Consensus-based guidelines for the provision of palliative and end-of-life care for people living with epidermolysis bullosa.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a cluster of rare, genetic skin and mucosal fragility disorders with multi-system and secondary effects, in which blistering and erosions occur in response to friction/mechanical trauma. Considering the incurable and potentially life-limiting nature of the condition and the challenges posed by its symptoms, a palliative approach to EB-related care is necessary. However, knowledge and experience related to the provision of EB palliative care is minimal. Evidence-based, best care guidelines are needed to establish a base of knowledge for practitioners to prevent or ease suffering while improving comfort at all stages of the illness, not just the end of life. METHODS: This consensus guideline (CG) was begun at the request of DEBRA International, an international organization dedicated to improvement of care, research, and dissemination of knowledge for EB patients, and represents the work of an international panel of medical experts in palliative care and EB, people living with EB, and people who provide care for individuals living with EB. Following a rigorous, evidence-based guideline development process, the author panel identified six clinical outcomes based on the results of a survey of people living with EB, carers, and medical experts in the field, as well as an exhaustive and systematic evaluation of literature. Recommendations for the best clinical provision of palliative care for people living with EB for each of the outcomes were reached through panel consensus of the available literature. RESULTS: This article presents evidence-based recommendations for the provision of palliative healthcare services that establishes a base of knowledge and practice for an interdisciplinary team approach to ease suffering and improve the quality of life for all people living with EB. Any specific differences in the provision of care between EB subtypes are noted. CONCLUSIONS: Because there is yet no cure for EB, this evidence-based CG is a means of optimizing and standardizing the IDT care needed to reduce suffering while improving comfort and overall quality of life for people living with this rare and often devastating condition.

CCL2 disrupts the adherens junction: implications for neuroinflammation.

Alterations to blood-brain barrier (BBB) adhesion molecules and junctional integrity during neuroinflammation can promote central nervous system (CNS) pathology. The chemokine CCL2 is elevated during CNS inflammation and is associated with endothelial dysfunction. The effects of CCL2 on endothelial adherens junctions (AJs) have not been defined. We demonstrate that CCL2 transiently induces Src-dependent disruption of human brain microvascular endothelial AJ. ß-Catenin is phosphorylated and traffics from the AJ to PECAM-1 (platelet endothelial cell adhesion molecule-1), where it is sequestered at the membrane. PECAM-1 is also tyrosine-phosphorylated, an event associated with recruitment of the phosphatase SHP-2 (Src homology 2 domain-containing protein phosphatase) to PECAM-1, ß-catenin release from PECAM-1, and reassociation of ß-catenin with the AJ. Surface localization of PECAM-1 is increased in response to CCL2. This may enable the endothelium to sustain CCL2-induced alterations in AJ and facilitate recruitment of leukocytes into the CNS. Our novel findings provide a mechanism for CCL2-mediated disruption of endothelial junctions that may contribute to BBB dysfunction and increased leukocyte recruitment in neuroinflammatory diseases.

PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation.

Of the 33 million people infected with the human immunodeficiency virus (HIV) worldwide, 40-60% of individuals will eventually develop neurocognitive sequelae that can be attributed to the presence of HIV-1 in the central nervous system (CNS) and its associated neuroinflammation despite antiretroviral therapy. PrP(C) (protease resistant protein, cellular isoform) is the nonpathological cellular isoform of the human prion protein that participates in many physiological processes that are disrupted during HIV-1 infection. However, its role in HIV-1 CNS disease is unknown. We demonstrate that PrP(C) is significantly increased in both the CNS of HIV-1-infected individuals with neurocognitive impairment and in SIV-infected macaques with encephalitis. PrP(C) is released into the cerebrospinal fluid, and its levels correlate with CNS compromise, suggesting it is a biomarker of HIV-associated neurocognitive impairment. We show that the chemokine (c-c Motif) Ligand-2 (CCL2) increases PrP(C) release from CNS cells, while HIV-1 infection alters PrP(C) release from peripheral blood mononuclear cells. Soluble PrP(C) mediates neuroinflammation by inducing astrocyte production of both CCL2 and interleukin 6. This report presents the first evidence that PrP(C) dysregulation occurs in cognitively impaired HIV-1-infected individuals and that PrP(C) participates in the pathogenesis of HIV-1-associated CNS disease.

A preliminary study of the effect of a diagnosis of concussion on PTSD symptoms and other psychiatric variables at the time of treatment seeking among veterans.

The aim of this study was to assess whether a diagnosis of concussion given at a Veterans Healthcare Administration secondary traumatic brain injury assessment impacted either posttraumatic stress disorder (PTSD) symptomatology or other variables at the time veterans sought treatment for PTSD. This retrospective study compared 61 male veterans with a history of military-related concussion and military-related PTSD to 83 male veterans with military-related PTSD but without a diagnosis of military-related concussion. There were no significant between-group differences in PTSD symptomatology. However, the cohort with a history of military concussion endorsed decreased ability to cope with PTSD symptoms, increased problems with physical health, and more pain complaints. If replicated, these results may guide the design of more effective interventions for veterans who receive diagnoses of PTSD and concussion.

Development of the Simulation-Positive Learning Evaluation (SIM-PLE) rubric for use in medical-surgical nursing high fidelity simulations.

Clinical nurse educators in a BSN program developed the SIM-PLE (Simulation-Positive Learning Evaluation) rubric to evaluate student performance in simulation. A pilot study was conducted over two semesters with junior level medical-surgical classes made up of approximately 110-130 students each semester, and the tool was revised and re-evaluated. Inter-rater reliability testing utilized 69 SIM-PLE rubric student evaluations (N = 69). Inter-rater reliability was assessed with comparison of lead faculty with three other instructors utilizing two raters for each simulation experience. The intraclass correlation coefficient (ICC) suggested high inter-rater reliability. The t-test difference was not significant. One-way analysis of variance (ANOVA) showed a significant difference in the Collaboration subcategory score. Univariate ANOVA indicated both raters scored consistently with each other overall and that they both scored JR1 differently than JR2. The pilot study and testing of interrater reliability of the rubric revealed positive findings. The role of the rubric in providing formative feedback during debrief sessions empowered students to analyze their own performance and/or experience to self-correct or improve their future practice based on these experiences.

Virtual Simulation to Increase Self-efficacy Through Deliberate Practice.

BACKGROUND: To reduce performance anxiety and increase engagement in medical-surgical simulations, virtual simulation (VS) was introduced prior to complex high-fidelity simulation to increase students' self-efficacy. PROBLEM: A presimulation preparation needed to be expanded for high-fidelity simulation involving emergent clinical situations. APPROACH: Combined frameworks of Ericsson's theory of deliberate practice and Bandura's self-efficacy theory were applied. Students completed VS scenarios until a specific score of mastery was obtained, and then the same scenario was repeated in the high-fidelity simulation laboratory. A modified self-efficacy scale survey was administered presimulation and postsimulation. Data were collected on 3 cohorts of students (n = 151) over an academic year. OUTCOMES: VS followed by high-fidelity simulation significantly increased student perception of self-efficacy in all 3 cohorts (P = .001, P = .037, P = .005). CONCLUSION: Preparation for high-fidelity simulation using VS increases self-efficacy and allows students to engage in the simulation experience, thus achieving higher levels of mastery through deliberate practice.

Role of CYP2B6 in stereoselective human methadone metabolism.

BACKGROUND: Metabolism and clearance of racemic methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. Initial in vitro studies attributed methadone metabolism to cytochrome P4503A4 (CYP3A4). CYP3A4 was also assumed responsible for methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary role for CYP3A4 and suggest that CYP2B6 may mediate methadone clearance. Expressed CYP2B6 and also CYP2C19 N-demethylate methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective methadone metabolism in human liver microsomes and in vivo. METHODS: N-demethylation of racemic methadone and individual enantiomers by expressed CYPs 2B6, 2C19, and 3A4 was evaluated. Stereoselective microsomal methadone metabolism was quantified, compared with CYP 2B6 and 3A4 content, and probed using CYP isoform-selective inhibitors. A crossover clinical investigation (control, CYP2B6 and CYP3A4 induction by rifampin, CYP3A inhibition by troleandomycin and grapefruit juice) evaluated stereoselective methadone disposition. RESULTS: At clinical concentrations, methadone enantiomer N-demethylation by recombinant CYPs 2B6, 3A4, and 2C19 was S > R, S = R, and S << R. Greater stereoselective metabolism (S > R) occurred in livers expressing high levels of CYP2B6 compared with CYP3A4. Clopidogrel, troleandomycin, and (+)-N-3-benzyl-nirvanol, selective inhibitors of CYPs 2B6, 3A4, and 2C19, respectively, inhibited microsomal methadone metabolism by 50-60%, 20-30%, and less than 10%. Only inhibition by clopidogrel was stereoselective. Clinically, rifampin diminished both R- and S-methadone plasma concentrations, but troleandomycin and grapefruit juice altered neither R- nor S-methadone concentrations. Plasma R/S-methadone ratios were increased by rifampin but unchanged by CYP3A inhibition. CONCLUSIONS: These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human methadone metabolism and disposition.

Peer Training Using Cognitive Rehearsal to Promote a Culture of Safety in Health Care.

Nursing students need opportunities to prepare for real-world problems that they may encounter as they enter the profession. Incivility and bullying behaviors persist in health care. The purpose of this project was to increase students' awareness of incivility and prepare them to respond to it. Two teaching methods were compared. Results supported that interactive civility training using cognitive rehearsal provided by nursing student peers was as effective as instruction from an expert.

Diagnostic and therapeutic challenges of EBV-positive mucocutaneous ulcer: a case report and systematic review of the literature.

BACKGROUND: Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a recently recognized B cell lymphoproliferative disorder that is driven by latent EBV infection and causes discrete ulcerations in the oropharynx, gastrointestinal tract, and skin. Local attenuation of immunosurveillance associated with iatrogenic immunosuppressant use, primary immunodeficiency, or age-associated immunosenescence has been implicated as a predisposing factor. This disorder is likely under reported, as it was only first defined in 2010 and shares histological features with other B-cell proliferative neoplasms. The first case series that described EBVMCU suggested that EBVMCU is generally self-limited and is likely to resolve without treatment. Since that publication, additional cases have been reported that describe a more heterogeneous clinical course, often requiring aggressive therapy. We now systematically review all published cases of EBVMCU and detail a case of aggressive and progressive EBVMCU, including diagnostic and management challenges, as well as successful treatment with radiation therapy. CASE PRESENTATION: A forty-nine year old woman presented with painful and debilitating multifocal oral EBVMCU that initially responded to four weekly doses of rituximab. Her disease relapsed within 3 months and continued to progress and cause significant morbidity. She was successfully treated with local external beam radiation therapy of 30 Gy in 15 fractions, with duration of response of at least 6 months. CONCLUSIONS: We suggest that although many patients with EBVMCU experience a self-limited course, for others EBVMCU can be a debilitating, persistent disorder that requires aggressive therapy to prevent disease progression. CD20- and CD30-directed antibody therapy, local radiation therapy, local surgical excision, systemic chemotherapy, and a combination of these therapies have all been successfully used to treat EBVMCU with high rates of durable clinical remission. As EBVMCU is not currently included in the 2008 WHO classification of lymphoproliferative disorders and no evidence-based guidelines or expert opinions have been proposed to guide therapy, this case report and systematic review provides a foundation on which to guide therapeutic decisions.

Protease resistant protein cellular isoform (PrP(c)) as a biomarker: clues into the pathogenesis of HAND.

HIV infection and HIV neurocognitive impairment are major global health problems. The prevalence of HIV associated neurocognitive disorders (HAND) is increasing as people with HIV are living longer due to the success of antiretroviral therapies. Our laboratory identified the soluble form of (sPrP(c)), the cellular non-pathogenic isoform of the prion protein, as a biomarker of HAND. In this review we discuss the published data addressing PrP(c) biology in normal conditions and pathologies, as well as the mechanisms of sPrP(c) shedding and secretion. Lastly, we discuss our studies that demonstrated that sPrP(c) is a biomarker of neurocognitive impairment in the HIV infected population.

Leukocyte transmigration across the blood-brain barrier: perspectives on neuroAIDS.

Leukocyte trafficking serves a critical function in central nervous system (CNS) immune surveillance. However, in many disease states leukocyte entry into the CNS is increased, which can disrupt the blood-brain barrier (BBB) and propagate neuroinflammation. These pathologic processes result in BBB permeability, glial activation, and neuronal compromise, all of which contribute to CNS damage. The resulting neuronal injury and loss are characteristic of many neuroinflammatory conditions including Alzheimer disease, multiple sclerosis, HIV-1 encephalopathy, sepsis, ischemia and reperfusion, and CNS tumors. HIV-1 encephalopathy is unique among these processes in that viral activity exacerbates CNS immune dysregulation and promotes chronic neuroinflammation and neurodegeneration. Thus, a significant number of HIV-1-infected persons exhibit neurocognitive and/or motor impairment. This review discusses the mechanisms that regulate leukocyte recruitment into the CNS and how HIV-1 infection dysregulates this process and contributes to neuropathology. Experimental BBB models to study leukocyte transmigration and the potential of targeting this transmigration across the BBB as a therapeutic strategy are also discussed.

Limb deficiency and prosthetic management. 1. Decision making in prosthetic prescription and management.

UNLABELLED: This self-directed learning module highlights decision making in prosthetic management in pediatric and adult patients. This chapter reviews classification of congenital limb deficiency and management of congenital pediatric upper-extremity amputees. Differences in management of amputees of various ages from infancy to old age is discussed. Case examples are used to formulate prosthetic prescriptions for transradial limb deficiency as well as knee disarticulation and transtibial level amputations. Common prosthetic gait deviations and anticipated functional levels are evaluated. OVERALL ARTICLE OBJECTIVE: To discuss prosthetic prescription and management in congenital limb deficiency and acquired amputations for patients of various ages.

Limb deficiency and prosthetic management. 2. Aging with limb loss.

UNLABELLED: This self-directed learning module highlights the issues faced by people aging with limb loss. It is part of the study guide on limb deficiency and vascular rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the impact that limb loss has on health and physical function throughout the life span. Case examples are used to illustrate what effect limb loss in childhood or young adulthood has on the incidence and management of new impairments or disease processes commonly associated with aging. OVERALL ARTICLE OBJECTIVE: To discuss the impact of early-life limb loss on the incidence and management of physiologic and functional changes associated with aging.

Limb deficiency and prosthetic management. 3. Complex limb deficiency.

UNLABELLED: This self-directed learning module highlights rehabilitation and prosthetic issues associated with complex limb deficiencies. It is part of the chapter on acquired limb deficiencies in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article discusses rehabilitation and prosthetic management of patients with amputations for complex limb deficiencies secondary to trauma. Mechanisms of injury, prosthetic issues, prosthetic components, and potential problems in prosthetic fitting will be discussed. OVERALL ARTICLE OBJECTIVE: To evaluate common problems associated with complex limb deficiency.

Advances in amputee care.

UNLABELLED: This self-directed learning module highlights the recent innovations in amputee care. It is part of the study guide on limb deficiency in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This focused review article describes the key elements of a successful comprehensive amputee program, the basic surgical considerations for upper- and lower-extremity amputation, and some of the more recent advances in prosthetic components. Further, an update is given on issues such as hand transplantation and the integration of robotics and artificial muscles for people with limb loss. OVERALL ARTICLE OBJECTIVE: (a) To discuss current issues and advances in the care of patients with amputation, (b) to describe the key elements in designing a comprehensive amputee care program, and (c) to discuss surgical considerations of limb preservation and amputation levels.

Limb deficiency and prosthetic management. 4. Comorbidities associated with limb loss.

UNLABELLED: This self-directed learning module highlights common comorbidities found in people with amputations and their impact on functional outcome. It is part of the study guide on limb deficiency and vascular rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article focuses on prosthetic considerations, functional outcome, and potential complications for a woman with the comorbidities of stroke and diabetes who experiences a dysvascular amputation. Formulation of the differential diagnosis, management of limb pain, and evaluation of the potential psychosocial issues arising after amputation are also discussed. OVERALL ARTICLE OBJECTIVE: To analyze common comorbidities of people with amputations and to delineate their impact on functional outcome.