Supporting underrepresented students in health sciences: a fuzzy cognitive mapping approach to program evaluation.

BACKGROUND: The Students Training in Academia, Health, and Research (STAHR) Program at the University of Missouri-Kansas City (UMKC) strives to help students from low-income families that have experienced educational challenges due to poverty and prepare them to enter, persist, and graduate from a health sciences degree program at UMKC. Students in the program participated in fuzzy cognitive mapping (FCM) sessions to ensure that all voices of the program were heard to improve program implementation, and student success, and contribute to an equitable educational environment. METHODS: Fuzzy Cognitive Mapping sessions for the 2020-2021 cohort of students (n = 52) were conducted to assess the strengths and weaknesses in program implementation, especially through the beginning of the COVID-19 pandemic. Students' maps were coded by a team of researchers and then confirmed using confirmatory factor analysis. RESULTS: Statistical analyses reveal that mentorship, workshops, and social support helped students to work toward their goal of obtaining a professional health sciences degree, while a lack of time, remote learning, and outside stressors inhibited their opportunities for success. CONCLUSIONS: The findings from a multipronged analysis of mapping data demonstrate the value of this innovative approach to the field, especially when looking to incorporate student voices.

Elusive Neck Carcinoma Simulating Idiopathic Intracranial Hypertension Due to Jugular Venous Outflow Obstruction - Case Report.

Few cases have been reported of extra-cranial tumours in the neck causing intracranial hypertension due to jugular vein compression and consequent outflow obstruction. We present a case of a patient presenting with transient vision loss due to intracranial hypertension of unidentifiable cause on initial imaging workup. Upon further evaluation, the patient was found to have a neck tumour compressing the right jugular vein with stenosis of the ipsilateral transverse sinus - both contributing to his intracranial hypertension. Atypical patients presenting with symptoms concerning for intracranial hypertension may benefit from imaging below the level of the head to evaluate for extra-cranial causes.

How does CBCT reconstruction algorithm impact on deformably mapped targets and accumulated dose distributions?

PURPOSE: We performed quantitative analysis of differences in deformable image registration (DIR) and deformable dose accumulation (DDA) computed on CBCT datasets reconstructed using the standard (Feldkamp-Davis-Kress: FDK_CBCT) and a novel iterative (iterative_CBCT) CBCT reconstruction algorithms. METHODS: Both FDK_CBCT and iterative_CBCT images were reconstructed for 323 fractions of treatment for 10 prostate cancer patients. Planning CT images were deformably registered to each CBCT image data set. After daily dose distributions were computed, they were mapped to planning CT to obtain deformed doses. Dosimetric and image registration results based CBCT images reconstructed by two algorithms were compared at three levels: (A) voxel doses over entire dose calculation volume, (B) clinical constraint results on targets and sensitive structures, and (C) contours propagated to CBCT images using DIR results based on three algorithms (SmartAdapt, Velocity, and Elastix) were compared with manually delineated contours as ground truth. RESULTS: (A) Average daily dose differences and average normalized DDA differences between FDK_CBCT and iterative_CBCT were ≤1 cGy. Maximum daily point dose differences increased from 0.22 ± 0.06 Gy (before the deformable dose mapping operation) to 1.33 ± 0.38 Gy after the deformable dose mapping. Maximum differences of normalized DDA per fraction were up to 0.80 Gy (0.42 ± 0.19 Gy). (B) Differences in target minimum doses were up to 8.31 Gy (-0.62 ± 4.60 Gy) and differences in critical structure doses were 0.70 ± 1.49 Gy. (C) For mapped prostate contours based on iterative_CBCT (relative to standard FDK_CBCT), dice similarity coefficient increased by 0.10 ± 0.09 (p < 0.0001), mass center distances decreased by 2.5 ± 3.0 mm (p < 0.00005), and Hausdorff distances decreased by 3.3 ± 4.4 mm (p < 0.00015). CONCLUSIONS: The new iterative CBCT reconstruction algorithm leads to different mapped volumes of interest, deformed and cumulative doses than results based on conventional FDK_CBCT.

Modeling AeroForm tissue expander for postmastectomy radiation therapy.

The AeroForm chest wall tissue expander (TE) is a silicon shell containing a metallic CO2 reservoir, placed surgically after mastectomy. The patient uses a remote control to release compressed CO2 from the reservoir to inflate the expander. AeroForm poses challenges in a radiation therapy setting: The high density of the metallic reservoir causes imaging artifacts on the planning CT, which encumber structure definition and cause misrepresentation of density information, in turn affecting dose calculation. Additionally, convolution-based dose calculation algorithms may not be well-suited to calculate dose in and around high-density materials. In this study, a model of the AeroForm TE was created in Eclipse treatment planning system (TPS). The TPS model was validated by comparing measured to calculated transmission through the AeroForm. Transmission was measured with various geometries using radiochromic film. Dose was calculated with both Varian's Anisotropic Analytical Algorithm (AAA) and Acuros External Beam (AXB) algorithms. AAA and AXB were compared using dose profile and gamma analyses. While both algorithms modeled direct transmission well, AXB better modeled lateral scatter from the AeroForm TE. Clinical significance was evaluated using clinical data from four patients with AeroForm TEs. The AeroForm TPS model was applied, and RT plans were optimized using AAA, then re-calculated with AXB. Structures of clinical significance were defined and dose volume histogram analysis was performed. Compared to AXB, AAA overestimates dose in the AeroForm device. Changes in clinically significant regions were patient- and plan-specific. This study proposes a clinical procedure for modeling the AeroForm in a commercial TPS, and discusses the limitations of dose calculation in and around the device. An understanding of dose calculation accuracy in the vicinity of the AeroForm is critical for assessing individual plan quality, appropriateness of different planning techniques and dose calculation algorithms, and even the decision to use the AeroForm in a postmastectomy radiation therapy setting.

On the improvement of CBCT image quality for soft tissue-based SRS localization.

PURPOSE: We explore the optimal cone-beam CT (CBCT) acquisition parameters to improve CBCT image quality to enhance intracranial stereotactic radiosurgery (SRS) localization and also assess the imaging dose levels associated with each imaging protocol. METHODS: Twenty-six CBCT acquisition protocols were generated on an Edge® linear accelerator (Varian Medical Systems, Palo Alto, CA) with different x-ray tube current and potential settings, gantry rotation trajectories, and gantry rotation speeds. To assess image quality, images of the Catphan 504 phantom were analyzed to evaluate the following image quality metrics: uniformity, HU constancy, spatial resolution, low contrast detection, noise level, and contrast-to-noise ratio (CNR). To evaluate the imaging dose for each protocol, the cone-beam dose index (CBDI) was measured. To validate the phantom results, further analysis was performed with an anthropomorphic head phantom as well as image data acquired for a clinical SRS patient. RESULTS: The Catphan data indicates that adjusting acquisition parameters had direct effects on the image noise level, low contrast detection, and CNR, but had minimal effects on uniformity, HU constancy, and spatial resolution. The noise level was reduced from 34.5 ± 0.3 to 18.5 ± 0.2 HU with a four-fold reduction in gantry speed, and to 18.7 ± 0.2 HU with a four-fold increase in tube current. Overall, the noise level was found to be proportional to inverse square root of imaging dose, and imaging dose was proportional to the product of total tube current-time product and the cube of the x-ray potential. Analysis of the anthropomorphic head phantom data and clinical SRS imaging data also indicates that noise is reduced with imaging dose increase. CONCLUSIONS: Our results indicate that optimization of the imaging protocol, and thereby an increase in the imaging dose, is warranted for improved soft-tissue visualization for intracranial SRS.

Tuning of AcurosXB source size setting for small intracranial targets.

This study details a method to evaluate the source size selection for small field intracranial stereotactic radiosurgery (SRS) deliveries in Eclipse treatment planning system (TPS) for AcurosXB dose calculation algorithm. Our method uses end-to-end dosimetric data to evaluate a total of five source size selections (0.50 mm, 0.75 mm, 1.00 mm, 1.25 mm, and 1.50 mm). The dosimetric leaf gap (DLG) was varied in this analysis (three DLG values were tested for each scenario). We also tested two MLC leaf designs (standard and high-definition MLC) and two delivery types for intracranial SRS (volumetric modulated arc therapy [VMAT] and dynamic conformal arc [DCA]). Thus, a total of 10 VMAT plans and 10 DCA plans were tested for each machine type (TrueBeam [standard MLC] and Edge [high-definition MLC]). Each plan was mapped to a solid water phantom and dose was calculated with each iteration of source size and DLG value (15 total dose calculations for each plan). To measure the dose, Gafchromic film was placed in the coronal plane of the solid water phantom at isocenter. The phantom was localized via on-board CBCT and the plans were delivered at planned gantry, collimator, and couch angles. The planned and measured film dose was compared using Gamma (3.0%, 0.3 mm) criteria. The vendor-recommended 1.00 mm source size was suitable for TrueBeam planning (both VMAT and DCA planning) and Edge DCA planning. However, for Edge VMAT planning, the 0.50 mm source size yielded the highest passing rates. The difference in dose calculation among the source size variations manifested primarily in two regions of the dose calculation: (1) the shoulder of the high-dose region, and (2) for small targets (volume ≤ 0.30 cc), in the central portion of the high-dose region. Selection of a larger than optimal source size can result in increased blurring of the shoulder for all target volume sizes tested, and can result in central axis dose discrepancies in excess of 10% for target volumes sizes ≤ 0.30 cc. Our results indicate a need for evaluation of the source size when AcurosXB is used to model intracranial SRS delivery, and our methods represent a feasible process for many clinics to perform tuning of the AcurosXB source size parameter.

Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy.

There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow-up liver biopsies, and from a phase III study of balaglitazone in patients with late-stage Type 2 diabetes (BALLET study) were analyzed for serological Pro-C3 levels in conjunction with other disease parameters. In the farglitazar study, a predefined cutoff value for Pro-C3 as a selection criterion led to the identification of subjects who 1) progressed by histological scores and 2) responded to therapy, as documented by attenuated fibrosis in liver biopsies. In the BALLET trial, subjects with the highest tertile of Pro-C3 levels responded to balaglitazone with reductions in levels of alanine aminotransferase and Pro-C3, as well as improved insulin sensitivity and lipid profile. Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis, and it can potentially identify patients most likely to benefit from antimetabolic and antifibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up antifibrotic drug development and validation.

Temporal Changes of PBDE Levels in California House Cats and a Link to Cat Hyperthyroidism.

In this study, we measured serum PBDE levels in California (CA) house cats during two time periods: 2008-2010 and 2012-2013 to assess the impacts of the decline in use of these materials after the bans. The median ∑19PBDE level in CA household cats (age ≥10 yr) was 3479 ng/g lipid in 2008-2010 (1st time period, n = 21) and 1518 ng/g lipid in 2012-2013 (2nd time period, n = 22), about 2 times lower than in the first time period (p = 0.006). In contrast, PCB and OCP levels showed no statistically significant changes. With better matched group size and age (HT = 11 vs non-HT = 11, age ≥10 yr) in the second time period, we found that ∑19PBDE level (mean ± SE ng/g lipid) was significantly higher in the HT group (3906 ± 1442) than those in the non-HT group (1125 ± 244) (p = 0.0030). Higher levels of PCBs and OCPs were also found in HT group. Despite the declines of PBDE levels, our findings indicate that the current levels of PBDEs, as well as PCBs and OCPs, may still pose health effects for house cats and, possibly, humans.

Targeting Endothelial Adhesion Molecule Transcription for Treatment of Inflammatory Disease: A Proof-of-Concept Study.

Targeting the endothelial adhesion molecules that control leukocyte trafficking into a tissue has been explored as a biological therapy for inflammatory diseases. However, these molecules also participate in leukocyte migration for immune surveillance, and inhibiting the physiological level of an adhesion molecule might promote infection or malignancy. We explored the concept of targeting endothelial adhesion molecule transcription during inflammation in a human system. Intercellular adhesion molecule 1 (ICAM-1) mediates leukocyte migration across the retinal endothelium in noninfectious posterior uveitis. We observed an increase in the transcription factor, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1), in parallel with ICAM-1, in human retinal endothelial cells treated with tumor necrosis factor-alpha (TNF-α), and identified putative binding sites for NF-κB1 within the ICAM-1 regulatory region. We targeted induced NF-κB1 expression in endothelial cells with small interfering (si)RNA. Knockdown of NF-κB1 significantly decreased cell surface expression of ICAM-1 protein induced by TNF-α but did not reduce constitutive ICAM-1 expression. Consistently, NF-κB1 knockdown significantly reduced leukocyte binding to cell monolayers in the presence of TNF-α but did not impact baseline binding. Findings of this proof-of-concept study indicate that induced transcription of endothelial adhesion molecules might be targeted therapeutically for inflammatory disease in humans.

Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C.

BACKGROUND & AIMS: Fibrogenesis results in release of certain extracellular matrix protein fragments into the circulation. We evaluated the diagnostic and prognostic performance of two novel serological markers, the precisely cleaved N-terminal propeptide of type III collagen (Pro-C3) and a peptide of helical collagen type III degradation (C3M), in chronic hepatitis C (CHC) patients. METHOD: Pro-C3 and C3M were measured by ELISA in plasma from CHC patients (n = 194) from a prior phase II antifibrotic trial (NCT00244751). Plasma samples and paired liver biopsies were obtained at baseline and after 1-year. Patients were stratified according to Ishak stages 2-4. Internal cross-validation was performed by bootstrap analysis. RESULTS: Pro-C3 levels were significantly higher in CHC patients in Ishak stage 4 compared to stage 2 (P < 0.001) or 3 (P < 0.01). Pro-C3 could significantly distinguish moderate (stage 4) from mild fibrosis (stage 2/3) (AUC = 0.72, P < 0.001). Importantly, an overall significance in Pro-C3 (P = 0.007) levels was observed between the groups of -1, 0, +1 and +2 change in Ishak stage at 12 months. Pro-C3 was significantly increased in group +1 (P = 0.030) and +2 (P = 0.021) compared to group 0. No significant differences were observed for C3M. In multivariate analysis, only baseline Pro-C3, but not FibroTest, had an independent association with fibrosis progression. CONCLUSIONS: Pro-C3 is a useful test to predict fibrogenesis and monitor disease progression. Moreover, it could differentiate mild from moderate disease. Pro-C3 may become a promising blood parameter be included in future studies for monitoring disease progression and eventually for evaluation of potential antifibrotic therapies.

A Data-Centric Strategy for Modern Biobanking.

Biobanking has been in existence for many decades and over that time has developed significantly. Biobanking originated from a need to collect, store and make available biological samples for a range of research purposes. It has changed as the understanding of biological processes has increased and new sample handling techniques have been developed to ensure samples were fit-for-purpose.As a result of these developments, modern biobanking is now facing two substantial new challenges. Firstly, new research methods such as next generation sequencing can generate datasets that are at an infinitely greater scale and resolution than previous methods. Secondly, as the understanding of diseases increases researchers require a far richer data set about the donors from which the sample originate.To retain a sample-centric strategy in a research environment that is increasingly dictated by data will place a biobank at a significant disadvantage and even result in the samples collected going unused. As a result biobanking is required to change strategic focus from a sample dominated perspective to a data-centric strategy.

Characteristics of nonfatal occupational injuries among U.S. workers with and without disabilities.

BACKGROUND: Workers with disabilities have a higher risk of nonfatal occupational injuries than workers without disabilities. The characteristics of these injuries are not well described. METHODS: Using 1997-2011 National Health Interview Survey (NHIS) data, we compared the nonfatal occupational injuries sustained by U.S. workers with and without disabilities. RESULTS: Overexertion or strenuous movements and falls accounted for 56.7% of all occupational injuries in workers with disabilities, compared with 45.6% in workers without a disability. Workers with disabilities were more frequently injured in the lower extremity (32.3% vs. 26.6%) or torso (22.9% vs. 16.9%). Workers with disabilities sustained more unspecified injuries (13.5% vs. 7.9%) and fewer open wound injuries (15.7% vs. 24.2%) than their counterparts without a disability. CONCLUSIONS: U.S. workers with disabilities had a higher rate of occupational injuries and these injuries tended to be more severe and were more likely to be caused by overexertion/ strenuous movement or falls.

Generation and verification of QFix kVue Calypso-compatible couch top model for a dedicated stereotactic linear accelerator with FFF beams.

This study details the generation, verification, and implementation of a treatment planning system (TPS) couch top model for patient support system used in conjunction with a dedicated stereotactic linear accelerator. Couch top model was created within the TPS using CT simulation images of the kVue Calpyso-compatible couchtop (with rails). Verification measurements were compared to TPS dose prediction for different energies (6 MV FFF and 10 MV FFF) and rail configurations (rails in and rails out) using: 1) central axis point-dose measurements with pinpoint chamber in water-equivalent phantom at 42 gantry angles for various field sizes (2 × 2 cm², 4 × 4 cm², 10 × 10 cm²); and 2) Gafchromic EBT3 film parallel to beam in acrylic slab to assess changes in surface and percent depth doses in PA geometry. To assess sensitivity of delivered dose to variations in patient lateral position, measurements at central axis using the pinpoint chamber geometry were taken at lateral couch displacements of 2, 5, and 10 mm for 6 MV FFF. The maximum percent difference for point-dose measurements was 3.24% (6 MV FFF) and 2.30% (10 MV FFF). The average percent difference for point-dose measurements was less than 1.10% for all beam energies and rail geometries. The maximum percent difference between calculated and measured dose can be as large as 13.0% if no couch model is used for dose calculation. The presence of the couch structures also impacts surface dose and PDD, which was evaluated with Gafchromic film measurements. The upstream shift in the depth of dose maximum (dmax) was found to be 10.5 mm for 6 MV FFF and 5.5 mm for 10 MV FFF for 'Rails In' configuration. Transmission of the treatment beam through the couch results in an increase in surface dose (absolute percentage) of approximately 50% for both photon energies (6 MV FFF and 10MV FFF). The largest sensitivity to lateral shifts occurred at the lateral boundary of the rail structures. The mean magnitude (standard deviation) of the deviation between shifted and centered measurements over all field sizes tested was 0.61% (0.61%) for 2 mm shifts, 0.46% (0.67%) for 5 mm shifts, and 0.86% (1.46%) for 10 mm shifts.

Characteristics of a novel treatment system for linear accelerator-based stereotactic radiosurgery.

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image-guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter-free (FFF) beams for both high definition (HD120) MLC and conical cone-based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end-to-end accuracy tests, have been performed. The end-to-end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone-beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth-dose curves acquired on the new linac-based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond D(max) were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2-1.8 mm (80%-20%) and 1.9-3.8 mm (90%-10%) relative to 10X FFF, which has 1.2-2.2mm and 2.3-5.1mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails-in), oblique, oblique (rails-out), oblique (rails-in) were: -2.0%, -2.5%, -15.6%, -2.5%, -5.0% for 6X FFF and -1.4%, -1.5%, -12.2%, -2.5%, -5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was -0.4 ± 0.2 mm, 0.1± 0.3mm, and 0.0 ± 0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston-Lutz tests over three months are 0.20 ± 0.03 mm and 0.66 ± 0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac-based SRS and SBRT treatment.

Multiplex protein analysis to determine fibrosis stage and progression in patients with chronic hepatitis C.

BACKGROUND & AIMS: Noninvasive tests cannot differentiate between adjacent stages of fibrosis, which limits assessment of disease progression and regression during therapy. We investigated whether levels of cytokines and extracellular matrix proteins in serum and biopsy samples can be used to determine actual stage of liver fibrosis in patients with chronic hepatitis C (CHC) and in prognosis. METHODS: We collected data from 383 treatment-naive patients with CHC from the Duke Hepatology Clinical Research Database and Biorepository, from 2006 through 2009, for use in the training set. Serum samples were obtained from 100 individuals without CHC (controls). We selected 37 serum biomarkers for customized array analysis by using the SearchLight multiplex sandwich enzyme-linked immunosorbent assay. Data from 434 treatment-naive patients with CHC, which were obtained from the Trent HCV cohort, were used in the validation analysis. Multivariable modeling, marker selection, and validation included randomForest and Obuchowski measures, with independent comparison with FibroSURE. RESULTS: Four serum markers (levels of hyaluronic acid, vascular cell adhesion molecule 1, alpha-2 macroglobulin, and retinol-binding protein 4) and age associated with fibrosis stage (F0-1, F2-3, or F4); these had Obuchowski measures of 0.85-0.89, with misclassification rates of 38% and 29% in training and validation sets, compared with 50% for the FibroSURE test. In the training set, area under the curve values for the multiplex markers were similar to those from the FibroSURE test: stages F0 vs F1 (0.51 vs 0.53), F1 vs F2 (0.60 vs 0.59), F2 vs F3 (0.69 vs 0.72), and F3 vs F4 (0.51 vs 0.52). Area under the curve values were similar in the validation cohort. In longitudinal analyses of 133 paired biopsies, 9 markers (level of alanine aminotransferase, γ-glutamyltransferase, hyaluronic acid, intracellular adhesion molecule 1, interleukin 4, CXCL10, CXCL9, and vascular cell adhesion molecule 1) were associated with change in the histologic activity index (P values ranging from .000 to .049), and 4 (granulocyte-macrophage colony-stimulating factor, interleukin 12, interleukin 2, and matrix metalloproteinase 13) were associated with a change in fibrosis stage (P values ranging from .001 to .042). CONCLUSIONS: We identified serum biomarkers that can be measured by multiplex enzyme-linked immunosorbent assay to determine levels of fibrosis in patients with CHC, although misclassification is frequent and results are comparable with those from the FibroSURE test. Changes in protein levels in biopsy samples were associated with progression of fibrosis in patients.

A double-blind, randomized, placebo-controlled study to assess the safety, antiviral activity and pharmacokinetics of GSK2336805 when given as monotherapy and in combination with peginterferon alfa-2a and ribavirin in hepatitis C virus genotype 1-infected treatment-naive subjects.

BACKGROUND & AIMS: GSK2336805 is a HCV NS5A inhibitor for chronic hepatitis C (CHC). In a prior Phase I study, GSK2336805 was well tolerated and had an antiviral and pharmacokinetic profile suitable for once-daily administration. This 28-day, double-blind, randomized, placebo-controlled study evaluated once daily GSK2336805 60 mg alone or in combination with peginterferon alfa-2a (180 µg per week) and ribavirin (1000-1200 mg daily) (PEG/RIBA) in treatment-naive genotype 1 CHC subjects. METHODS: Five centres enrolled 16 subjects in the USA and Puerto Rico who received GSK2336805 + PEG/RIBA or placebo + PEG/RIBA. RESULTS: Following a single monotherapy dose of GSK2336805 on day 1, median reduction from baseline in HCV RNA was -2.96 log10 (N = 11) vs. -0.13 log10 (N = 4) for placebo. With the addition of PEG/RIBA on day 2, subjects receiving GSK2336805 exhibited greater decreases in viral load over the 28-day treatment period as compared with placebo. At day 28, median reduction from baseline was -4.86 log10 (N = 9) in the GSK2336805 + PEG/RIBA group as compared with -1.98 log10 (N = 4) in the placebo + PEG/RIBA group. At day 28, rapid virological response (RVR) occurred in 8/11 (73%) of the GSK2336805 + PEG/RIBA subjects as compared with 1/4 (25%) of the placebo + PEG/RIBA subjects. Adverse events were consistent with those reported in clinical trials of peginterferon and ribavirin, and no unique adverse events appeared to be associated with GSK2336805. CONCLUSIONS: GSK2336805 is a potent NS5A inhibitor that showed a substantial antiviral effect as a monotherapy and in combination with peginterferon and ribavirin. ClinicalTrials.gov Identifier: NCT01439373.

An uncertainty-aware deep learning architecture with outlier mitigation for prostate gland segmentation in radiotherapy treatment planning.

PURPOSE: Task automation is essential for efficient and consistent image segmentation in radiation oncology. We report on a deep learning architecture, comprising a U-Net and a variational autoencoder (VAE) for automatic contouring of the prostate gland incorporating interobserver variation for radiotherapy treatment planning. The U-Net/VAE generates an ensemble set of segmentations for each image CT slice. A novel outlier mitigation (OM) technique was implemented to enhance the model segmentation accuracy. METHODS: The primary source dataset (source_prim) consisted of 19 200 CT slices (from 300 patient planning CT image datasets) with manually contoured prostate glands. A smaller secondary source dataset (source_sec) comprised 640 CT slices (from 10 patient CT datasets), where prostate glands were segmented by 5 independent physicians on each dataset to account for interobserver variability. Data augmentation via random rotation (<5 degrees), cropping, and horizontal flipping was applied to each dataset to increase sample size by a factor of 100. A probabilistic hierarchical U-Net with VAE was implemented and pretrained using the augmented source_prim dataset for 30 epochs. Model parameters of the U-Net/VAE were fine-tuned using the augmented source_sec dataset for 100 epochs. After the first round of training, outlier contours in the training dataset were automatically detected and replaced by the most accurate contours (based on Dice similarity coefficient, DSC) generated by the model. The U-Net/OM-VAE was retrained using the revised training dataset. Metrics for comparison included DSC, Hausdorff distance (HD, mm), normalized cross-correlation (NCC) coefficient, and center-of-mass (COM) distance (mm). RESULTS: Results for U-Net/OM-VAE with outliers replaced in the training dataset versus U-Net/VAE without OM were as follows: DSC = 0.82 ± 0.01 versus 0.80 ± 0.02 (p = 0.019), HD = 9.18 ± 1.22 versus 10.18 ± 1.35 mm (p = 0.043), NCC = 0.59 ± 0.07 versus 0.62 ± 0.06, and COM = 3.36 ± 0.81 versus 4.77 ± 0.96 mm over the average of 15 contours. For the average of 15 highest accuracy contours, values were as follows: DSC = 0.90 ± 0.02 versus 0.85 ± 0.02, HD = 5.47 ± 0.02 versus 7.54 ± 1.36 mm, and COM = 1.03 ± 0.58 versus 1.46 ± 0.68 mm (p < 0.03 for all metrics). Results for the U-Net/OM-VAE with outliers removed were as follows: DSC = 0.78 ± 0.01, HD = 10.65 ± 1.95 mm, NCC = 0.46 ± 0.10, COM = 4.17 ± 0.79 mm for the average of 15 contours, and DSC = 0.88 ± 0.02, HD = 7.00 ± 1.17 mm, COM = 1.58 ± 0.63 mm for the average of 15 highest accuracy contours. All metrics for U-Net/VAE trained on the source_prim and source_sec datasets via pretraining, followed by fine-tuning, show statistically significant improvement over that trained on the source_sec dataset only. Finally, all metrics for U-Net/VAE with or without OM showed statistically significant improvement over those for the standard U-Net. CONCLUSIONS: A VAE combined with a hierarchical U-Net and an OM strategy (U-Net/OM-VAE) demonstrates promise toward capturing interobserver variability and produces accurate prostate auto-contours for radiotherapy planning. The availability of multiple contours for each CT slice enables clinicians to determine trade-offs in selecting the "best fitting" contour on each CT slice. Mitigation of outlier contours in the training dataset improves prediction accuracy, but one must be wary of reduction in variability in the training dataset.

Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection.

Hepatitis C virus (HCV) modulates host lipid metabolism as part of its lifecycle and is dependent upon VLDL for co-assembly and secretion. HCV dyslipidemia is associated with steatosis, insulin resistance, IL28B genotype and disease progression. Apolipoprotein E (ApoE) is an important lipid transport protein, a key constituent of VLDL, and is involved in immunomodulation. Our aims were to determine the role of APOE regional polymorphisms on host lipids, IL28B genotype and disease severity in chronic HCV (CHC) patients. The study cohort included 732 CHC patients with available DNA for genotype determination of four polymorphisms in the chromosome 19 region that encompasses the TOMM40, APOE and APOC1 genes. Serum lipid analysis and apolipoproteins levels were measured using an immunoturbidimetric assay. APOE rs7412 polymorphism (capturing the ε2 isoform) was significantly associated with serum ApoE levels in both Caucasians and African-American patients (p = 2.3 × 10(-11)) and explained 7 % of variance in serum ApoE. Among IL28B-CC patients (n = 196), the rs429358 (defines ε4 isoform) and TOMM40 '523' S polymorphisms were associated with 12 % of variance in ApoB levels. Patients homozygous for the APOE ε3 isoform had a greater than twofold increased odds of F2-F4 fibrosis (p = 1.8 × 10(-5)), independent of serum lipid and lipoprotein levels. There were no associations between APOE polymorphisms and serum HDL-C, APO-CIII and triglycerides. In CHC patients, genetic heterogeneity in the APOE/TOMM40 genomic region is significantly associated with variation in serum ApoE and ApoB levels, and also with fibrosis suggesting a pleiotropic attribute of this genomic region.

Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C.

BACKGROUND & AIMS: IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC. METHODS: Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT. RESULTS: CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs. 22.5% (9/40; p=0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p=0.001) of CC patients in the Duke cohort. CONCLUSIONS: IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection.