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.
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.
PMCID: PMC3402216  PMID: 22613012
Herpes simplex virus; Isothermal helicase-dependent amplification; Disposable detection device
10.  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.
PMCID: PMC3258271  PMID: 22144537
11.  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.
PMCID: PMC3392017  PMID: 20358593
idiopathic scoliosis; triple curve; genomic; chromosomes; familial; loci; screen; identification; spine; genes
12.  A Rapid and Simple Isothermal Nucleic Acid Amplification Test for Detection of Herpes Simplex Virus Types 1 and 2 
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.
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.
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.
Adequate analytical and clinical performance of the IsoAmp® HSV assay was demonstrated. This assay is simple to perform and has acceptable inter-laboratory reproducibility.
PMCID: PMC3018672  PMID: 20947417
herpes simplex viruses; isothermal helicase-dependent amplification; disposable detection device
13.  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.
PMCID: PMC3220699  PMID: 22125637
14.  Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment 
Pediatrics  2010;126(4):e865-e873.
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.
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.
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.
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.
PMCID: PMC3045840  PMID: 20876174
Candidiasis; premature infant; risk factors
15.  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.
PMCID: PMC3122789  PMID: 21270213
16.  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.
PMCID: PMC3122859  PMID: 21307220
17.  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.
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.
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).
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.
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.
PMCID: PMC2928583  PMID: 20733416
adolescent idiopathic scoliosis; melatonin; genetics
18.  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.
PMCID: PMC2937743  PMID: 20610679
19.  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.
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.
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.
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.
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.
PMCID: PMC2808704  PMID: 20081511
chromosome 17; genomic screen; linkage analysis; idiopathic scoliosis
20.  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.
PMCID: PMC2989415  PMID: 18497370
21.  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
22.  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.
PMCID: PMC3116573  PMID: 21686242
PNA; bacteral detection; drug resistance; S. aureus; RCA
23.  Factors That Influence the Receipt of Eye Care 
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.
Twenty focus groups were conducted. Analyses entailed debriefing sessions, coding, and interpreting transcribed data.
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.
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.
PMCID: PMC2941200  PMID: 18241139
health education; health professionals; vision; receipt of care; qualitative research
24.  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.
PMCID: PMC3169243  PMID: 21994809
25.  Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure: HF-ACTION Randomized Controlled Trial 
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.
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.
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.
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.
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 Identifier: NCT00047437
PMCID: PMC2916661  PMID: 19351941

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