744 research outputs found

    Metastatic squamous cell carcinoma in a RDEB patient treated with pembrolizumab

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    A case of metastatic squamous cell carcinoma in a patient with recessive dystrophic epidermolysis bullosa that was responsive to pembrolizumab, a programmed cell death protein 1 inhibitor. Purpose: Cutaneous squamous cell carcinomas (SCCs) are the leading cause of death in patients with recessive dystrophic epidermolysis bullosa (RDEB). Management of SCCs in these patients is challenging with higher rates of recurrence and lymph nodes metastases. Although surgery is the first-line treatment in the majority of cases, certain clinical situations, such as local recurrence, or regional or distant metastasis, may call for nonsurgical treatment such as chemotherapy. We report the complex management of SCCs in a young female patient with RDEB whose nodal disease responded successfully to programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab. Design: Patient is a 29-year-old female with a long-standing history of RDEB that has been complicated by multifocal and recurrent SCC of the skin. She initially presented in 2015, at the age of 24, for SCC of the skin that was treated with a combination of Mohs micrographic surgery (MMS), wide local excision, and laser-assisted topical delivery of aminolevulinic acid. Over the following 6 months she developed several additional invasive SCCs. Surgical resection was again attempted, however, pathology revealed positive deep and lateral margins at 2 excision sites. Computed tomography (CT) scan at this time revealed bilateral pulmonary nodules and axillary nodes concerning for early metastatic disease. Left axillary node biopsy performed however, was negative for metastatic disease and these were thought to be consistent with a reactive process. Oncology recommended off-label palliative use of cetuximab given her multifocal disease and higher risk of metastasis in RDEB patients. She completed 4 cycles of cetuximab complicated by sepsis due to group G streptococcus, likely from a cutaneous source, as well as a grade 2 EGFR-associated acneiform eruption. After 4 cycles, her CT remained stable and there was no evidence of cutaneous recurrence, so the decision was made to discontinue cetuximab at this time. However, two years following the cessation of cetuximab she developed multiple cutaneous recurrences and a surveillance CT scan showed enlargement of her left axillary lymph nodes to a mass of 3.7 x 4.0 cm in size. Nodal biopsy revealed metastatic SCC and molecular testing performed showed that 100% of tumor cells (tumor proportion score) were positive for PD-L1 staining. The decision was made to start pembrolizumab as off label therapy with plans to pursue axillary node excision after she completed treatment. At the completion of 4 cycles of pembrolizumab, a repeat CT scan showed improvement in the enlarged nodes with reduction to 2.2 x 1.4 cm in size and regional lymph node resection was successfully performed. Summary: Pembrolizumab was the first PD-1 inhibitor approved by the FDA for metastatic melanoma. Recently in clinical trials, a new PD-1 inhibitor cemiplimab showed a 50% response rate in the treatment of cutaneous SCC and became the first systemic drug in it’s class to be approved for the treatment of locally advanced or metastatic cutaneous SCC. We report the first case of metastatic SCC in a RDEB patient that responded to treatment with PD-1 inhibitor, pembrolizumab. Conclusion: Immunotherapy with PD-1 inhibitors, such as pembrolizumab may be an alternative treatment modality for SCC in RDEB patients with late stage or metastatic disease. Further larger scale studies are warranted to determine the utility of PD-1 inhibitors in the multimodal management of these high-risk patients.https://scholarlycommons.henryford.com/merf2020caserpt/1006/thumbnail.jp

    Addressing the impact of fracture during indentation of molecular crystals

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    There are inherent challenges in mechanical testing of anisotropic molecular crystals, one of which being their propensity for brittle fracture, which can limit the usage conditions of the material as well as the range of conditions in which mechanical testing results are valid. Molecular crystals, which contain the families of many energetic materials and pharmaceutical materials (in addition to ice), are commonly considered to be both compliant and brittle, and in most common forms the materials are used as small crystalline powders suspended in binders rather than in pure polycrystalline aggregates. Indentation testing on molecular crystals has previously been shown to be able to quantify modulus, hardness, and yield points in materials ranging from sucrose [1] to energetics and pharmaceuticals [2], [3]. To quantify the fracture response in materials that cannot be subjected to traditional toughness tests due to limited particle size and morphology, a technique is used in which nanoindentation tests are performed on a material with probes of varying acuity, and analysis of the unloading portion of the resulting load-depth curve indicates presence or lack thereof of radial cracking [4]. This technique has been used to define a radial cracking threshold for the secondary explosives HMX (cyclotetramethylenetetranitramine) and PETN (pentaerythritol tetranitrate) of 4 mN as well as a cracking threshold beginning at 100 mN for the pharmaceutical idoxuridine. The low indentation fracture toughness in the explosives may be the reason for difficulty that has been seen previously in accurately obtaining mechanical property measurements over a wide range of depths in these materials. Please click Additional Files below to see the full abstract

    A Case of Metastatic Squamous Cell Carcinoma in a Patient with Recessive Dystrophic Epidermolysis Bullosa that was Responsive to Pembrolizumab, a Programmed Cell Death Protein 1 Inhibitor

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    A case of metastatic squamous cell carcinoma in a patient with recessive dystrophic epidermolysis bullosa that was responsive to pembrolizumab, a programmed cell death protein 1 inhibitor. Purpose: Cutaneous squamous cell carcinomas (SCCs) are the leading cause of death in patients with recessive dystrophic epidermolysis bullosa (RDEB). Management of SCCs in these patients is challenging with higher rates of recurrence and lymph nodes metastases. Although surgery is the first-line treatment in the majority of cases, certain clinical situations, such as local recurrence, or regional or distant metastasis, may call for nonsurgical treatment such as chemotherapy. We report the complex management of SCCs in a young female patient with RDEB whose nodal disease responded successfully to programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab. Design: Patient is a 29-year-old female with a long-standing history of RDEB that has been complicated by multifocal and recurrent SCC of the skin. She initially presented in 2015, at the age of 24, for SCC of the skin that was treated with a combination of Mohs micrographic surgery (MMS), wide local excision, and laser-assisted topical delivery of aminolevulinic acid. Over the following 6 months she developed several additional invasive SCCs. Surgical resection was again attempted, however, pathology revealed positive deep and lateral margins at 2 excision sites. Computed tomography (CT) scan at this time revealed bilateral pulmonary nodules and axillary nodes concerning for early metastatic disease. Left axillary node biopsy performed however, was negative for metastatic disease and these were thought to be consistent with a reactive process. Oncology recommended off-label palliative use of cetuximab given her multifocal disease and higher risk of metastasis in RDEB patients. She completed 4 cycles of cetuximab complicated by sepsis due to group G streptococcus, likely from a cutaneous source, as well as a grade 2 EGFR-associated acneiform eruption. After 4 cycles, her CT remained stable and there was no evidence of cutaneous recurrence, so the decision was made to discontinue cetuximab at this time. However, two years following the cessation of cetuximab she developed multiple cutaneous recurrences and a surveillance CT scan showed enlargement of her left axillary lymph nodes to a mass of 3.7 x 4.0 cm in size. Nodal biospy revealed metastatic SCC and molecular testing performed showed that 100% of tumor cells (tumor proportion score) were positive for PD-L1 staining. The decision was made to start pembrolizumab as off label therapy with plans to pursue axillary node excision after she completed treatment. At the completion of 4 cycles of pembrolizumab, a repeat CT scan showed improvement in the enlarged nodes with reduction to 2.2 x 1.4 cm in size and regional lymph node resection was successfully performed. Summary: Pembrolizumab was the first PD-1 inhibitor approved by the FDA for metastatic melanoma. Recently in clinical trials, a new PD-1 inhibitor cemiplimab showed a 50% response rate in the treatment of cutaneous SCC and became the first systemic drug in it’s class to be approved for the treatment of locally advanced or metastatic cutaneous SCC. We report the first case of metastatic SCC in a RDEB patient that responded to treatment with PD-1 inhibitor, pembrolizumab. Conclusion: Immunotherapy with PD-1 inhibitors, such as pembrolizumab may be an alternative treatment modality for SCC in RDEB patients with late stage or metastatic disease. Further larger scale studies are warranted to determine the utility of PD-1 inhibitors in the multimodal management of these high-risk patients.https://scholarlycommons.henryford.com/merf2020caserpt/1131/thumbnail.jp

    Improvement Research Carried Out Through Networked Communities: Accelerating Learning about Practices that Support More Productive Student Mindsets

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    The research on academic mindsets shows significant promise for addressing important problems facing educators. However, the history of educational reform is replete with good ideas for improvement that fail to realize the promises that accompany their introduction. As a field, we are quick to implement new ideas but slow to learn how to execute well on them. If we continue to implement reform as we always have, we will continue to get what we have always gotten. Accelerating the field's capacity to learn in and through practice to improve is one key to transforming the good ideas discussed at the White House meeting into tools, interventions, and professional development initiatives that achieve effectiveness reliably at scale. Toward this end, this paper discusses the function of networked communities engaged in improvement research and illustrates the application of these ideas in promoting greater student success in community colleges. Specifically, this white paper:* Introduces improvement research and networked communities as ideas that we believe can enhance educators' capacities to advance positive change. * Explains why improvement research requires a different kind of measures -- what we call practical measurement -- that are distinct from those commonly used by schools for accountability or by researchers for theory development.* Illustrates through a case study how systematic improvement work to promote student mindsets can be carried out. The case is based on the Carnegie Foundation's effort to address the poor success rates for students in developmental math at community colleges.Specifically, this case details:- How a practical theory and set of practical measures were created to assess the causes of "productive persistence" -- the set of "non-cognitive factors" thought to powerfully affect community college student success. In doing this work, a broad set of potential factors was distilled into a digestible framework that was useful topractitioners working with researchers, and a large set of potential measures was reduced to a practical (3-minute) set of assessments.- How these measures were used by researchers and practitioners for practical purposes -- specifically, to assess changes, predict which students were at-risk for course failure, and set priorities for improvement work.-How we organized researchersto work with practitioners to accelerate field-based experimentation on everyday practices that promote academic mindsets(what we call alpha labs), and how we organized practitioners to work with researchers to test, revise, refine, and iteratively improve their everyday practices (using plando-study-act cycles).While significant progress has already occurred, robust, practical, reliable efforts to improve students' mindsets remains at an early formative stage. We hope the ideas presented here are an instructive starting point for new efforts that might attempt to address other problems facing educators, most notably issues of inequality and underperformance in K-12 settings

    How School Contexts Shape the Relations Among Adolescents' Beliefs, Peer Victimization, and Depressive Symptoms

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    The present research examined how school contexts shape the extent to which beliefs about the potential for change (implicit theories) interact with social adversity to predict depressive symptoms. A preregistered multilevel regression analysis using data from 6,237 ninth-grade adolescents in 25 U.S. high schools showed a three-way interaction: Implicit theories moderated the associations between victimization and depressive symptoms only in schools with high levels of school-level victimization, but not in schools with low victimization levels. In high-victimization schools, adolescents who believed that people cannot change (an entity theory of personality) were more depressed when they were victimized more frequently. Thus, the mental health correlates of adolescents' implicit theories depend on both personal experiences and the norms in the context

    Marine Socio-Environmental Covariates: queryable global layers of environmental and anthropogenic variables for marine ecosystem studies

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    Biophysical conditions, including climate, environmental stress, and habitat availability, are key drivers of many ecological processes (e.g., community assembly and productivity) and associated ecosystem services (e.g., carbon sequestration and fishery production). Furthermore, anthropogenic impacts such as coastal development and fishing can have drastic effects on the structure and function of marine ecosystems. Scientists need to account for environmental variation and human impacts to accurately model, manage, and conserve marine ecosystems. Although there are many types of environmental data available from global remote sensing and open-source data products, some are inaccessible to potential end-users because they exist as global layers in high temporal and spatial resolutions which require considerable computational power to process. Additionally, coastal locations often suffer from missing data or data quality issues which limit the utility of some global marine products for coastal sites. Herein we present the Marine Socio-Environmental Covariates dataset for the global oceans, which consists of environmental and anthropogenic variables summarized in ecologically relevant ways. The dataset includes four sets of environmental variables related to biophysical conditions (net primary productivity models corrected for shallow-water reflectance, wave energy including sheltered-coastline corrections) and landscape context (coral reef and land cover within varying radii). We also present two sets of anthropogenic variables, human population density (within varying radii) and distance to large population center, which can serve as indicators of local human impacts. We have paired global, summarized layers available for download with an online data querying platform that allows users to extract data for specific point locations with finer control of summary statistics. In creating these global layers and online platform, we hope to make the data accessible to a wide array of end-users with the goal of advancing marine ecosystem studies

    John Erskine (1721-1803) : disseminator of enlightened evangelical Calvinism

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    John Erskine was the leading Evangelical in the Church of Scotland in the latter half of the eighteenth century. Educated in an enlightened setting at Edinburgh University, he learned to appreciate the epistemology of John Locke and other empiricists alongside key Scottish Enlightenment figures such as his ecclesiastical rival, William Robertson. Although groomed to follow in his father’s footsteps as a lawyer, Erskine changed career paths in order to become a minister of the Kirk. He was deeply moved by the endemic revivals in the west of Scotland and determined that his contribution to the burgeoning Evangelical movement on both sides of the Atlantic would be much greater as a clergyman than a lawyer. Yet Erskine was no ‘enthusiast’. He integrated the style and moral teachings of the Enlightenment into his discourses and posited new theories on traditional views of Calvinism in his theological treatises. Erskine’s thought, however, never transgressed the boundaries of orthodoxy. His goal was to update Evangelical Calvinism with the new style and techniques of the Enlightenment without sacrificing the gospel message. While Erskine was widely recognised as an able preacher and theologian, his primary contribution to Evangelicalism was as a disseminator. He sent correspondents like the New England pastor Jonathan Edwards countless religious and philosophical works so that he and others could learn about current ideas, update their writings to conform to the Age of Reason and provide an apologetic against perceived heretical authors. Erskine also was crucial in the publishing of books and pamphlets by some of the best Evangelical theologians in America and Britain. Within his lifetime, Erskine’s main contribution to Evangelicalism was as a propagator of an enlightened form of Calvinism.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
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