Publications by authors named "Marepalli B Rao"

30 Publications

  • Page 1 of 1

Non-invasive evaluation of toxicity in vitreoretinal domain following insertion of sustained release methotrexate micro-implant.

Exp Eye Res 2021 Apr 19;205:108505. Epub 2021 Feb 19.

Department of Mechanical and Materials Engineering, University of Cincinnati, Cincinnati, OH, USA. Electronic address:

Purpose: To evaluate the safety and toxicity profile of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based sustained release methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes using non-invasive testing that included electroretinography (ERG), ultrasound biomicroscopy (US), slit-lamp biomicroscopy (SLB), funduscopy, and intraocular pressure (IOP).

Methods: PLGA-coated CS-based micro-implants containing 400 μg of MTX and placebo (without drug) micro-implants were surgically-implanted in the vitreous of the right and the left eyes, respectively, in each of the thirty New Zealand rabbits. ERG, US, SLB, funduscopy, and IOP were assessed in both eyes at pre-determined time points (days: 1, 3, 7, 14, 28 and 56). The safety of micro-implants was assessed by analyzing the ERG data using different statistical models, to quantify and compare the functional integrity of the retina. Further, US, funduscopy, SLB and IOP determined the condition of the retina, the micro-implant and associated intraocular features.

Results: Statistical analyses of the ERG data showed unchanged functional integrity of retina between eyes with the PLGA-coated CS-based MTX micro-implant and the placebo micro-implant. US analysis showed that micro-implants were stationary throughout the study. SLB, funduscopy and IOP further confirmed that there were no abnormalities in the intraocular physiology.

Conclusion: The findings from ERG, US, SLB, funduscopy, and IOP showed no detectable adverse effects caused by our biodegradable micro-implants. These non-invasive techniques appeared to show lack of significant ocular toxicity over time in spite of degradation and changes in morphology of the micro-implants following intraocular implantation.
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http://dx.doi.org/10.1016/j.exer.2021.108505DOI Listing
April 2021

Accelerated sonothrombolysis with Definity in a xenographic porcine cerebral thromboembolism model.

Sci Rep 2021 Feb 17;11(1):3987. Epub 2021 Feb 17.

Department of Biomedical Engineering, College of Engineering and Applied Sciences, University of Cincinnati, CVC 3921, 0586, 231 Albert Sabin Way, Cincinnati, OH, 45267-0586, USA.

Adjuvant ultrasound at 2 MHz with or without an ultrasound contrast agent improves the rate of thrombus resolution by recombinant tissue plasminogen activator (rt-PA) in laboratory and clinical studies. A sub-megahertz approach can further expand this therapy to a subset of patients with an insufficient temporal bone window, improving efficacy in unselected patient populations. The aim of this study was to determine if a clinical ultrasound contrast agent (UCA), Definity, and 220 kHz pulsed ultrasound accelerated rt-PA thrombolysis in a preclinical animal model of vascular occlusion. The effect of Definity and ultrasound on thrombus clearance was first investigated in vitro and subsequently tested in a xenographic porcine cerebral thromboembolism model in vivo. Two different microcatheter designs (end-hole, multi-side-hole) were used to infuse rt-PA and Definity at the proximal edge or directly into clots, respectively. Sonothrombolysis with Definity increased clot mass loss relative to saline or rt-PA alone in vitro, only when rt-PA was administered directly into clots via a multi-side-hole microcatheter. Combined treatment with rt-PA, Definity, and ultrasound in vivo increased the rate of reperfusion up to 45 min faster than clots treated with rt-PA or saline. In this porcine cerebral thromboembolism model employing retracted human clots, 220 kHz ultrasound, in conjunction with Definity increased the probability of early successful reperfusion with rt-PA.
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http://dx.doi.org/10.1038/s41598-021-83442-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889614PMC
February 2021

Benralizumab for Chronic Spontaneous Urticaria.

N Engl J Med 2020 10;383(14):1389-1391

University of Cincinnati College of Medicine, Cincinnati, OH.

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http://dx.doi.org/10.1056/NEJMc2016395DOI Listing
October 2020

In vivo ultrasound thermal ablation control using echo decorrelation imaging in rabbit liver and VX2 tumor.

PLoS One 2019 5;14(12):e0226001. Epub 2019 Dec 5.

Dept of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, United States of America.

The utility of echo decorrelation imaging feedback for real-time control of in vivo ultrasound thermal ablation was assessed in rabbit liver with VX2 tumor. High-intensity focused ultrasound (HIFU) and unfocused (bulk) ablation were performed using 5 MHz linear image-ablate arrays. Treatments comprised up to nine lower-power sonications, followed by up to nine higher-power sonications, ceasing when the average cumulative echo decorrelation within a control region of interest exceeded a predefined threshold (- 2.3, log10-scaled echo decorrelation per millisecond, corresponding to 90% specificity for tumor ablation prediction in previous in vivo experiments). This threshold was exceeded in all cases for both HIFU (N = 12) and bulk (N = 8) ablation. Controlled HIFU trials achieved a significantly higher average ablation rate compared to comparable ablation trials without image-based control, reported previously. Both controlled HIFU and bulk ablation trials required significantly less treatment time than these previous uncontrolled trials. Prediction of local liver and VX2 tumor ablation using echo decorrelation was tested using receiver operator characteristic curve analysis, showing prediction capability statistically equivalent to uncontrolled trials. Compared to uncontrolled trials, controlled trials resulted in smaller thermal ablation regions and higher contrast between echo decorrelation in treated vs. untreated regions. These results indicate that control using echo decorrelation imaging may reduce treatment duration and increase treatment reliability for in vivo thermal ablation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226001PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894854PMC
March 2020

LEI: A Novel Allele Frequency-Based Feature Selection Method for Multi-ancestry Admixed Populations.

Sci Rep 2019 07 31;9(1):11103. Epub 2019 Jul 31.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, 45229, USA.

Next-generation sequencing technologies now make it possible to sequence and genotype hundreds of thousands of genetic markers across the human genome. Selection of informative markers for the comprehensive characterization of individual genomic makeup using a high dimensional genomics dataset has become a common practice in evolutionary biology and human genetics. Although several feature selection approaches exist to determine the ancestry proportion in two-way admixed populations including African Americans, there are limited statistical tools developed for the feature selection approaches in three-way admixed populations (including Latino populations). Herein, we present a new likelihood-based feature selection method called Lancaster Estimator of Independence (LEI) that utilizes allele frequency information to prioritize the most informative features useful to determine ancestry proportion from multiple ancestral populations in admixed individuals. The ability of LEI to leverage summary-level statistics from allele frequency data, thereby avoiding the many restrictions (and big data issues) that can accompany access to individual-level genotype data, is appealing to minimize the computation and time-consuming ancestry inference in an admixed population. We compared our allele-frequency based approach with genotype-based approach in estimating admixed proportions in three-way admixed population scenarios. Our results showed ancestry estimates using the top-ranked features from LEI were comparable with the estimates using features from genotype-based methods in three-way admixed population. We provide an easy-to-use R code to assist researchers in using the LEI tool to develop allele frequency-based informative features to conduct admixture mapping studies from mixed samples of multiple ancestry origin.
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http://dx.doi.org/10.1038/s41598-019-47012-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668412PMC
July 2019

Application of a Landmark-Based Method for Acoustic Analysis of Dysphonic Speech.

J Voice 2020 Jul 12;34(4):645.e11-645.e18. Epub 2019 Jan 12.

Department of Communication Sciences and Disorders, College of Allied Health Sciences, University of Cincinnati, Cincinnati, Ohio.

Aim: Speakers with dysphonia often report difficulty with maintaining intelligibility in noisy environments; however, there is no objective method for characterizing this difficulty. Landmark-based analysis is a linguistically-motived, knowledge-based speech analysis technique, which may serve as the basis of acoustic tool for describing the intelligibility deficit. As the first step toward development of such a tool, this study examined whether Landmark-based analysis could describe acoustic differences between normal and dysphonic speech.

Method: The recordings subjected to the Landmark-based analysis were the first sentence of the Rainbow Passage from 33 speakers with normal voice and 36 speakers with dysphonia. These recordings were selected from the Kay Elemetrics Database of Disordered Voice. The between-group difference was evaluated based on counts of certain Landmarks (LM).

Results: The average counts of all LMs were significantly greater in normal speech, t(66.85) = 2.36, P = 0.02. When the group-difference was examined for each LM, dysphonic speech had more [g] and [b] LMs and fewer [s] LMs than normal speech (P < 0.01 for all cases). A classification tree model identified [+s] and [+b] LMs are the primary predictors for the dysphonic speech. The model's misclassification rate was 7.24%.

Conclusions: This preliminary investigation demonstrates that LM-based analysis is capable of differentiating dysphonic speech from normal speech. This encouraging result rationalizes future examinations of LM analysis in other areas of interest. For example, LM-based measures could conceivably be used as to quantify general intelligibility, and/or provide insight into underlying mechanisms of intelligibility deficits.
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http://dx.doi.org/10.1016/j.jvoice.2018.12.017DOI Listing
July 2020

Characterization of cavitation-radiated acoustic power using diffraction correction.

J Acoust Soc Am 2018 12;144(6):3563

Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA.

A method is developed for compensating absolute pressure measurements made by a calibrated passive cavitation detector (PCD) to estimate the average acoustic power radiated from a region of interest (ROI) defined to encompass all cavitating bubbles. A diffraction correction factor for conversion of PCD-measured pressures to cavitation-radiated acoustic power per unit area or volume is derived as a simple analytic expression, accounting for position- and frequency-dependent PCD sensitivity. This approach can be applied to measurements made by any PCD without precise knowledge of the number, spatial, or temporal distribution of cavitating bubbles. The diffraction correction factor is validated in simulation for a wide range of ROI dimensions and frequencies. The correction factor is also applied to emission measurements obtained during ultrasound-enhanced sonophoresis experiments, allowing comparison of stable cavitation levels between therapeutic configurations with different source center frequencies. Results incorporating sonication at both 0.41 and 2.0 MHz indicate that increases in skin permeability correlate strongly with the acoustic power of subharmonic emissions radiated per unit skin area.
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http://dx.doi.org/10.1121/1.5083831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308017PMC
December 2018

Using poly(l-lactic acid) and poly(ɛ-caprolactone) blends to fabricate self-expanding, watertight and biodegradable surgical patches for potential fetoscopic myelomeningocele repair.

J Biomed Mater Res B Appl Biomater 2019 02 16;107(2):295-305. Epub 2018 May 16.

Structural Tissue Evaluation and Engineering Laboratory, Department of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, 45221.

Our study focuses on the development and characterization of a self-expanding, watertight and biodegradable patch for fetoscopic myelomeningocele (MMC) prenatal repair. We fabricated poly(l-lactic acid) (PLA) and poly(ɛ-caprolactone) (PCL) blend films by solution casting. Formulation c with average glass transition temperature of 37.6 ± 1.2°C was chosen for temporospatial recovery. Favorable results from surface studies reflected homogeneous dispersion of polymers in the blend. The cytotoxicity was studied in human foreskin fibroblasts. The blend film was cytocompatible, evidenced by matching percentage of live cells in exposed and control solutions. Subsequently, liquid water permeability experiments confirmed watertight nature of films. Finally, in vitro degradation was investigated in phosphate buffered saline (PBS) and amniotic fluid (AF) separately for 16 weeks. Similar weight loss (n = 6, p = 0.912) and significantly different (n = 3, p = 0.025) surface roughness was observed in PBS and AF, respectively, at 16 weeks. Functional group analysis displayed increasing carbonyl and hydroxyl bonds in PBS and AF, respectively, over time, indicating progression of hydrolytic degradation. Favorable characterization results provide strong evidence to employ PLA-PCL blend films as surgical patches in fetoscopic MMC repair. Designed patch serves as standalone system to successfully tackle impending hurdles of MMC repair and proves to be a superior alternative compared to existing patches. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 295-305, 2019.
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http://dx.doi.org/10.1002/jbm.b.34121DOI Listing
February 2019

Effects of Population Variability on Knee Loading During Simulated Human Gait.

Ann Biomed Eng 2018 Feb 20;46(2):284-297. Epub 2017 Nov 20.

Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA.

Cadaveric simulation models allow researchers to study native tissues in situ. However, as tests are conducted using donor specimens with unmatched kinematics, techniques that impose population average motions are subject to deviation from true physiologic conditions. This study aimed to identify factors which explain the kinetic variability observed during robotic simulations of a single human gait motion using a sample of human cadaver knees. Twelve human cadaver limbs (58 ± 16 years) were subjected to tibiofemoral geometrical analysis and cyclical stiffness testing in each anatomical degree of freedom. A simulated gait motion was then applied to each specimen. Resulting kinetics, specimen geometries, and various representations of tissue stiffness were reduced to functional attributes using principal component analysis and fit to a generalized linear prediction model. The capacity of knee topography to generate force was the largest contributor to kinetic variation in compression. Overall joint size, femoral notch height, translational laxity, and ad/abduction stiffness significantly contributed to kinetic variation in medial/lateral and anterior/posterior forces and associated torques. Future studies will investigate customizing kinematic paths to better simulate native conditions and reduce sampling variation, improving biomechanical test methods and evaluation strategies for future orthopedic techniques.
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http://dx.doi.org/10.1007/s10439-017-1956-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771862PMC
February 2018

Aryl Hydrocarbon Receptor Ablation in Cardiomyocytes Protects Male Mice From Heart Dysfunction Induced by NKX2.5 Haploinsufficiency.

Toxicol Sci 2017 Nov;160(1):74-82

Department of Environmental Health and Center for Environmental Genetics.

Epidemiological studies in humans and research in vertebrates indicates that developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous and biopersistent environmental toxicant, is associated with incidence of early congenital heart disease in the embryo and later in the adult. TCDD-mediated toxicity depends on the aryl hydrocarbon receptor (AHR) but the role of the TCDD-activated AHR in cardiac function is not well-defined. To characterize the mechanisms responsible for AHR-mediated disruption of heart function, we generated several mouse strains with cardiomyocyte-specific Ahr gene knockout. Here, we report results on one of these strains in which the Ahr gene was deleted by cre recombinase regulated by the promoter of the cardiomyocyte-specific Nkx2.5 gene. We crossed mice with loxP-targeted Ahrfx/fx alleles with Nkx2.5+/cre mice bearing a "knock-in" cre recombinase gene integrated into one of the Nkx2.5 alleles. In these mice, loss of one Nkx2.5 allele is associated with disrupted cardiac development. In males, Nkx2.5 hemizygosity resulted in cardiac haploinsufficiency characterized by hypertrophy, dilated cardiomyopathy, and impaired ejection fraction. Ahr ablation protected Nkx2.5+/cre haploinsufficient males from cardiac dysfunction while inducing a significant increase in body weight. These effects were absent or largely blunted in females. Starting at 3 months of age, mice were exposed by oral gavage to 1 μg/kg/week of TCDD or control vehicle for an additional 2 months. TCDD exposure restored cardiac physiology in aging males, appearing to compensate for the heart dysfunction caused by Nkx2.5 hemizygosity. Our findings underscore the conclusion that deletion of the Ahr gene in cardiomyocytes protects males from heart dysfunction due to NKX2.5 haploinsufficiency.
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http://dx.doi.org/10.1093/toxsci/kfx164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837197PMC
November 2017

Noninvasive Electroretinography Assessment of Intravitreal Sustained-Release Methotrexate Microimplants in Rabbit Eyes.

J Ocul Pharmacol Ther 2016 11 18;32(9):583-594. Epub 2016 Oct 18.

1 Department of Mechanical and Materials Engineering, University of Cincinnati , Cincinnati, Ohio.

Purpose: The purpose of this study is to noninvasively evaluate the safety and toxicity of a chitosan (CS) and polylactic acid (PLA)-based sustained-release methotrexate (MTX) intravitreal microimplant in normal rabbit eyes using electroretinography (ERG).

Methods: PLA-coated CS-based microimplants containing 400 μg of MTX and placebo microimplants (without drug) were surgically implanted in the vitreous of the right and the left eyes, respectively, in each of the 8 New Zealand rabbits using minimally invasive technique. At each predetermined time points (days 5, 12, 19, and 33), ERG was conducted on 2 rabbits to evaluate the safety of the microimplants administered in each eye. ERG was carried out using 2 protocols, scotopic and photopic, on each eye prior to surgery (PS) and prior to euthanasia (PE) conditions. The safety of the microimplants was assessed using statistical analysis of the ERG data (B/A ratio analysis, oscillatory potential analysis, and Naka-Rushton analysis) and subsequently quantifying and comparing functional integrity of the retina between the PS and PE conditions of each eye.

Results: Statistical analysis of the ERG data showed no change in retinal functional integrity because of the PLA-coated CS-based MTX microimplant and the placebo microimplant. ERG analysis also revealed absence of any evident bioelectrical dysfunction caused by the microimplants.

Conclusion: ERGs were performed to determine whether the microimplants containing MTX and the placebo microimplants were associated with any profound retinal bioelectrical dysfunction that might be attributable to toxicity not apparent on histological studies of such eyes. The results shown in this report indicate that there were no such evident adverse effects of the microimplants or contained drug.
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http://dx.doi.org/10.1089/jop.2016.0006DOI Listing
November 2016

Echo Decorrelation Imaging of Rabbit Liver and VX2 Tumor during In Vivo Ultrasound Ablation.

Ultrasound Med Biol 2017 01 4;43(1):176-186. Epub 2016 Oct 4.

Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, USA. Electronic address:

In open surgical procedures, image-ablate ultrasound arrays performed thermal ablation and imaging on rabbit liver lobes with implanted VX2 tumor. Treatments included unfocused (bulk ultrasound ablation, N = 10) and focused (high-intensity focused ultrasound ablation, N = 13) exposure conditions. Echo decorrelation and integrated backscatter images were formed from pulse-echo data recorded during rest periods after each therapy pulse. Echo decorrelation images were corrected for artifacts using decorrelation measured prior to ablation. Ablation prediction performance was assessed using receiver operating characteristic curves. Results revealed significantly increased echo decorrelation and integrated backscatter in both ablated liver and ablated tumor relative to unablated tissue, with larger differences observed in liver than in tumor. For receiver operating characteristic curves computed from all ablation exposures, both echo decorrelation and integrated backscatter predicted liver and tumor ablation with statistically significant success, and echo decorrelation was significantly better as a predictor of liver ablation. These results indicate echo decorrelation imaging is a successful predictor of local thermal ablation in both normal liver and tumor tissue, with potential for real-time therapy monitoring.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.08.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5140680PMC
January 2017

Dependence of ultrasound echo decorrelation on local tissue temperature during ex vivo radiofrequency ablation.

Phys Med Biol 2016 Mar 4;61(6):2356-71. Epub 2016 Mar 4.

Department of Biomedical, Chemical, and Environmental Engineering, University of Cincinnati, Cincinnati, OH, USA.

This study investigates echo decorrelation imaging, an ultrasound method for thermal ablation monitoring. The effect of tissue temperature on the mapped echo decorrelation parameter was assessed in radiofrequency ablation experiments performed on ex vivo bovine liver tissue. Echo decorrelation maps were compared with corresponding tissue temperatures simulated using the finite element method. For both echo decorrelation imaging and integrated backscatter imaging, the mapped tissue parameters correlated significantly but weakly with local tissue temperature. Receiver operating characteristic (ROC) curves were used to assess the ability of echo decorrelation and integrated backscatter to predict tissue temperature greater than 40, 60, and 80 °C. Significantly higher area under the ROC curve (AUROC) values were obtained for prediction of tissue temperatures greater than 40, 60, and 80 °C using echo decorrelation imaging (AUROC = 0.871, 0.948 and 0.966) compared to integrated backscatter imaging (AUROC = 0.865, 0.877 and 0.832).
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http://dx.doi.org/10.1088/0031-9155/61/6/2356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038931PMC
March 2016

Fish and Shellfish Intake and Diabetes in a Costal Population of the Adriatic.

Coll Antropol 2015 Jun;39(2):401-9

The objective of the study was to examine the association between fish and shellfish intake and diabetes in an island population, and the design of the study was Cross-sectional. Two independent population-based field surveys were conducted in Hvar Island of the eastern Adriatic coast of Croatia in May 2007 and May 2008, with a total of 1,379 adult participants. In multivariable logistic regression models, total fish intake was positively associated with diabetes prevalence in the total population (OR(Q4 vs. Q1) = 1.64; 95% CI = 1.01-2.66; p-trend = 0.09). Oily fish intake also exhibited a positive association with diabetes prevalence in the total population (OR(Q4 vs. Q1) = 2.22; 95% CI = 1.35-3.64; p-trend = 0.01) and in analyses stratified by body mass index, males and those with a high waist circumference. The study suggests an association between oily fish intake and diabetes in the population of the Hvar Island in Croatia. Longitudinal studies incorporating measures of persistent organic pollutants and local cooking practices are warranted to identify factors in fatty fish that may influence the development or persistence of diabetes.
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June 2015

Risk factors for acute kidney injury during aminoglycoside therapy in patients with cystic fibrosis.

Pediatr Nephrol 2015 Oct 26;30(10):1879-88. Epub 2015 Apr 26.

Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA,

Background: Aminoglycoside (AG) therapy is a common cause of acute kidney injury (AKI) in cystic fibrosis (CF) patients. The aim of this study was to identify factors associated with AKI during intravenous AG courses in this population.

Methods: This was a matched case-control study utilizing two independent cohorts of hospitalized CF patients receiving ≥ 3 days of intravenous AG at Cincinnati Children's Hospital Medical Center and Children's of Alabama. All admissions with AKI (cases, N = 82) were matched to two randomly selected admissions without AKI (controls, N = 164) by center, gender, and age ±3 years of the case. AKI was defined as a 1.5-fold increase in the baseline serum creatinine (SCr) level or by an increase in SCr level of 0.3 mg/dL within 48 h. Admissions with AKI before day 4 or without at least weekly SCr monitoring were excluded from the analysis. Factors were compared between cases and controls using simple and multiple conditional logistic regression.

Results: Multivariable analysis identified receipt of an AG within 90 days prior to admission, longer duration of AG therapy, low serum albumin, and receipt of trimethoprim/sulfamethoxazole as independent risk factors for developing AKI. Infection with Staphylococcus aureus diminished the odds of developing AKI.

Conclusions: This study identifies risk factors contributing to AG-associated AKI in CF patients. These findings can be used to anticipate high-risk scenarios and limit AKI in CF patients under clinical care.
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http://dx.doi.org/10.1007/s00467-015-3097-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576343PMC
October 2015

Experience with Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen.

Biol Blood Marrow Transplant 2015 Aug 10;21(8):1460-70. Epub 2015 Apr 10.

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens are increasingly used for the hematopoietic cell transplantation (HCT) of pediatric and young adult patients with nonmalignant diseases. Early experience suggests that these regimens are associated with good survival but a high incidence of mixed chimerism, which we have previously shown to be influenced by the alemtuzumab schedule. We hypothesized that the underlying diagnosis and donor graft source would also affect the development of mixed chimerism and that the majority of patients would survive RIC HCT without graft loss. To examine this, we conducted a retrospective study of 206 patients with metabolic diseases, non-Fanconi anemia marrow failure disorders, and primary immune deficiencies who underwent 210 consecutive RIC HCT procedures at Cincinnati Children's Hospital. Ninety-seven percent of the patients engrafted. Mixed donor and recipient chimerism developed in 46% of patients. Patients with marrow failure had a low risk of mixed chimerism (hazard ratio [HR], .208; 95% confidence interval [CI], .061 to .709; P = .012). The risk of mixed chimerism was high in patients who received a cord blood graft (HR, 3.122; 95% CI, 1.236 to 7.888; P = .016). As expected, patients who received a proximal or higher dose per kilogram of alemtuzumab schedule also experienced higher rates of mixed chimerism (all HR > 2, all P < .05). At the time of last follow-up (median, 654 days; range, 13 to 3337), over 75% of patients had greater than 90% whole blood donor chimerism. A second transplantation was performed in 5% of patients. Three-year survival without retransplantation was 84% (95% CI, 71% to 98%) for patients who underwent transplantation with an HLA-matched sibling donor. Survival without retransplantation was negatively affected by lack of a matched related donor, increasing age, and development of grades III and IV acute graft-versus-host disease. We conclude that alemtuzumab, fludarabine, and melphalan RIC HCT offers good results for many patients and that the risk of developing mixed chimerism is influenced by underlying diagnosis, graft source, and alemtuzumab dosing.
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http://dx.doi.org/10.1016/j.bbmt.2015.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603747PMC
August 2015

Prevalence and predictors of aortic dilation as a novel cardiovascular complication in children with end-stage renal disease.

Clin Nephrol 2015 May;83(5):262-71

Background: Cardiovascular disease is the leading cause of death in children with end-stage renal disease (ESRD). Isolated aortic dilation (AD) is rare in children. We aimed to determine the prevalence and the risk factors for AD in children with ESRD.

Methods And Study Design: We reviewed records of all ESRD patients followed mat our institution from January 2007 to October 2012. AD was defined as Z-score > 2 in the dimension of at least one of the following echocardiographic aortic parameters: annulus, root at the sinus, sino-tubular junction, or ascending aorta.

Results: The records of 78 patients on dialysis and 19 kidney transplant recipients were available. 30 patients (30.9%) had AD. Multivariate analysis revealed independent associations of AD with body mass index (BMI) Z-score (OR = 0.52, 95% confidence interval (CI): 0.35 - 0.78) and ESRD secondary to glomerular disease (OR = 4.58, 95% CI: 1.45 - 14.46). We developed a classification and regression tree (CART) model to identify patients at low vs. high AD risk. Our model classified 62 patients of the cohort (64%) to be high- or lowrisk, with a positive predictive value of 89% and a negative predictive value of 100%.

Conclusion: Our data suggest that AD, as a possible marker of aortopathy and early aneurysm formation, is a novel and prevalent cardiovascular complication in ESRD children. Glomerular disease and low BMI Zscore appear to be potent predictors. CART modeling helps identify high-risk children, potentially guiding decisions regarding targeted echocardiographic evaluations.
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http://dx.doi.org/10.5414/CN108489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535175PMC
May 2015

Systematic review of risk factors for surgical site infection in pediatric scoliosis surgery.

Spine J 2015 Jun 18;15(6):1422-31. Epub 2015 Mar 18.

Department of Anesthesiology and Department of Pediatrics, 3333 Burnet Ave, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

Background Context: Risk factors for surgical site infection (SSI) in children derived from the studies in the adult population are potentially misleading because of differences in pathophysiology and management.

Purpose: This systematic review addresses the key question: What are the risk factors for SSI in pediatric patients undergoing scoliosis surgery?

Study Design: This is a qualitative systematic literature review.

Patient Sample: Retrospective and observational trials of children undergoing scoliosis surgery reported on the occurrence of risk factors for SSI and the occurrence of SSI.

Methods: Pubmed (Medline), Ovid Evidence-Based Medicine Reviews (EBMR), Scopus, and Cumulative Index to Nursing and Allied Health (CINAHL) were searched electronically for relevant articles in all the languages between January 1, 1991 and August 27, 2012, and cross-references were checked. Two independent reviewers identified articles and appraised quality with the Agency for Healthcare Research and Quality (AHRQ) criteria based on a weighted scoring of 0 to 100.

Results: Our search identified 135 abstracts and 14 studies meeting the inclusion criteria. The AHRQ grading showed that five articles were high quality with a score of greater than 67, and five articles were moderate quality with a score between 50 and 67. The percent agreement between the two independent reviewers was 84%, and kappa agreement score was 0.91 (95% confidence interval [CI]: 0.78-1.03). There were 76 risk factors identified, of which 22 factors were reported in more than one study. Odds ratios and 95% CIs were reported inconsistently. Pooled p analysis of high- and moderate-quality articles identified five risk factors predictive of SSI: inappropriate antibiotic use (p=.001), neuromuscular scoliosis (p=.014), instrumentation (p=.023), increased hospital stay days (p=.003), and residual postoperative curve (p=.003).

Conclusions: The systematic review identified inappropriate antibiotic use, neuromuscular scoliosis, instrumentation, increased hospital stay days, and residual postoperative curve as risk factors for SSI after pediatric scoliosis surgery.
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http://dx.doi.org/10.1016/j.spinee.2015.03.005DOI Listing
June 2015

Characteristics of inpatient anterior cruciate ligament reconstructions and concomitant injuries.

Knee Surg Sports Traumatol Arthrosc 2016 Sep 16;24(9):2778-2786. Epub 2014 Dec 16.

Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA.

Purpose: The purpose of this epidemiologic study was to quantify the incidence, expense, and concomitant injuries for anterior cruciate ligament reconstruction (ACLR) procedures in the USA from 2003 to 2011 that required an inpatient stay. It was hypothesized that the relative reported rates of concomitant knee injuries would be greater with the MCL and menisci compared to all other concomitant knee injuries.

Methods: The National Inpatient Sample from 2003 to 2011 was retrospectively sampled using ICD-9-CM codes to identify ACLR patients and to extrapolate national averages.

Results: Between the years of 2003-2011, an average of 9,037 ± 1,728 inpatient hospitalization included ACLRs, of which 4,252 ± 1,824 were primarily due to the ACLR. Inpatient visits primarily due to ACLR involved an average hospitalization of 1.7 ± 0.2 days and cost $30,118 ± 9,066 per patient. Knee injuries that were commonly reported along with inpatient ACLRs included medial meniscus damage (18.1 %), lateral meniscus damage (16.8 %), collateral ligament repairs (12.3 %), and medial collateral ligament strains (6.9 %). Prevalence of meniscus injuries was consistent across years, but MCL-related injuries increased over time.

Conclusions: ACLR-related inpatient hospitalizations account for approximately 7.1 % of the total ACLRs performed annually in the USA. Inpatient ACLR procedures continue to decrease in frequency; however, the mean cost per patient increased. Meniscus and collateral ligament injuries were the most commonly reported concomitant knee injuries. The clinical relevance of this investigation is that it informs, on a large clinical cohort of patients, the current state of incidence and expense for ACLR surgeries in an inpatient setting.

Level Of Evidence: Prognostic, retrospective study, Level II.
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http://dx.doi.org/10.1007/s00167-014-3478-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469632PMC
September 2016

Relations between acoustic cavitation and skin resistance during intermediate- and high-frequency sonophoresis.

J Control Release 2014 Nov 15;194:266-77. Epub 2014 Aug 15.

Biomedical Engineering Program, University of Cincinnati, Cincinnati, OH, USA. Electronic address:

Enhanced skin permeability is known to be achieved during sonophoresis due to ultrasound-induced cavitation. However, the mechanistic role of cavitation during sonophoresis has been extensively investigated only for low-frequency (LFS, <100 kHz) applications. Here, mechanisms of permeability-enhancing stable and inertial cavitation were investigated by passively monitoring subharmonic and broadband emissions arising from cavitation isolated within or external to porcine skin in vitro during intermediate- (IFS, 100-700 kHz) and high-frequency sonophoresis (HFS, >1 MHz). The electrical resistance of skin, a surrogate measure of the permeability of skin to a variety of compounds, was measured to quantify the reduction and subsequent recovery of the skin barrier during and after exposure to pulsed (1 second pulse, 20% duty cycle) 0.41 and 2.0 MHz ultrasound over a range of acoustic powers (0-21.7 W) for 30 min. During IFS, significant skin resistance reductions and acoustic emissions from cavitation were measured exclusively when cavitation was isolated outside of the skin. Time-dependent skin resistance reductions measured during IFS correlated significantly with subharmonic and broadband emission levels. During HFS, significant skin resistance reductions were accompanied by significant acoustic emissions from cavitation measured during trials that isolated cavitation activity either outside of skin or within skin. Time-dependent skin resistance reductions measured during HFS correlated significantly greater with subharmonic than with broadband emission levels. The reduction of the skin barrier due to sonophoresis was reversible in all trials; however, effects incurred during IFS recovered more slowly and persisted over a longer period of time than HFS. These results quantitatively demonstrate the significance of cavitation during sonophoresis and suggest that the mechanisms and post-treatment longevity of permeability enhancement due to IFS and HFS treatments are different.
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http://dx.doi.org/10.1016/j.jconrel.2014.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050987PMC
November 2014

Daily serum creatinine monitoring promotes earlier detection of acute kidney injury in children and adolescents with cystic fibrosis.

J Cyst Fibros 2014 Jul 6;13(4):435-41. Epub 2014 Apr 6.

The Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background: The epidemiology of aminoglycoside-associated acute kidney injury (AG-AKI) has not been well described in pediatric patients with cystic fibrosis (CF). We aimed to assess the impact of daily serum creatinine (SCr) measurement on detection of AG-AKI at our institution.

Methods: We examined a cohort of hospitalized patients with CF who received an intravenous (IV) aminoglycoside for ≥ 3 days. We compared the rate, timing, and medical management surrounding detection of AG-AKI during 2 periods: January 2010-May 2011 (Era 1, SCr measured at the discretion of the medical team, N=124) and June 2011-June 2012 (Era 2, SCr measured daily, N=103). Our primary outcome was detection of AG-AKI defined as ≥ 50% increase in SCr from baseline (lowest value in prior 6 months), or ≥ 0.3mg/dL rise within 48 h, occurring after day 2.

Results: The use of once daily tobramycin (p=0.02) and IV fluids (p<0.001) was higher during Era 2, while AG courses were shorter (p=0.04), and fewer concomitant nephrotoxins (p=0.04) were given; higher daily tobramycin doses (p<0.001) were administered. Although the rate of AG-AKI was not significantly different (12% during Era 1 vs. 20% during Era 2, p=0.09), the number of AG-AKI days detected increased (5.5 vs. 2.9 per 100 AG days, p=0.003), and detection occurred earlier (median 6 vs. 9 days, log rank test p=0.02) during the daily SCr period.

Conclusions: Daily SCr measurement promoted earlier and increased detection of AG-AKI in patients with CF at our institution. We suggest systematic evaluation for AKI during aminoglycoside administration in patients with CF.
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http://dx.doi.org/10.1016/j.jcf.2014.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058368PMC
July 2014

In vivo thermal ablation monitoring using ultrasound echo decorrelation imaging.

Ultrasound Med Biol 2014 Jan 14;40(1):102-14. Epub 2013 Nov 14.

Biomedical Engineering Program, University of Cincinnati, Cincinnati, Ohio, USA.

Previous work indicated that ultrasound echo decorrelation imaging can track and quantify changes in echo signals to predict thermal damage during in vitro radiofrequency ablation (RFA). In the in vivo studies reported here, the feasibility of using echo decorrelation imaging as a treatment monitoring tool was assessed. RFA was performed on normal swine liver (N = 5), and ultrasound ablation using image-ablate arrays was performed on rabbit liver implanted with VX2 tumors (N = 2). Echo decorrelation and integrated backscatter were computed from Hilbert transformed pulse-echo data acquired during RFA and ultrasound ablation treatments. Receiver operating characteristic (ROC) curves were employed to assess the ability of echo decorrelation imaging and integrated backscatter to predict ablation. Area under the ROC curves (AUROC) was determined for RFA and ultrasound ablation using echo decorrelation imaging. Ablation was predicted more accurately using echo decorrelation imaging (AUROC = 0.832 and 0.776 for RFA and ultrasound ablation, respectively) than using integrated backscatter (AUROC = 0.734 and 0.494).
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http://dx.doi.org/10.1016/j.ultrasmedbio.2013.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849110PMC
January 2014

Dietary patterns in adults from an Adriatic Island of Croatia and their associations with metabolic syndrome and its components.

Coll Antropol 2013 Jun;37(2):335-42

University of Cincinnati, College of Medicine, Department of Environmental Health, Cincinnati, Ohio 45267, USA.

Adriatic islanders have a high prevalence of metabolic syndrome (MetS) although they have traditionally practiced an active lifestyle and adhered to a Mediterranean diet. We performed a cross-sectional study to identify dietary patterns in a sample of 1442 adults from the island of Hvar, and determined whether MetS and its components: waist-circumference, serum triglycerides, fasting plasma glucose, HDL-cholesterol, and blood pressure, were related to an altered pattern of the traditional Mediterranean diet. Dietary intake was assessed by a food frequency questionnaire. MetS was defined using the International Diabetes Federation criteria. Our study showed that dietary patterns in this population have diversified from the traditional diet. Principal component analysis identified three major patterns. The meat, alcohol, and fish pattern (MAFp), sweets, grains, and fats pattern (SGFp), and an olive-oil, vegetables, and fruits pattern (OVFp) explained 30.6% of total dietary variance. The MAFp associated significantly with MetS (p = 0.027) and high plasma glucose (p = 0.006).
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June 2013

Vitamin D deficiency and low bone mineral density in pediatric and young adult intestinal failure.

J Pediatr Gastroenterol Nutr 2013 Sep;57(3):372-6

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children Hospital Medical Center, Cincinnati, OH, USA.

Objectives: The aim of the present study was to determine the prevalence and predisposing factors for vitamin D deficiency and low bone mineral density (BMD) in patients with intestinal failure (IF).

Methods: A retrospective review of patients with IF managed at the Cincinnati Children's Hospital Medical Center. IF was defined as history of parenteral nutrition (PN) >30 days. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25 (OH) D) <20 ng/dL. Reduced BMD was defined using dual x-ray absorptiometry z score ≤-2. A binary logistic regression model was used to test for association of significant risk factors and the outcome variables after univariate analyses.

Results: One hundred and twenty-three patients with median age of 4 years (range 3-22 years) were evaluated. Forty-nine (39.8%) patients had at least a documented serum 25 (OH) D deficiency during the study interval, whereas 10 of 80 patients (12.5%) with dual x-ray absorptiometry scans completed had a low BMD z score. Age at study entry was associated with both 25 (OH) D deficiency (P = 0.01) and low BMD z score (P = 0.03). Exclusive PN at study entry was associated with reduced bone mass (P = 0.03). There was no significant association between vitamin D deficiency and low BMD z score (P = 0.31).

Conclusions: The risk of 25 (OH) D deficiency and low BMD z score increases with age among patients with IF. Strategies for monitoring and preventing abnormal bone health in older children receiving exclusive PN need to be developed and evaluated.
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http://dx.doi.org/10.1097/MPG.0b013e31829c10ebDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757114PMC
September 2013

Outcome of very low birth weight infants with abnormal antenatal Doppler flow patterns: a prospective cohort study.

Indian Pediatr 2013 Sep 5;50(9):847-52. Epub 2013 Mar 5.

Departments of Pediatrics and *Obstetrics and Gynecology, Fernandez Hospital, Boggulkunta, Hyderabad, Andhra Pradesh, India; #Division of Biostatistics, Dept. of Environmental Health University of Cincinnati, 3223, Eden Avenue, Cincinnati, Ohio 45267; USA and Divisions of Neonatology and Pulmonary Biology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. Correspondence to: Dr Srinivas Murki, Consultant Neonatologist, Fernandez Hospital, Boggulakunta, Hyderabad.

Background: Fetal growth restriction and abnormal Doppler flow studies are commonly associated. Neonatal outcomes are not well known particularly in developing countries, where the burden of the disease is the highest.

Objective: To determine outcomes of preterm infants with history of absent/reversed end-diastolic umbilical artery Doppler flow (AREDF) vs. infants with forward end-diastolic flow (FEDF).

Design: Cohort study.

Setting: Tertiary care perinatal center in India.

Participants: 103 AREDF very low birth weight (<1500 gm) (VLBW) infants and 117 FEDF VLBW infants were prospectively enrolled.

Results: At 40 weeks adjusted post-menstrual age, AREDF vs. FEDF group had a higher risk for death in the NICU (12% vs. 1%), respiratory distress syndrome (33% vs. 19%), and cystic periventricular leukomalacia (12% vs. 1%). At 12-18 months corrected age, AREDF vs. FEDF group had a trend towards increased risk for cerebral palsy (7% vs. 1%, P=0.06). After logistic regression analysis, adjusting for confounders, AREDF was independently associated only with mortality in the NICU.

Conclusions: AREDF is an independent predictor of adverse outcomes in preterm infants in a developing country setting.
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http://dx.doi.org/10.1007/s13312-013-0235-5DOI Listing
September 2013

Therapeutic enhancement of protective immunity during experimental leishmaniasis.

PLoS Negl Trop Dis 2011 Sep 6;5(9):e1316. Epub 2011 Sep 6.

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

Background: Leishmaniasis remains a significant cause of morbidity and mortality in the tropics. Available therapies are problematic due to toxicity, treatment duration and emerging drug resistance. Mouse models of leishmaniasis have demonstrated that disease outcome depends critically on the balance between effector and regulatory CD4(+) T cell responses, something mirrored in descriptive studies of human disease. Recombinant IL-2/diphtheria toxin fusion protein (rIL-2/DTx), a drug that is FDA-approved for the treatment of cutaneous T cell lymphoma, has been reported to deplete regulatory CD4(+) T cells.

Methodology/principal Findings: We investigated the potential efficacy of rIL-2/DTx as adjunctive therapy for experimental infection with Leishmania major. Treatment with rIL-2/DTx suppressed lesional regulatory T cell numbers and was associated with significantly increased antigen-specific IFN-γ production, enhanced lesion resolution and decreased parasite burden. Combined administration of rIL-2/DTx and sodium stibogluconate had additive biological and therapeutic effects, allowing for reduced duration or dose of sodium stibogluconate therapy.

Conclusions/significance: These data suggest that pharmacological suppression of immune counterregulation using a commercially available drug originally developed for cancer therapy may have practical therapeutic utility in leishmaniasis. Rational reinvestigation of the efficacy of drugs approved for other indications in experimental models of neglected tropical diseases has promise in providing new candidates to the drug discovery pipeline.
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http://dx.doi.org/10.1371/journal.pntd.0001316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167777PMC
September 2011

Survival of patients with small cell carcinoma of the prostate during 1973-2003: a population-based study.

BJU Int 2012 Mar 23;109(6):824-30. Epub 2011 Aug 23.

Divisions of Urology Biostatistics, University of Cincinnati, Cincinnati, OH, USA.

Objective: To describe the survival of patients with primary small cell carcinoma (SCC) of the prostate and assess prognostic factors based on a large population sample.

Patients And Methods: A total of 241 cases of SCC of the prostate were reported to the Surveillance, Epidemiology, and End Results (SEER) registries from 1973 to 2003 of which 191 cases were included in our study. We used the Kaplan-Meier method for estimating survival, and Cox proportional hazard regression modelling to evaluate prognostic variables.

Results: The overall age-adjusted incidence rate was 0.278 per 1,000,000 (95% confidence interval, 0.239-0.323). In all, 60.5% presented as metastatic disease compared with 39.5% who presented as local/regional disease (P= 0.012). The 12, 24, 36, 48 and 60 months observed survival rates were 47.9%, 27.5%, 19%, 17% and 14.3% respectively. On univariate analyses, age <60, concomitant low-grade prostatic adenocarcinoma, absence of metastasis, prostatectomy and radiation therapy were favourable prognostic factors. In multivariate regression modelling, age, pathology and stage were strong predictors of survival.

Conclusions: Using the SEER database, we present the largest study describing the epidemiology of primary SCC of the prostate. We found age, concomitant low-grade prostatic adenocarcinoma, and stage of the disease to be the strongest predictors of survival for patients with prostatic SCC. Future studies evaluating a broader range of clinical and molecular markers are needed to refine the prognostic model of this relatively rare disease.
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http://dx.doi.org/10.1111/j.1464-410X.2011.10523.xDOI Listing
March 2012

Association between SNP heterozygosity and quantitative traits in the Framingham Heart Study.

Ann Hum Genet 2009 Jul;73(Pt 4):465-73

Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.

Associations between multilocus heterozygosity and fitness traits, also termed heterozygosity and fitness correlations (HFCs), have been reported in numerous organisms. These studies, in general, indicate a positive relationship between heterozygosity and fitness traits. We studied the association between genome-wide heterozygosity at 706 non-synonymous and synonymous SNPs and 19 quantitative traits, including morphological, biochemical and fitness traits in the Framingham Heart Study. Statistically significant association was found between heterozygosity and systolic and diastolic blood pressures as well as left ventricular diameter and wall thickness. These results suggest that heterozygosity may be associated with traits, such as blood pressure that closely track environmental variations. Balancing selection may be operating in the maintenance of heterozygosity and the major components of blood pressure and hypertension. Genome wide SNP heterozygosity may be used to understand the phenomenon of dominance as well as the evolutionary basis of many quantitative traits in humans.
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http://dx.doi.org/10.1111/j.1469-1809.2009.00514.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760672PMC
July 2009

Improving noninvasive methods of assessing liver fibrosis in patients with hepatitis C virus/human immunodeficiency virus co-infection.

Clin Gastroenterol Hepatol 2009 Apr 25;7(4):471-80, 480.e1-2. Epub 2008 Dec 25.

Infectious Disease Epidemiology, Merck and Co, Inc, North Wales, Pennsylvania 19545-1099, USA.

Background & Aims: Liver fibrosis is a significant concern for patients with hepatitis C virus/human immunodeficiency virus co-infection. Fibrosis staging by biopsy is accurate, but costly and invasive. Several fibrosis prediction models using noninvasive biomarkers have been developed but are suboptimal in co-infected patients. We compared results from different staging models and ordinal regression with biopsy data.

Methods: Data from the Adult Acquired Immune Deficiency Syndrome Clinical Trials Group protocol A5178 were used to evaluate 5 models of fibrosis staging; areas under receiver-operator characteristic curves (AUROC) were assessed. Individual covariates were assessed with univariable regression and then entered into an ordinal logistic regression model from which a stage-wise index was developed.

Results: Data from 173 patients were evaluated; 85% were on antiretroviral therapy, 31.2% had severe fibrosis (F3/F4), and 14% had cirrhosis (F4). Differences in CD4+ cell and platelets counts and international normalized ratio values were observed between those with and without F3/F4. Among existing models, the FIB-4 index ([age x AST])/[platelet count x (ALT)(1/2)]) performed best, with 88% specificity for F4 and greater than 86% negative predictive values for F3/F4, although AUROC values were low (0.56 +/- 0.03 for F3/F4). By using patients' demographic, clinical, and laboratory data, the ordinal regression model outperformed others, with an AUROC of 0.85 (standard error, 0.03) for predicting stage F3/F4 and 0.89 (standard error, 0.05) for stage 3 alone.

Conclusions: Current noninvasive methods of fibrosis assessment have poor discriminatory capacity in hepatitis C virus/human immunodeficiency virus co-infected patients. Ordinal regression analysis outperformed other noninvasive fibrosis prediction models. Longitudinal studies with paired biopsies will assist in refining the Ordinal Regression Index.
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http://dx.doi.org/10.1016/j.cgh.2008.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159915PMC
April 2009