Analysis of stopping criteria for the EM algorithm in the context of patient grouping according to length of stay

The expectation maximisation (EM) algorithm is an iterative maximum likelihood procedure often used for estimating the parameters of a mixture model. Theoretically, increases in the likelihood function are guaranteed as the algorithm iteratively improves upon previously derived parameter estimates. The algorithm is considered to converge when all parameter estimates become stable and no further improvements can be made to the likelihood value. However, to reduce computational time, it is often common practice for the algorithm to be stopped before complete convergence using heuristic approaches. In this paper, we consider various stopping criteria and evaluate their effect on fitting Gaussian mixture models (GMMs) to patient length of stay (LOS) data. Although the GMM can be successfully fitted to positively skewed data such as LOS, the fitting procedure often requires many iterations of the EM algorithm. To our knowledge, no previous study has evaluated the effect of different stopping criteria on fitting GMMs to skewed distributions. Hence, the aim of this paper is to evaluate the effect of various stopping criteria in order to select and justify their use within a patient spell classification methodology. Results illustrate that criteria based on the difference in the likelihood value and on the GMM parameters may not always be a good indicator for stopping the algorithm. In fact we show that the values of the difference in the variance parameters should be used instead, as these parameters are the last to stabilise. In addition, we also specify threshold values for the other stopping criteria

The role of cultural heritage in visitor narratives of peatlands: analysis of online user-generated reviews from three peatland sites in England

yesUser-generated reviews of visitor attractions, on publicly available websites, such as Tripadvisor, are frequently used in tourism research but feature less often in published cultural heritage research. In this paper, we describe a qualitative analysis of the text from user-generated reviews of three peatland heritage landscapes in the United Kingdom – Ilkley Moor, Thorne and Hatfield Moors, and Shapwick Heath – to better understand the role tangible and intangible cultural heritage play in visitor perceptions and narratives of these sites. Our analysis indicates that visitors tend to emphasise natural over cultural heritage of peatland landscapes and hold plural, highly contextual and sometimes dissonant perceptions; there is no single story of peatlands. This presents both challenges and opportunities for building public appreciation of peatland cultural heritage. User-generated reviews offer, as-yet under-explored, potential data for use by heritage researchers and managers who seek to explore how visitors understand and use sites, and may also contribute to the emerging intangible heritage of heritage landscapes.Research Development Fund Publication Prize Award winner, June 2021

Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms

Differential Post-Exercise Blood Pressure Responses between Blacks and Caucasians

Post-exercise hypotension (PEH) is widely observed in Caucasians (CA) and is associated with histamine receptors 1- and 2- (H1R and H2R) mediated post-exercise vasodilation. However, it appears that blacks (BL) may not exhibit PEH following aerobic exercise. Hence, this study sought to determine the extent to which BL develop PEH, and the contri- bution of histamine receptors to PEH (or lack thereof) in this population. Forty-nine (22 BL, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either a combined H1R and H2R antagonist (fexofenadine and ranitidine) or a con- trol placebo. Supine blood pressure (BP), cardiac output and peripheral vascular resistance measurements were obtained at baseline, as well as at 30 min, 60 min and 90 min after 45 min of treadmill exercise at 70% heart rate reserve. Exercise increased diastolic BP in young BL but not in CA. Post-exercise diastolic BP was also elevated in BL after exercise with histamine receptor blockade. Moreover, H1R and H2R blockade elicited differential responses in stroke volume between BL and CA at rest, and the difference remained follow- ing exercise. Our findings show differential BP responses following exercise in BL and CA, and a potential role of histamine receptors in mediating basal and post-exercise stroke vol- ume in BL. The heightened BP and vascular responses to exercise stimulus is consistent with the greater CVD risk in BL

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye

Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Mu ̈ ller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss

Business Registration and Firm Performance: Some Lessons From India

The aim of this paper is to evaluate the impacts on future firm performance of a firm deciding to register from the outset of its operations. Until now, the assumption has been that starting up registered is linked to higher future firm performance. Reporting World Bank Enterprise Survey (WBES) data collected in 2014 on 9,281 formal enterprises in India, and controlling for other determinants of firm performance as well as the endogeneity of the registration decision, the finding is that formal enterprises that start up unregistered and spend longer unregistered have significantly higher subsequent annual sales and employment growth rates compared with those registered from the outset. When the number of years spent unregistered is included, there are also productivity gains from delaying registration. The tentative explanation is that in this weak institutional environment, the advantages of registering from the outset are outweighed by the benefits of deferring registration. Evaluating the policy implications, the argument is that there is a need to shift away from the conventional eradication approach toward unregistered startups based on the assumption they are unproductive, and toward a more facilitating approach that improves the benefits of being registered and tackles the systemic formal institutional deficiencies that lead entrepreneurs to delay their decision to register

Informal entrepreneurship in developing economies: the impacts of starting-up unregistered on firm performance

To advance understanding of the entrepreneurship process in developing economies, this paper evaluates whether registered enterprises that initially avoid the cost of registration, and focus their resources on overcoming other liabilities of newness, lay a stronger foundation for subsequent growth. Analyzing World Bank Enterprise Survey data across 127 countries, and controlling for other firm performance determinants, registered enterprises that started-up unregistered and spent longer operating unregistered are revealed to have significantly higher subsequent annual sales, employment and productivity growth rates compared with those that registered from the outset. The theoretical and policy implications are then discussed