Derivation and validation of a novel risk score to predict need for haemostatic intervention in acute upper gastrointestinal bleeding (London Haemostat Score)

Background: Acute Upper Gastrointestinal Bleeding (AUGIB) is a common medical emergency which takes up considerable healthcare resources. However, only approximately 20-30% of bleeds require urgent haemostatic intervention. Current standard of care is for all patients admitted to hospital to undergo endoscopy within 24 hours for risk stratification, but this is difficult to achieve in practice, invasive and costly. Aim To develop a novel non-endoscopic risk stratification tool for AUGIB to predict the need for haemostatic intervention by endoscopic, radiological or surgical treatments. We compared this with the Glasgow-Blatchford Score (GBS). Design: Model development was carried out using a derivation (n=466) and prospectively collected validation cohort (n=404) of patients who were admitted with AUGIB to three large hospitals in London, UK (2015-2020). Univariable and multivariable logistic regression analysis was used to identify variables that were associated with increased or decreased chances of requiring haemostatic intervention. This model was converted into a risk scoring system, the London Haemostat Score (LHS). Results: The LHS was more accurate at predicting need for haemostatic intervention than the GBS, in the derivation cohort (Area Under the Receiver Operating Curve [AUROC] 0.82; 95% Confidence Interval (CI), 0.78-0.86 vs 0.72; 95% CI, 0.67-0.77; p<0.001) and validation cohort (AUROC 0.80; 95% CI, 0.75-0.85 vs 0.72; 95% CI, 0.67-0.78; p<0.001). At cut-off scores at which LHS and GBS identified patients who required haemostatic intervention with 98% sensitivity, the specificity of the LHS was 41% vs 18% with the GBS (p<0.001). This could translate to 32% of inpatient endoscopies for AUGIB being avoided at a cost of only a 0.5% false negative rate. Conclusions: The London Haemostat score is accurate at predicting the need for haemostatic intervention in AUGIB and could be used identify a proportion of low-risk patients who can undergo delayed or outpatient endoscopy. Validation in other geographical settings is required before routine clinical use

Genetic background modifies amyloidosis in a mouse model of ATTR neuropathy

AbstractPenetrance and age of onset of ATTRV30M amyloidotic neuropathy varies significantly among different populations. This variability has been attributed to both genetic and environmental modifiers. We studied the effect of genetic background on phenotype in two lines of transgenic mice bearing the same ATTRV30M transgene. Amyloid deposition, transthyretin (TTR), megalin, clusterin and disease markers of endoplasmic reticulum stress, the ubiquitin-proteasome system, apoptosis, and complement activation were assessed with WB and immunohistochemistry in donor and recipient tissue. Our results indicate that genetic background modulates amyloid deposition by influencing TTR handling in recipient tissue and may partly account for the marked variability in penetrance observed in various world populations

Analysis of photonic-crystal problems with MLFMA and approximate Schur preconditioners

We consider fast and accurate solutions of electromagnetics problems involving three-dimensional photonic crystals (PhCs). Problems are formulated with the combined tangential formulation (CTF) and the electric and magnetic current combined-field integral equation (JMCFIE) discretized with the Rao-Wilton-Glisson functions. Matrix equations are solved iteratively by the multilevel fast multipole algorithm. Since PhC problems are difficult to solve iteratively, robust preconditioning techniques are required to accelerate iterative solutions. We show that novel approximate Schur preconditioners enable efficient solutions of PhC problems by reducing the number of iterations significantly for both CTF and JMCFIE. ©2009 IEEE

Neuronal migration and ventral subtype identity in the telencephalon depend on SOX1

Little is known about the molecular mechanisms and intrinsic factors that are responsible for the emergence of neuronal subtype identity. Several transcription factors that are expressed mainly in precursors of the ventral telencephalon have been shown to control neuronal specification, but it has been unclear whether subtype identity is also specified in these precursors, or if this happens in postmitotic neurons, and whether it involves the same or different factors. SOX1, an HMG box transcription factor, is expressed widely in neural precursors along with the two other SOXB1 subfamily members, SOX2 and SOX3, and all three have been implicated in neurogenesis. SOX1 is also uniquely expressed at a high level in the majority of telencephalic neurons that constitute the ventral striatum (VS). These neurons are missing in Sox1-null mutant mice. In the present study, we have addressed the requirement for SOX1 at a cellular level, revealing both the nature and timing of the defect. By generating a novel Sox1-null allele expressing β-galactosidase, we found that the VS precursors and their early neuronal differentiation are unaffected in the absence of SOX1, but the prospective neurons fail to migrate to their appropriate position. Furthermore, the migration of non-Sox1-expressing VS neurons (such as those expressing Pax6) was also affected in the absence of SOX1, suggesting that Sox1-expressing neurons play a role in structuring the area of the VS. To test whether SOX1 is required in postmitotic cells for the emergence of VS neuronal identity, we generated mice in which Sox1 expression was directed to all ventral telencephalic precursors, but to only a very few VS neurons. These mice again lacked most of the VS, indicating that SOX1 expression in precursors is not sufficient for VS development. Conversely, the few neurons in which Sox1 expression was maintained were able to migrate to the VS. In conclusion, Sox1 expression in precursors is not sufficient for VS neuronal identity and migration, but this is accomplished in postmitotic cells, which require the continued presence of SOX1. Our data also suggest that other SOXB1 members showing expression in specific neuronal populations are likely to play continuous roles from the establishment of precursors to their final differentiation

Malignant peripheral nerve sheath tumor of the breast: case report

<p>Abstract</p> <p>Background</p> <p>Malignant peripheral nerve sheath tumor is a rare soft tissue sarcoma of ectomesenchymal origin. It is the malignant counterpart of benign soft tissue tumors like neurofibromas and schwannomas and may often follow them. Common sites include deeper soft tissues, usually in the proximity of a nerve trunk. Breast is an extremely rare location of this lesion and presentation as a breast lump in the absence of pain or previous benign neural tumor is even rarer.</p> <p>Case presentation</p> <p>A 38-year-old female presented with complaints of painless, hard breast lump for three months which was clinically suspected to be a ductal carcinoma with inconclusive fine needle aspiration cytology. Histopathology revealed a malignant spindle cell tumor which was confirmed to be malignant peripheral nerve sheath tumor on the basis of immunopositivity for vimentin, neurone specific enolase and S-100.</p> <p>Conclusion</p> <p>To the best of our knowledge only six such case reports have been published in literature. The differential diagnosis of malignant peripheral nerve sheath tumor should be considered by the clinician as well as the pathologists in the work-up of a breast neoplasm as treatment and prognosis of this rare malignancy is different.</p

Sox1 is required for the specification of a novel p2-derived interneuron subtype in the mouse ventral spinal cord

During mouse development, the ventral spinal cord becomes organized into five progenitor domains that express different combinations of transcription factors and generate different subsets of neurons and glia. One of these domains, known as the p2 domain, generates two subtypes of interneurons, V2a and V2b. Here we have used genetic fate mapping and loss-of-function analysis to show that the transcription factor Sox1 is expressed in, and is required for, a third type of p2-derived interneuron, which we named V2c. These are close relatives of V2b interneurons, and, in the absence of Sox1, they switch to the V2b fate. In addition, we show that late-born V2a and V2b interneurons are heterogeneous, and subsets of these cells express the transcription factor Pax6. Our data demonstrate that interneuron diversification in the p2 domain is more complex than previously thought and directly implicate Sox1 in this proces

Biological effects of particles from the paris subway system

Particulate matter (PM) from atmospheric pollution can easily deposit in the lungs and induce recruitment of inflammatory cells, a source of inflammatory cytokines, oxidants, and matrix metalloproteases (MMPs), which are important players in lung structural homeostasis. In many large cities, the subway system is a potent source of PM emission, but little is known about the biological effects of PM from this source. We performed a comprehensive study to evaluate the biological effects of PM sampled at two sites (RER and Metro) in the Paris subway system. Murine macrophages (RAW 264.7) and C57Bl/6 mice, respectively, were exposed to 0.01-10 microg/cm2 and 5-100 microg/mouse subway PM or reference materials [carbon black (CB), titanium dioxide (TiO2), or diesel exhaust particles (DEPs)]. We analyzed cell viability, production of cellular and lung proinflammatory cytokines [tumor necrosis factor alpha (TNFalpha), macrophage inflammatory protein (MIP-2), KC (the murin analog of interleukin-8), and granulocyte macrophage-colony stimulating factor (GM-CSF)], and mRNA or protein expression of MMP-2, -9, and -12 and heme oxygenase-1 (HO-1). Deferoxamine and polymixin B were used to evaluate the roles of iron and endotoxin, respectively. Noncytotoxic concentrations of subway PM (but not CB, TiO2, or DEPs) induced a time- and dose-dependent increase in TNFalpha and MIP-2 production by RAW 264.7 cells, in a manner involving, at least in part, PM iron content (34% inhibition of TNF production 8 h after stimulation of RAW 264.7 cells with 10 microg/cm2 RER particles pretreated with deferoxamine). Similar increased cytokine production was transiently observed in vivo in mice and was accompanied by an increased neutrophil cellularity of bronchoalveolar lavage (84.83+/-0.98% of polymorphonuclear neutrophils for RER-treated mice after 24 h vs 7.33+/-0.99% for vehicle-treated animals). Subway PM induced an increased expression of MMP-12 and HO-1 both in vitro and in vivo. PM from the Paris subway system has transient biological effects. Further studies are needed to better understand the pathophysiological implications of these findings

Applying the Roofline Performance Model to the Intel Xeon Phi Knights Landing Processor

The Roofline Performance Model is a visually intuitive method used to bound the sustained peak floating-point performance of any given arithmetic kernel on any given processor architecture. In the Roofline, performance is nominally measured in floating-point operations per second as a function of arithmetic intensity (operations per byte of data). In this study we determine the Roofline for the Intel Knights Landing (KNL) processor, determining the sustained peak memory bandwidth and floating-point performance for all levels of the memory hierarchy, in all the different KNL cluster modes.We then determine arithmetic intensity and performance for a suite of application kernels being targeted for the KNL based supercomputer Cori, and make comparisons to current Intel Xeon processors. Cori is the National Energy Research Scientific Computing Center’s (NERSC) next generation supercomputer. Scheduled for deployment mid-2016, it will be one of the earliest and largest KNL deployments in the world

The influence of staff training and education on prosthetic and orthotic service quality : a scoping review

Background: Education and training in prosthetics and orthotics typically comply with International Society for Prosthetics and Orthotics standards based on three categories of prosthetic and orthotic professionals. Objective: This scoping study sought to describe the evidence base available to answer the question, How are prosthetic and orthotic services influenced by the training of staff providing them? Study design: Scoping review. Methods: A structured search of the peer-reviewed literature catalogued in major electronic databases yielded 3039 papers. Following review of title and abstract, 93 articles were considered relevant. Full-text review reduced this number to 25. Results: Only two articles were identified as providing direct evidence of the effects of training and education on service provision. While both suggested that there was an impact, it is difficult to see how the more specific conclusions of either could be generalised. The other 23 articles provide a useful background to a range of issues including the specification of competencies that training programmes should deliver (3 articles), descriptions of a range of training programmes and the effects of training and education on student knowledge and skills. Conclusion: Although it is considered axiomatic, the service quality is dependent on practitioner education and training. There is insufficient evidence to establish whether levels of training and education in prosthetics and orthotics have an effect on the quality of prosthetic and orthotic services. Clinical relevance: There is very little evidence about the effects of training and education of prosthetists and orthotists on service quality. While this is a somewhat negative finding, we feel that it is important to bring this to the attention of the prosthetics and orthotics community