Simulation sample sizes for Monte Carlo partial EVPI calculations

Partial expected value of perfect information (EVPI) quantifies the value of removing uncertainty about unknown parameters in a decision model. EVPIs can be computed via Monte Carlo methods. An outer loop samples values of the parameters of interest, and an inner loop samples the remaining parameters from their conditional distribution. This nested Monte Carlo approach can result in biased estimates if small numbers of inner samples are used and can require a large number of model runs for accurate partial EVPI estimates. We present a simple algorithm to estimate the EVPI bias and confidence interval width for a specified number of inner and outer samples. The algorithm uses a relatively small number of model runs (we suggest approximately 600), is quick to compute, and can help determine how many outer and inner iterations are needed for a desired level of accuracy. We test our algorithm using three case studies. (C) 2010 Elsevier B.V. All rights reserved

Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites

The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.Work in the DJH laboratory is supported by the Medical Research Council under grant ML/L007266/1. All calculations were performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/) provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England, and were funded by the EPSRC under grants EP/F032773/1 and EP/J017639/1

Identification of body fat tissues in MRI data

In recent years non-invasive medical diagnostic techniques have been used widely in medical investigations. Among the various imaging modalities available, Magnetic Resonance Imaging is very attractive as it produces multi-slice images where the contrast between various types of body tissues such as muscle, ligaments and fat is well defined. The aim of this paper is to describe the implementation of an unsupervised image analysis algorithm able to identify the body fat tissues from a sequence of MR images encoded in DICOM format. The developed algorithm consists of three main steps. The first step pre-processes the MR images in order to reduce the level of noise. The second step extracts the image areas representing fat tissues by using an unsupervised clustering algorithm. Finally, image refinements are applied to reclassify the pixels adjacent to the initial fat estimate and to eliminate outliers. The experimental data indicates that the proposed implementation returns accurate results and furthermore is robust to noise and to greyscale in-homogeneity

Innate Pathways of Immune Activation in Transplantation

Studies of the immune mechanisms of allograft rejection have predominantly focused on the adaptive immune system that includes T cells and B cells. Recent investigations into the innate immune system, which recognizes foreign antigens through more evolutionarily primitive pathways, have demonstrated a critical role of the innate immune system in the regulation of the adaptive immune system. Innate immunity has been extensively studied in its role as the host's first-line defense against microbial pathogens; however, it is becoming increasingly recognized for its ability to also recognize host-derived molecules that result from tissue damage. The capacity of endogenous damage signals acting through the innate immune system to lower immune thresholds and promote immune recognition and rejection of transplant grafts is only beginning to be appreciated. An improved understanding of these pathways may reveal novel therapeutic targets to decrease graft alloreactivity and increase graft longevity

Academic Major, Gender, Personal Values, And Reactions To An Ethical Dilemma

Recent corporate scandals have increased public interest in the area of business ethics.  This study examines the relationship of gender and choice of academic major to personal values and to ethical choices, and the relationship of personal values to ethical choices.  Two hundred fifty three subjects read a case that presented a tax evasion dilemma.  The subjects responded to a series of action statements related to the ethical dilemma and completed a personal values survey.  The responses to the action statements were used to calculate a tax compliance score.  Participants were also asked to make a choice as to whether the taxpayer should or should not report all of the taxable income.  The results indicate that both the tax compliance score and the tax payment choice differed by gender and academic major.  Furthermore, gender differences were found on five of the ten personal value constructs and academic major differences were found on four of the ten personal value constructs.  With regard to the relationship of personal values to ethical choices, it was found that three of the personal value constructs were correlated with the compliance score and the tax payment decision

Development of a measure of barriers to laparoscopic adjustable gastric banding (LAGB) aftercare attendance

Background: Regular aftercare attendance following laparoscopic adjustable gastric banding (LAGB) is associated with greater weight loss and fewer post-surgical complications. Despite high reported rates of attrition from LAGB aftercare, the reasons for non-attendance have not been thoroughly explored. The aim of the current study was to describe the scale development, explore the factor structure and evaluate the psychometric properties of the Gastric Banding Aftercare Attendance Questionnaire (GBAAQ)—a tool that measures barriers to aftercare attendance in LAGB patients. Methods: One hundred and eighty-three participants completed the GBAAQ; 107 regular attendees and 76 non-attendees. Results: A factor analysis identified four factors (Treatment Approach, Time Constraints, Stress and Pressures, Uncomfortable Participating) that demonstrated good known-groups validity and internal consistency. Conclusions: Although further validation is needed, the results of the present study provide preliminary support for the validity of the GBAAQ. Knowledge about the barriers to LAGB aftercare attendance can be used to identify those most at risk of non-attendance and can inform strategies aimed at reducing non-attendance

New Horizons in Hepatitis B and C in the Older Adult

Hepatitis C (HCV) and hepatitis B (HBV), are blood-borne viruses that can cause acute hepatitis; but are clinically relevant because chronic infection is associated with development of cirrhosis and hepatocellular carcinoma. Both these viruses are becoming more common in the older population, due to the ageing of generations exposed to the risk factors associated with infection; intravenous drug use, multiple sexual partners and men who have sex with men. This review will cover the natural history and epidemiology of these infections as well as the revolution in drug therapy that now allows cure of HCV infection and complete control of HBV infection.</p

Numb Chin Syndrome: Atypical presentation of metastatic breast cancer

Introduction/Background: Numb chin syndrome (NCS) is an uncommon but known complication of cancer. Prompt recognition is imperative to directed treatment. In some instances, numb chin may be complicated by other findings. &nbsp; Case Report: A 53-year-old female with past medical history of estrogen receptor positive invasive ductal breast carcinoma underwent partial mastectomy, chemotherapy, and radiation. After 6 years remission, new lung and liver metastases occurred, and chemotherapy resumed. &nbsp;Imaging was negative.&nbsp; Eight weeks later, she developed left chin numbness followed by progressive difficulty retaining food and drink.&nbsp; Her left lower lip weakened. &nbsp; Neurological examination revealed left lower lip weakness (showing a “droop” with attempted smile). &nbsp;The area of decreased sensation to sharp touch had expanded from the left chin to the nasolabial fold.&nbsp; The remainder of her neurological examination was unremarkable. Contrast-enhanced MRI was repeated which revealed a 1.9 cm enhancing left parotid mass. &nbsp; Summary/Conclusion: NCS is defined as an ipsilateral loss of chin sensation. If there is no history of trauma or dental injury and especially if the presentation is atypical, then cancer is the most likely etiology. This case began as an uncomplicated NCS that rapidly expanded to involve a greater portion of the trigeminal nerve distribution, in addition to a branch of the facial nerve.&nbsp; Thus, each focal deficit was not the result of separate distal nerve lesions, but rather partial proximal cranial neuropathies at their parotid gland propinquity