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Background: The role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV–pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children. Methods: Balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_Ees, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method. Results: LV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH. Conclusions: The PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency. [ABSTRACT FROM AUTHOR]

Drug-induced kidney toxicity is a significant contributor to acute kidney injury. Nephrotoxic drugs need to be identified during nonclinical testing to highlight potential risk translatable to the intended patient population. When nonclinical kidney toxicity signals arise, scientists and physicians affiliated with clinical trials need to be familiar with commonly encountered drug-induced perturbations in the kidney, terminology, and how these changes relate to clinical risk. Mechanistic and translational toxicologic studies beyond routine histopathology and clinical pathology approaches may be needed to elucidate the pathogenesis and human relevance to inform clinical risk assessment. Investigational studies may help elucidate specific sites of injury within the nephron, the presence of reactive metabolites, mechanisms of membrane transport or tissue distribution, potential drug-drug interactions, or the ability to recover function after drug withdrawal. Cutting-edge techniques such as in vitro alternative platforms, humanized animal models, translational imaging/microscopy or circulating/secretory biomarkers, omics platforms at the interface of genes, proteins, metabolites, or advanced molecular and biochemical approaches provide toxicologists and pathologists with a wide variety of potential experimental modalities to investigate mechanisms of kidney toxicity. [ABSTRACT FROM AUTHOR]

Ubiquitination of proliferating cell nuclear antigen (PCNA) at lysine 164 (K164) activates DNA damage tolerance pathways. Currently, we lack a comprehensive understanding of how PCNA K164 ubiquitination promotes genome stability. To evaluate this, we generated stable cell lines expressing PCNAK164R from the endogenous PCNA locus. Our data reveal that the inability to ubiquitinate K164 causes perturbations in global DNA replication. Persistent replication stress generates under-replicated regions and is exacerbated by the DNA polymerase inhibitor aphidicolin. We show that these phenotypes are due, in part, to impaired Fanconi anemia group D2 protein (FANCD2)-dependent mitotic DNA synthesis (MiDAS) in PCNA K164R cells. FANCD2 mono-ubiquitination is significantly reduced in PCNA K164R mutants, leading to reduced chromatin association and foci formation, both prerequisites for FANCD2-dependent MiDAS. Furthermore, K164 ubiquitination coordinates direct PCNA/FANCD2 colocalization in mitotic nuclei. Here, we show that PCNA K164 ubiquitination maintains human genome stability by promoting FANCD2-dependent MiDAS to prevent the accumulation of under-replicated DNA. [Display omitted] • PCNA K164 ubiquitination promotes mitotic DNA synthesis in non-transformed human cells • Robust FANCD2 ubiquitination, chromatin association, and foci formation rely on PCNA K164 • PCNA and FANCD2 association in G2/M-phase nuclei requires PCNA ubiquitination at K164 Leung et al. show that FANCD2-dependent mitotic DNA synthesis (MiDAS) in non-transformed human cells relies on PCNA lysine 164 (K164) ubiquitination. Specifically, PCNA K164 ubiquitination promotes FANCD2 ubiquitination and recruitment to under-replicated regions and coordinates interactions in mitotic nuclei to promote MiDAS. [ABSTRACT FROM AUTHOR]

Abstract Objective Elastic properties of the thoracic aorta are responsible for buffering systemic afterload, and may be particularly important in patients with Fontan circulation, in whom heart failure is a major source of attrition. The purpose of this study was to characterize regional stiffness in the ascending and descending aorta in patients with hypoplastic left heart syndrome and single left ventricle morphology after Fontan operation by cardiac magnetic resonance imaging, and to assess whether changes in aortic stiffness are associated with the ventricular function. Methods Phase-contrast-derived pulse-wave velocity (PWV) and relative-area change (RAC) were measured in the ascending and descending aorta of patients with hypoplastic left heart syndrome (n = 9), patients with single left ventricle circulation (n = 18), and normal controls (n = 8) by magnetic resonance imaging. Stiffness metrics were then correlated with the ventricular volumetric and functional indices. Results Patients with hypoplastic left heart syndrome had elevated ascending aortic PWV along with reduced RAC when compared with controls (both P values <.001). Patients with a single left ventricle presented no change in PWV but had reduced RAC in comparison to controls (P <.01). There were no differences in PWV and RAC between all considered groups in the descending aorta. PWV and RAC measured in the ascending aorta correlated with end-systolic and end-diastolic volume indices, ventricular ejection fraction, and ventricular-vascular coupling ratio. Conclusions Aortic stiffness is most elevated in patients with hypoplastic left heart syndrome, yet patients with single left ventricle morphology show signs of abnormal stiffness as well in the form of reduced aortic strain. Stiffness indices measured in the ascending aorta were associated with overall ventricular function and measures of aortoventricular coupling in both patient populations. [ABSTRACT FROM AUTHOR]

Abstract Worldwide, many coral reef ecosystems have shifted from coral to algal dominance, yet the ecological function of these emergent communities remains relatively unknown. Turbinaria ornata, a macroalga with a rapidly expanding range in the South Pacific, forms dense stands on hard substrate, likely providing ecological services unique from corals. While generally unpalatable, T. ornata can function as a secondary foundation species and hosts an epibiont community that may provide overlooked trophic resources in phase shifted reef ecosystems. Results from video recorded field experiments designed to quantify consumer pressure on T. ornata epibionts showed that both consumer pressure and epibiont cover increased with thallus size. Additionally, most fish species, including herbivores, omnivores, and detritivores, exhibited higher bite rates on thalli with epibionts compared to thali with epibionts experimentally removed. Juvenile parrotfishes were responsible for 50% of total bites recorded and also had the highest bite rates. Results indicate that epibionts, particularly on large T. ornata , are a food resource for a diversity of fishes, representing a previously undescribed function of this macroalga in coral reef ecosystems. Exploring the functions of macroalgal dominated reef communities will be increasingly important as reefs continue to phase shift toward macroalgal dominance in the Anthropocene. Highlights • The ecological function of macroalgal communities on reefs is relatively unknown. • Turbinaria ornata is an unpalatable macroalga rapidly expanding in the South Pacific. • T. ornata host an epibiont community that is a newly available, overlooked resource. • Field work showed a diverse fish community targeted epibionts on larger thalli. • Exploring macroalgal functions on phase shifted rifts is important in the Anthropocene. [ABSTRACT FROM AUTHOR]

Objective Central aortic stiffness and chronic obstructive pulmonary disease (COPD) are associated with increased incidence of devastating aortopathies. However, the exact mechanism leading to elevated aortic stiffness in patients with COPD is unknown. The purpose of this study was to quantify flow and shear hemodynamic indices, known markers of vascular remodeling, in the thoracic aorta of patients with mild to moderate COPD (n = 16) and to compare these results with an age-matched control group (n = 10). Methods Four-dimensional flow magnetic resonance imaging has been applied to measure hemodynamic wall shear stress (WSS) at four specific planes along the ascending aorta, aortic arch, and proximal descending aorta for all subjects. Peak systolic WSS and time-averaged WSS, which respectively reflect magnitude and temporal shear variability, were calculated at standardized planes. Aortic deformation was measured by means of relative area change (RAC) at the midlevel of the ascending and descending aorta. Results Compared with controls, patients with COPD had significantly reduced RAC in the mid ascending aorta (9% vs 18%; P < .0001) and descending aorta (15% vs 19%; P = .0206). Peak systolic WSS in COPD patients was significantly reduced in all considered planes, with the most dramatic difference occurring in the descending aorta (0.46 vs 0.86 N/m 2 ; P < .0001). Peak systolic WSS and time-averaged WSS were both significantly correlated with aortic RAC at each evaluated plane. Conclusions Reduced flow shear metrics assessed at specific aortic regions correlated with RAC, a marker of aortic stiffness. Reduced hemodynamic WSS may then contribute to central aortic stiffening and perpetuate the risk for development of severe aortopathy. [ABSTRACT FROM AUTHOR]

Abstract: Recent clinical studies of pulmonary arterial hypertension (PAH) have found correlations between increased pulmonary vascular stiffness (PVS) and poorer disease outcomes. However, mechanistic questions remain about the relationships amongst PVS, RV power, and vascular hemodynamics in the setting of progressive PAH that are difficult or impossible to answer using direct measurements. Clinically validated patient-specific computational modeling may allow exploration of these issues through perturbation-based predictive testing. Here we use a simple patient-specific model to answer four questions: how do hemodynamics change as PAH worsens? How does increasing PVS impact hemodynamics and RV power? For a patient with moderate PAH, what are the consequences if the pressures increase modestly yet sufficiently to engage collagen in those vessels? What impact does pressure-reducing vasodilator treatment have on hemodynamics? Twenty-one sets of model-predicted impedance and mean PA pressure (mPAP) show good agreement with clinical measurements, thereby validating the model. Worsening was modeled using data from three PAH outcomes groups; these show not only the expected increase in mPAP, but also an increase in pressure pulsatility. Interestingly, chronically increasing mPAP decreased WSS, suggesting that increased PA cross-sectional area affected WSS greater than increased PVS. For a patient with moderately high PVR (12.7 WU) with elastin-based upstream vascular remodeling, moving from elastin-dominant vessel behavior to collagen-dominant behavior caused substantial increases in mPAP, pressure and WSS pulsatility. For the same patient, reducing PVR through a simulated vasodilator to a value equivalent to mild PAH did not decrease pressure pulsatility and dramatically increased WSS pulsatility. Overall, these results suggest a close association between PVS and hemodynamics and that hemodynamics may play an important role in progressing PAH. These support the hypothesis that treatments should target decreasing or reversing upstream vascular remodeling in addition to decreasing mean pressures. [Copyright &y& Elsevier]

Abstract: The hemodynamic state of the pulmonary arteries is challenging to routinely measure in children due to the vascular circuit''s position in the lungs. The resulting relative scarcity of quantitative clinical diagnostic and prognostic information impairs management of diseases such as pulmonary hypertension, or high blood pressure of the pulmonary circuit, and invites new techniques of measurement. Here we examine recent applications of macro-scale computational mechanics methods for fluids and solids – traditionally used by engineers in the design and virtual testing of complex metal and composite structures – applied to study the pulmonary vasculature, both in healthy and diseased states. In four subject areas, we briefly outline advances in computational methodology and provide examples of clinical relevance. [Copyright &y& Elsevier]

BACKGROUND: Nurses have been involved in prescribing in England since 1996, and to date over 41,000 nurses are registered with the Nursing and Midwifery Council as prescribers. The majority of evaluative research on nurse prescribing is descriptive and relies on self-report and assessment of patient satisfaction. OBJECTIVES: To explore and test nurse prescribers' pharmacological knowledge and decision-making. DESIGN: An exploratory approach to test the usefulness of patient scenarios in addressing the reasons why nurses decide whether or not to prescribe was utilised. Semi-structured interviews with nurse prescribers using patient scenarios were used as proxy methods of assessment of how nurses made their prescribing decisions. SETTING: Two primary care trusts in the southeast of England were the settings for this study. PARTICIPANTS: Purposive sampling to ensure there was a mixed group of prescribers was used to enable detailed exploration of the research objectives and to obtain in-depth understanding of the complex activities involved in nurse prescribing. METHODS: Interviews and case scenarios. The use of cognitive continuum theory guided the analysis. RESULTS: The majority of participants were unable to identify the issues involved in all the scenarios; they also failed to provide an acceptable solution to the problem, suggesting that they would refer the patient to the general practitioner. A similar number described themselves as 'very confident' while seven participants felt that they were 'not confident' in dealing with medication issues, four of whom were practising prescribing. CONCLUSIONS: The effects of social and institutional factors are important in the decision-making process. The lack of appropriate pharmacological knowledge coupled with lack of confidence in prescribing was demonstrated. The scenarios used in this study indicate that nurses are perhaps knowledgeable in their small area of practise but flounder outside this. Further research could be conducted with a larger sample and with more scenarios to explore the decision-making and the pharmacological knowledge base of nurse prescribers, particularly in the light of government policy to extend prescribing rights to non-medical prescribers, including pharmacists. [ABSTRACT FROM AUTHOR]

Background: Pulmonary vascular resistance (PVR) is the current standard for evaluating reactivity in children with pulmonary arterial hypertension (PAH). However, PVR measures only the mean component of right ventricular afterload and neglects pulsatile effects. We recently developed and validated a method to measure pulmonary vascular input impedance, which revealed excellent correlation between the zero harmonic impedance value and PVR and suggested a correlation between higher-harmonic impedance values and pulmonary vascular stiffness. Here we show that input impedance can be measured routinely and easily in the catheterization laboratory, that impedance provides PVR and pulmonary vascular stiffness from a single measurement, and that impedance is a better predictor of disease outcomes compared with PVR. Methods: Pressure and velocity waveforms within the main pulmonary artery were measured during right heart catheterization of patients with normal pulmonary artery hemodynamics (n = 14) and those with PAH undergoing reactivity evaluation (49 subjects, 95 conditions). A correction factor needed to transform velocity into flow was obtained by calibrating against cardiac output. Input impedance was obtained off-line by dividing Fourier-transformed pressure and flow waveforms. Results: Exceptional correlation was found between the indexed zero harmonic of impedance and indexed PVR (y = 1.095x + 1.381, R 2 = 0.9620). In addition, the modulus sum of the first 2 harmonics of impedance was found to best correlate with indexed pulse pressure over stroke volume (y = 13.39x − 0.8058, R 2 = 0.7962). among a subset of patients with PAH (n = 25), cumulative logistic regression between outcomes to total indexed impedance was better (R L 2 = 0.4012) than between outcomes and indexed PVR (R L 2 = 0.3131). Conclusions: Input impedance can be consistently and easily obtained from pulse-wave Doppler and a single catheter pressure measurement, provides comprehensive characterization of the main components of RV afterload, and better predicts patient outcomes compared with PVR alone. [Copyright &y& Elsevier]

AIMS: To explore patients' and staffs' perceptions of a pilot service which dispatched a nurse and paramedic to low-priority ambulance calls. However, Methods: Patients' opinions of both pilot and standard service groups were obtained through qualitative questionnaire data and individual interviews. Staffs' perceptions were explored via two focus groups. Questionnaires were sent to a convenience sample of 128 patients attended by the pilot service and 128 patients receiving the standard service. Initially 19 questionnaire participants agreed to be interviewed. Focus group participants (n=11) included nurses and paramedics involved in the pilot service. Results: Sixty-four questionnaires were returned and 11 interviews were conducted. Patients receiving the pilot service were enthusiastic about opportunities for care to be provided in their home. Involvement in the pilot service was a positive experience for staff. They felt confident in managing calls effectively because of their combined knowledge and skills, and believed that the quality of patient care had been improved. They also experienced increased job satisfaction and skills development. Conclusion: Both patients and staff expressed positive views about the pilot service. Patients appreciated being treated at home and staff believed that working together provided more appropriate care for patients and enhanced interprofessional development. [ABSTRACT FROM AUTHOR]

This paper details one of the findings of a large phenomenological study into the effects of nurse-patient encounters on clinical learning and practice. Every nurse faces the challenge of caring for a patient with cancer at some point in his or her nursing career. The participants, 392 nurses, were asked to provide an account of a care episode from their practice. These narrative/clinical exemplars were for a patient with a diagnosis of cancer and participants were asked to discuss the impact this encounter had on clinical learning and clinical practice. Each day nurses work through the daily grind of the job and occasionally encounter a person, who inspires them, someone they admire because of their courage. Responses from the participants identified a number of such people. Nurses used powerful language, brave, strong, courageous, to describe these patients. The diagnosis of cancer is a daunting prospect and is seen as a challenge physically and emotionally. Participants spoke of their admiration, affection and their sadness when describing the nurse-patient encounters. The life-threatening potential of cancer for the patient and the perception of potential and actual suffering does impact on nurses, their learning and their clinical practice. The struggle against such a daunting adversary places patients diagnosed with cancer in a position to be seen by nurses as people with immense courage. Participants clearly felt the influence of patients' courage, personally and professionally. Many spoke of the inspirational qualities of their patients. Participants detailed learning from the encounters and reflected with great insight on themselves and their practice. The identified nurse-patient encounters were seen to have changed their clinical practice forever. [ABSTRACT FROM AUTHOR]

BACKGROUND: Against the backdrop in the western world of increasing prevalence of chronic disease, active and informed patients and a policy emphasis on self-management, this English study explored health professionals' responses to expert patients. OBJECTIVES: To: DESIGN: A grounded theory approach was utilised with two concurrent data strands. SETTING: A relatively affluent English county including community, primary and secondary care settings. PARTICIPANTS: Via purposeful and theoretical sampling 100 health professionals (nurses, doctors, physiotherapists) and 100 adults affected by chronic disease participated. METHODS: Focus groups, interviews and observation. RESULTS: Nurses were found to be most anxious about expert patients when compared to other professionals, which appeared to be linked with a lack of professional confidence and unfounded fears regarding litigation. However, nurse specialists often provided a negative case for this. As a whole, nurses were most able to meet the emotional needs of patients, but apart from nurse specialists did not articulate this as a skill. CONCLUSION: Apart from nurse specialists the majority of nurses appeared limited in appropriately facilitating self-management. It is suggested that this is linked to an ongoing nursing culture of patient as passive, an over-emphasis on empirical knowledge and a feeling of vulnerability on the nurses' part towards expert patients. The findings also indicate a rhetoric rather than reality of autonomous nursing roles within the chronic disease management agenda. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Prolonged exposure to normobaric hyperoxia (NH) is associated with blood leukocyte activation and sequestration in the lung. Whether NH-induced leukocyte activation and sequestration can affect extrapulmonary organs or blood cellular profile has not been systematically investigated. We studied simultaneous changes in blood cellular profile and pulmonary, renal, and intestinal histology during NH and after return to air breathing (“weaning”). Materials and Methods: One-day-old rats were exposed to 2 to 4 days of NH (Fio 2 >0.98) or normoxia (Fio 2 = 0.21), with or without weaning. Pups were then euthanized and 100 μL of blood was collected (cardiac puncture) for differential white blood cells analysis (n = 12 per group). The lungs, a piece of distal ileum, and the left kidney were removed for histologic evaluation. Results: Both NH and weaning generated significant increases in blood neutrophil count, whereas lymphocyte population was significantly increased only after weaning (P < .05; analysis of variance with Bonferroni correction for multiple comparisons). Normobaric hyperoxia created mild increases in the renal tubular necrosis, dilation, regeneration, and interstitial inflammation. A significant increase in the intestinal serosal and submucosal vasodialation and vascularization occurred 1 day after weaning from 4 days of NH (P < .001). These extrapulmonary events coincided with the development of histologic manifestations of pulmonary oxygen toxicity. Conclusions: Development of pulmonary oxygen toxicity in neonatal rats is associated with significant changes in differential leukocyte counts and histologic alterations in the kidney and ileum. We speculate that activation of circulating leukocytes and/or direct effect of NH may affect certain peripheral organs independently from the NH-induced pulmonary pathology. [Copyright &y& Elsevier]

Abstract: Septic arthritis requires early clinical recognition and prompt treatment if articular cartilage damage and its sequelae are to be avoided. This case highlights the importance of considering a communication between the ankle and subtalar joint. This communication is acknowledged amongst foot and ankle surgeons, but yet there has been no documentation of such a phenomenon. This case may demonstrates what is either a developmental feature, a pathological process associated with synovitis or a normal variant. As early treatment of septic arthritis of the ankle significantly affects the outcome [Changgeng Yi, Lee CH, Chen YJ, Ueng SW, Hsu RW. Septic arthritis of the ankle joint. Chang Gung Med J 2000;23(7):420–6], this case report highlights the important role of early Magnetic Resonance Imaging (MRI) in the management of such cases. Therefore, early magnetic resonance imaging or if not available an intra-operative contrast angiography of the ankle and subtalar joints should be considered in all cases of septic arthritis of the ankle. [Copyright &y& Elsevier]

Ectomesenchymal chondromyxoid tumors are rare, benign neoplasms of the head and neck most commonly found within the oral cavity. While histopathological evaluation has been the primary focus of prior studies, clinical characterization of this rare entity currently remains sparse. Thus, this study was performed to provide insights into the clinical characteristics of ectomesenchymal chondromyxoid tumors to aid clinicians in distinguishing the lesion from other benign and malignant processes for a more accurate diagnosis and treatment. Moreover, this study includes a unique case of ectomesenchymal chondromyxoid tumor arising in the base of tongue, now the fourth to arise at that anatomic site. Including this case, a systematic review of the literature identified only 60 individual cases reported thus far. This study provides a detailed analysis of all 60 cases including demographics, clinical presentation, radiographic imaging, follow-up, and recurrence rate. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Preeclampsia often results in altered hemodynamics and structurally remodeled umbilical arteries in the fetus – alterations that may be associated with arterial stiffening. We therefore hypothesized that the mechanical function of preeclamptic (PE) umbilical arteries had increased stiffness compared to control. Study design: Umbilical arteries were collected from control (n =9) and PE (n =6) pregnancies without any other complications. Samples were tested uniaxially in axial and circumferential directions for the passive mechanics. The umbilical artery was modeled as a fiber reinforced hyperelastic material in both control and PE conditions. Results: The PE arteries were stiffer than control arteries at stresses of 20–160mmHg in the axial direction and 65–200mmHg in the circumferential direction (P <0.05). The PE umbilical arteries exhibited a 58% and 48% increase in circumferential moduli at the systolic and diastolic blood pressure respectively compared to the controls (P <0.05). A hyperelastic model showed a substantial increase in both isotropic and anisotropic contribution in the mechanical behavior. Collectively, the changes observed correlated to a higher collagen fiber density in the PE group with increased hyperelastic material parameters (P <0.05). Conclusion: PE umbilical arteries demonstrated stiffer biomechanics compared to the controls due to the change in collagen fiber content. These altered biomechanical and structural changes provide a potential snapshot into systemic vasculature remodeling occurring in the newborn. [Copyright &y& Elsevier]

This paper draws on the work of Paley and Duncan et al in order to extend and engender debate regarding the use of Concept Analysis frameworks. Despite the apparent plethora of Concept Analysis frameworks used in nursing studies we found that over half of those used were derived from the work of one author. This paper explores the suitability and use of these frameworks and is set at a time when the numbers of published concept analysis papers are increasing. For the purpose of this study thirteen commonly used frameworks, identified from the nursing journals 1993 to 2005, were explored to reveal their origins, ontological and philosophical stance, and any common elements. The frameworks were critiqued and links made between their antecedents. It was noted if the articles contained discussion of any possible tensions between the ontological perspective of the framework used, the process of analysis, praxis and possible nursing theory developments. It was found that the thirteen identified frameworks are mainly based on hermeneutic propositions regarding understandings and are interpretive procedures founded on self-reflective modes of discovery. Six frameworks rely on or include the use of casuistry. Seven of the frameworks identified are predicated on, or adapt the work of Wilson, a school master writing for his pupils. Wilson's framework has a simplistic eleven step, binary and reductionist structure. Other frameworks identified include Morse et al's framework which this article suggests employs a contestable theory of concept maturity. Based on the findings revealed through our exploration of the use of concept analysis frameworks in the nursing literature, concerns were raised regarding the unjustified adaptation and alterations and the uncritical use of the frameworks. There is little evidence that these frameworks provide the necessary depth, rigor or replicability to enable the development in nursing theory which they underpin. [ABSTRACT FROM AUTHOR]

Background: The effects of nonphysiological flow generated by continuous-flow (CF) left ventricular assist devices (LVADs) on the aorta remain poorly understood.Objectives: The authors sought to quantify indexes of fibrosis and determine the molecular signature of post-CF-LVAD vascular remodeling.Methods: Paired aortic tissue was collected at CF-LVAD implant and subsequently at transplant from 22 patients. Aortic wall morphometry and fibrillar collagen content (a measure of fibrosis) was quantified. In addition, whole-transcriptome profiling by RNA sequencing and follow-up immunohistochemistry were performed to evaluate CF-LVAD-mediated changes in aortic mRNA and protein expression.Results: The mean age was 52 ± 12 years, with a mean duration of CF-LVAD of 224 ± 193 days (range 45-798 days). There was a significant increase in the thickness of the collagen-rich adventitial layer from 218 ± 110 μm pre-LVAD to 410 ± 209 μm post-LVAD (P < 0.01). Furthermore, there was an increase in intimal and medial mean fibrillar collagen intensity from 22 ± 11 a.u. pre-LVAD to 41 ± 24 a.u. post-LVAD (P < 0.0001). The magnitude of this increase in fibrosis was greater among patients with longer durations of CF-LVAD support. CF-LVAD led to profound down-regulation in expression of extracellular matrix-degrading enzymes, such as matrix metalloproteinase-19 and ADAMTS4, whereas no evidence of fibroblast activation was noted.Conclusions: There is aortic remodeling and fibrosis after CF-LVAD that correlates with the duration of support. This fibrosis is due, at least in part, to suppression of extracellular matrix-degrading enzyme expression. Further research is needed to examine the contribution of nonphysiological flow patterns on vascular function and whether modulation of pulsatility may improve vascular remodeling and long-term outcomes. [ABSTRACT FROM AUTHOR]

• Oxidative stress induces proteolytic processing of p75NTR in mesencephalic cells. • This p75NTR activation requires metalloprotease and γ‑secretase activity. • ROS-induced p75NTR cleavage occurs via a neurotrophin-independent mechanism. • c‑Jun N‑terminal Kinase signaling facilitates ligand-independent p75NTR processing. The p75 neurotrophin receptor (p75NTR) is a multifunctional protein that regulates cellular responses to pathological conditions in specific regions of the nervous system. Activation of p75NTR in certain neuronal populations induces proteolytic processing of the receptor, thereby generating p75NTR fragments that facilitate downstream signaling. Expression of p75NTR has been reported in neurons of the ventral midbrain, but p75NTR signaling mechanisms in such cells are poorly understood. Here, we used Lund Human Mesencephalic cells, a population of neuronal cells derived from the ventral mesencephalon, to evaluate the effects of oxidative stress on p75NTR signaling. Subjection of the cells to oxidative stress resulted in decreased cell-surface localization of p75NTR and intracellular accumulation of p75NTR fragments. Oxidative stress-induced p75NTR processing was reduced by pharmacological inhibition of metalloproteases or γ-secretase, but was unaltered by blockade of the ligand-binding domain of p75NTR. Furthermore, inhibition of c-Jun N-terminal Kinase (JNK) decreased p75NTR cleavage induced by oxidative damage. Altogether, these results support a mechanism of p75NTR activation in which oxidative stress stimulates JNK signaling, thereby facilitating p75NTR processing via a ligand-independent mechanism involving induction of metalloprotease and γ-secretase activity. These findings reveal a novel role for JNK in ligand-independent p75NTR signaling, and, considering the susceptibility of mesencephalic neurons to oxidative damage associated with Parkinson's disease (PD), merit further investigation into the effects of p75NTR on PD-related neurodegeneration. [ABSTRACT FROM AUTHOR]

This meeting report is based on presentations given at the first Drug Safety Africa Meeting in Potchefstroom, South Africa from November 20–22, 2018 at the North-West University campus. There were 134 attendees (including 26 speakers and 34 students) from the pharmaceutical industry, academia, regulatory agencies as well as 6 exhibitors. These meeting proceedings are designed to inform the content that was presented in terms of Safety Pharmacology (SP) and Toxicology methods and models that are used by the pharmaceutical industry to characterize the safety profile of novel small chemical or biological molecules. The first part of this report includes an overview of the core battery studies defined by cardiovascular, central nervous system (CNS) and respiratory studies. Approaches to evaluating drug effects on the renal and gastrointestinal systems and murine phenotyping were also discussed. Subsequently, toxicological approaches were presented including standard strategies and options for early identification and characterization of risks associated with a novel therapeutic, the types of toxicology studies conducted and relevance to risk assessment supporting first-in-human (FIH) clinical trials and target organ toxicity. Biopharmaceutical development and principles of immunotoxicology were discussed as well as emerging technologies. An additional poster session was held that included 18 posters on advanced studies and topics by South African researchers, postgraduate students and postdoctoral fellows. [ABSTRACT FROM AUTHOR]

Background Electrical and right ventricular (RV) mechanical dyssynchrony has been previously described in pediatric pulmonary arterial hypertension (PAH), but less is known about the relationship between electrical dyssynchrony and biventricular function. In this study we applied cardiac magnetic resonance (CMR) imaging to evaluate biventricular size and function with a focus on left ventricular (LV) strain mechanics in pediatric PAH patients with and without electrical dyssynchrony. Methods Fifty-six children with PAH and comprehensive CMR evaluation were stratified based on QRS duration z -score, with electrical dyssynchrony defined as z -score ≥2. Comprehensive biventricular volumetric, dyssynchrony, and strain analysis was performed. Results Nineteen PAH patients had or developed electrical dyssynchrony. Patients with electrical dyssynchrony had significantly reduced RV ejection fraction (35% vs 50%, p = 0.003) and greater end-diastolic (168 vs 112 ml/m 2 , p = 0.041) and end-systolic (119 vs 57, ml/m 2 , p = 0.026) volumes. Patients with electrical dyssynchrony had reduced RV longitudinal strain (–14% vs –19%, p = 0.007), LV circumferential strain measured at the free wall (–19% vs –22%, p = 0.047), and the LV longitudinal strain in the septal region (–10% vs –15%, p = 0.0268). LV mechanical intraventricular dyssynchrony was reduced in patients with electrical dyssynchrony at the LV free wall (43 vs 19 ms, p = 0.019). Conclusions The electrical dyssynchrony is associated with the reduced LV strain, enlarged RV volumes, and reduced biventricular function in children with PAH. CMR assessment of biventricular mechanical function with respect to QRS duration may help to detect pathophysiologic processes associated with progressed PAH. [ABSTRACT FROM AUTHOR]

Background: Total joint replacement of the 1st metatarso-phalangeal Joint (MTPJ) has been controversial as arthrodesis remains a good option for patients with end stage 1st MTPJ arthritis. We present a multi centre service evaluation of the ROTO-glide device METHODS: 33 ROTO-glide procedures were carried out in 30 patients across 7 sites within the UK. Exclusion criteria - hallux valgus and arthritis, age below 45 years and over 80 years, inflammatory joint disease. Patient assessed pre and post operatively with AOFAS and Oxford forefoot (MOXFQ) scores and plain radiographs. All patients carried out the same post operative protocol RESULTS: Average age at patients was 58.6 years (45-77). Follow up average was 16.9 months (12-29). Pre-op AOFAS scores average 41.4 (17-67) and post op average 76 (29-100) and the MOXFQ summary index decreased from an average of 43 (20-64) pre op to an average of 17 (0-51) post op. Average total range of motion pre operatively was 32° and post operatively was 61°. There were 2 post operative complications but no revisions were necessary.Conclusions: The early results of this multi centre service evaluation of the ROTO-glide 1st MTPJ replacement support its continued use and evaluation of the prosthesis further. [ABSTRACT FROM AUTHOR]

A constitutive model for a fiber reinforced hyperelastic material was applied to understand arterial fiber remodeling in a sheep model of Intrauterine Growth Restriction (IUGR). IUGR is associated altered hemodynamics characterized by increased resistance to blood flow in the placenta and elevated fetal arterial pressure and pulsatility. The constitutive model describes the collagen contribution to the mechanics within the arterial wall in both control and IUGR carotid artery through defining the material modulus and the orientation of the microstructure. A sheep model of placental insufficiency induced IUGR (PI-IUGR) was created by exposure of the pregnant ewe to elevated ambient tempera-tures. Experimental data was collected using pressure-diameter measurements to measure passive compliance in control and PI-IUGR carotid arteries. The constitutive model was optimized to fit the experimental data predicting the material parameters. Specifically' the collagen fiber predicted angle (Y) in the control artery was 49.9° from the circumferential axis while the PI-IUGR was 16.6° with a 23.5% increase in fiber orientation (k). Quantitative assessment of collagen fiber orientation in secondary harmonic generation images confirmed the shift in orientation between the two groups. Together these suggest vascular remodeling of the ECM fiber orientation plays a major role in arterial stiffening in the PI-IUGR near-term fetal sheep. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: There are currently few widely accepted noninvasive detection methods for drug-induced vascular damage. Circulating endothelial progenitor cell (EPC) enumeration in humans has recently gained attention as a potential biomarker of vascular injury/endothelial damage/dysfunction. The rat is commonly used in preclinical drug development toxicity testing and lacks consensus noninvasive methodologies for immunophenotypic identification of EPCs. Identification of immunophenotypic markers of EPCs in the rat would enable transfer of technologies use`d in human for potential development of biomarkers for vascular injury the rat. Therefore, the aim of this work was to develop methods to consistently identify a discreet population of EPCs from rat peripheral blood. Methods: EPCs were identified phenotypically from rat blood using cell culture, immunolabeling, fluorescence microscopy, and flow cytometry. EPCs isolated using immunolabeling coupled with magnetic separation and flow cytometric cell sorting were characterized genotypically using mRNA analysis. Results: A modified colony forming unit (CFU)-Hill assay confirmed existence of immature EPCs in peripheral blood. Extended in vitro culture resulted in a morphology and immunophenotype consistent with mature endothelial cells as noted by positive staining for CD31, von Willebrand factor, rat endothelial cell antigen, and negative staining for smooth muscle cell α-actin. The majority of the cells identified as LDL+/CD11b/c− did not stain positively for either vWF or CD31. EPC populations isolated using magnetic separation and cell sorting were consistently positive for PECAM1, EDN1, FLK1, VWF, ITGAD, CCR1, IP30, and MMP2 mRNA expression. Cells identified as EPCs express cell-surface and gene expression markers consistent with endothelial cells and endothelial progenitor cell populations. Discussion: Vascular trauma induces transient mobilization of EPCs in humans and their enumeration and characterization have been proposed as a surrogate biomarker for assessment of vascular injury. Potential exists for using rat circulating EPCs as a surrogate sampling population for biomarker development in drug-related injury in preclinical toxicity studies. A prerequisite to biomarker development is the ability to consistently identify a discreet population of EPCs from peripheral rat blood. This work describes novel methods for isolation and validation of phenotypically and genotypically consistent populations of rat EPCs from peripheral blood. These methods are well suited for potential future use in validation of enumeration and/or biomarker development methods in the rat. [Copyright &y& Elsevier]

Although Cryptosridium spp. are found throughout the world and in multiple environmental conditions, few data are available that explore the possibility of an association between specific environmental parameters and the species or strain of Cryptosporidium. This study examines the potential association between a particular Cryptosporidium species/strain found in calves and soil provinces in Georgia. USA. Necropsy cases spanning the years 1996-2002 were tested. No significant differences (P = 0.962. ;C" test of homogeneity) between numbers of positive cases were noted among soil provinces. Phylogenetic analysis of the sequences for the PCR products revealed sequence similarity of the products with Cryptosporidium parvum strain CI. Although, clinical Cryptosporidiosis in calves was not found to be affected by soil province and may be caused by a single genotype, other genotypes may be responsible for subclinical infection and warrant further investigation. [ABSTRACT FROM AUTHOR]

Aims: Cardiovascular disease (CVD) is the major cause of mortality in type 1 diabetes (T1D). Biomarkers, N-terminal pro-brain natriuretic peptide (NT-proBNP) and copeptin have been linked with measures of CVD, but their relationship in adolescents with T1D remains incompletely understood. Accordingly, we examined the associations between NT-proBNP and copeptin and hemodynamic markers of central aortic stiffness in adolescents with T1D.Methods: In this pilot study, forty-nine pubertal adolescents with T1D (mean age 17 ± 2 years, median [Q1-Q3] Tanner Stage 5 [5, 5] and HbA1c 8.5 ± 1.5%), from the EMERALD study, were assessed for copeptin and NT-proBNP, and indices of central aortic stiffness non-invasively assessed by MRI. Pearson correlations and generalized linear regression models, adjusting for confounders, were applied to examine the relationships between biomarkers and vascular measures.Results: Copeptin correlated independently with both ascending aortic (AA) (β ± SE: -4.28 ± 1.87, p = 0.03) and descending aortic (DA) relative area change (RAC) (-3.41 ± 1.55, p = 0.04). NT-proBNP was independently associated with DA time-averaged wall shear stress (WSSTA) (0.87 ± 0.25, p = 0.001) and DA maximum wall shear stress (WSSmax) (2.45 ± 1.00, p = 0.02).Conclusions: Serum copeptin and NT-proBNP may be associated with central aortic stiffness and elevated WSS in youth with T1D, potentially offering a non-invasive way to identify and monitor the development of early CVD in an at-risk population. [ABSTRACT FROM AUTHOR]