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Abstract Head and neck cancers, particularly oropharyngeal cancers (OPC), have been increasingly associated with human papillomavirus (HPV) infections, specifically HPV16. The current methods for HPV16 detection primarily rely on p16 staining or PCR techniques. However, it is important to note the limitations of conventional PCR, as the presence of viral DNA does not always indicate an ongoing viral infection. Moreover, these tests heavily rely on the availability of tissue samples, which can present challenges in certain situations. In this study, we developed a RT-qPCR biplex approach to detect HPV16 oncogenes E6 and E7 RNA in saliva samples from OPC patients. Salivary supernatant was used as the liquid biopsy source. We successfully obtained RNA from salivary supernatant, preserving its integrity as indicated by the detection of several housekeeping genes. Our biplex approach accurately detected E6 and E7 RNA in HPV16-positive cell lines, tissues, and finally in OPC salivary samples. Importantly, the assay specifically targeted HPV16 and not HPV18. This biplexing technique allowed for reduced sample input without compromising specificity. In summary, our approach demonstrates the potential to detect viable HPV16 in saliva from OPC patients. Since the assay measures HPV16 RNA, it provides insights into the transcriptional activity of the virus. This could guide clinical decision-making and treatment planning for individuals with HPV-related OPC.

ObjectiveTo explore independence, usability, and self-reported quality of life (QOL) in eligible persons with spinal cord injury (SCI) who used a standing powered wheelchair over a 12-week period. Setting: VA SCI research facility.ParticipantsFour participants with chronic SCI who use a wheelchair as the primary means of mobility.InterventionA standing power wheelchair was used three times a week (3.5 h/session) for 12 weeks in a supervised setting. Main Outcome Measures: safety, usability and feasibility, blood pressure in seated and standing positions, bowel, bladder, and pain item banks from the SCI-QOL Physical-Medical-Health domain, and overall user satisfaction with the device.ResultsParticipants consistently maintained normal blood pressure responses between seated and standing positions throughout the training sessions and learned to perform all the mobility tasks safely and independently. Participants reported improvements on the SCI-QOL and were generally satisfied with the upright standing power wheelchair.ConclusionsIn this small case series of chronic, non-ambulatory individuals with SCI, the standing powered wheelchair was shown to be safe and efficacious.

Objective: This article describes a case of polymicrobial Arcanobacterium haemolyticum pharyngitis and sinusitis complicated by intracranial complications and reviews similar cases in the literature Case summary: A 21-year-old immunocompetent male presented with symptoms of sore throat, rhinorrhoea, lethargy, headache, and rash. Imaging demonstrated sinusitis, pre-septal sinusitis, peritonsillar abscess formation, subdural empyema and cerebritis. He was managed with endoscopic sinus surgery, craniotomy for evacuation of subdural empyema and antibiotics. Microbiological samples demonstrated growth of A. haemolyticum, strep. anginosus, and fusobacterium necrophorum. He subsequently developed a cerebral abscess requiring stereotactic needle drainage. After a prolonged course of antibiotics, the patient was discharge and made a good recovery. Discussion: A. haemolyticum is an uncommon cause of non-streptococcal pharyngitis that may occur alongside other microorganisms and is rarely associated with severe intracranial complications. This organism and its antibiotic susceptibility patterns should be considered in complicated upper respiratory tract infections in immunocompetent hosts. Penicillins and macrolide antibiotics form the mainstay of therapy for A. haemolyticum.

This paper reports a temperature-dependent ASM-HEMT for modeling GaN HEMTs at elevated temperatures. Modifications to the standard ASM-HEMT were developed to accurately capture the DC and RF measurements collected at varying chuck temperatures. Several results are reported which validate the model including DC-IV, pulsed-IV, scattering-parameter, and load-pull measurements. The model is then used to extrapolate the performance of the GaN HEMT to twice the operating temperature at which the model was validated. This work could be useful for understanding and modeling GaN HEMTs in high-temperature environment applications.

This article presents a set of measured benchmarks for the noise and gain performance of six different millimeter-wave (mm-wave) gallium nitride (GaN) high electron mobility transistor (HEMT) technologies fabricated at four different foundries in the United States. Measurements of the GaN transistors were collected on two independent noise parameter (NP) systems from 8–50 GHz and 75–110 GHz. The resulting raw NPs were stitched together to yield ultra broadband 8–110 GHz smoothed NPs. Several comparisons and summaries of the minimum noise figure and associated gain are reported for the six different GaN technologies. This work seeks to provide an initial database for noise and gain of GaN HEMTs at mm-wave frequencies to quantify progress on technology in the future.

This article presents an empirical investigation of calibration effects on load-pull measurements collected on wafer and at W-band frequencies. An analysis of scattering parameter (S-parameter) measurements provides insight into how small-signal metrics germane to load pull are affected by choice of the calibration technique. It is found that off-wafer line-reflect-reflect-match (LRRM) calibrated measurements of the same transistor with different probes exhibit drastically different maximum small-signal gains compared to equivalent on-wafer multiline thru-reflect-line (mTRL) calibrated measurements. Load-pull measurements are heavily influenced by choice of calibration algorithm, and LRRM calibrated large-signal measurements collected with different waveguide probes yield variations in large-signal gain of over 2 dB and variations in peak PAE of over 24 percentage points. The equivalent on-wafer mTRL calibrated load-pull measurements collected with different waveguide probes are consistent to within 0.1 dB for large-signal gain and 1 percentage point for peak PAE. This work provides quantitative evidence that on-wafer mTRL calibration with well-designed calibration structures is preferred for large-signal measurements collected at millimeter-wave frequencies. If utilization of on-wafer mTRL calibration is not possible, this work suggests using similar measurement setups, i.e., waveguide probes, calibration standards, etc., for evaluating on-wafer unmatched transistors in a consistent manner.

Abstract Introduction Sporadic medullary thyroid cancer accounts for 75% of all medullary thyroid cancers and presents at a more advanced disease stage than its hereditary counterparts. Yet there is little evidence to support risk stratification of patients according to risk of recurrence. Methods A systematic review and meta-analysis was performed investigating clinical and pathological factors that are associated with recurrent disease in patients with medullary thyroid cancer. Results 10 studies totalling 458 patients were included in the meta-analyses. T3 and T4 disease (OR 9.33 (95% CI 2.5 – 34.82) p = 0.0009.), AJCC stage III and IV disease (OR 13.34 (95% CI 2.9 – 60.3) p = 0.0008) and the presence of nodal disease (OR 7.28 (95% CI 7.2–43.3) p = 0.03) were all associated with recurrent disease. RET mutations (OR 0.08 (95% CI -0.03–0.19) p = 0.17) and RET 918 T mutations (OR 1.77 (95% CI 0.804.0) P = 0.17) were not associated with disease recurrence. It was not possible to pool data with respect to extrathyroidal extension, extracapsular extension, peri-neural and lymphovascular invasion and RAS mutations. Conclusion T3 and T4 disease, AJCC stage III and IV disease and the presence of nodal disease are associated with recurrent disease. The heterogeneous reporting of recurrence and the lack of individual patient data precludes larger scale meta-analyses. Future research in this area should involve collaboration to establish standardised definitions of disease recurrence.

There is growing awareness of the need for greater acknowledgement of underwater prehistoric cultural resources as part of management and regulation of the seabed around many maritime countries, especially those with large indigenous populations and history such as Australia. Prehistoric cultural places and landscapes inundated by Post-glacial sea-level rise on Australia’s continental shelf remain largely out-of-sight and out-of-mind, hence awareness and hence legal protection of this resource is lacking. There is a clear need for greater integration of archaeology and cultural heritage management within the marine sciences as well as a greater awareness of this resource as part of a common heritage more generally. This paper explores some of the dichotomies between Western and Indigenous cultures in valuing and managing the seabed. We argue that in developing science-policy, an attempt at least needs to be made to bridge both the gap between the nature and culture perspectives, and the jurisdictional divide between land and sea. Part of the answer lies in a convergence of Indigenous knowledge with Western science approaches, focused around our understanding of physical processes impacting past and present coastal landscapes and on the seabed itself. We explore several case studies from northern and Western Australia that are trying to do this, and which are helping to provide a greater appreciation of the inundated landscapes of the inner shelf as part of a common heritage.

The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8+ T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.

The plethora of human activities and their pressures and impacts in the oceans require managing at local, national, regional and international scales. This requires management responses in a programme of measures to determine (a) the area in which the human activities take place, (b) the area covered by the pressures generated by the activities on the prevailing habitats and species in which pressures are defined as the mechanisms of change, and (c) the area over which any adverse effects (and even benefits) occur on both the natural and human systems. The spatial and temporal scales of these leads to the concepts of activity-, pressures-, effects- and management responses-footprints, defined here. These footprints cover areas from tens of m2 to millions of km2, and, in the case of management responses, from a large number of local instruments to a few global instruments thereby giving rise to what is termed the management response-footprint pyramids. This may operate from either bottom-up or top-down directions, whether as the result of local societal demands for clean, healthy, productive and diverse seas or by diktat from national, supranational and global bodies such as the United Nations. These concepts are explained and illustrated using marine examples based on experience from many jurisdictions.

Abstract Background Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses. Herein, we investigate the role of XBP1 in maintaining morphological and functional integrity in retinal neurons during adulthood and the early stages of aging. Methods The basal and induced levels of XBP1 activation in the retina were measured in young adult and aged mice. Conditional knockout (cKO) of XBP1 in retinal neurons was achieved by crossing XBP1 floxed mice with a retina specific Cre-recombinase line (Chx10-Cre). Retinal morphology, neuronal populations including photoreceptors, bipolar cells, and retinal ganglion cells (RGCs), synaptic structure, and microglial activation were examined with immunohistochemistry and staining of retinal sections. Retinal function was evaluated with light-adapted (photopic) and dark adapted (scotopic) electroretinograms. Retinal mitochondrial function and metabolism was assessed by Seahorse XFe24 Extracellular Flux Analyzer. Results The retinas of aged wild type (WT) mice display a significantly reduced basal level of Xbp1s and compromised activation of ER stress response. In XBP1 cKO mice, significant structural degeneration of the retina, evidenced by thinning of retinal layers and a loss of RGCs, and functional defects indicated by diminished photopic and scotopic ERG b-waves are observed at the age of 12–14 months. Furthermore, discontinuous and disorganized synaptic laminae, colocalized with activated microglia, in the inner plexiform layer is found in the XBP1 cKO retinas. In addition, cKO mice demonstrate a significant increase in ectopic synapses between bipolar cells and photoreceptors, which is strikingly similar to WT mice at 20–24 months of age. These changes are associated with defective retinal glycolysis while mitochondrial respiratory function appears normal in the cKO retina. Conclusions XBP1 cKO mice at 12–14 months of age show significant structural, functional, and metabolic deficits that closely resemble WT mice twice that age. Our findings suggest that the absence of XBP1, a critical component of the UPR, accelerates age-related retinal neurodegeneration.

PRMT1 is an arginine methyltransferase involved in a variety of cell functions. Here the authors delete PRMT1 specifically in mature B cells to show the importance of arginine methylation for B cell proliferation, differentiation and survival, and thereby for humoral immunity.

Summary: Background: Health effects of air pollution on diabetes have been scarcely studied in developing countries. We aimed to explore the associations of long-term exposure to ambient particulate matter (PM) and gaseous pollutants with diabetes prevalence and glucose-homoeostasis markers in China. Methods: Between April 1 and Dec 31, 2009, we recruited a total of 15 477 participants aged 18–74 years using a random number generator and a four-staged, stratified and cluster sampling strategy from a large cross-sectional study (the 33 Communities Chinese Health Study) from three cities in Liaoning province, northeastern China. Fasting and 2 h insulin and glucose concentrations and the homoeostasis model assessment of insulin resistance index and β-cell function were used as glucose-homoeostasis markers. Diabetes was defined according to the American Diabetes Association's recommendations. We calculated exposure to air pollutants using data from monitoring stations (PM with an aerodynamic diameter of 10 μm or less [PM10], sulphur dioxide, nitrogen dioxide, and ozone) and a spatial statistical model (PM with an aerodynamic diameter of 1 μm or less [PM1] and 2·5 μm or less [PM2·5]). We used two-level logistic regression and linear regression analyses to assess associations between exposure and outcomes, controlling for confounders. Findings: All the studied pollutants were significantly associated with increased diabetes prevalence (eg, the adjusted odds ratios associated with an increase in IQR for PM1, PM2·5, and PM10 were 1·13, 95% CI 1·04–1·22; 1·14, 1·03–1·25; and 1·20, 1·12–1·28, respectively). These air pollutants were also associated with higher concentrations of fasting glucose (0·04–0·09 mmol/L), 2 h glucose (0·10–0·19 mmol/L), and 2 h insulin (0·70–2·74 μU/L). No association was observed for the remaining biomarkers. Stratified analyses indicated greater effects on the individuals who were younger (

‘Biodiversity’ is one of the most common keywords used in environmental sciences, spanning from research to management, nature conservation and consultancy. Despite this, our understanding of the underlying concepts varies greatly, between and within disciplines as well as among the scientists themselves. Biodiversity can refer to descriptions or assessments of the status and condition of all or selected groups of organisms, from the genetic variability, to the species, populations, communities, and ecosystems. However, a concept of biodiversity also must encompass understanding the interactions and functions on all levels from individuals up to the whole ecosystem, including changes related to natural and anthropogenic environmental pressures. While biodiversity as such is an abstract and relative concept rooted in the spatial domain, it is central to most international, European and national governance initiatives aimed at protecting the marine environment. These rely on status assessments of biodiversity which typically require numerical targets and specific reference values, to allow comparison in space and/or time, often in association with some external structuring factors such as physical and biogeochemical conditions. Given that our ability to apply and interpret such assessments requires a solid conceptual understanding of marine biodiversity, here we define this and show how the abstract concept can and needs to be interpreted and subsequently applied in biodiversity assessments.

This paper presents a typology of stakeholders for effective participatory processes and co-design of solutions to complex social-environmental issues and a roadmap stepwise methodology for balanced and productive stakeholder engagement. Definitions are given of terminology that is frequently used interchangeably such as stakeholders, social actors and interested parties. Eleven research questions about participative processes are addressed, based on more than 30 years of experience in water, estuarine, coastal and marine management. A stepwise roadmap, supported by illustrative tables based on case-studies, shows how a balanced stakeholder selection and real engagement maybe achieved. The paper brings these together in the context of several up-to-date concepts such as complex, nested governance, the 10 tenets for integrated, successful and sustainable marine management, the System Approach Framework and the evolution of DPSIR into DAPSI(W)R(M) framework. Examples given are based on the implementation of the Marine Strategy Framework Directive, the Water Framework Directive, the Environmental Impact Assessment Directive, the Framework for Marine Spatial Planning Directive, as well as for Regional Sea Conventions. The paper also shows how tools that have been developed in recent projects can be put to use to implement policy and maximize the effectiveness of stakeholder participation.

By 2020, European Union Member States should achieve Good Environmental Status (GES) for eleven environmental quality descriptors for their marine waters to fulfill the Marine Strategy Framework Directive (MSFD). By the end of 2015, in coordination with the Regional Seas Conventions, each EU Member States was required to develop a marine strategy for their waters, together with other countries within the same marine region or sub-region. Coherent monitoring programs, submitted in 2014, form a key component of this strategy, which then aimed to lead to a Program of Measures (submitted in 2015). The European DEVOTES FP7 project has produced and interrogated a catalogue of EU marine monitoring related to MSFD descriptors 1 (biological diversity), 2 (non-indigenous species), 4 (food webs) and 6 (seafloor integrity). Here we detail the monitoring activity at the regional and sub-regional level for these descriptors, as well as for 11 biodiversity components, 22 habitats and the 37 anthropogenic pressures addressed. The metadata collated for existing European monitoring networks were subject to a SWOT (strengths, weaknesses, opportunities and threats) analysis. This interrogation has indicated case studies to address the following questions: a) what are the types of monitoring currently in place?; b) who does what and how?; c) is the monitoring fit-for-purpose for addressing the MSFD requirements?, and d) what are the impediments to better monitoring (e.g. costs, shared responsibilities between countries, overlaps, co-ordination)? We recommend the future means, to overcome the identified impediments and develop more robust monitoring strategies and as such the results are especially relevant to implementing coordinated monitoring networks throughout Europe, for marine policy makers, government agencies and regulatory bodies. It is emphasized that while many of the recommendations given here require better, more extensive and perhaps more costly monitoring, this is required to avoid any legal challenges to the assessments or to bodies and industries accused of causing a deterioration in marine quality. More importantly the monitoring is required to demonstrate the efficacy of management measures employed. Furthermore, given the similarity in marine management approaches in other developed systems, we consider that the recommendations are also of relevance to other regimes worldwide.

Determining and assessing the links between human pressures and state-changes in marine and coastal ecosystems remains a challenge. Although there are several conceptual frameworks for describing these links, the DPSIR (Drivers – Pressures – State change – Impact – Response) framework has been widely adopted. Two possible reasons for this are: either the framework fulfils a major role, resulting from convergent evolution, or the framework is used often merely because it is used often, albeit uncritically. This comprehensive review, with lessons learned after two decades of use, shows that the approach is needed and there has been a convergent evolution in approach for coastal and marine ecosystem management. There are now 25 derivative schemes and a widespread and increasing usage of the DPSIR-type conceptual framework as a means of structuring and analyzing information in management and decision-making across ecosystems. However, there is less use of DPSIR in fully marine ecosystems and even this was mainly restricted to European literature. Around half of the studies are explicitly conceptual, not illustrating a solid case study. Despite its popularity since the early 1990s among the scientific community and the recommendation of several international institutions for its application, the framework has notable weaknesses to be addressed. These primarily relate to the long standing variation in interpretation (mainly between natural and social scientists) of the different components (particularly P, S and I) and to over-simplification of environmental problems such that cause-effect relationships cannot be adequately understood by treating the different DPSIR components as being mutually exclusive. More complex, nested, conceptual models and models with improved clarity are required to assess pressure-state change links in marine and coastal ecosystems. Our analysis shows that, because of its complexity, marine assessment and management constitutes a ’wicked problem’ and that there is an increasing need for a unifying approach, especially with the implementation of holistic regulations (e.g. European Directives). We emphasize the value of merging natural and social sciences and in showing similarities across human and natural environmental health. We show that previous approaches have adequately given conceptual and generic models but specificity and quantification is required.

Human activities, both established and emerging, increasingly affect the provision of marine ecosystem services that deliver societal and economic benefits. Monitoring the status of marine ecosystems and determining how human activities change their capacity to sustain benefits for society requires an evidence-based Integrated Ecosystem Assessment approach that incorporates knowledge of ecosystem functioning and services). Although there are diverse methods to assess the status of individual ecosystem components, none assesses the health of marine ecosystems holistically, integrating information from multiple ecosystem components. Similarly, while acknowledging the availability of several methods to measure single pressures and assess their impacts, evaluation of cumulative effects of multiple pressures remains scarce. Therefore, an integrative assessment requires us to first understand the response of marine ecosystems to human activities and their pressures and then develop innovative, cost-effective monitoring tools that enable collection of data to assess the health status of large marine areas. Conceptually, combining this knowledge of effective monitoring methods with cost-benefit analyses will help identify appropriate management measures to improve environmental status economically and efficiently. The European project DEVOTES (DEVelopment Of innovative Tools for understanding marine biodiversity and assessing good Environmental Status) specifically addressed these topics in order to support policy makers and managers in implementing the European Marine Strategy Framework Directive. Here, we synthesize our main innovative findings, placing these within the context of recent wider research, and identifying gaps and the major future challenges.

Conceptual models summarize, visualize and explain actual or predicted situations and how they might be tackled. In recent years, Pressure-State-Response (P-S-R) frameworks have been central to conceptualizing marine ecosystem issues and then translating those to stakeholders, environmental managers and researchers. Society is concerned about the risks to the natural and human system posed by those Pressures (thus needing risk assessment) and then needs to act to minimize or compensate those risks (as risk management). This research relates this to the DPSIR (Drivers-Pressure-State(change)-Impact-Response) hierarchical framework using standardized terminology/definitions and lists of impacting Activities and Pressures affecting ecosystem components, incorporating the European Marine Strategy Framework Directive (MSFD) legal decision components. This uses the example of fishing activity and the pressure of trawling from abrasion on the seabed and its effects on particular components. The mechanisms of Pressure acting on State changes are highlighted here as an additional refinement to DPSIR. The approach moves from conceptual models to actual assessments including: assessment methodologies (interactive matrices, ecosystem modeling, Bayesian Belief Networks, Bow-tie approach, some assessment tools) data availability, confidence, scaling, cumulative effects and multiple simultaneous Pressures, which more often occur in multi-use and multi-user areas. In defining and describing the DPSIR Conceptual Framework we consider its use in re-world ecosystems affected by multiple pressures or multiple mechanisms of single pressures, and show how it facilitates management and assessment issues with particular relevance to the MSFD.

Mainstream machine learning approaches to predictive analytics consistently prove their ability to perform well using a variety of datasets, although the task of identifying an optimally-performing machine learning approach for any given dataset becomes much less intuitive. Methods such as ensemble and transformation modeling have been developed to improve upon individual base learners and datasets with large degrees of variance. Despite the increased generalizability and flexibility of ensemble approaches, the cost often involves sacrificing inference for predictive ability. This paper introduces an alternative approach to ensemble modeling, combining the predictive ability of an ensemble framework with localized model construction through the incorporation of cluster analysis as a pre-processing technique. The workflow not only outperforms independent base learners and comparative ensemble methods, but also preserves local inferential capability by manipulating cluster parameters and maintaining interpretable relative importance values and non-transformed coefficients for the overall consideration of variable importance. This paper demonstrates the ensemble technique on a dataset to estimate rates of health insurance coverage across the state of Missouri, where the cluster pre-processing assists in understanding both local and global variable importance and interactions when predicting high concentration areas of low health insurance coverage based on demographic, socioeconomic, and geospatial variables.

Trophic interactions play a key role in nursery habitats, and by affecting growth and condition of the juveniles, may control the quality of a given estuarine nursery. This study investigated the trophic ecology of flounder (Platichthys flesus) and common sole (Solea solea) juveniles in the Lima estuary nursery. Feeding location, main organic matter sources, and prey of the target species were assessed by carbon (δ13C) and nitrogen (δ15N) stable isotopes, as well as by stomach content analysis. The juveniles, macroinvertebrates, and sediment and water column samples were collected in August 2014 in the lower, middle and upper sections of the Lima estuary. The diet of 0+ flounder relied upon prey from the upper estuary (salinity >5), namely Chironomid larvae and Corophium spp. which showed the role of the upper estuary prey to the 0+ flounder diet and suggest the relative site fidelity of the young juveniles. In contrast, 1+ flounder juveniles had a diverse diet based on bivalves, polychaetes and crustaceans, and a variable stable isotope signature indicating they fed in different areas along the estuary. The 1+ sole juveniles also fed on polychaetes, crustaceans, and bivalves, but the stable isotope values suggested a dependence on the lower estuary (salinity >30) and marine food web sources. Such differential use of food may be understood as a strategic approach to reduce intra- and interspecific competition and thus ensuring the use of Lima estuary as nursery area for these two flatfish species.

Objectives: This paper evaluates the drivers of profitability for a large sample of U.S. hospitals. Following a methodology frequently used by financial analysts, we use a DuPont analysis as a framework to evaluate the quality of earnings. By decomposing returns on equity (ROE) into profit margin, total asset turnover, and capital structure, the DuPont analysis reveals what drives overall profitability. Methods: Profit margin, the efficiency with which services are rendered (total asset turnover), and capital structure is calculated for 3,255 U.S. hospitals between 2007 and 2012 using data from the Centers for Medicare & Medicaid Services’ Healthcare Cost Report Information System (CMS Form 2552). The sample is then stratified by ownership, size, system affiliation, teaching status, critical access designation, and urban or non-urban location. Those hospital characteristics and interaction terms are then regressed (OLS) against the ROE and the respective DuPont components. Sensitivity to regression methodology is also investigated using a seemingly unrelated regression. Results: When the sample is stratified by hospital characteristics, the results indicate investor-owned hospitals have higher profit margins, higher efficiency, and are substantially more leveraged. Hospitals in systems are found to have higher ROE, margins, and efficiency but are associated with less leverage. In addition, a number of important and significant interactions between teaching status, ownership, location, critical access designation, and inclusion in a system are documented. Many of the significant relationships, most notably not-for-profit ownership, lose significance or are predominately associated with one interaction effect when interaction terms are introduced as explanatory variables. Results are not sensitive to the alternative methodology. Conclusion: The results of the DuPont analysis suggest that although there appears to be convergence in the behavior of NFP and IO hospitals, significant financial differences remain depending on their respective hospital characteristics. Those differences are tempered or exacerbated by location, size, teaching status, system affiliation, and critical access designation. With the exception of cost-based reimbursement for critical access hospitals, emerging payment systems are placing additional financial pressures on hospitals. The financial pressures being applied treat hospitals as a monolithic category and, given the delicate and often negative ROE for many hospitals, the long-term stability of the healthcare facility infrastructure may be negatively impacted.