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1.  Language performance in postmenopausal women with and without hormone therapy and men 
Aging health  2012;8(6):625-632.
Aims
In the current study, we explored the potential effects of hormone therapy (HT) on language functioning in healthy, postmenopausal women and compared them with men of similar ages.
Materials & methods
Language functioning on tasks of verbal fluency and object naming was examined in 100 participants (mean age: 61.9 years; 33 HT users, 15 HT non-users and 52 men) at baseline and follow-up (mean follow-up time period: 2.6 years).
Results
At baseline, men had higher composite language scores than HT users. However, HT users demonstrated more improvement over time compared with men, whereas HT non-users performed similarly to men, with no improvement over time. Longer duration of HT use was not associated with improved performance on language tests.
Conclusion
These results suggest an association between HT use and better language ability in postmenopausal women.
doi:10.2217/ahe.12.66
PMCID: PMC4332702
cognitive decline; estrogen; hormone therapy; language functioning; postmenopausal women
2.  Stability of the pneumococcal population structure in Massachusetts as PCV13 was introduced 
Background
The success of 7-valent pneumococcal conjugate vaccination (PCV-7) introduced to the US childhood immunization schedule in 2000 was partially offset by increases in invasive pneumococcal disease (IPD) and pneumococcal carriage due to non-vaccine serotypes, in particular 19A, in the years that followed. A 13-valent conjugate vaccine (PCV-13) was introduced in 2010. As part of an ongoing study of the response of the Massachusetts pneumococcal population to conjugate vaccination, we report the findings from the samples collected in 2011, as PCV-13 was introduced.
Methods
We used multilocus sequence typing (MLST) to analyze 367 pneumococcal isolates carried by Massachusetts children (aged 3 months-7 years) collected during the winter of 2010–11 and used eBURST software to compare the pneumococcal population structure with that found in previous years.
Results
One hundred and four distinct sequence types (STs) were found, including 24 that had not been previously recorded. Comparison with a similar sample collected in 2009 revealed no significant overall difference in the ST composition (p = 0.39, classification index). However, we describe clonal dynamics within the important replacement serotypes 19A, 15B/C, and 6C, and clonal expansion of ST 433 and ST 432, which are respectively serotype 22F and 21 clones.
Conclusions
While little overall change in serotypes or STs was evident, multiple changes in the frequency of individual STs and or serotypes may plausibly be ascribed to the introduction of PCV-13. This 2011 sample documents the initial impact of PCV-13 and will be important for comparison with future studies of the evolution of the pneumococcal population in Massachusetts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0797-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-015-0797-z
PMCID: PMC4336693
Pneumococcal conjugate vaccine; Streptococcus pneumoniae; Colonization; Molecular epidemiology; MLST
3.  Age of first arrest varies by gambling status in a cohort of young adults 
Background and objectives
To describe the association between social and problem gambling and first criminal arrest by age 23 in a cohort of urban, mainly African-American youth. Methods: Data for this study was derived from several annual interviews being completed on a community sample of 617 participants during late adolescence until age 23. Information on gambling status, engagement in deviant behaviors, illegal drug use, and arrest history were collected through yearly interviews. Analysis was carried out using Nelson-Aalen cumulative hazard models and simple and adjusted Cox proportional hazards models.
Results
More problem gamblers had been arrested before age 23 than social gamblers and non-gamblers, i.e. 65% of problem gamblers were arrested before age 23, compared to 38% of social gamblers and 24% non-gamblers. Social gambling was only significantly associated with the hazard of first arrest by age 23 in the unadjusted model (HR: 1.6, p<.001), but not after adjustment for covariates (HR: 1.1, p=0.47). Problem gambling was significantly associated with the hazard of first arrest by age 23 years in the unadjusted (HR: 3.6,p<.001) and adjusted models (HR:1.6, p=0.05).
Conclusions and Scientific Significance
Problem gambling was significantly associated with earlier age of being arrested. Dilution effects after adjustment for several deviant behaviors and illegal drug use by age 17 suggest that youth exposed to certain common factors may result in engagement in multiple risky behaviors, including problem gambling. Studies are needed to investigate the developmental pathways that lead to these combined behaviors among youth.
doi:10.1111/j.1521-0391.2014.12121.x
PMCID: PMC4328151  PMID: 24628694
gambling; adolescent; arrest; juvenile delinquency; risk
4.  Responding to Vaccine Safety Signals during Pandemic Influenza: A Modeling Study 
PLoS ONE  2014;9(12):e115553.
Background
Managing emerging vaccine safety signals during an influenza pandemic is challenging. Federal regulators must balance vaccine risks against benefits while maintaining public confidence in the public health system.
Methods
We developed a multi-criteria decision analysis model to explore regulatory decision-making in the context of emerging vaccine safety signals during a pandemic. We simulated vaccine safety surveillance system capabilities and used an age-structured compartmental model to develop potential pandemic scenarios. We used an expert-derived multi-attribute utility function to evaluate potential regulatory responses by combining four outcome measures into a single measure of interest: 1) expected vaccination benefit from averted influenza; 2) expected vaccination risk from vaccine-associated febrile seizures; 3) expected vaccination risk from vaccine-associated Guillain-Barre Syndrome; and 4) expected change in vaccine-seeking behavior in future influenza seasons.
Results
Over multiple scenarios, risk communication, with or without suspension of vaccination of high-risk persons, were the consistently preferred regulatory responses over no action or general suspension when safety signals were detected during a pandemic influenza. On average, the expert panel valued near-term vaccine-related outcomes relative to long-term projected outcomes by 3∶1. However, when decision-makers had minimal ability to influence near-term outcomes, the response was selected primarily by projected impacts on future vaccine-seeking behavior.
Conclusions
The selected regulatory response depends on how quickly a vaccine safety signal is identified relative to the peak of the pandemic and the initiation of vaccination. Our analysis suggested two areas for future investment: efforts to improve the size and timeliness of the surveillance system and behavioral research to understand changes in vaccine-seeking behavior.
doi:10.1371/journal.pone.0115553
PMCID: PMC4275236  PMID: 25536228
5.  Improved Blood Pressure Control Associated With a Large-Scale Hypertension Program 
JAMA  2013;310(7):699-705.
Importance
Hypertension control for large populations remains a major challenge.
Objective
To describe a large-scale hypertension program in northern California and to compare rates of hypertension control of the program to statewide and national estimates.
Design, Setting, and Patients
The Kaiser Permanente Northern California (KPNC) Hypertension program included a multi-faceted approach to blood pressure control. Patients identified with hypertension within an integrated health care delivery system in northern California from 2001–2009 were included. The comparison group included insured patients in California between 2006–2009 who were included in the Healthcare Effectiveness Data and Information Set (HEDIS) commercial measurement by California health insurance plans participating in the National Committee for Quality Assurance (NQCA) quality measure reporting process. A secondary comparison group was the reported national mean NCQA HEDIS commercial rates of hypertension control from 2001–2009 from health plans that participated in the NQCA HEDIS quality measure reporting process.
Main Outcome Measure
Hypertension control as defined by NCQA HEDIS.
Results
The KPNC hypertension registry established in 2001 included 349,937 patients and grew to 652,763 by 2009. The NCQA HEDIS commercial measurement for hypertension control increased from 44% to 80% during the study period. In contrast, the national mean NCQA HEDIS commercial measurement increased modestly from 55.4% to 64.1%. California mean NCQA HEDIS commercial rates of hypertension were similar to those reported nationally from 2006–2009. (63.4% to 69.4%).
Conclusion and Relevance
Among adults diagnosed with hypertension, implementation of a large-scale hypertension program was associated with a significant increase in hypertension control compared with state and national control rates.
doi:10.1001/jama.2013.108769
PMCID: PMC4270203  PMID: 23989679
Hypertension; Single pill combination Therapy; Angiotensin Enzyme Converting Inhibitor; Hydrochlorothiazide; Quality
6.  Consumption of non–cow’s milk beverages and serum vitamin D levels in early childhood 
Background:
Vitamin D fortification of non–cow’s milk beverages is voluntary in North America. The effect of consuming non–cow’s milk beverages on serum 25-hydroxyvitamin D levels in children is unclear. We studied the association between non–cow’s milk consumption and 25-hydroxyvitamin D levels in healthy preschool-aged children. We also explored whether cow’s milk consumption modified this association and analyzed the association between daily non–cow’s milk and cow’s milk consumption.
Methods:
In this cross-sectional study, we recruited children 1–6 years of age attending routinely scheduled well-child visits. Survey responses, and anthropometric and laboratory measurements were collected. The association between non–cow’s milk consumption and 25-hydroxyvitamin D levels was tested using multiple linear regression and logistic regression. Cow’s milk consumption was explored as an effect modifier using an interaction term. The association between daily intake of non–cow’s milk and cow’s milk was explored using multiple linear regression.
Results:
A total of 2831 children were included. The interaction between non–cow’s milk and cow’s milk consumption was statistically significant (p = 0.03). Drinking non–cow’s milk beverages was associated with a 4.2-nmol/L decrease in 25-hydroxyvitamin D level per 250-mL cup consumed among children who also drank cow’s milk (p = 0.008). Children who drank only non–cow’s milk were at higher risk of having a 25-hydroxyvitamin D level below 50 nmol/L than children who drank only cow’s milk (odds ratio 2.7, 95% confidence interval 1.6 to 4.7).
Interpretation:
Consumption of non–cow’s milk beverages was associated with decreased serum 25-hydroxyvitamin D levels in early childhood. This association was modified by cow’s milk consumption, which suggests a trade-off between consumption of cow’s milk fortified with higher levels of vitamin D and non–cow’s milk with lower vitamin D content.
doi:10.1503/cmaj.140555
PMCID: PMC4234713  PMID: 25332367
7.  PROTAMINE-INDUCED IMMUNE THROMBOCYTOPENIA 
Transfusion  2013;53(10):2158-2163.
Background
Protamine is widely used to reverse the anticoagulant effects of heparin. Although mild thrombocytopenia is common in patients given protamine after cardiac procedures, acute severe thrombocytopenia has not been described. We encountered a patient who experienced profound thrombocytopenia and bleeding shortly after administration of protamine and performed studies to characterize the responsible mechanism.
Study design and methods
Patient serum was studied for antibodies that recognize protamine, heparin/protamine complexes and platelets pre-treated with protamine using flow cytometry, ELISA and serotonin release from labeled platelets.
Results
A high titer IgG antibody was detected in patient serum that recognizes protamine in a complex with heparin or platelet surface glycosaminoglycans (GAG) and activates platelets pre-treated with protamine at concentrations achieved in vivo following protamine infusion. The antibody is distinctly different from those found in patients with heparin-induced thrombocytopenia on the basis of its failure to recognize heparin in a complex with platelet factor 4 (PF4) and to release serotonin from labeled platelets in the absence of protamine.
Conclusions
Findings made suggest that the patient’s antibody is specific for conformational changes induced in protamine when it reacts with heparin or a platelet surface GAG. Development of severe thrombocytopenia following treatment of this patient with protamine defines a previously undescribed mechanism of drug-induced immune thrombocytopenia. Patients given protamine who produce this type of antibody may be at risk to experience thrombocytopenia if given the drug a second time while antibody is still present.
doi:10.1111/trf.12112
PMCID: PMC3655112  PMID: 23384227
heparin; protamine; thrombocytopenia
8.  Heparin-Induced Thrombocytopenia 
Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. HIT is frequently considered in the differential diagnosis of thrombocytopenia occurring in patients on heparin therapy. HIT is a challenging diagnosis because of routine heparin use in hospitalized patients, the common occurrence of thrombocytopenia, and high rates of anti-PF4/heparin seroconversions in patients treated with heparin. This chapter will summarize our diagnostic approach to HIT by underscoring critical elements of the clinical and laboratory evaluation.
doi:10.1182/asheducation-2013.1.668
PMCID: PMC4153428  PMID: 24319250
platelet factor 4; PF4; heparin; PF4/H complexes; HIT
9.  Reduction in hSOD1 copy number significantly impacts ALS phenotype presentation in G37R (line 29) mice: implications for the assessment of putative therapeutic agents 
Background
In vivo animal models of familial amyotrophic lateral sclerosis (fALS) are widely used to delineate the potential role that genetic mutations play in the neurodegenerative process. While these models are extensively used for establishing the safety and efficacy of putative therapeutics during pre-clinical development, effective clinical translation of pharmacological interventions has been largely unsuccessful.
Results
In this report we compare a recent cohort of G37R (line 29) mice generated from mating wild-type females with transgenic males obtained commercially to a previous set of offspring produced with transgenic male breeders from a colony established at a local collaborator’s facility. Commercially derived progeny presented with a tightly clustered genomic signature for the mutant human superoxide dismutase1 transgene (hSOD1) locus, and exhibited a greater than two-fold reduction in the number of transgene copies present in the genome compared to offspring derived locally. Decrease in transgene levels corresponded with delayed ALS progression and a significant increase in overall lifespan (146%).
Conclusions
These results highlight some key challenges inherent to the use of G37R (line 29) animals in pre-clinical studies for the development of ALS therapeutics. Without stringent assessment of mutant SOD1 copy number/protein levels, heterogeneity of transgene levels within cohorts may influence the behavioural and pathological presentation of disease and thus calls to question the validity of any detected therapeutic effects. Nuanced changes in mutant SOD1 copy number that currently remain unreported may undermine research endeavours, delay efforts for clinical translation, and compromise the rigor of animal studies by limiting reproducibility amongst research groups.
doi:10.1186/1477-5751-13-14
PMCID: PMC4134475  PMID: 25103619
SOD1; ALS; Copy number variation; G93A; G37R
10.  Similar Verbal Fluency Patterns in Amnestic Mild Cognitive Impairment and Alzheimer's Disease 
Disproportionately greater deficits in semantic relative to phonemic verbal fluency are seen in Alzheimer's disease (AD) and have been attributed to neurodegenerative changes in the temporal lobe. Amnestic (AMN) mild cognitive impairment (MCI), which often represents incipient AD, is also characterized by early temporal lobe neuropathology, but previous comparisons of verbal fluency between AD and AMN MCI have yielded mixed results. We examined semantic and phonemic verbal fluency performance in 399 individuals (78 AD, 138 AMN MCI, 72 non-amnestic MCI, and 111 cognitively normal controls). Similar verbal fluency patterns were seen in AMN MCI and AD; both groups exhibited disproportionately poorer performance on semantic verbal fluency relative to normal controls. However, relative verbal fluency indices performed more poorly than individual semantic or phonemic verbal fluency indices for discriminating AMN MCI or AD participants from normal controls, suggesting that they are unlikely to provide additional utility for predicting progression from MCI to AD.
doi:10.1093/arclin/act039
PMCID: PMC3711375  PMID: 23752677
Mild cognitive impairment; Alzheimer's disease; Verbal fluency; Dementia; Assessment; Cognition
11.  Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia 
Schizophrenia research  2011;131(0):43-51.
We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r2>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10×10−3 and rs2274736, P=1.21×10−3). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86–0.97, P=5.45×10−3 and rs2401751, OR = 0.92, 95% CI: 0.86–0.97, P=5.29×10−3). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR = 1.08, 95% CI: 1.02-1.14, P=6.43×10−3). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.
doi:10.1016/j.schres.2011.06.023
PMCID: PMC4117700  PMID: 21752600
Data-mining; Informatic prioritization; Genetic association study; PTPN21; Non-synonymous SNP
12.  Neuroanatomical correlates of emotional blunting in behavioral variant frontotemporal dementia and early-onset Alzheimer’s disease 
Background
Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia.
Objective
We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimer’s disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume.
Methods
Twenty-five individuals with bvFTD (n=11) and early-onset AD (n=14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry (TBM). Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores.
Results
The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant.
Conclusions
Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB may be a useful diagnostic instrument for identifying a key clinical feature of bvFTD and appears to measure symptoms that are localized to the right anterior temporal lobe.
doi:10.3233/JAD-132219
PMCID: PMC4111835  PMID: 24685626
Frontotemporal Dementia; Alzheimer’s Disease; Early Onset; Magnetic Resonance Imaging; emotional blunting
13.  Does Adolescent Gambling Co-occur with Young Fatherhood? 
Background
Young fatherhood is associated with various adverse outcomes. This study aims to describe the relationship of adolescent gambling with young fatherhood (by age 20) while adjusting for several young fatherhood antecedents.
Methods
Data were from 294 males who have been followed for 16 years since entering first grade in nine inner city public schools (86% African Americans, 81% of the original male cohort). Self-reports of impregnation (including age) and gambling were collected during late adolescence. Nelson-Aalen curves and Cox regression models assessed the hazard of young fatherhood among adolescent nongamblers, social gamblers, and problem gamblers.
Results
More Young Fathers than Nonfathers reported adolescent social (49.2% vs 42.5%) and problem gambling (28.3% vs 13.2%, p<.001). Problem gamblers were the most likely to impregnate someone by age 20, followed by Social Gamblers, then Nongamblers. Problem gambling (aHR=3.16, 95% CI=1.75, 5.72, p<.001) had the highest increased hazards of young fatherhood, followed by social gambling (aHR=1.95, 95% CI=1.30, 2.94, p=.001), high school drop out (aHR=1.75, 95% CI=1.14, 2.70, p=.01), and subsidized lunch status (aHR=1.69, 95% CI=1.01, 2.38, p=.04).
Conclusion
Adolescent male gamblers, particularly problem gamblers, were more likely than their nongambling peers to become fathers by the age of 20. Such a result shows that there is a subpopulation of males who are at high risk for adverse outcomes such as young parenthood and problem behaviors. Only through further studies could the needs of this subpopulation be better assessed so that appropriate assistance could be delivered to better the lives of such individuals.
doi:10.1111/j.1521-0391.2013.12026.x
PMCID: PMC3694727  PMID: 23795883
14.  Outpatient antibiotic prescribing in the United States: 2000 to 2010 
BMC Medicine  2014;12:96.
Background
The use of antibiotics is the single most important driver in antibiotic resistance. Nevertheless, antibiotic overuse remains common. Decline in antibiotic prescribing in the United States coincided with the launch of national educational campaigns in the 1990s and other interventions, including the introduction of routine infant immunizations with the pneumococcal conjugate vaccine (PCV-7); however, it is unknown if these trends have been sustained through recent measurements.
Methods
We performed an analysis of nationally representative data from the Medical Expenditure Panel Surveys from 2000 to 2010. Trends in population-based prescribing were examined for overall antibiotics, broad-spectrum antibiotics, antibiotics for acute respiratory tract infections (ARTIs) and antibiotics prescribed during ARTI visits. Rates were reported for three age groups: children and adolescents (<18 years), adults (18 to 64 years), and older adults (≥65 years).
Results
An estimated 1.4 billion antibiotics were dispensed over the study period. Overall antibiotic prescribing decreased 18% (risk ratio (RR) 0.82, 95% confidence interval (95% CI) 0.72 to 0.94) among children and adolescents, remained unchanged for adults, and increased 30% (1.30, 1.14 to 1.49) among older adults. Rates of broad-spectrum antibiotic prescriptions doubled from 2000 to 2010 (2.11, 1.81 to 2.47). Proportions of broad-spectrum antibiotic prescribing increased across all age groups: 79% (1.79, 1.52 to 2.11) for children and adolescents, 143% (2.43, 2.07 to 2.86) for adults and 68% (1.68, 1.45 to 1.94) for older adults. ARTI antibiotic prescribing decreased 57% (0.43, 0.35 to 0.52) among children and adolescents and 38% (0.62, 0.48 to 0.80) among adults; however, it remained unchanged among older adults. While the number of ARTI visits declined by 19%, patients with ARTI visits were more likely to receive an antibiotic (73% versus 64%; P <0.001) in 2010 than in 2000.
Conclusions
Antibiotic use has decreased among children and adolescents, but has increased for older adults. Broad-spectrum antibiotic prescribing continues to be on the rise. Public policy initiatives to promote the judicious use of antibiotics should continue and programs targeting older adults should be developed.
doi:10.1186/1741-7015-12-96
PMCID: PMC4066694  PMID: 24916809
Antibiotic; Prescribing; Ambulatory care; Antibiotic resistance; Surveillance
15.  Diagnosis and Management of Heparin-Induced Thrombocytopenia 
doi:10.1016/j.hoc.2013.02.001
PMCID: PMC3668315  PMID: 23714311
platelet factor 4; PF4; heparin; PF4/H complexes; HIT
16.  Induction Mortality and Resource Utilization in Children Treated for Acute Myeloid Leukemia at Free-Standing Pediatric Hospitals in the United States 
Cancer  2013;119(10):1916-1923.
Background
Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients.
Methods
The Pediatric Health Information System database was used to identify children treated for presumed de novo AML between 1999 and 2010. Induction mortality, risk factors for induction mortality, and resource utilization by induction regimen were estimated using standard frequentist statistics, logistic regression and Poisson regression, respectively.
Results
A total of 1686 patients were identified with an overall induction case fatality rate of 5.4% that decreased from 9.8% in 2003 to 2.1% in 2009 (p= 0.0023). The case fatality rate was 9.0% in the intensively-timed DCTER induction and 3.8% for ADE induction (adjusted OR=2.2, 95% CI 1.1-4.5). Patients treated with intensively-timed DCTER regimens had significantly greater antibiotic, red cell/platelet transfusion, analgesic, vasopressor, renal replacement therapy, and radiographic resource utilization than patients treated with ADE regimens. Resource utilization was substantially higher than reported in published pediatric AML clinical trials.
Conclusions
Induction mortality for children with AML decreased significantly as ADE use increased. In addition to higher associated mortality, intensively-timed DCTER regimens had a correspondingly higher use of health care resources. Using resource utilization data as a proxy for adverse events, adverse event rates reported on clinical trials substantially underestimated the clinical toxicities of all pediatric AML induction regimens.
doi:10.1002/cncr.27957
PMCID: PMC3648620  PMID: 23436301
Pediatric Acute Myeloid Leukemia; Induction Mortality; Adverse Events Monitoring; Healthcare Administrative Database; Resource Utilization
17.  Mechanostructural Adaptations Preceding Post-Pneumonectomy Lung Growth 
Experimental lung research  2012;38(8):396-405.
In many species, pneumonectomy results in compensatory growth in the remaining lung. Although the late mechanical consequences of murine pneumonectomy are known, little is known about the anatomic adaptations and respiratory mechanics during compensatory lung growth. To investigate the structural and mechanical changes during compensatory growth, mice were studied for 21 days after left pneumonectomy using microCT and respiratory system impedance (FlexiVent). Anatomic changes after left pneumonectomy included minimal mediastinal shift or chestwall remodeling, but significant displacement of the heart and cardiac lobe. Mean displacement of the cardiac lobe centroid was 5.2±0.8mm. Lung impedance measurements were used to investigate the associated changes in respiratory mechanics. Quasi-static pressure-volume loops demonstrated progressive increase in volumes with decreased distensibility. Measures of quasi-static compliance and elastance were increased at all time points post pneumonectomy (p < 0.01). Oscillatory mechanics demonstrated a significant change in tissue impedance on the 3rd day after pneumonectomy. The input impedance on day 3 after pneumonectomy demonstrated a significant increase in tissue damping (5.8 versus 4.3 cmH2O/ml) and elastance (36.7 versus 26.6 cmH2O/ml) when compared to controls. At all points, hysteresivity was unchanged (0.17). We conclude that the timing and duration of the mechanical changes was consistent with a mechanical signal for compensatory growth.
doi:10.3109/01902148.2012.715364
PMCID: PMC4020359  PMID: 22905715
18.  Migration of CD11b+ Accessory Cells During Murine Lung Regeneration 
Stem cell research  2013;10(3):267-277.
In many mammalian species, the removal of one lung leads to growth of the remaining lung to near-baseline levels. In studying post-pneumonectomy mice, we used morphometric measures to demonstrate neoalveolarization within 21 days of pneumonectomy. Of note, the detailed histology during this period demonstrated no significant pulmonary inflammation. To identify occult blood-borne cells, we used a parabiotic model (wild-type/GFP) of post-pneumonectomy lung growth. Flow cytometry of post-pneumonectomy lung digests demonstrated a rapid increase in the number of cells expressing the hematopoietic membrane molecule CD11b; 64.5% of the entire GFP+ population were CD11b+. Fluorescence microscopy demonstrated that the CD11b+ peripheral blood cells migrated into both the interstitial tissue and alveolar airspace compartments. Pneumonectomy in mice deficient in CD11b (CD18-/- mutants) demonstrated near-absent leukocyte migration into the airspace compartment (p<.001) and impaired lung growth as demonstrated by lung weight (p<.05) and lung volume (p<.05). Transcriptional activity of the partitioned CD11b+ cells demonstrated significantly increased transcription of Angpt1, Il1b, and Mmp8, Mmp9, Ncam1, Sele, Sell, Selp in the alveolar airspace and Adamts2, Ecm1, Egf, Mmp7, Npr1, Tgfb2 in the interstitial tissue (>4-fold regulation; p<.05). These data suggest that blood-borne CD11b+ cells represent a population of accessory cells contributing to post-pneumonectomy lung growth.
doi:10.1016/j.scr.2012.12.006
PMCID: PMC3622126  PMID: 23376466
lung regeneration; parabiotic mice; hematopoietic CD11b+ cells
19.  In Vivo Optical Signatures of Neuronal Death in a Mouse Model of Alzheimer’s Disease 
Lasers in surgery and medicine  2013;46(1):27-33.
Background
There currently is a need for cost-effective, quantitative techniques to evaluate the gradual progression of Alzheimer’s disease (AD). Measurement techniques based on diffuse optical spectroscopy can detect blood perfusion and brain cellular composition changes, through measuring the absorption (μa) and reduced scattering (μs′) coefficients, respectively, using non-ionizing near-infrared light. Previous work has shown that brain perfusion deficits in an AD mouse model can be detected. The objective of this study was to determine if μs′ is sensitive to the inflammation and neuron death found in AD.
Methods
We used spatial frequency domain imaging (SFDI) to form quantitative maps of μa and μs′ in 3-month old male CaM/Tet-DTA mice harboring transgenes for the doxycyline-regulated neuronal expression of diphtheria toxin. When doxycycline is removed from the diet, CaM/ Tet-DTA mice develop progressive neuronal loss in forebrain neurons. Mice (n =5) were imaged longitudinally immediately prior to and after 23 days of lesion induction, and μa and μs′ (30 wavelengths, 650–970 nm) were compared to properties obtained from Tet-DTA controls (n =5). Neuron death and infiltration of inflammatory cells in brain cortical slices was confirmed with immunohistochemistry.
Results
No significant difference in baseline scattering and absorption were measured between CaM/Tet-DTA mice and controls. After 23 days of lesion induction, brain cortical μs′ was 11–16% higher in the CaM/Tet-DTA mice than in controls (P <0.03). Longitudinal imaging showed no significant difference in μs′ between the first and 23rd day of imaging in controls. Removing doxycycline from the diet was associated with a significant decrease in total hemoglobin concentrations (119 ± 9 μM vs. 91 ± 8 μM) (P <0.05) in controls, but not in CaM/Tet-DTA mice.
Conclusions
Neuronal death and brain inflammation are associated with increased tissue scattering (μs′) and this optical biomarker may be useful in pre-clinical AD therapy evaluation or monitoring of disease progression in AD patients.
doi:10.1002/lsm.22206
PMCID: PMC4001800  PMID: 24284732
diffuse optical spectroscopy; absorption; scattering; spatial frequency domain imaging; neuron death; inflammation
20.  The Medicare Policy of Payment Adjustment for Health Care-Associated Infections: Perspectives on Potential Unintended Consequences 
In 2008, the Centers for Medicare & Medicaid Services introduced a new policy to adjust payment to hospitals for health care-associated infections (HAIs) not present on admission. Interviews with 36 hospital infection preventionists across the United States explored the perspectives of these key stakeholders on the potential unintended consequences of the current policy. Responses were analyzed using an iterative coding process where themes were developed from the data. Participants’ descriptions of unintended impacts of the policy centered around three themes. Results suggest the policy has focused more attention on targeted HAIs and has affected hospital staff; relatively fewer systems changes have ensued. Some consequences of the policy, such as infection preventionists having less time to devote to HAIs other than those in the policy or having less time to implement prevention activities, may have undesirable effects on HAI rates if hospitals do not recognize and react to potential time and resource gaps.
doi:10.1177/1077558711413606
PMCID: PMC3998710  PMID: 21810797
health care quality; health care-associated infections; Medicare
22.  Including Catheter-Associated Urinary Tract Infections in the 2008 CMS Payment Policy: A Qualitative Analysis 
Urologic nursing  2013;33(1):15-23.
Research Summary
Background
With its 2008 reimbursement policy change, the Centers for Medicare and Medicaid Services (CMS) sought to link payment and quality. CMS stopped reimbursing hospitals for additional treatment costs due to hospital-acquired conditions, such as catheter-associated urinary tract infections (CAUTIs). Little is yet known about the impact of this policy.
Objective
To examine stakeholders’ views about the inclusion of CAUTIs in the 2008 CMS payment policy and its potential impact on hospital practices.
Methods
A cross-sectional qualitative study was conducted using semi-structured interviews of infection preventionists. This included 36 infection preventionists from a purposive sample of non-federal, acute care U.S. hospitals. An interview guide refined through iterative development was used, and interviews were audio-recorded, transcribed, and coded thematically. Qualitative methodology employed grounded theory tools, including open coding and constant comparative analysis.
Results
Two main themes emerged: 1) participants’ attitudes toward the inclusion of CAUTIs in the CMS policy, including issues of the infection’s significance, opportunity costs, and financial incentives; and 2) participants’ views about advances in clinical organizational behaviors and limited defensive practice.
Conclusions
Equivocal attitudes toward CMS’ policy targeting CAUTIs were somewhat discordant with the reported improvements in CAUTI prevention in response to the policy. Perhaps “stick” pay-for-performance policies can complement “carrot” policies in coaxing quality improvement. To support such a conclusion, the field needs more research on multiple stakeholders’ views on other selected hospital-acquired conditions in the policy. CMS could also benefit from continued feedback from stakeholders on the policy and its perceived consequences.
Level of Evidence – VI
(Polit & Beck, 2012)
PMCID: PMC3998716  PMID: 23556374
Catheter-associated urinary tract infection (CAUTI); health care-associated infection (HAI); infection prevention; Medicare; reimbursement; qualitative
23.  Perceived impact of the Medicare policy to adjust payment for health care-associated infections 
Background
In 2008, the Centers for Medicare and Medicaid Services (CMS) ceased additional payment for hospitalizations resulting in complications deemed preventable, including several health care-associated infections. We sought to understand the impact of the CMS payment policy on infection prevention efforts.
Methods
A national survey of infection preventionists from a random sample of US hospitals was conducted in December 2010.
Results
Eighty-one percent reported increased attention to HAIs targeted by the CMS policy, whereas one-third reported spending less time on nontargeted HAIs. Only 15% reported increased funding for infection control as a result of the CMS policy, whereas most reported stable (77%) funding. Respondents reported faster removal of urinary (71%) and central venous (50%) catheters as a result of the CMS policy, whereas routine urine and blood cultures on admission occurred infrequently (27% and 13%, respectively). Resource shifting (ie, less time spent on nontargeted HAIs) occurred more commonly in large hospitals (odds ratio, 2.3; 95% confidence interval: 1.0–5.1; P = .038) but less often in hospitals where front-line staff were receptive to changes in clinical processes (odds ratio, 0.5; 95% confidence interval: 0.3–0.8; P = .005).
Conclusion
Infection preventionists reported greater hospital attention to preventing targeted HAIs as a result of the CMS nonpayment policy. Whether the increased focus and greater engagement in HAI prevention practices has led to better patient outcomes is unclear.
doi:10.1016/j.ajic.2011.11.003
PMCID: PMC3998719  PMID: 22541855
Non-payment for preventable complications; Unintended consequences; Organizational culture; Organizational resources
25.  Impulsivity Trajectories and Gambling in Adolescence among Urban Male Youth 
Addiction (Abingdon, England)  2013;108(4):780-788.
Aim
Building on the recent emerging literature on the impulsivity trajectory-gambling association, this study investigated the association between developmental trajectories of teacher-rated impulsivity in early adolescence (ages 11–15) and subsequent gambling and gambling problems (i.e. at-risk and problem gambling) by age 19.
Design
Prospective cohort design.
Setting
Urban communities in Baltimore, Maryland.
Participants
The sample consists of 310 predominately minority (87%) and low SES (70%) males followed from first grade to late adolescence.
Measurements
Impulsivity was measured using teacher ratings of classroom behavior. Self-reported gambling behavior was assessed using the South Oaks Gambling Screen-Revised for Adolescents (SOGS-RA).
Findings
Results from a conventional growth model suggest the intercept of the impulsivity development (as measured by the repeated assessments of impulsivity across the entire developmental period) was significantly associated with gambling. Results from a general growth mixture model evidenced two distinct trajectories: a high impulsivity trajectory (41% the sample) and a low impulsivity trajectory (59% of the sample). Despite its non-significant association with any gambling, heterogeneity in impulsivity development was significantly associated with gambling problems. Specifically, being in the high impulsivity trajectory doubled the odds of meeting criteria for at-risk or problem gambling (OR= 2.09[1.02, 4.27]) and tripled the odds of meeting criteria for problem gambling (OR=2.84[1.02, 7.91])
Conclusions
Development in impulsivity is strongly associated with problem/at-risk gambling in adolescence among urban male youth. Findings highlight the importance of distinguishing gambling problems from any gambling when evaluating programs aimed at reducing youth gambling problems through reducing impulsivity.
doi:10.1111/add.12049
PMCID: PMC3586388  PMID: 23130867
Impulsivity; Gambling; Problem gambling; Convention growth model; General growth mixture model

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