A volume-independent conformity index for stereotactic radiosurgery.

PURPOSE: To develop a volume-independent conformity metric called the Gaussian Weighted Conformity Index (GWCI) to evaluate stereotactic radiosurgery/radiotherapy (SRS/SRT) plans for small brain tumors. METHODS: A signed bi-directional local distance (BLD) between the prescription isodose line and the target contour is determined for each point along the tumor contour (positive distance represents under-coverage). A similarity score function (SF) is derived from Gaussian function, penalizing under- and over-coverage at each point by assigning standard deviations of the Gaussian function. Each point along the dose line contour is scored with this SF. The average of the similarity scores determines the GWCI. A total of 40 targets from 18 patients who received Gamma-Knife SRS/SRT treatments were analyzed to determine appropriate penalty criteria. The resulting GWCIs for test cases already deemed clinically acceptable are presented and compared to the same cases scored with the New Conformity Index to determine the influence of tumor volumes on the two conformity indices (CIs). RESULTS: A total of four penalty combinations were tested based on the signed BLDs from the 40 targets. A GWCI of 0.9 is proposed as a cutoff for plan acceptability. The GWCI exhibits no target volume dependency as designed. CONCLUSION: A limitation of current CIs, volume dependency, becomes apparent when applied to SRS/SRT plans. The GWCI appears to be a more robust index, which penalizes over- and under-coverage of tumors and is not skewed by the tumor volume.

NRG Oncology Survey on Practice and Technology Use in SRT and SBRT Delivery.

PURPOSE: To assess stereotactic radiotherapy (SRT)/stereotactic body radiotherapy (SBRT) practices by polling clinics participating in multi-institutional clinical trials. METHODS: The NRG Oncology Medical Physics Subcommittee distributed a survey consisting of 23 questions, which covered general technologies, policies, and procedures used in the Radiation Oncology field for the delivery of SRT/SBRT (9 questions), and site-specific questions for brain SRT, lung SBRT, and prostate SBRT (14 questions). Surveys were distributed to 1,996 radiotherapy institutions included on the membership rosters of the five National Clinical Trials Network (NCTN) groups. Patient setup, motion management, target localization, prescriptions, and treatment delivery technique data were reported back by 568 institutions (28%). RESULTS: 97.5% of respondents treat lung SBRT patients, 77.0% perform brain SRT, and 29.1% deliver prostate SBRT. 48.8% of clinics require a physicist present for every fraction of SBRT, 18.5% require a physicist present for the initial SBRT fraction only, and 14.9% require a physicist present for the entire first fraction, including set-up approval for all subsequent fractions. 55.3% require physician approval for all fractions, and 86.7% do not reposition without x-ray imaging. For brain SRT, most institutions (83.9%) use a planning target volume (PTV) margin of 2 mm or less. Lung SBRT PTV margins of 3 mm or more are used in 80.6% of clinics. Volumetric modulated arc therapy (VMAT) is the dominant delivery method in 62.8% of SRT treatments, 70.9% of lung SBRT, and 68.3% of prostate SBRT. CONCLUSION: This report characterizes SRT/SBRT practices in radiotherapy clinics participating in clinical trials. Data made available here allows the radiotherapy community to compare their practice with that of other clinics, determine what is achievable, and assess areas for improvement.

Clinical Study of Using Biometrics to Identify Patient and Procedure.

PURPOSE: To reduce patient and procedure identification errors by human interactions in radiotherapy delivery and surgery, a Biometric Automated Patient and Procedure Identification System (BAPPIS) was developed. BAPPIS is a patient identification and treatment procedure verification system using fingerprints. METHODS: The system was developed using C++, the Microsoft Foundation Class Library, the Oracle database system, and a fingerprint scanner. To register a patient, the BAPPIS system requires three steps: capturing a photograph using a web camera for photo identification, taking at least two fingerprints, and recording other specific patient information including name, date of birth, allergies, etc. To identify a patient, the BAPPIS reads a fingerprint, identifies the patient, verifies with a second fingerprint to confirm when multiple patients have same fingerprint features, and connects to the patient's record in electronic medical record (EMR) systems. To validate the system, 143 and 21 patients ranging from 36 to 98 years of ages were recruited from radiotherapy and breast surgery, respectively. The registration process for surgery patients includes an additional module, which has a 3D patient model. A surgeon could mark 'O' on the model and save a snap shot of patient in the preparation room. In the surgery room, a webcam displayed the patient's real-time image next to the 3D model. This may prevent a possible surgical mistake. RESULTS: 1,271 (96.9%) of 1,311 fingerprints were verified by BAPPIS using patients' 2nd fingerprints from 143 patients as the system designed. A false positive recognition was not reported. The 96.9% completion ratio is because the operator did not verify with another fingerprint after identifying the first fingerprint. The reason may be due to lack of training at the beginning of the study. CONCLUSION: We successfully demonstrated the use of BAPPIS to correctly identify and recall patient's record in EMR. BAPPIS may significantly reduce errors by limiting the number of non-automated steps.

A Two-Tiered In Vitro Approach to De-Risk Drug Candidates for Potential Bile Salt Export Pump Inhibition Liabilities in Drug Discovery.

Hepatocellular accumulation of bile salts by inhibition of bile salt export pump (BSEP/ABCB11) may result in cholestasis and is one proposed mechanism of drug-induced liver injury (DILI). To understand the relationship between BSEP inhibition and DILI, we evaluated 64 DILI-positive and 57 DILI-negative compounds in BSEP, multidrug resistance protein (MRP) 2, MRP3, and MRP4 vesicular inhibition assays. An empirical cutoff (5 µM) for BSEP inhibition was established based on a relationship between BSEP IC50 values and the calculated maximal unbound concentration at the inlet of the human liver (fu*Iin,max, assay specificity = 98%). Including inhibition of MRP2-4 did not increase DILI predictivity. To further understand the potential to inhibit bile salt transport, a selected subset of 30 compounds were tested for inhibition of taurocholate (TCA) transport in a long-term human hepatocyte micropatterned co-culture (MPCC) system. The resulting IC50 for TCA in vitro biliary clearance and biliary excretion index (BEI) in MPCCs were compared with the compound's fu*Iin,max to assess potential risk for bile salt transport perturbation. The data show high specificity (89%). Nine out of 15 compounds showed an IC50 value in the BSEP vesicular assay of <5µM, but the BEI IC50 was more than 10-fold the fu*Iin,max, suggesting that inhibition of BSEP in vivo is unlikely. The data indicate that although BSEP inhibition measured in membrane vesicles correlates with DILI risk, that measurement of this assay activity is insufficient. A two-tiered strategy incorporating MPCCs is presented to reduce BSEP inhibition potential and improve DILI risk. SIGNIFICANCE STATEMENT: This work describes a two-tiered in vitro approach to de-risk compounds for potential bile salt export pump inhibition liabilities in drug discovery utilizing membrane vesicles and a long-term human hepatocyte micropatterned co-culture system. Cutoffs to maximize specificity were established based on in vitro data from a set of 121 DILI-positive and -negative compounds and associated calculated maximal unbound concentration at the inlet of the human liver based on the highest clinical dose.

Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury.

Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach.

Quantitative Transcriptional Biomarkers of Xenobiotic Receptor Activation in Rat Liver for the Early Assessment of Drug Safety Liabilities.

The robust transcriptional plasticity of liver mediated through xenobiotic receptors underlies its ability to respond rapidly and effectively to diverse chemical stressors. Thus, drug-induced gene expression changes in liver serve not only as biomarkers of liver injury, but also as mechanistic sentinels of adaptation in metabolism, detoxification, and tissue protection from chemicals. Modern RNA sequencing methods offer an unmatched opportunity to quantitatively monitor these processes in parallel and to contextualize the spectrum of dose-dependent stress, adaptation, protection, and injury responses induced in liver by drug treatments. Using this approach, we profiled the transcriptional changes in rat liver following daily oral administration of 120 different compounds, many of which are known to be associated with clinical risk for drug-induced liver injury by diverse mechanisms. Clustering, correlation, and linear modeling analyses were used to identify and optimize coexpressed gene signatures modulated by drug treatment. Here, we specifically focused on prioritizing 9 key signatures for their pragmatic utility for routine monitoring in initial rat tolerability studies just prior to entering drug development. These signatures are associated with 5 canonical xenobiotic nuclear receptors (AHR, CAR, PXR, PPARα, ER), 3 mediators of reactive metabolite-mediated stress responses (NRF2, NRF1, P53), and 1 liver response following activation of the innate immune response. Comparing paradigm chemical inducers of each receptor to the other compounds surveyed enabled us to identify sets of optimized gene expression panels and associated scoring algorithms proposed as quantitative mechanistic biomarkers with high sensitivity, specificity, and quantitative accuracy. These findings were further qualified using public datasets, Open TG-GATEs and DrugMatrix, and internal development compounds. With broader collaboration and additional qualification, the quantitative toxicogenomic framework described here could inform candidate selection prior to committing to drug development, as well as complement and provide a deeper understanding of the conventional toxicology study endpoints used later in drug development.

NCTN Assessment on Current Applications of Radiomics in Oncology.

Radiomics is a fast-growing research area based on converting standard-of-care imaging into quantitative minable data and building subsequent predictive models to personalize treatment. Radiomics has been proposed as a study objective in clinical trial concepts and a potential biomarker for stratifying patients across interventional treatment arms. In recognizing the growing importance of radiomics in oncology, a group of medical physicists and clinicians from NRG Oncology reviewed the current status of the field and identified critical issues, providing a general assessment and early recommendations for incorporation in oncology studies.

NRG Oncology medical physicists' manpower survey quantifying support demands for multi-institutional clinical trials.

PURPOSE: A survey was created by NRG to assess a medical physicists' percent full time equivalent (FTE) contribution to multi-institutional clinical trials. A 2012 American Society for Radiation Oncology report, "Safety Is No Accident," quantified medical physics staffing contributions in FTE factors for clinical departments. No quantification of FTE effort associated with clinical trials was included. METHODS: To address this lack of information, the NRG Medical Physics Subcommittee decided to obtain manpower data from the medical physics community to quantify the amount of time medical physicists spent supporting clinical trials. A survey, consisting of 16 questions, was designed to obtain information regarding physicists' time spent supporting clinical trials. The survey was distributed to medical physicists at 1996 radiation therapy institutions included on the membership rosters of the 5 National Clinical Trials Network clinical trial groups. RESULTS: Of the 451 institutions who responded, 50% (226) reported currently participating in radiation therapy trials. On average, the designated physicist at each institution spent 2.4 hours (standard deviation [SD], 5.5) per week supervising or interacting with clinical trial staff. On average, 1.2 hours (SD, 3.1), 1.8 hours (SD, 3.9), and 0.6 hours (SD, 1.1) per week were spent on trial patient simulations, treatment plan reviews, and maintaining a Digital Imaging and Communications in Medicine server, respectively. For all trial credentialing activities, physicists spent an average of 32 hours (SD, 57.2) yearly. Reading protocols and supporting dosimetrists, clinicians, and therapists took an average of 2.1 hours (SD, 3.4) per week. Physicists also attended clinical trial meetings, on average, 1.2 hours (SD, 1.9) per month. CONCLUSION: On average, physicist spent a nontrivial total of 9 hours per week (0.21 FTE) supporting an average of 10 active clinical trials. This time commitment indicates the complexity of radiation therapy clinical trials and should be taken into account when staffing radiation therapy institutions.

Pre-fusion RSV F strongly boosts pre-fusion specific neutralizing responses in cattle pre-exposed to bovine RSV.

Human respiratory syncytial virus (hRSV) is responsible for serious lower respiratory tract disease in infants and in older adults, and remains an important vaccine need. RSV fusion (F) glycoprotein is a key target for neutralizing antibodies. RSV F stabilized in its pre-fusion conformation (DS-Cav1 F) induces high neutralizing antibody titers in naïve animals, but it remains unknown to what extent pre-fusion F can boost pre-existing neutralizing responses in RSV seropositive adults. We here assess DS-Cav1 F immunogenicity in seropositive cattle pre-exposed to bovine RSV, a virus closely related to hRSV. A single immunization with non-adjuvanted DS-Cav1 F strongly boosts RSV neutralizing responses, directed towards pre-fusion F-specific epitopes, whereas a post-fusion F is unable to do so. Vaccination with pre-fusion F thus represents a promising strategy for maternal immunization and for other RSV vaccine target populations such as older adults.

Cytocompatibility evaluation of NiMnSn meta-magnetic shape memory alloys for biomedical applications.

Recently, magnetic shape memory alloys (MSMAs) have emerged as an interesting extension to conventional shape memory alloys (SMAs) due to their capacity to undergo reversible deformation in response to an externally applied magnetic field. Meta-magnetic SMAs (M-MSMAs) are a class of MSMAs that are able to transform magnetic energy to mechanical work by harnessing a magnetic-field induced phase transformation, and thus have the capacity to impose up to 10 times greater stress than conventional MSMAs. As such, M-MSMAs may hold substantial promise in biomedical applications requiring extracorporeal device activation. In the present study, the cytotoxicity and ion release from an Ni50 Mn36 Sn14 atomic percent composition M-MSMA were evaluated using NIH/3T3 fibroblasts. Initial studies showed that the viability of cells exposed to NiMnSn ion leachants was 60 to 67% of tissue culture polystyrene (TCP) controls over 10 to 14 days of culture. This represents a significant improvement in cytocompatibility relative to NiMnGa alloys, one of the most extensively studied MSMA systems, which have been reported to induce 80% cell death in only 48 h. Furthermore, NiMnSn M-MSMA associated cell viability was increased to 80% of TCP controls following layer-by-layer alloy coating with poly(allylamine hydrochloride)/poly(acrylic acid) [PAH/PAA]. Ion release measures revealed that the PAH/PAA coatings decreased total Sn and Mn ion release by 50% and 25%, respectively, and optical microscopy evaluation indicated that the coatings reduced NiMnSn surface oxidation. To our knowledge, this study presents the first cytotoxicity evaluation of NiMnSn M-MSMAs and lays the groundwork for their further biological evaluation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 853-863, 2016.

Structure of HCMV glycoprotein B in the postfusion conformation bound to a neutralizing human antibody.

Human cytomegalovirus (HCMV) poses a significant threat to immunocompromised individuals and neonates infected in utero. Glycoprotein B (gB), the herpesvirus fusion protein, is a target for neutralizing antibodies and a vaccine candidate due to its indispensable role in infection. Here we show the crystal structure of the HCMV gB ectodomain bound to the Fab fragment of 1G2, a neutralizing human monoclonal antibody isolated from a seropositive subject. The gB/1G2 interaction is dominated by aromatic residues in the 1G2 heavy chain CDR3 protruding into a hydrophobic cleft in the gB antigenic domain 5 (AD-5). Structural analysis and comparison with HSV gB suggest the location of additional neutralizing antibody binding sites on HCMV gB. Finally, immunoprecipitation experiments reveal that 1G2 can bind to HCMV virion gB suggesting that its epitope is exposed and accessible on the virus surface. Our data will support the development of vaccines and therapeutic antibodies against HCMV infection.

Quantitative evaluation of image segmentation incorporating medical consideration functions.

PURPOSE: A quantitative and objective metric, the medical similarity index (MSI), has been developed for evaluating the accuracy of a medical image segmentation relative to a reference segmentation. The MSI uses the medical consideration function (MCF) as its basis. METHODS: Currently, no indices provide quantitative evaluations of segmentation accuracy with medical considerations. Variations in segmentation can occur due to individual skill levels and medical relevance--curable or palliative intent, boundary uncertainty due to volume averaging, contrast levels, spatial resolution, and unresolved motion all affect the accuracy of a patient segmentation. Current accuracy measuring indices are not medically relevant. For example, undercontouring the tumor volume is not differentiated from overcontouring tumor. Dice similarity coefficient (DSC) and Hausdorff distance (HD) are two similarity measures often used. However, these metrics consider only geometric difference without considering medical implications. Two segments (under- vs overcontouring tumor) with similar DSC and HD measures could produce significantly different medical treatment results. The authors are proposing a MSI involving a user-defined MCF derived from an asymmetric Gaussian function. The shape of the MCF can be determined by a user, reflecting the anatomical location and characteristics of a particular tissue, organ, or tumor type. The peak of MCF is set along the reference contour; the inner and outer slopes are selected by the user. The discrepancy between the test and reference contours is calculated at each pixel by using a bidirectional local distance measure. The MCF value corresponding to that distance is summed and averaged to produce the MSI. Synthetic segmentations and clinical data from a 15 multi-institutional trial for a head-and-neck case are scored and compared by using MSI, DSC, and Hausdorff distance. RESULTS: The MSI was shown to reflect medical considerations through the choice of MCF penalties for under- and overcontouring. Existing similarity scores were either insensitive to medical realities or simply inaccurate. CONCLUSIONS: The medical similarity index, a segmentation evaluation metric based on medical considerations, has been proposed, developed, and tested to incorporate clinically relevant considerations beyond geometric parameters alone.

Quantitative Analysis Tools and Digital Phantoms for Deformable Image Registration Quality Assurance.

This article proposes quantitative analysis tools and digital phantoms to quantify intrinsic errors of deformable image registration (DIR) systems and establish quality assurance (QA) procedures for clinical use of DIR systems utilizing local and global error analysis methods with clinically realistic digital image phantoms. Landmark-based image registration verifications are suitable only for images with significant feature points. To address this shortfall, we adapted a deformation vector field (DVF) comparison approach with new analysis techniques to quantify the results. Digital image phantoms are derived from data sets of actual patient images (a reference image set, R, a test image set, T). Image sets from the same patient taken at different times are registered with deformable methods producing a reference DVFref. Applying DVFref to the original reference image deforms T into a new image R'. The data set, R', T, and DVFref, is from a realistic truth set and therefore can be used to analyze any DIR system and expose intrinsic errors by comparing DVFref and DVFtest. For quantitative error analysis, calculating and delineating differences between DVFs, 2 methods were used, (1) a local error analysis tool that displays deformation error magnitudes with color mapping on each image slice and (2) a global error analysis tool that calculates a deformation error histogram, which describes a cumulative probability function of errors for each anatomical structure. Three digital image phantoms were generated from three patients with a head and neck, a lung and a liver cancer. The DIR QA was evaluated using the case with head and neck.

Human cytomegalovirus gH/gL/UL128/UL130/UL131A complex elicits potently neutralizing antibodies in mice.

Human cytomegalovirus (HCMV) is a member of the ß-herpesvirus family that causes significant disease worldwide. Although evidence exists that neutralizing antibodies and cytotoxic T cell responses to HCMV antigens can prevent HCMV disease and/or infection, there are no approved vaccines to prevent HCMV disease. Over the past 10 years, multiple HCMV vaccines have been tested in man but only partial protection has been achieved in these studies. HCMV contains multiple surface-expressed glycoproteins that are critical to viral entry, including gB, the gM/gN complex, the gH/gL complex, and a pentameric gH/gL/UL128/UL130/UL131A complex. Recently we showed that viral replicon particles (VRPs) expressing the gH/gL complex elicited more potently neutralizing antibodies than VRPs expressing gB in mice. Here we compare the immunogenicity of VRPs encoding the HCMV gH/gL and pentameric complexes, as well as purified gH/gL and pentameric complexes administered in the presence or absence of the MF59 adjuvant. The results of these studies indicate that the pentameric complex elicits significantly higher levels of neutralizing antibodies than the gH/gL complex, and that MF59 significantly increases the potency of each complex. In addition, we show that animals immunized with pentamer encoding VRPs or the pentameric subunit produce antibodies that recognize a broad range of antigenic sites on the complex. Taken together, these studies support the utility of the pentameric complex in HCMV vaccine candidates.

Vectored co-delivery of human cytomegalovirus gH and gL proteins elicits potent complement-independent neutralizing antibodies.

Human cytomegalovirus (hCMV) is prevalent worldwide with infection generally being asymptomatic. Nevertheless, hCMV infection can lead to significant morbidity and mortality. Primary infection of seronegative women or reactivation/re-infection of seropositive women during pregnancy can result in transmission to the fetus, leading to severe neurological defects. In addition, hCMV is the most common viral infection in immunosuppressed organ transplant recipients and can produce serious complications. Hence, a safe and effective vaccine to prevent hCMV infection is an unmet medical need. Neutralizing antibodies to several hCMV glycoproteins, and complexes thereof, have been identified in individuals following hCMV infection. Interestingly, a portion of the CMV-specific neutralizing antibody responses are directed to epitopes found on glycoprotein complexes but not the individual proteins. Using an alphavirus replicon particle (VRP) vaccine platform, we showed that bicistronic VRPs encoding hCMV gH and gL glycoproteins produce gH/gL complexes in vitro. Furthermore, mice vaccinated with these gH/gL-expressing VRPs produced broadly cross-reactive complement-independent neutralizing antibodies to hCMV. These neutralizing antibody responses were of higher titer than those elicited in mice vaccinated with monocistronic VRPs encoding gH or gL antigens, and they were substantially more potent than those raised by VRPs encoding gB. These findings underscore the utility of co-delivery of glycoprotein components such as gH and gL for eliciting potent, broadly neutralizing immune responses against hCMV, and indicate that the gH/gL complex represents a potential target for future hCMV vaccine development.

Bidirectional local distance measure for comparing segmentations.

PURPOSE: To accurately quantify the local difference between two contour surfaces in two- or three-dimensional space, a new, robust point-to-surface distance measure is developed. METHODS: To evaluate and visualize the local surface differences, point-to-surface distance measures have been utilized. However, previously well-known point-to-surface distance measures have critical shortfalls. Previous distance measures termed "normal distance (ND)," "radial distance," or "minimum distance (MD)" can report erroneous results at certain points where the surfaces under comparison meet certain conditions. These skewed results are due to the monodirectional characteristics of these methods. ComGrad distance was also proposed to overcome asymmetric characteristics of previous point-to-surface distance measures, but their critical incapability of dealing with a fold or concave contours. In this regard, a new distance measure termed the bidirectional local distance (BLD) is proposed which minimizes errors of the previous methods by taking into account the bidirectional characteristics with the forward and backward directions. BLD measure works through three steps which calculate the maximum value between the forward minimum distance (FMinD) and the backward maximum distance (BMaxD) at each point. The first step calculates the FMinD as the minimum distance to the test surface from a point, p(ref) on the reference surface. The second step involves calculating the minimum distances at every point on the test surface to the reference surface. During the last step, the BMaxD is calculated as the maximum distance among the minimum distances found at p(ref) on the reference surface. Tests are performed on two- and three-dimensional artificial contour sets in comparison to MD and ND measure techniques. Three-dimensional tests performed on actual liver and head-and-neck cancer patients. RESULTS: The proposed BLD measure provides local distances between segmentations, even in situations where ND, MD, or ComGrad measures fail. In particular, the standard deviation measure is not distorted at certain geometries where ND, MD, and ComGrad measures report skewed results. CONCLUSIONS: The proposed measure provides more reliable statistics on contour comparisons. From the statistics, specific local and global distances can be extracted. Bidirectional local distance is a reliable distance measure in comparing two- or three-dimensional organ segmentations.

Composite Radiation Dose Representation Using Fuzzy Set Theory.

Composite plans created from different image sets are generated through Deformable Image Registration (DIR) and present a challenge in accurately presenting uncertainties, which vary with anatomy. Our effort focuses on the application of Fuzzy Set theory to provide an accurate dose representation of such a composite treatment plan. The accuracy of the DIR is generally verified through geometrical visual checks, including the confirmation of the corresponding anatomies with edge features, such as bone or organ boundaries. However, the remaining volume of the image (mostly soft tissues) has few significant image features and therefore greater uncertainty. We fuzzified the deformation vector and derived a Fuzzy composite dose. The fuzzification was implemented using Gaussian functions based on the varying uncertainties in the DIR. After establishing the theoretical basis for this new approach, we present two-and three-dimensional examples as proof-of-concept. Using Fuzzy Set theory, composite dose plans displaying locality-based uncertainties were successfully created, providing information previously unavailable to clinicians. Previous to Fuzzy Set dose presentations, clinicians had no measure of confidence in the accuracy of a composite dose plan. Using fuzzified composite dose presentations, clinicians can determine a safe additional dose to previously treated anatomy. This will possibly increase the treatment success rate and reduce the rate of complications.

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV).

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

Spatially weighted mutual information image registration for image guided radiation therapy.

PURPOSE: To develop a new metric for image registration that incorporates the (sub)pixelwise differential importance along spatial location and to demonstrate its application for image guided radiation therapy (IGRT). METHODS: It is well known that rigid-body image registration with mutual information is dependent on the size and location of the image subset on which the alignment analysis is based [the designated region of interest (ROI)]. Therefore, careful review and manual adjustments of the resulting registration are frequently necessary. Although there were some investigations of weighted mutual information (WMI), these efforts could not apply the differential importance to a particular spatial location since WMI only applies the weight to the joint histogram space. The authors developed the spatially weighted mutual information (SWMI) metric by incorporating an adaptable weight function with spatial localization into mutual information. SWMI enables the user to apply the selected transform to medically "important" areas such as tumors and critical structures, so SWMI is neither dominated by, nor neglects the neighboring structures. Since SWMI can be utilized with any weight function form, the authors presented two examples of weight functions for IGRT application: A Gaussian-shaped weight function (GW) applied to a user-defined location and a structures-of-interest (SOI) based weight function. An image registration example using a synthesized 2D image is presented to illustrate the efficacy of SWMI. The convergence and feasibility of the registration method as applied to clinical imaging is illustrated by fusing a prostate treatment planning CT with a clinical cone beam CT (CBCT) image set acquired for patient alignment. Forty-one trials are run to test the speed of convergence. The authors also applied SWMI registration using two types of weight functions to two head and neck cases and a prostate case with clinically acquired CBCT/ MVCT image sets. The SWMI registration with a Gaussian weight function (SWMI-GW) was tested between two different imaging modalities: CT and MRI image sets. RESULTS: SWMI-GW converges 10% faster than registration using mutual information with an ROI. SWMI-GW as well as SWMI with SOI-based weight function (SWMI-SOI) shows better compensation of the target organ's deformation and neighboring critical organs' deformation. SWMI-GW was also used to successfully fuse MRI and CT images. CONCLUSIONS: Rigid-body image registration using our SWMI-GW and SWMI-SOI as cost functions can achieve better registration results in (a) designated image region(s) as well as faster convergence. With the theoretical foundation established, we believe SWMI could be extended to larger clinical testing.

Rape myth acceptance, sexual trauma history, and posttraumatic stress disorder.

The prediction of false rape-related beliefs (rape myth acceptance [RMA]) was examined using the Illinois Rape Myth Acceptance Scale (Payne, Lonsway, & Fitzgerald, 1999) among a nonclinical sample of 258 male and female college students. Predictor variables included measures of attitudes toward women, gender role identity (GRI), sexual trauma history, and posttraumatic stress disorder (PTSD) symptom severity. Using linear regression and testing interaction effects, negative attitudes toward women significantly predicted greater RMA for individuals without a sexual trauma history. However, neither attitudes toward women nor GRI were significant predictors of RMA for individuals with a sexual trauma history. PTSD did not moderate RMA's relationship with attitudes toward women and GRI. This study has clinical implications for treatment as well as for the development of rape myth-dispelling programs.