Combined Effect of Hot Extrusion and Heat Treatment on the Mechanical Behavior of 7055 AA Processed via Spray Metal Forming

The mechanical properties of 7xxx series alloys can be tailored by subjecting them to deformation pro- cessing and heat treatment. In the present study dealing with spray forming of 7055 AA, extrusion and heat treatment involving solutionizing followed by peak aging resulted in improved mechanical behavior. The strength and ductility obtained are comparable to that of extruded and heat treated as-cast 7055 AA (Mondal et al., 2011) [1]. Spray forming offers an alternate route to develop high strength aluminum alloys and the current study is an attempt that draws closer to the target value of 1GPa strength and 10% ductility for high strength aluminum alloys

Leadership and governance : learning outcomes and competencies required of the family physician in the district health system

CITATION:Mash, R., et al. 2016. Leadership and governance : learning outcomes and competencies required of the family physician in the district health system. South African Family Practice, 58(6):232-235, doi:10.1080/20786190.2016.1148338.The original publication is available at http://www.tandfonline.comThe South African National Development Plan expects the family physician to be a leader of clinical governance within the district health services. The family physician must also help to strengthen the services through leadership in all his/her other roles as a clinician, consultant, capacity-builder, clinical trainer and champion of community-orientated primary care. In order to deliver on these expectations the nine training programmes must ensure that they prepare registrars appropriately for leadership and clinical governance. Currently training programmes differ considerably in what they teach and in workplace-based training and assessment. This article reports on a national process to reach consensus on what training is required for family physicians in this area. The process outlined the key conceptual principles and competencies required for leadership, clinical and corporate governance; it culminates in a new set of learning outcomes for the training of family physicians.http://www.tandfonline.com/doi/full/10.1080/20786190.2016.1148338Publisher's versio

Pathway Signature and Cellular Differentiation in Clear Cell Renal Cell Carcinoma

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The purpose of this study is to define a biological pathway signature and a cellular differentiation program in ccRCC. METHODOLOGY: We performed gene expression profiling of early-stage ccRCC and patient-matched normal renal tissue using Affymetrix HG-U133a and HG-U133b GeneChips combined with a comprehensive bioinformatic analyses, including pathway analysis. The results were validated by real time PCR and IHC on two independent sample sets. Cellular differentiation experiments were performed on ccRCC cell lines and their matched normal renal epithelial cells, in differentiation media, to determine their mesenchymal differentiation potential. PRINCIPAL FINDINGS: We identified a unique pathway signature with three major biological alterations-loss of normal renal function, down-regulated metabolism, and immune activation-which revealed an adipogenic gene expression signature linked to the hallmark lipid-laden clear cell morphology of ccRCC. Culturing normal renal and ccRCC cells in differentiation media showed that only ccRCC cells were induced to undergo adipogenic and, surprisingly, osteogenic differentiation. A gene expression signature consistent with epithelial mesenchymal transition (EMT) was identified for ccRCC. We revealed significant down-regulation of four developmental transcription factors (GATA3, TFCP2L1, TFAP2B, DMRT2) that are important for normal renal development. CONCLUSIONS: ccRCC is characterized by a lack of epithelial differentiation, mesenchymal/adipogenic transdifferentiation, and pluripotent mesenchymal stem cell-like differentiation capacity in vitro. We suggest that down-regulation of developmental transcription factors may mediate the aberrant differentiation in ccRCC. We propose a model in which normal renal epithelial cells undergo dedifferentiation, EMT, and adipogenic transdifferentiation, resulting in ccRCC. Because ccRCC cells grown in adipogenic media regain the characteristic ccRCC phenotype, we have identified a new in vitro ccRCC cell model more resembling ccRCC tumor morphology

The Myosin Va Head Domain Binds to the Neurofilament-L Rod and Modulates Endoplasmic Reticulum (ER) Content and Distribution within Axons

The neurofilament light subunit (NF-L) binds to myosin Va (Myo Va) in neurons but the sites of interaction and functional significance are not clear. We show by deletion analysis that motor domain of Myo Va binds to the NF-L rod domain that forms the NF backbone. Loss of NF-L and Myo Va binding from axons significantly reduces the axonal content of ER, and redistributes ER to the periphery of axon. Our data are consistent with a novel function for NFs as a scaffold in axons for maintaining the content and proper distribution of vesicular organelles, mediated in part by Myo Va. Based on observations that the Myo Va motor domain binds to intermediate filament (IF) proteins of several classes, Myo Va interactions with IFs may serve similar roles in organizing organelle topography in different cell types

The QT interval and risk of incident atrial fibrillation

Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine

Erythropoietin: a multimodal neuroprotective agent

The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and stimulates angiogenesis and neurogenesis. These mechanisms underlie its potent tissue protective effects in experimental models of stroke, cerebral hemorrhage, traumatic brain injury, neuroinflammatory and neurodegenerative disease. The preclinical data in support of the use of EPO in brain disease have already been translated to first clinical pilot studies with encouraging results with the use of EPO as a neuroprotective agent

The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.

Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells has not been defined. We investigated the effect of using third signal cytokines IL-12 or IFN-α to rescue the exhausted CD8 T cell response characteristic of patients persistently infected with hepatitis B virus (HBV). We found that IL-12, but not IFN-α, potently augmented the capacity of HBV-specific CD8 T cells to produce effector cytokines upon stimulation by cognate antigen. Functional recovery mediated by IL-12 was accompanied by down-modulation of the hallmark inhibitory receptor PD-1 and an increase in the transcription factor T-bet. PD-1 down-regulation was observed in HBV but not CMV-specific T cells, in line with our finding that the highly functional CMV response was not further enhanced by IL-12. IL-12 enhanced a number of characteristics of HBV-specific T cells important for viral control: cytotoxicity, polyfunctionality and multispecificity. Furthermore, IL-12 significantly decreased the pro-apoptotic molecule Bim, which is capable of mediating premature attrition of HBV-specific CD8 T cells. Combining IL-12 with blockade of the PD-1 pathway further increased CD8 functionality in the majority of patients. These data provide new insights into the distinct signalling requirements of exhausted T cells and the potential to recover responses optimised to control persistent viral infections

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Development of Methodical Approaches to the Assortment Management of Pharmacy Networks by Principles of Categorycal Management

The most responsible business is determining the correct strategic course of the pharmaceutical organization and the directions of increasing its competitiveness, as it forms the priorities of its activities in the relatively long-term perspective. Management of assortment is one of the most important functions of any pharmacy. The modern markets characterized as "the market of buyers" actively demands the introduction of pharmacy networks of modern tools and technology management of product assortment.The aim of the work is to develop methodological approaches to managing the assortment of pharmacy networks on the principles of categorical management.Methods. Systematic and logical analysis, methods of comparative, documentary, structural-functional and economic-statistical analysis were used in this work.Results of the research. The algorithm for managing the product assortment in pharmacy networks was developed for efficient management of the assortment of pharmacy networks, which is based on the principles of categorical management, and involves: definition of product categories, their internal structure and signs, upon which the medicines will be grouped (according to ATC classification (first level)); analysis of the main financial and economic indicators by the selected product categories; determining the role of each product category in accordance with its influence on the achievement of pharmacy network's goals; studying the demand for each product category and its internal content; assessment of the current state of commodity categories, its structure and determination of possible changes in the work with its assortment content in the future; optimization for each product category of the entire chain of movement of goods from the purchase and formation of inventory to direct sales; substantiation of assortment policy on selected criteria and evaluation its efficiency; implementation assortment policy. The proposed methodological approaches were worked out on the example of one of the investigated pharmacy networks.Conclusions. It was proved that categorical management is an instrument of management assortment policy of pharmacy networks, which allows to allocate groups of pharmaceutical products, which will be aimed at fulfilling certain goals of pharmacy networks, which respectively will promote implementation of the strategy of pharmacy networks developmen