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1.  A Persuasive and Social mHealth Application for Physical Activity: A Usability and Feasibility Study 
JMIR mHealth and uHealth  2014;2(2):e25.
Background
Advances in smartphones and the wide usage of social networking systems offer opportunities for the development of innovative interventions to promote physical activity. To that end, we developed a persuasive and social mHealth application designed to monitor and motivate users to walk more every day.
Objective
The objectives of this project were to conduct a focused review on the fundamental characteristics of mHealth for physical activity promotion, to develop an mHealth application that meets such characteristics, and to conduct a feasibility study to deploy the application in everyday life.
Methods
This project started as an analytical study to review the fundamental characteristics of the technologies used in physical activity monitoring and promotion. Then, it was followed by a technical development of the application. Next, a 4 week deployment was conducted where participants used the application as part of their daily life. A think-aloud method and in-depth semistructured interviews were conducted following the deployment. A qualitative description method was used to thematically analyze the interviews. Feasibility measures included, adherence to the program, user-system interactions, motivation to use, and experience with physical activity and online social interactions.
Results
There were seven fundamental characteristics of physical activity monitoring and promotion that were identified, which were then used as a foundation to develop the application. There were fourteen participants that enrolled in the application evaluation. The age range was from 24 to 45; body mass index ranged from 18.5 to 42.98, with 4 of the subjects falling into the category “obese”. Half of them were experienced with smartphones, and all were familiar with a social network system. There were thirteen participants that completed the study; one was excluded. Overall, participants gave high scores to almost all of the usability factors examined, with averages of 4.52 out of a 5.00 maximum. Over 29 days, participants used the application for a total of 119,380 minutes (average=7.57 hours/day/participant; SD 1.56).
Conclusions
Based on the fundamental characteristics, the application was successfully developed. The usability results suggest that the system is usable and user satisfaction was high. Deploying the application was shown to be feasible for the promotion of daily physical activity.
doi:10.2196/mhealth.2902
PMCID: PMC4114463  PMID: 25099928
mobile applications; mHealth; self-management; social support; persuasion; physical activity; usability; feasibility studies; pedometer
2.  Team Building: Electronic Management-Clinical Translational Research (eM-CTR) Systems 
Classical drug exposure: response studies in clinical pharmacology represent the quintessential prototype for Bench to Bedside-Clinical Translational Research. A fundamental premise of this approach is for a multidisciplinary team of researchers to design and execute complex, in-depth mechanistic studies conducted in relatively small groups of subjects. The infrastructure support for this genre of clinical research is not well-handled by scaling down of infrastructure used for large Phase III clinical trials. We describe a novel, integrated strategy, whose focus is to support and manage a study using an Information Hub, Communication Hub, and Data Hub design. This design is illustrated by an application to a series of varied projects sponsored by Special Clinical Centers of Research in chronic obstructive pulmonary disease at the University of Pittsburgh. In contrast to classical informatics support, it is readily scalable to large studies. Our experience suggests the culture consequences of research group self-empowerment is not only economically efficient but transformative to the research process.
doi:10.1111/j.1752-8062.2009.00157.x
PMCID: PMC3687802  PMID: 20443940
institutional management teams; organization and administration; information services; information storage and retrieval
3.  Radiographic Emphysema Predicts Low Bone Mineral Density in a Tobacco-exposed Cohort 
Rationale: Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied.
Objectives: We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers.
Methods: One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed.
Measurements and Main Results: No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P = 0.0003). Quantitative emphysema, but not CT-measured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio = 2.55; 95% confidence interval, 1.24–5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use.
Conclusions: Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.
doi:10.1164/rccm.201004-0666OC
PMCID: PMC3086755  PMID: 20935108
pulmonary disease, chronic obstructive; emphysema; osteoporosis
4.  A UPLC-MS/MS assay of the “Pittsburgh Cocktail”: six CYP probe-drug/metabolites from human plasma and urine using stable isotope dilution 
The Analyst  2010;136(3):605-612.
The efficiency of drug metabolism by a single enzyme can be measured as the fractional metabolic clearance which can be used as a measure of whole body activity for that enzyme. Measurement of activity of multiple enzymes simultaneously is feasible using a cocktail approach however analytical approach using different assays for drug probes can be cumbersome. A quantitative ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based method for the rapid measurement of six cytochrome P450 (CYP) probe drugs and their relevant metabolites, is described. The six specific probe substrates/metabolites, are caffeine/paraxanthine (CYP1A2), flurbiprofen/4′-hydroxyflurbiprofen (CYP2C9), mephenytoin/4′-hydroxymephenytoin (CYP2C19), debrisoquine/4-hydroxydebrisoquine (CYP2D6), chlorzoxazone/6′-hydroxychlorzoxazone (CYP2E1) and dapsone/N-monoacetyldapsone (NAT2). These probes were quantified by stable isotope dilution from plasma and urine. The present workflow provides a robust, fast and sensitive assay for the “Pittsburgh Cocktail”, and has been successfully applied to a clinical phenotyping study of liver disease. A representative group of 17 controls and patients with chronic liver disease were administered orally caffeine (100mg), chlorzoxazone (250mg), debrisoquine (10mg), mephenytoin (100mg) flurbiprofen (50mg) and dapsone (100mg). Urine (0 through 8 h) and plasma (4 and 8 h) samples were analyzed for drug/metabolite amounts by stable isotope dilution UPLC-MS/MS. The phenotypic activity of drug metabolizing enzymes was investigated with 17 patient samples. Selected reaction monitoring (SRM) was optimized for each drug and metabolite. In the method developed, analytes were resolved by reversed-phase by development of a gradient using a water/methanol solvent system. SRM of each analyte was performed in duplicate on a triple quadrupole mass spectrometer utilizing an 8 min analytical method each, one with the source operating in the positive mode and one in the negative mode, using the same solvent system. This method enabled quantification of each drug (caffeine, chlorzoxazone, debrisoquine, mephenytoin, flurbiprofen, and dapsone) and its resulting primary metabolite in urine or plasma in patient samples. The method developed and the data herein demonstrate a robust quantitative assay to examine changes in CYP enzymes both independently or as part of a cocktail. The clinical use of a combination of probe drugs with UPLC-MS/MS is a highly efficient tool for the assessment of CYP enzyme activity in liver disease.
doi:10.1039/c0an00643b
PMCID: PMC3115584  PMID: 21107456
CYP; Mass spectrometry; stable isotope dilution; phenotyping; drug cocktail
5.  Therapeutic equivalence in survival for hepatic arterial chemoembolization and 90Yttrium microspheres (Y90) treatments in unresectable hepatocellular carcinoma: a 2 cohort study 
Cancer  2010;116(5):1305-1314.
BACKGROUND
Intra-hepatic arterial 90Yttrium (Y90) microspheres (Theraspheres) have been proposed as a less toxic, invasive therapeutic option to trans-hepatic arterial chemoembolization (TACE) for surgically unresectable hepatocellular carcinoma (HCC). TACE has been shown to prolong survival. However, long term survival remains uncertain.
METHODS
A 2 cohort experience of the treatment of advanced, unresectable and biopsy-proven HCC in North American patients is presented. 691 patients received repetitive cisplatin-based chemoembolization and a following 99 patient cohort with similar treatment criteria, received a planned single dose of Y90. Over this time period, an additional 142 patients were followed without treatment (total: 932 patients).
RESULTS
Overall survival was slightly better in the Y90 group compared to TACE, median of 11.5 vs. 8.5 months. However, selection criteria indicated a small but significant bias towards milder disease in the Y90 group. Using stratification in a 3 tier model, with cases dichotomized by bilirubin of less than 1.5 mg/dL, patients without PVT or with low alpha-fetoprotein plasma levels of less than 25 units/dL, analysis of survival in clinical subgroups showed that the 2 treatments resulted in similar survival. Similarly, patients with PVT or a high alpha-fetoprotein also had similar survival in the 2 treatment groups.
CONCLUSION
Given the present evidence of therapeutic equivalence in survival, Y90 and TACE seem to be equivalent regional therapies for patients with unresectable, non-metastatic HCC.
doi:10.1002/cncr.24884
PMCID: PMC2829376  PMID: 20066715
HCC; hepatoma; chemotherapy; Yttrium; internal radiation
6.  Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation 
Objective
To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over time after transplantation.
Methods
Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods.
Results
The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean ± SD, 6.4 ± 5.1) was significantly higher than that after 1 month after surgery (2.1 ± 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 ± 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 ± 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 ± 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 ± 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups.
Conclusions
We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic ratio, occurs in the first month after sugery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation.
doi:10.1016/S0009-9236(98)90161-8
PMCID: PMC2978967  PMID: 9542473
7.  Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study 
Hepatology International  2009;4(1):396-405.
Objectives
967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end point.
Results
We found that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated AFP or bilirubin, or alkaline phosphatase, were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, even in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient sub groups based on liver function and tumor characteristics and found clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant factors. We also used a purely mathematical approach to derive subgroups and a prognostic model for individual patients. Interestingly, the two approaches gave similar predictive information, which opens the possibility of a more detailed mathematical analysis in the future. The results of this large dataset show that amongst non-surgical HCC patients, there are clear subsets with longer survival.
Conclusion
The data supports the concept of heterogeneity of HCC. The three factors, bilirubin, AFP, and PVT predominate in prognosis.
doi:10.1007/s12072-009-9157-7
PMCID: PMC2836439  PMID: 20305756
8.  The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2009;4(8):e6865.
Background
Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD.
Methodology/Principal Findings
Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status.
Conclusions/Significance
Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.
doi:10.1371/journal.pone.0006865
PMCID: PMC2730536  PMID: 19718453
9.  Gender-based outcomes differences in unresectable hepatocellular carcinoma 
Hepatology International  2007;2(1):95-101.
Purpose
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. HCC is notably more prevalent in males worldwide, with reported male:female ratios ranging from 2:1 to 8:1. The reasons for sex differences in the incidence of HCC are unclear. Furthermore, differences in rates of disease progression and longevity are not well studied and few series have compared the clinicopathologic characteristics of patients and their impact on survival with specific reference to gender in a large sample set.
Methods
The present study is a large single-institution study of 1138 HCC cases referred to a single individual carried out over a period of 17 years. The primary endpoint measure was over-all survival measured in months, which was defined as the time between the date of diagnosis and date of death. Differences in median survival for each subgroup analysis in survival rates were compared by log rank test.
Results
There are differences in both the distribution of evidence of disease progression at the time of diagnosis and the time for survival following diagnosis in patients with HCC between the two genders. Females had a longer survival than males in subsets matched for residual liver function and tumor extension, suggesting that the natural history of HCC is different between men and women.
Conclusion
The present study provides evidence that female gender provides a distinct survival advantage over males in unresectable HCC presenting with similar tumor characteristics, liver function, and coexisting liver disease.
doi:10.1007/s12072-007-9041-2
PMCID: PMC2716876  PMID: 19669284
Gender; Outcome; Unresectable hepatocellular carcinoma; Survival; Female
10.  Exogenous and Endogenous Determinants of Blood Trihalomethane Levels after Showering 
Background
We previously conducted a study to assess whether household exposures to tap water increased an individual’s internal dose of trihalomethanes (THMs). Increases in blood THM levels among subjects who showered or bathed were variable, with increased levels tending to cluster in two groups.
Objectives
Our goal was to assess the importance of personal characteristics, previous exposures, genetic polymorphisms, and environmental exposures in determining THM concentrations in blood after showering.
Methods
One hundred study participants completed a health symptom questionnaire, a 48-hr food and water consumption diary, and took a 10-min shower in a controlled setting. We examined THM levels in blood samples collected at baseline and 10 and 30 min after the shower. We assessed the significance of personal characteristics, previous exposures to THMs, and specific gene polymorphisms in predicting postshower blood THM concentrations.
Results
We did not observe the clustering of blood THM concentrations observed in our earlier study. We found that environmental THM concentrations were important predictors of blood THM concentrations immediately after showering. For example, the chloroform concentration in the shower stall air was the most important predictor of blood chloroform levels 10 min after the shower (p < 0.001). Personal characteristics, previous exposures to THMs, and specific polymorphisms in CYP2D6 and GSTT1 genes were significant predictors of both baseline and postshowering blood THM concentrations as well as of changes in THM concentrations associated with showering.
Conclusion
The inclusion of information about individual physiologic characteristics and environmental measurements would be valuable in future studies to assess human health effects from exposures to THMs in tap water.
doi:10.1289/ehp.10049
PMCID: PMC2199304  PMID: 18197300
CYP2D6; CYP2E1; disinfection by-products; drinking water disinfection; GSTT1; showering exposures; trihalomethanes
11.  Inverse association of plasma IL-13 and inflammatory chemokines with lung function impairment in stable COPD: a cross-sectional cohort study 
Respiratory Research  2007;8(1):64.
Background
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by varying degrees of airflow limitation and diffusion impairment. There is increasing evidence to suggest that COPD is also characterized by systemic inflammation. The primary goal of this study was to identify soluble proteins in plasma that associate with the severity of airflow limitation in a COPD cohort with stable disease. A secondary goal was to assess whether unique markers associate with diffusion impairment, based on diffusion capacity of carbon monoxide (DLCO), independent of the forced expiratory volume in 1 second (FEV1).
Methods
A cross sectional study of 73 COPD subjects was performed in order to examine the association of 25 different plasma proteins with the severity of lung function impairment, as defined by the baseline measurements of the % predicted FEV1 and the % predicted DLCO. Plasma protein concentrations were assayed using multiplexed immunobead-based cytokine profiling. Associations between lung function and protein concentrations were adjusted for age, gender, pack years smoking history, current smoking, inhaled corticosteroid use, systemic corticosteroid use and statin use.
Results
Plasma concentrations of CCL2/monocyte chemoattractant protein-1 (CCL2/MCP-1), CCL4/macrophage inflammatory protein-1β (CCL4/MIP -1β), CCL11/eotaxin, and interleukin-13 (IL-13) were inversely associated with the % FEV1. Plasma concentrations of soluble Fas were associated with the % DLCO, whereas CXCL9/monokine induced by interferon-γ (CXCL9/Mig), granulocyte- colony stimulating factor (G-CSF) and IL-13 showed inverse relationships with the % DLCO.
Conclusion
Systemic inflammation in a COPD cohort is characterized by cytokines implicated in inflammatory cell recruitment and airway remodeling. Plasma concentrations of IL-13 and chemoattractants for monocytes, T lymphocytes, and eosinophils show associations with increasing severity of disease. Soluble Fas, G-CSF and CXCL9/Mig may be unique markers that associate with disease characterized by disproportionate abnormalities in DLCO independent of the FEV1.
doi:10.1186/1465-9921-8-64
PMCID: PMC2064925  PMID: 17868461
12.  A Pharmacokinetic Study of Amphotericin B Lipid Complex Injection (Abelcet) in Patients with Definite or Probable Systemic Fungal Infections 
Antimicrobial Agents and Chemotherapy  2000;44(10):2900-2902.
This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.
PMCID: PMC90176  PMID: 10991885
13.  Indomethacin is a Placental Vasodilator in the Dog 
The effect of 8 mg/kg of indomethacin on uterine blood flow, prostaglandin production, and intraamniotic fluid pressure was examined in late pregnant dogs. Uterine blood flow was measured with 15 μm radiolabeled microspheres. Because we found that a significant percentage of the microspheres shunted through the placental circulation into the lungs, we calculated placental blood flow by adding the shunted microspheres through the placenta to the nonshunted microspheres in the placenta. Total uterine blood flow significantly increased from 271±69 ml/min during control period to 371±72 ml/min (P < 0.01) 30 min after indomethacin. This increase was attributable to the change in blood flow to the placental circulation (222±58 to 325±63 ml/min; P < 0.01). Associated with these hemodynamic changes we found an almost complete suppression of uterine prostaglandin E2 production (1,654±305 to 51±25 pg/ml; P < 0.01) as measured by gas chromatography-mass spectrometry. In addition, we found that indomethacin treatment resulted in uterine relaxation as measured by intraamniotic fluid pressure changes (11.2±1.3 mm Hg to 8.5±1.2 mm Hg; P < 0.001).
We conclude that indomethacin causes an increase in placental blood flow without any change in flow to the rest of the uterus, and that this dose of the drug inhibits greater than 95% of uterine prostaglandin production. In addition, indomethacin is responsible for uterine relaxation. The increase in placental blood flow after indomethacin is probably a result of uterine relaxation, which is secondary to prostaglandin synthesis inhibition.
PMCID: PMC371731  PMID: 659627
14.  Increased Clearance of Antipyrine and d-Propranolol after Phenobarbital Treatment in the Monkey 
Journal of Clinical Investigation  1974;53(4):1101-1107.
The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179±15 to 239±27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.
PMCID: PMC333095  PMID: 4205524
15.  Rapid computation of rates with a simple nomogram1 
doi:10.1901/jaba.1968.1-251
PMCID: PMC1311007  PMID: 16795183

Results 1-15 (15)