Browsing by Subject "Endpoint Determination"
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Item Open Access ACE-inhibition increases podocyte number in experimental glomerular disease independent of proliferation.(Journal of the renin-angiotensin-aldosterone system : JRAAS, 2015-06) Zhang, Jiong; Yanez, David; Floege, Anna; Lichtnekert, Julia; Krofft, Ronald D; Liu, Zhi-Hong; Pippin, Jeffrey W; Shankland, Stuart JObjective
The objective of this article is to test the effects of angiotensin-converting enzyme (ACE)-inhibition on glomerular epithelial cell number in an inducible experimental model of focal segmental glomerulosclerosis (FSGS).Background
Although ACE-inhibition has been shown to limit podocyte loss by enhancing survival, little is known about its effect on podocyte number following an abrupt decline in disease.Methods
Experimental FSGS was induced with cytotoxic antipodocyte antibody. Following induction, groups were randomized to receive the ACE-inhibitor enalapril, the smooth muscle relaxant hydralazine (blood pressure control) or drinking water. Blood pressure, kidney function and histology were measured seven and 14 days following disease induction.Results
Both glomerulosclerosis and urinary albumin-to-creatinine ratio were less in the ACE-inhibition arm at day 14. At day 7 of disease, mean podocyte numbers were 26% and 29% lower in the enalapril and hydralazine arms, respectively, compared to normal mice in which no antibody was injected. At day 14, the mean podocyte number was only 18% lower in the enalapril arm, but was 39% lower in the hydralazine arm compared to normal mice. Podocyte proliferation did not occur at any time in any group. Compared to water- or hydralazine-treated mice with FSGS, the enalapril arm had a higher mean number of glomerular parietal epithelial cells that co-expressed the podocyte proteins WT-1 and synaptopodin, as well as phospho-ERK.Conclusion
The results show following an abrupt decline in podocyte number, the initiation of ACE-inhibition but not hydralazine, was accompanied by higher podocyte number in the absence of proliferation. This was accompanied by a higher number of parietal epithelial cells that co-express podocyte proteins. Increasing podocyte number appears to be accompanied by reduced glomerulosclerosis.Item Open Access Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial.(American heart journal, 2019-02) Held, Claes; White, Harvey D; Stewart, Ralph AH; Davies, Richard; Sampson, Shani; Chiswell, Karen; Silverstein, Adam; Lopes, Renato D; Heldestad, Ulrika; Budaj, Andrzej; Mahaffey, Kenneth W; Wallentin, Lars; STABILITY InvestigatorsBackground
Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease.Methods
Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results.Results
In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]).Conclusions
The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.Item Open Access Relationship of T2-Weighted MRI Myocardial Hyperintensity and the Ischemic Area-At-Risk.(Circ Res, 2015-07-17) Kim, Han W; Van Assche, Lowie; Jennings, Robert B; Wince, W Benjamin; Jensen, Christoph J; Rehwald, Wolfgang G; Wendell, David C; Bhatti, Lubna; Spatz, Deneen M; Parker, Michele A; Jenista, Elizabeth R; Klem, Igor; Crowley, Anna Lisa C; Chen, Enn-Ling; Judd, Robert M; Kim, Raymond JRATIONALE: After acute myocardial infarction (MI), delineating the area-at-risk (AAR) is crucial for measuring how much, if any, ischemic myocardium has been salvaged. T2-weighted MRI is promoted as an excellent method to delineate the AAR. However, the evidence supporting the validity of this method to measure the AAR is indirect, and it has never been validated with direct anatomic measurements. OBJECTIVE: To determine whether T2-weighted MRI delineates the AAR. METHODS AND RESULTS: Twenty-one canines and 24 patients with acute MI were studied. We compared bright-blood and black-blood T2-weighted MRI with images of the AAR and MI by histopathology in canines and with MI by in vivo delayed-enhancement MRI in canines and patients. Abnormal regions on MRI and pathology were compared by (a) quantitative measurement of the transmural-extent of the abnormality and (b) picture matching of contours. We found no relationship between the transmural-extent of T2-hyperintense regions and that of the AAR (bright-blood-T2: r=0.06, P=0.69; black-blood-T2: r=0.01, P=0.97). Instead, there was a strong correlation with that of infarction (bright-blood-T2: r=0.94, P<0.0001; black-blood-T2: r=0.95, P<0.0001). Additionally, contour analysis demonstrated a fingerprint match of T2-hyperintense regions with the intricate contour of infarcted regions by delayed-enhancement MRI. Similarly, in patients there was a close correspondence between contours of T2-hyperintense and infarcted regions, and the transmural-extent of these regions were highly correlated (bright-blood-T2: r=0.82, P<0.0001; black-blood-T2: r=0.83, P<0.0001). CONCLUSION: T2-weighted MRI does not depict the AAR. Accordingly, T2-weighted MRI should not be used to measure myocardial salvage, either to inform patient management decisions or to evaluate novel therapies for acute MI.Item Open Access Stiffness After Pan-Lumbar Arthrodesis for Adult Spinal Deformity Does Not Significantly Impact Patient Functional Status or Satisfaction Irrespective of Proximal Endpoint.(Spine, 2017-08) Hart, Robert A; Hiratzka, Jayme; Kane, Marie S; Lafage, Virginie; Klineberg, Eric; Ames, Christopher P; Line, Breton G; Schwab, Frank; Scheer, Justin K; Bess, Shay; Hamilton, David K; Shaffrey, Christopher I; Mundis, Greg; Smith, Justin S; Burton, Douglas C; Sciubba, Daniel M; Deviren, Vedat; Boachie-Adjei, Oheneba; International Spine Study GroupStudy design
Prospective, multicenter.Objective
To determine if stiffness significantly affects function or satisfaction after pan-lumbar arthrodesis.Summary of background data
The Lumbar Stiffness Disability Index (LSDI) is a validated measure of the effect of lumbar stiffness on functional activities. Data suggests that patients undergoing fusion of the entire lumbar spine are at greatest risk of functional limitations from stiffness.Methods
The LSDI, Short Form 36, Scoliosis Research Society-22, and Oswestry Disability Index were administered preoperatively and at 2-year minimum follow-up to 103 spinal deformity patients from 11 centers. Patients were separated according to the proximal arthrodesis level; upper thoracic (T2-5) to pelvis (UT-Pelvis) or thoraco-lumbar (T10-T12) to pelvis (TL-Pelvis). Outcome scores were compared using Student t test or Tukey-Kramer Honest Significant Difference Analysis of Variance. Regression analysis of final LSDI scores versus Scoliosis Research Society-22 Satisfaction scores was performed.Results
Mean ages, baseline values, and final scores of all outcome parameters were statistically equivalent in the two groups. Final LSDI scores did not change significantly from baseline in the UT-Pelvis (P = 0.478) or TL-Pelvis (P = 0.301) groups. In contrast, highly significant improvements (P ≤ 0.0001) from baseline were seen in both groups for other health-related QoL measures. The 2-year Satisfaction scores were statistically equivalent in the two groups, and the correlation between final LSDI and Satisfaction scores in the entire cohort was not significant (R = 0.013, P = 0.146).Conclusion
Patients undergoing pan-lumbar arthrodesis for adult spinal deformity did not experience substantial increases in disability due to stiffness of the low back, although they did report significant improvements in other health-related QoL measures. Further, LSDI scores did not correlate with patient satisfaction. There were no significant differences in perceived stiffness effects whether arthrodesis stopped in the thoracolumbar or upper thoracic regions. We hope these results will be useful to spine surgeons and patients during preoperative planning and discussions.Level of evidence
2.Item Open Access The imaging viewpoint: how imaging affects determination of progression-free survival.(Clin Cancer Res, 2013-05-15) Sullivan, Daniel Carl; Schwartz, Lawrence H; Zhao, BinshengTumor measurements on computed tomgoraphic or MRI scans and/or the appearance of new lesions on any of a variety of imaging studies including positron emission tomographic scans are key determinants for assessing progression-free survival as an endpoint in many clinical trials of therapies for solid tumors. Test-retest tumor measurement reproducibility may vary considerably across serial scans on the same patient unless rigorous attention is paid to standardization of image acquisition parameters and unless measurements are made by trained, experienced observers using validated objective methods. Target lesion selection also must be done with care to choose lesions that are or will be reproducibly measurable. Likewise, new lesions will be missed or misinterpreted on follow-up imaging studies unless those imaging studies are obtained using techniques suitable for detecting early, small lesions. Reader variability is clearly a major component of the problem. The increasing availability of semiautomatic image processing algorithms will help ameliorate that issue. In addition, an array of internationally accepted guidelines, standards, and accreditation programs now exist to help address these problems.Item Open Access The lung cancer exercise training study: a randomized trial of aerobic training, resistance training, or both in postsurgical lung cancer patients: rationale and design.(BMC Cancer, 2010-04-21) Jones, Lee W; Eves, Neil D; Kraus, William E; Potti, Anil; Crawford, Jeffrey; Blumenthal, James A; Peterson, Bercedis L; Douglas, Pamela SBACKGROUND: The Lung Cancer Exercise Training Study (LUNGEVITY) is a randomized trial to investigate the efficacy of different types of exercise training on cardiorespiratory fitness (VO2peak), patient-reported outcomes, and the organ components that govern VO2peak in post-operative non-small cell lung cancer (NSCLC) patients. METHODS/DESIGN: Using a single-center, randomized design, 160 subjects (40 patients/study arm) with histologically confirmed stage I-IIIA NSCLC following curative-intent complete surgical resection at Duke University Medical Center (DUMC) will be potentially eligible for this trial. Following baseline assessments, eligible participants will be randomly assigned to one of four conditions: (1) aerobic training alone, (2) resistance training alone, (3) the combination of aerobic and resistance training, or (4) attention-control (progressive stretching). The ultimate goal for all exercise training groups will be 3 supervised exercise sessions per week an intensity above 70% of the individually determined VO2peak for aerobic training and an intensity between 60 and 80% of one-repetition maximum for resistance training, for 30-45 minutes/session. Progressive stretching will be matched to the exercise groups in terms of program length (i.e., 16 weeks), social interaction (participants will receive one-on-one instruction), and duration (30-45 mins/session). The primary study endpoint is VO2peak. Secondary endpoints include: patient-reported outcomes (PROs) (e.g., quality of life, fatigue, depression, etc.) and organ components of the oxygen cascade (i.e., pulmonary function, cardiac function, skeletal muscle function). All endpoints will be assessed at baseline and postintervention (16 weeks). Substudies will include genetic studies regarding individual responses to an exercise stimulus, theoretical determinants of exercise adherence, examination of the psychological mediators of the exercise - PRO relationship, and exercise-induced changes in gene expression. DISCUSSION: VO2peak is becoming increasingly recognized as an outcome of major importance in NSCLC. LUNGEVITY will identify the optimal form of exercise training for NSCLC survivors as well as provide insight into the physiological mechanisms underlying this effect. Overall, this study will contribute to the establishment of clinical exercise therapy rehabilitation guidelines for patients across the entire NSCLC continuum. TRIAL REGISTRATION: NCT00018255.Item Open Access Translational toxicology: a developmental focus for integrated research strategies.(BMC pharmacology & toxicology, 2013-01) Hughes, Claude; Waters, Michael; Allen, David; Obasanjo, IyaboBACKGROUND: Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of "translational toxicology" be taken to mean? DISCUSSION: Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures.The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan; 2) Defining modes of action and relevance of data from animal models; 3) Use of mathematical models to develop plausible predictions as the basis for: 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. SUMMARY: Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics.