Effects of congressional modernization laws on public access to innovative medical device technologies

The Federal Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid (CMS) play key roles in making Class III, medical devices available to the public, and they are required by law to meet statutory deadlines for applications under review. Historically, both agencies have failed to meet their respective statutory requirements. Since these failures affect patient access and may adversely impact public health, Congress has enacted several “modernization” laws. However, the effectiveness of these modernization laws has not been adequately studied or established for Class III medical devices. ^ The aim of this research study was, therefore, to analyze how these modernization laws may have affected public access to medical devices. Two questions were addressed: (1) How have the FDA modernization laws affected the time to approval for medical device premarket approval applications (PMAs)? (2) How has the CMS modernization law affected the time to approval for national coverage decisions (NCDs)? The data for this research study were collected from publicly available databases for the period January 1, 1995, through December 31, 2008. These dates were selected to ensure that a sufficient period of time was captured to measure pre- and post-modernization effects on time to approval. All records containing original PMAs were obtained from the FDA database, and all records containing NCDs were obtained from the CMS database. Source documents, including FDA premarket approval letters and CMS national coverage decision memoranda, were reviewed to obtain additional data not found in the search results. Analyses were conducted to determine the effects of the pre- and post-modernization laws on time to approval. Secondary analyses of FDA subcategories were conducted to uncover any causal factors that might explain differences in time to approval and to compare with the primary trends. The primary analysis showed that the FDA modernization laws of 1997 and 2002 initially reduced PMA time to approval; after the 2002 modernization law, the time to approval began increasing and continued to increase through December 2008. The non-combined, subcategory approval trends were similar to the primary analysis trends. The combined, subcategory analysis showed no clear trends with the exception of non-implantable devices, for which time to approval trended down after 1997. The CMS modernization law of 2003 reduced NCD time to approval, a trend that continued through December 2008. This study also showed that approximately 86% of PMA devices do not receive NCDs. ^ As a result of this research study, recommendations are offered to help resolve statutory non-compliance and access issues, as follows: (1) Authorities should examine underlying causal factors for the observed trends; (2) Process improvements should be made to better coordinate FDA and CMS activities to include sharing data, reducing duplication, and establishing clear criteria for “safe and effective” and “reasonable and necessary”; (3) A common identifier should be established to allow tracking and trending of applications between FDA and CMS databases; (4) Statutory requirements may need to be revised; and (5) An investigation should be undertaken to determine why NCDs are not issued for the majority of PMAs. Any process improvements should be made without creating additional safety risks and adversely impacting public health. Finally, additional studies are needed to fully characterize and better understand the trends identified in this research study.^

Body image rating scales to assess obesity

Obesity prevalence in the U.S. has increased during the last three decades with major impact on public health. Screening for obesity in a population with unknown weight status can be time- and resource-consuming, but the information is valuable for prioritizing and allocating scarce resources. The challenge remains to properly assess obesity with the available methods. Body Image Rating Scales (BIRS) have initially been developed to assess body image disturbances, but also seem useful as an alternative method in assessing obesity prevalence. Several different BIRS exists. In this project I reviewed the literature that exists regarding the use of BIRS, and its advantages and limitations for the assessment of obesity status with regards to BMI. The result yielded nine publications that examined eight different scales and their correlation with BMI, ranging from r=.59 for self-reported BMI to r=.94 for measured BMI. One concern is the lack of standardization of this method to assess obesity, given the range of different scales. While many methods for obesity assessment are available, the simplicity, ease of use and cost-effectiveness of BIRS make it very appealing. BIRS remain a potentially attractive option to assess the weight status of a large population with minimal requirements in assets and time, especially in situations where measuring instruments are not available, or when height or weight could not be recalled.^

Automated soldier medical readiness: Prevalence of " medically not ready" using data from the electronic soldier readiness processing system (ESRP)

Identifying accurate numbers of soldiers determined to be medically not ready after completing soldier readiness processing may help inform Army leadership about ongoing pressures on the military involved in long conflict with regular deployment. In Army soldiers screened using the SRP checklist for deployment, what is the prevalence of soldiers determined to be medically not ready? Study group. 15,289 soldiers screened at all 25 Army deployment platform sites with the eSRP checklist over a 4-month period (June 20, 2009 to October 20, 2009). The data included for analysis included age, rank, component, gender and final deployment medical readiness status from MEDPROS database. Methods.^ This information was compiled and univariate analysis using chi-square was conducted for each of the key variables by medical readiness status. Results. Descriptive epidemiology Of the total sample 1548 (9.7%) were female and 14319 (90.2%) were male. Enlisted soldiers made up 13,543 (88.6%) of the sample and officers 1,746 (11.4%). In the sample, 1533 (10.0%) were soldiers over the age of 40 and 13756 (90.0%) were age 18-40. Reserve, National Guard and Active Duty made up 1,931 (12.6%), 2,942 (19.2%) and 10,416 (68.1%) respectively. Univariate analysis. Overall 1226 (8.0%) of the soldiers screened were determined to be medically not ready for deployment. Biggest predictive factor was female gender OR (2.8; 2.57-3.28) p<0.001. Followed by enlisted rank OR (2.01; 1.60-2.53) p<0.001. Reserve component OR (1.33; 1.16-1.53) p<0.001 and Guard OR (0.37; 0.30-0.46) p<0.001. For age > 40 demonstrated OR (1.2; 1.09-1.50) p<0.003. Overall the results underscore there may be key demographic groups relating to medical readiness that can be targeted with programs and funding to improve overall military medical readiness.^

Design and Optimization of Four-dimensional Cone-beam Computed Tomography in Image-guided Radiation Therapy

The influence of respiratory motion on patient anatomy poses a challenge to accurate radiation therapy, especially in lung cancer treatment. Modern radiation therapy planning uses models of tumor respiratory motion to account for target motion in targeting. The tumor motion model can be verified on a per-treatment session basis with four-dimensional cone-beam computed tomography (4D-CBCT), which acquires an image set of the dynamic target throughout the respiratory cycle during the therapy session. 4D-CBCT is undersampled if the scan time is too short. However, short scan time is desirable in clinical practice to reduce patient setup time. This dissertation presents the design and optimization of 4D-CBCT to reduce the impact of undersampling artifacts with short scan times. This work measures the impact of undersampling artifacts on the accuracy of target motion measurement under different sampling conditions and for various object sizes and motions. The results provide a minimum scan time such that the target tracking error is less than a specified tolerance. This work also presents new image reconstruction algorithms for reducing undersampling artifacts in undersampled datasets by taking advantage of the assumption that the relevant motion of interest is contained within a volume-of-interest (VOI). It is shown that the VOI-based reconstruction provides more accurate image intensity than standard reconstruction. The VOI-based reconstruction produced 43% fewer least-squares error inside the VOI and 84% fewer error throughout the image in a study designed to simulate target motion. The VOI-based reconstruction approach can reduce acquisition time and improve image quality in 4D-CBCT.

Radiomics of NSCLC: Quantitative CT Image Feature Characterization and Tumor Shrinkage Prediction

Radiomics is the high-throughput extraction and analysis of quantitative image features. For non-small cell lung cancer (NSCLC) patients, radiomics can be applied to standard of care computed tomography (CT) images to improve tumor diagnosis, staging, and response assessment. The first objective of this work was to show that CT image features extracted from pre-treatment NSCLC tumors could be used to predict tumor shrinkage in response to therapy. This is important since tumor shrinkage is an important cancer treatment endpoint that is correlated with probability of disease progression and overall survival. Accurate prediction of tumor shrinkage could also lead to individually customized treatment plans. To accomplish this objective, 64 stage NSCLC patients with similar treatments were all imaged using the same CT scanner and protocol. Quantitative image features were extracted and principal component regression with simulated annealing subset selection was used to predict shrinkage. Cross validation and permutation tests were used to validate the results. The optimal model gave a strong correlation between the observed and predicted shrinkages with . The second objective of this work was to identify sets of NSCLC CT image features that are reproducible, non-redundant, and informative across multiple machines. Feature sets with these qualities are needed for NSCLC radiomics models to be robust to machine variation and spurious correlation. To accomplish this objective, test-retest CT image pairs were obtained from 56 NSCLC patients imaged on three CT machines from two institutions. For each machine, quantitative image features with concordance correlation coefficient values greater than 0.90 were considered reproducible. Multi-machine reproducible feature sets were created by taking the intersection of individual machine reproducible feature sets. Redundant features were removed through hierarchical clustering. The findings showed that image feature reproducibility and redundancy depended on both the CT machine and the CT image type (average cine 4D-CT imaging vs. end-exhale cine 4D-CT imaging vs. helical inspiratory breath-hold 3D CT). For each image type, a set of cross-machine reproducible, non-redundant, and informative image features was identified. Compared to end-exhale 4D-CT and breath-hold 3D-CT, average 4D-CT derived image features showed superior multi-machine reproducibility and are the best candidates for clinical correlation.

Examining the Relationship Between Media Use and Aggression, Sexuality, and Body Image

Objectives: The primary purpose of this research is to understand the media's impact on individual attitudes and behaviors related to aggression, sexuality, and body image. This research is of particular importance because it uses up-to-date data reflecting effects based on the current media environment. Additionally, it includes a racially diverse sample. Methods: A survey of 407 students at a large, public university was conducted. The survey instrument contained general measures related to media consumption, including overall television, video game, and internet use, as well as more specific questions related to particular types of media, such as pornography. For the dependent variables, questions were included that measured both attitudes and behaviors related to aggression, sexuality, and body image. Results: Consistent with predictions, media use impacted both attitudes and behaviors related to aggression, sexuality, and body image. Specifically, overall television consumption led to increased levels of aggression (r=.18, pr=.20, pr=.24, pr=.42, pr=.40, p Conclusions: The media continue to play an important role in the development of attitudes and behaviors. It is warranted, therefore, to continue to investigate what media can cause negative outcomes, as well as to determine how those outcomes vary based on race and gender.

Design, Synthesis and Development of Transporter Targeting Agents for Image-guided Therapy and Drug Delivery

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with 99mTc and 68Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both 99mTc-N4amG and 99mTc-GP were stable up to 6 hours, whereas 68Ga-GP was stable up to 2 hours. Cell culture studies confirmed radiolabeled N4amG and GP could penetrate the cell membrane through nucleoside transporters and amino acid transporters, respectively. Up to 40% of intracellular 99mTc-N4amG and 99mTc-GP was found within cell nucleus following 2 hours of incubation. Flow cytometry analysis revealed 99mTc-N4amG was a cell cycle S phase-specific agent. There was a significant difference of the uptake of 99mTc-GP between pre- and post- paclitaxel-treated cells, which suggests that 99mTc-GP may be useful in chemotherapy treatment monitoring. Moreover, radiolabeled N4amG and GP were tested in vivo using tumor-bearing animal models. 99mTc-N4amG showed an increase in tumor-to-muscle count density ratios up to 5 at 4 hour imaging. Both 99mTc-labeled agents showed decreased tumor uptake after paclitaxel treatment. Immunohistochemistry analysis demonstrated that the uptake of 99mTc-N4amG was correlated with Ki-67 expression. Both 99mTc-N4amG and 99mTc-GP could differentiate between tumor and inflammation in animal studies. Furthermore, 68Ga-GP was compared to 18F-FDG in rabbit PET imaging studies. 68Ga-GP had lower tumor standardized uptake values (SUV), but similar uptake dynamics, and different biodistribution compared with 18F-FDG. Finally, to demonstrate that GP can be a potential drug carrier for cancer theranostics, several drugs, including doxorubicin, were selected to be conjugated to GP. Imaging studies demonstrated that tumor uptake of GP-drug conjugates was increased as a function of time. GP-doxorubicin (GP-DOX) showed a slow-release pattern in in vitro cytotoxicity assay and exhibited anti-cancer efficacy with reduced toxicity in in vivo tumor growth delay study. In conclusion, both N4amG and GP are transporter-based targeting agents. Radiolabeled N4amG can be used for tumor cell proliferation assessment. GP is a potential agent for image-guided therapy and drug delivery.

Associations of perceived body image and subjective social status with levels of physical activity in Mexican American adolescents

The current study is a secondary data analysis of a prospective cohort study that examined demographic and psychosocial variables and their associations with physical activity levels in Mexican-American adolescents in Houston, Texas. Body image, subjective social status, and anxiety were the main variables of interest. The sample included 952 unrelated Mexican-American adolescents in Houston, Texas. The majority (84.2%) of the study population did not meet physical activity standards prescribed by the CDC.^ In a multivariate model controlling for age, socioeconomic status, gender, general body image, preferred body image, subjective social status, and anxiety, gender and subjective social status were found to be the strongest determinants of physical activity levels. Males and those with a high subjective social status were more likely to participate in physical activity than those with low subjective status. Lower levels of anxiety and a more positive body image were also found to be associated with higher levels of physical activity. In multivariate analyses gender and subjective social status showed the strongest associations with physical activity.^

A dual resonance, image -guided, volume localization technique for magnetic resonance spectroscopy

An interleaved, dual resonance, volume localization technique for $\sp1$H/$\sp{31}$P magnetic resonance spectroscopy has been designed, implemented on a 2 T imager/spectrometer, and verified with phantom studies.^ Localization techniques, including several single voxel techniques and spectroscopic imaging, were implemented, and studies were performed to compare the efficiency of each sequence of $\sp1$H/$\sp{31}$P spectral acquisitions. The sequence chosen was a hybrid of the stimulated echo single voxel technique and the spectroscopic imaging technique.^ Water suppression during the $\sp1$H spectral acquisitions was accomplished by the use of three narrow bandwidth RF saturation pulses in combination with three spoiler gradients. The spoiler gradient amplitudes were selected on the basis of a numerical solution of the Bloch equations. A post-acquisition water suppression algorithm was used to minimize any residual water signal.^ For interleaved $\sp1$H/$\sp{31}$P acquisitions, a dual resonance RF coil was constructed and interfaced to the existing RF detection system via a custom-designed dual resonance transcoupler and switching system. Programmable attenuators were incorporated to allow for changes in receiver and transmitter attenuation "on the fly".^ To provide the rapidly switched gradient fields required for the $\sp1$H/$\sp{31}$P acquisitions, an actively screened gradient coil system was designed and implemented. With this system, gradient field rise times on the order of 100 $\mu$s were obtained. These rapid switching times were necessary for minimizing intrasequence delays and for improving localization quality and water suppression efficiency.^ The interleaved $\sp1$H/$\sp{31}$P volume localization technique was tested using a two-compartment phantom. Analysis of the data showed that the spectral contamination was less than three percent. One-to-one spatial correspondence of the $\sp1$H and $\sp{31}$P spectra was verified and allowed for direct correlation of the spectral data with a standard magnetic resonance image. ^

Satellite image map of King George Island, Antarctica

A new topographic database for King George Island, one of the most visited areas in Antarctica, is presented. Data from differential GPS surveys, gained during the summers 1997/98 and 1999/2000, were combined with up to date coastlines from a SPOT satellite image mosaic, and topographic information from maps as well as from the Antarctic Digital Database. A digital terrain model (DTM) was generated using ARC/INFO GIS. From contour lines derived from the DTM and the satellite image mosaic a satellite image map was assembled. Extensive information on data accuracy, the database as well as on the criteria applied to select place names is given in the multilingual map. A lack of accurate topographic information in the eastern part of the island was identified. It was concluded that additional topographic surveying or radar interferometry should be conducted to improve the data quality in this area. In three case studies, the potential applications of the improved topographic database are demonstrated. The first two examples comprise the verification of glacier velocities and the study of glacier retreat from the various input data-sets as well as the use of the DTM for climatological modelling. The last case study focuses on the use of the new digital database as a basic GIS (Geographic Information System) layer for environmental monitoring and management on King George Island.

The Global Plankton Database: an inventory and data from the Former Soviet Union expeditions

At present time, there is a lack of knowledge on the interannual climate-related variability of zooplankton communities of the tropical Atlantic, central Mediterranean Sea, Caspian Sea, and Aral Sea, due to the absence of appropriate databases. In the mid latitudes, the North Atlantic Oscillation (NAO) is the dominant mode of atmospheric fluctuations over eastern North America, the northern Atlantic Ocean and Europe. Therefore, one of the issues that need to be addressed through data synthesis is the evaluation of interannual patterns in species abundance and species diversity over these regions in regard to the NAO. The database has been used to investigate the ecological role of the NAO in interannual variations of mesozooplankton abundance and biomass along the zonal array of the NAO influence. Basic approach to the proposed research involved: (1) development of co-operation between experts and data holders in Ukraine, Russia, Kazakhstan, Azerbaijan, UK, and USA to rescue and compile the oceanographic data sets and release them on CD-ROM, (2) organization and compilation of a database based on FSU cruises to the above regions, (3) analysis of the basin-scale interannual variability of the zooplankton species abundance, biomass, and species diversity.

Database of Ice-Rich Yedoma Permafrost (IRYP)

Vast portions of Arctic and sub-Arctic Siberia, Alaska and the Yukon Territory are covered by ice-rich silty to sandy deposits that are containing large ice wedges, resulting from syngenetic sedimentation and freezing. Accompanied by wedge-ice growth in polygonal landscapes, the sedimentation process was driven by cold continental climatic and environmental conditions in unglaciated regions during the late Pleistocene, inducing the accumulation of the unique Yedoma deposits up to >50 meters thick. Because of fast incorporation of organic material into syngenetic permafrost during its formation, Yedoma deposits include well-preserved organic matter. Ice-rich deposits like Yedoma are especially prone to degradation triggered by climate changes or human activity. When Yedoma deposits degrade, large amounts of sequestered organic carbon as well as other nutrients are released and become part of active biogeochemical cycling. This could be of global significance for future climate warming as increased permafrost thaw is likely to lead to a positive feedback through enhanced greenhouse gas fluxes. Therefore, a detailed assessment of the current Yedoma deposit coverage and its volume is of importance to estimate its potential response to future climate changes. We synthesized the map of the coverage and thickness estimation, which will provide critical data needed for further research. In particular, this preliminary Yedoma map is a great step forward to understand the spatial heterogeneity of Yedoma deposits and its regional coverage. There will be further applications in the context of reconstructing paleo-environmental dynamics and past ecosystems like the mammoth-steppe-tundra, or ground ice distribution including future thermokarst vulnerability. Moreover, the map will be a crucial improvement of the data basis needed to refine the present-day Yedoma permafrost organic carbon inventory, which is assumed to be between 83±12 (Strauss et al., 2013, doi:10.1002/2013GL058088) and 129±30 (Walter Anthony et al., 2014, doi:10.1038/nature13560) gigatonnes (Gt) of organic carbon in perennially-frozen archives. Hence, here we synthesize data on the circum-Arctic and sub-Arctic distribution and thickness of Yedoma for compiling a preliminary circum-polar Yedoma map. For compiling this map, we used (1) maps of the previous Yedoma coverage estimates, (2) included the digitized areas from Grosse et al. (2013) as well as extracted areas of potential Yedoma distribution from additional surface geological and Quaternary geological maps (1.: 1:500,000: Q-51-V,G; P-51-A,B; P-52-A,B; Q-52-V,G; P-52-V,G; Q-51-A,B; R-51-V,G; R-52-V,G; R-52-A,B; 2.: 1:1,000,000: P-50-51; P-52-53; P-58-59; Q-42-43; Q-44-45; Q-50-51; Q-52-53; Q-54-55; Q-56-57; Q-58-59; Q-60-1; R-(40)-42; R-43-(45); R-(45)-47; R-48-(50); R-51; R-53-(55); R-(55)-57; R-58-(60); S-44-46; S-47-49; S-50-52; S-53-55; 3.: 1:2,500,000: Quaternary map of the territory of Russian Federation, 4.: Alaska Permafrost Map). The digitalization was done using GIS techniques (ArcGIS) and vectorization of raster Images (Adobe Photoshop and Illustrator). Data on Yedoma thickness are obtained from boreholes and exposures reported in the scientific literature. The map and database are still preliminary and will have to undergo a technical and scientific vetting and review process. In their current form, we included a range of attributes for Yedoma area polygons based on lithological and stratigraphical information from the original source maps as well as a confidence level for our classification of an area as Yedoma (3 stages: confirmed, likely, or uncertain). In its current version, our database includes more than 365 boreholes and exposures and more than 2000 digitized Yedoma areas. We expect that the database will continue to grow. In this preliminary stage, we estimate the Northern Hemisphere Yedoma deposit area to cover approximately 625,000 km². We estimate that 53% of the total Yedoma area today is located in the tundra zone, 47% in the taiga zone. Separated from west to east, 29% of the Yedoma area is found in North America and 71 % in North Asia. The latter include 9% in West Siberia, 11% in Central Siberia, 44% in East Siberia and 7% in Far East Russia. Adding the recent maximum Yedoma region (including all Yedoma uplands, thermokarst lakes and basins, and river valleys) of 1.4 million km² (Strauss et al., 2013, doi:10.1002/2013GL058088) and postulating that Yedoma occupied up to 80% of the adjacent formerly exposed and now flooded Beringia shelves (1.9 million km², down to 125 m below modern sea level, between 105°E - 128°W and >68°N), we assume that the Last Glacial Maximum Yedoma region likely covered more than 3 million km² of Beringia. Acknowledgements: This project is part of the Action Group "The Yedoma Region: A Synthesis of Circum-Arctic Distribution and Thickness" (funded by the International Permafrost Association (IPA) to J. Strauss) and is embedded into the Permafrost Carbon Network (working group Yedoma Carbon Stocks). We acknowledge the support by the European Research Council (Starting Grant #338335), the German Federal Ministry of Education and Research (Grant 01DM12011 and "CarboPerm" (03G0836A)), the Initiative and Networking Fund of the Helmholtz Association (#ERC-0013) and the German Federal Environment Agency (UBA, project UFOPLAN FKZ 3712 41 106).

DAEDALUS at ImageCLEF Medical Retrieval 2011: Textual, Visual and Multimodal Experiments

This paper describes the participation of DAEDALUS at ImageCLEF 2011 Medical Retrieval task. We have focused on multimodal (or mixed) experiments that combine textual and visual retrieval. The main objective of our research has been to evaluate the effect on the medical retrieval process of the existence of an extended corpus that is annotated with the image type, associated to both the image itself and also to its textual description. For this purpose, an image classifier has been developed to tag each document with its class (1st level of the hierarchy: Radiology, Microscopy, Photograph, Graphic, Other) and subclass (2nd level: AN, CT, MR, etc.). For the textual-based experiments, several runs using different semantic expansion techniques have been performed. For the visual-based retrieval, different runs are defined by the corpus used in the retrieval process and the strategy for obtaining the class and/or subclass. The best results are achieved in runs that make use of the image subclass based on the classification of the sample images. Although different multimodal strategies have been submitted, none of them has shown to be able to provide results that are at least comparable to the ones achieved by the textual retrieval alone. We believe that we have been unable to find a metric for the assessment of the relevance of the results provided by the visual and textual processes