Center for Clinical Investigation

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Center for Clinical Investigation

Sun City Center, United States

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Mehra R.,Case Comprehensive Cancer Center | Mehra R.,Center for Clinical Investigation | Xu F.,Center for Clinical Investigation | Babineau D.C.,Center for Clinical Investigation | And 6 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Individuals with sleep-disordered breathing (SDB) are at increased cardiovascular risk, possibly due to SDB-related stresses contributing to atherosclerosis. Objectives:We postulate that pathways associated with a prothrombotic potential are up-regulated in SDB. Methods: Morning and evening plasminogen activator inhibitor-1 (PAI-1), morning fibrinogen, and morning D-dimer were measured in 537 Cleveland Family Study adults. Piecewise multivariable linear mixed models estimated relative mean change or mean change in the biomarker per 5-unit increase in apnea-hypopnea index (AHI) in two groups: AHI less than 15 and AHI greater than or equal to 15, and hypoxia defined as percentage of sleep time with SaO2 less than 90% (<2%, ≥2%). Measurements and Main Results: Nonlinear associations were demonstrated: morning and evening PAI-1 increased by 12% (95% confidence interval [CI], 5-20%; P<0.001) and 11% (95% CI, 2-20%; P= 0.01), respectively per 5-unit AHI increase until an AHI of 15,when no further increase in PAI-1 was demonstrated. The association between AHI and morning PAI-1 remained significant after adjusting for evening PAI-1 level (10%; 95% CI, 3-17%; P<0.01). Morning fibrinogen increased on average by 8.4 mg/dl (95% CI, 3.12-13.65; P = 0.002) per five-unit AHI increase until an AHI of 15. There was no association between AHI and morning D-dimer. Hypoxia severity was not associated with thrombotic marker levels. Conclusions: PAI-1 and fibrinogen levels increase monotonically with AHI at degrees of SDB considered mildly to moderately abnormal, suggesting that even mild SDB levels may increase prothrombotic processes. There may be a plateau in this effect, occurring at levels considered to reflect only moderate SDB severity. These relationships with mild-to-moderate SDB were not observed with D-dimer.


Li A.,Harvard University | Makar R.S.,Harvard University | Hurwitz S.,Harvard University | Hurwitz S.,Center for Clinical Investigation | And 9 more authors.
Transfusion | Year: 2016

BACKGROUND: Therapeutic plasma exchange (TPE) is a proven treatment for thrombotic thrombocytopenic purpura (TTP) characterized by severe ADAMTS13 deficiency, but the efficacy of TPE in suspected TTP with an ADAMTS13 activity level of more than 10% remains controversial. STUDY DESIGN AND METHODS: We conducted a propensity score (PS)-matched study of 186 adult patients included in the Harvard Thrombotic Microangiopathy (TMA) Research Collaborative registry who presented with TMA suggestive of TTP but an ADAMTS13 activity level of more than 10%. RESULTS: Before matching, patients treated with TPE (n = 71) differed from untreated patients (n = 115) by several clinical measures. PS matching was performed to address clinical disparities between the two groups and resulted in a well-balanced cohort of 59 TPE-treated patients paired with 59 untreated controls, all of whom had TMA. After matching, we observed no significant difference in the primary outcome of 90-day survival between the treated and untreated groups (hazard ratio, 0.88; 95% confidence interval [CI], 0.44-1.77; p = 0.72). In-hospital mortality (odds ratio [OR], 0.77; 95% CI, 0.34-1.75; p = 0.53) and the percentage of patients with platelet count recovery (OR, 1.58; 95% CI, 0.77-3.26; p = 0.21) also did not differ significantly between the two matched groups. CONCLUSION: Our data suggest that routine use of TPE in the diverse group of TMA patients without severe ADAMTS13 deficiency may not significantly improve outcomes. © 2016 AABB


Kadiyala V.,Center for Pancreatic Disease | Lee L.S.,Center for Pancreatic Disease | Banks P.A.,Center for Pancreatic Disease | Suleiman S.,Center for Pancreatic Disease | And 6 more authors.
Journal of the Pancreas | Year: 2013

Objective To compare pancreatic duct cell function in smokers (current and past) and never smokers by measurement of secretin-stimulated peak bicarbonate concentration ([HCO3 -]) in endoscopic collected pancreatic fluid (PF). Methods This retrospective study was cross-sectional in design, recording demographic information (age, gender, etc.), smoking status (former, current, never), alcohol intake, clinical data (imaging, endoscopy), and laboratory results (peak PF [HCO3 -]) from subjects evaluated for pancreatic disease at a tertiary pancreas center. Univariate and multivariate statistical analysis (SAS Version 9.2, Cary, NC, USA) was performed to assess the relationship between cigarette smoking and secretin-stimulated pancreatic fluid bicarbonate concentration. Results A total of 131 subjects underwent pancreatic fluid collection (endoscopic pancreatic function test, ePFT) for bicarbonate analysis: 25.2% (33 out of 131) past smokers, 31.3% (41 out of 131) current smokers, and 43.5% (57 out of 131) were never smokers. Measures of Association: The mean peak PF [HCO3 -] in never smokers (81.3±18.5 mEq/L) was statistically higher (indicating better duct cell function) when compared to past smokers (66.8±24.7 mEq/L, P=0.005) and current smokers (70.0±20.2 mEq/L, P=0.005). However, the mean peak [HCO3 -] in past smokers was not statistically different from that in current smokers (P=0.575), and therefore, the two smoking groups were combined to form a single "smokers cohort". When compared to the never smokers, the smokers cohort was older (P=0.037) and had a greater proportion of subjects with definite chronic pancreatitis imaging (P=0.010), alcohol consumption ≥20 g/day (P=0.012), and abnormal peak PF [HCO3-] (P<0.001). Risk-Based Estimates: Cigarette smoking (risk ratio, RR: 2.2, 95% CI: 1.3-3.5; P<0.001), diagnosis of definite chronic pancreatitis imaging (RR: 2.2, 95% CI: 1.6- 3.2; P<0.001) and alcohol consumption ≥20 g/day (RR: 1.6, 95% CI: 1.1-2.4; P=0.033) were all associated with low mean peak PF [HCO3 -] (indicating duct cell secretory dysfunction). Multivariate Analysis: Smoking (odds ratio, OR: 3.8, 95% CI: 1.6-9.1; P=0.003) and definite chronic pancreatitis imaging (OR: 5.7, 95% CI: 2.2-14.8; P<0.001) were determined to be independent predictors of low peak PF [HCO3 -], controlling for age, gender, and alcohol intake. Furthermore there was no interaction between smoking status and alcohol intake in predicting duct cell dysfunction (P=0.571). Conclusion Measurement of pancreatic fluid bicarbonate in smokers reveals that cigarette smoking (past and current) is an independent risk factor for pancreatic duct cell secretory dysfunction (low PF [HCO3 -]). Furthermore, the risk of duct cell dysfunction in subjects who smoked was approximately twice the risk (RR: 2.2) in never smokers. Further in depth, translational research approaches to pancreatic fluid analysis may help unravel mechanisms of cigarette smoking induced pancreatic duct cell injury.


Davis E.M.,University of Pittsburgh | Appel L.J.,Johns Hopkins University | Wang X.,Center for Clinical Investigation | Greene T.,University of Utah | And 6 more authors.
Hypertension | Year: 2011

Blood pressure (BP) guidelines that set target BP levels often rely on analyses of achieved BP from hypertension treatment trials. The objective of this article was to compare the results of analyses of achieved BP to intention-to-treat analyses on renal disease progression. Participants (n=1094) in the African-American Study of Kidney Disease and Hypertension Trial were randomly assigned to either usual BP goal defined by a mean arterial pressure goal of 102 to 107 mm Hg or lower BP goal defined by a mean arterial pressure goal of ≤92 mm Hg. Median follow-up was 3.7 years. Primary outcomes were rate of decline in measured glomerular filtration rate and a composite of a decrease in glomerular filtration rate by >50% or >25 mL/min per 1.73 m 2, requirement for dialysis, transplantation, or death. Intention-to-treat analyses showed no evidence of a BP effect on either the rate of decline in glomerular filtration rate or the clinical composite outcome. In contrast, the achieved BP analyses showed that each 10-mm Hg increment in mean follow-up achieved mean arterial pressure was associated with a 0.35 mL/min per 1.73 m2 (95% CI: 0.08 to 0.62 mL/min per 1.73 m; P=0.01) faster mean glomerular filtration rate decline and a 17% (95% CI: 5% to 32%; P=0.006) increased risk of the clinical composite outcome. Analyses based on achieved BP lead to markedly different inferences than traditional intention-to-treat analyses, attributed in part to confounding of achieved BP with comorbidities, disease severity, and adherence. Clinicians and policy makers should exercise caution when making treatment recommendations based on analyses relating outcomes to achieved BP. © 2011 American Heart Association, Inc.


Muller M.,North Carolina State University | Ait-Belkacem D.,ESPCI ParisTech | Hessabi M.,University of Paris Descartes | Gennisson J.-L.,ESPCI ParisTech | And 12 more authors.
Ultrasound in Medicine and Biology | Year: 2015

The quantitative assessment of the cervix is crucial for the estimation of pre-term delivery risk and the prediction of the success of labor induction. We conducted a cross-sectional study using shear wave elastography based on the supersonic shear imaging technique. The shear wave speed (SWS) of the lower anterior part of the cervix was quantified over an 8-mm region of interest in 157 pregnant women. Cervical SWS is slightly but significantly reduced in patients diagnosed with pre-term labor and in patients who actually delivered pre-term. © 2015 World Federation for Ultrasound in Medicine and Biology.


Chen Y.,Center for Clinical Investigation | Chen Y.,Case Western Reserve University | Xu R.,Center for Clinical Investigation
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2015

We propose a phenome-based strategy to identify novel disease associated genes for PD, and investigated the translational potential of the predicted genes in drug discovery. Different from previous studies, we incorporated multiple disease phenotypic similarity networks, and integrated them with a genetic network to infer novel candidate genes. We validated the approach in two experiments: the 15 known PD genes from OMIM were averagely ranked within the top 0.8%, and the top-ranked genes were enriched for 669 PD genes from GWAS. In addition, our approach prioritized the target genes for both FDA-approved PD drugs and candidate PD drugs in clinical trials. The result provides empirical evidence that our computational gene prediction approach has the translational potential in PD drug discovery. © Springer International Publishing Switzerland 2015.


Billings M.E.,Puget Sound Health Care System | Billings M.E.,University of Washington | Auckley D.,Center for Sleep Medicine | Auckley D.,Case Western Reserve University | And 9 more authors.
Sleep | Year: 2011

Study Objectives: There are few established predictors of CPAP adherence; poor adherence limits its effectiveness. We investigated whether race, education level, and residential economic status predict CPAP adherence in participants enrolled in a trial with standard access to treatment. Design: A multi-center randomized trial of home vs. lab-based evaluation and treatment of OSA assessing adherence to CPAP at 1 and 3 months. Setting: Seven AASM-accredited sleep centers in 5 U.S. cities. Participants: Subjects with moderate to severe OSA (AHI ≥ 15 and Epworth Sleepiness Scale score > 12) who completed follow-up at 1 and/or 3 months (n = 135). Measurements and Results: Subjects' demographic data were collected upon enrollment; CPAP use at 1 and 3 months was assessed at clinic follow-up. In unadjusted analyses, CPAP adherence (average minutes per night of CPAP use) at 3 months was lower in black subjects and in subjects from lower socioeconomic status ZIP codes. In adjusted analyses using multivariate linear regression, black race was predictive of CPAP adherence at one month (P = 0.03). At 3 months, black race was predictive in analyses only when ZIP code SES was not adjusted for. Conclusion: Black race and lower socioeconomic residential areas are associated with poorer adherence to CPAP in subjects with standardized access to care and treatment. Disparities remain despite provision of standardized care in a clinical trial setting. Future research is needed to identify barriers to adherence and to develop interventions tailored to improve CPAP adherence in at risk populations. Portable Monitoring for Diagnosis and Management of Sleep Apnea (HomePAP) Clinical Trial Information: NIH clinical trials registry number: NCT00642486. URL: http://clinicaltrials.gov/show/ NCT00642486.


Bernard R.S.,Stanford University | Williams S.E.,Stanford University | Storfer-Isser A.,Center for Clinical Investigation | Rhine W.,Stanford University | And 3 more authors.
Journal of Traumatic Stress | Year: 2011

Parents of hospitalized premature infants are at risk for developing psychological symptoms. This randomized controlled pilot study examined the effectiveness of a brief cognitive-behavioral intervention in reducing traumatic and depressive symptoms in mothers 1 month after their infant's discharge from the hospital. Fifty-six mothers were randomly assigned to the intervention or control group. Results showed that mothers experienced high levels of symptoms initially and at follow-up. At follow-up, there was a trend for mothers in the intervention group to report lower levels of depression (p = .06; Cohen's f = .318), but levels of traumatic symptoms were similar for both groups. Brief psychological interventions may reduce depressive symptoms in this population. Estimates of the effect sizes can be used to inform future intervention studies. © 2011 International Society for Traumatic Stress Studies.


Li A.,Harvard Medical SchoolBoston | Makar R.S.,Harvard Medical SchoolBoston | Hurwitz S.,Center for Clinical Investigation | Uhl L.,Harvard Medical SchoolBoston | And 3 more authors.
Transfusion | Year: 2016

BACKGROUND: Therapeutic plasma exchange (TPE) is a proven treatment for thrombotic thrombocytopenic purpura (TTP) characterized by severe ADAMTS13 deficiency, but the efficacy of TPE in suspected TTP with an ADAMTS13 activity level of more than 10% remains controversial. STUDY DESIGN AND METHODS: We conducted a propensity score (PS)-matched study of 186 adult patients included in the Harvard Thrombotic Microangiopathy (TMA) Research Collaborative registry who presented with TMA suggestive of TTP but an ADAMTS13 activity level of more than 10%. RESULTS: Before matching, patients treated with TPE (n=71) differed from untreated patients (n=115) by several clinical measures. PS matching was performed to address clinical disparities between the two groups and resulted in a well-balanced cohort of 59 TPE-treated patients paired with 59 untreated controls, all of whom had TMA. After matching, we observed no significant difference in the primary outcome of 90-day survival between the treated and untreated groups (hazard ratio, 0.88; 95% confidence interval [CI], 0.44-1.77; p=0.72). In-hospital mortality (odds ratio [OR], 0.77; 95% CI, 0.34-1.75; p=0.53) and the percentage of patients with platelet count recovery (OR, 1.58; 95% CI, 0.77-3.26; p=0.21) also did not differ significantly between the two matched groups. CONCLUSION: Our data suggest that routine use of TPE in the diverse group of TMA patients without severe ADAMTS13 deficiency may not significantly improve outcomes. © 2016 AABB.


Munos E.,Hopital Cardiologique du Haut Leveque | Munos E.,University of Bordeaux Segalen | Calderon J.,Hopital Cardiologique du Haut Leveque | Pillois X.,Center for Clinical Investigation | And 11 more authors.
Perfusion | Year: 2011

Background: Left ventricle dysfunction and co-morbidities are responsible for a large number of complications after coronary artery bypass graft (CABG) surgery. The best strategy for these patients, including the use or not and type of extracorporeal circulation (ECC), the use of minimized ECC (MECC), or conventional ECC (CECC), remains unclear. The aim of the present study was to investigate the potential effect of on-pump beating-heart (OPBH) surgery with the help of MECC for CABG in patients with a high-risk EuroSCORE and to compare this strategy to three other different procedures, including OPCAB and MECC or CECC with cardiac arrest. Methods: Patients were included if their EuroSCORE was strictly >" xbd="1427" xhg="1404" ybd="1477" yhg="1440"/>9. Four groups were retrospectively compared: an OPCAB, an OPBH, a MECC and a CECC group under cardiac arrest. Results: 214 patients, mean age 74.26 ± 8.5 years, 68.7% male, were operated. Mean EuroSCORE was 12.1 ± 2.9, left ventricular (LV) function 37.4 ± 12.3%, recent myocardial infarction (MI) 49.5%, renal failure 48.1%, chronic obstructive pulmonary disease (COPD) 42.2%, and peripheral vascular disease (PVD) 55.6%. Mean number of grafts per patient was 2.4 ± 0.7. Our study showed that it was possible, in very high-risk patients, to carry out revascularisation with OPBH similar to that using MECC or CECC under cardiac arrest (p=NS). This technique reduces troponin release (3.23 vs 6.56, p<0.01), postoperative myocardial complications (2% vs 8%, p<0.01), cardiotonic drug prescription (15.7% vs 31.3%, p<0.01), ventilation time (4.57H vs 6.48H, p<0.01) and length of stay (LOS) in ICU (2.16 vs 2.53, p=0.02). Conclusion: The OPBH method seems to be safe, secure and effective in this population of very high-risk patients, reducing early complications and multi-organ failure. OPBH surgery, combining MECC without aortic cross-clamping, makes it possible to perform complete revascularization and is an interesting alternative for CABG in high-risk patients. © The Author(s) 2011.

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