Multi-parametric classification of Alzheimer's disease and mild cognitive impairment: the impact of quantitative magnetization transfer MR imaging

Multi-parametric and quantitative magnetic resonance imaging (MRI) techniques have come into the focus of interest, both as a research and diagnostic modality for the evaluation of patients suffering from mild cognitive decline and overt dementia. In this study we address the question, if disease related quantitative magnetization transfer effects (qMT) within the intra- and extracellular matrices of the hippocampus may aid in the differentiation between clinically diagnosed patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI) and healthy controls. We evaluated 22 patients with AD (n=12) and MCI (n=10) and 22 healthy elderly (n=12) and younger (n=10) controls with multi-parametric MRI. Neuropsychological testing was performed in patients and elderly controls (n=34). In order to quantify the qMT effects, the absorption spectrum was sampled at relevant off-resonance frequencies. The qMT-parameters were calculated according to a two-pool spin-bath model including the T1- and T2 relaxation parameters of the free pool, determined in separate experiments. Histograms (fixed bin-size) of the normalized qMT-parameter values (z-scores) within the anterior and posterior hippocampus (hippocampal head and body) were subjected to a fuzzy-c-means classification algorithm with downstreamed PCA projection. The within-cluster sums of point-to-centroid distances were used to examine the effects of qMT- and diffusion anisotropy parameters on the discrimination of healthy volunteers, patients with Alzheimer and MCIs. The qMT-parameters T2(r) (T2 of the restricted pool) and F (fractional pool size) differentiated between the three groups (control, MCI and AD) in the anterior hippocampus. In our cohort, the MT ratio, as proposed in previous reports, did not differentiate between MCI and AD or healthy controls and MCI, but between healthy controls and AD.

Maximising the impact of research: the NCCR North-South approach: Fourth NCCR North-South Report on Effectiveness

Interest is growing in the impact that science can have on reducing poverty in the global South. If we understand impact as the “demonstrable contribution that excellent research makes to society and the economy”, the concept encompasses a variety of contributions of research-related knowledge and skills that benefit people and the environment. One reason for the growing interest in impact in this context is research councils’ increasing focus on documenting the social and environmental benefits of science, as indicated by the above quotation from the British research councils. Another reason is that research funding agencies from the private and public sectors are now more interested in social innovations for solving problems on the ground. Research can indeed influence policymakers’ views, policy development, funding patterns, and implementation or practice. This is promising for those who would like to improve – and prove – the influence research can have on policy and practice. It is also of importance for better understanding the intended and unintended effects of research. This report presents the NCCR North-South approach to increasing the impact of development-oriented research. It explains how we can maximise our impact and how we can assess whether our efforts have worked, based on six case studies from around the world. The report is of interest to all researchers who wish to respond to policy and practice from their point of view and who are keen on publicising their evidence. It is also relevant to those who teach how to maximise research impact.

Governance of Digital Game Environments and Cultural Diversity : Transdisciplinary Enquiries

Digital game environments are of increasing economic, social and cultural value. As their influence on diverse facets of life grows, states have felt compelled to intervene and secure some public interests. Yet, the contours of a comprehensive governance model are far from recognisable and governments are grappling with the complexity and fluidity of online games and virtual worlds as private spaces and as experimentation fields for creativity and innovation. This book contributes to a more comprehensive and fine-grained understanding of digital game environments, which is a precondition for addressing any of the pressing governance questions posed. Particular attention is given to the concept and policy objective of cultural diversity, which also offers a unique entry point into the discussion of the appropriate legal regulation of digital games. Governance of Digital Game Environments and Cultural Diversity will be of interest to researchers of media law, internet law and governance, cultural studies, anthropology and sociology. As the book addresses a highly topical theme, it will attract the attention of policymakers at national, regional and international levels and will also serve as a great resource tool for scholars in new media and, in particular, digital games and virtual worlds.

Governance of Digital Game Environments and Cultural Diversity : Transdisciplinary Enquiries. Preface

Digital game environments are of increasing economic, social and cultural value. As their influence on diverse facets of life grows, states have felt compelled to intervene and secure some public interests. Yet, the contours of a comprehensive governance model are far from recognisable and governments are grappling with the complexity and fluidity of online games and virtual worlds as private spaces and as experimentation fields for creativity and innovation. This book contributes to a more comprehensive and fine-grained understanding of digital game environments, which is a precondition for addressing any of the pressing governance questions posed. Particular attention is given to the concept and policy objective of cultural diversity, which also offers a unique entry point into the discussion of the appropriate legal regulation of digital games. Governance of Digital Game Environments and Cultural Diversity will be of interest to researchers of media law, internet law and governance, cultural studies, anthropology and sociology. As the book addresses a highly topical theme, it will attract the attention of policymakers at national, regional and international levels and will also serve as a great resource tool for scholars in new media and, in particular, digital games and virtual worlds.

Fast parallel kriging-based stepwise uncertainty reduction with application to the identification of an excursion set

Stepwise uncertainty reduction (SUR) strategies aim at constructing a sequence of points for evaluating a function  f in such a way that the residual uncertainty about a quantity of interest progressively decreases to zero. Using such strategies in the framework of Gaussian process modeling has been shown to be efficient for estimating the volume of excursion of f above a fixed threshold. However, SUR strategies remain cumbersome to use in practice because of their high computational complexity, and the fact that they deliver a single point at each iteration. In this article we introduce several multipoint sampling criteria, allowing the selection of batches of points at which f can be evaluated in parallel. Such criteria are of particular interest when f is costly to evaluate and several CPUs are simultaneously available. We also manage to drastically reduce the computational cost of these strategies through the use of closed form formulas. We illustrate their performances in various numerical experiments, including a nuclear safety test case. Basic notions about kriging, auxiliary problems, complexity calculations, R code, and data are available online as supplementary materials.

What does professionalisation mean? Perceptions of professionalisation in swiss sport federations

Introduction: Organisational changes in sports federations are often associated with a drift from a volunteer driven to an increasingly business-like phenomenon (Shilbury & Ferkins, 2011). This process of transfor-mation is be called as “professionalization”. Accordingly, professionalization seems to be an appropriate strategy for sport organisations in order to meet organizational pressure due to challenges of a more complex and dynamic changing environment adequately. Despite the increasing research interest and the attempts for systematization on the phenomenon of professionalization it still remains unclear what does the term professionalization exactly mean (Dowling et al., 2014). Thus, there is a lack of a consistent concept of professionalization that is needed in order to explore different facets and perspectives of this phenomenon more validly. Against this background following question emerged: What is the suitable concept of professionalization for analyzing the actual ongoing processes of change, adaption or transformation in sport federations? Methods: Dealing with this question, following two-step approach was choosen: (1) In a first step a scholar’s perspective at professionalisation of sport organisations will be displayed in order to explore both the common ground as well as divergences and inconsistencies in previous approaches. Therefore, a literature review is indicated. (2) In a second step, and in contrast to previous studies we will consider a practical point of view by a so called second-order observation of experts to gain valuable insights into current thinking and acting towards professionalization in sport federations. In doing so, a hermeneutical approach is used, which is about understanding the meaning of contexts by grasping the everyday world, and draw insight and meaning from it (Shilbury et al., 2013). Accordance with hermeneutics, the explorative interpretive knowledge of expert interviews was used. The interviews were conducted with a sample of six selected experts, who have both dedicated insider knowledge and the overall view of all Swiss sport federations. Results and discussion: The summaries of literature review could be categorized into two research currents. The one defines professionalization as a structural process towards professional status of occupations. The other defines it in a broader sense as an organisational change towards a business-like approach. Whereas the first perspective there is a broad scientific consensus that second isn’t that clear, however. Explorative analysis of interview data reveals different themes in relation to professionalization of sports federation. First theme deals with a changed philosophy as more strategic alignment towards for-profit, efficiency and quality orientation. Second theme refers to paid work associated with more competence orientation and balanced governance between paid and voluntary work. Third theme deals with acting shift towards more rationalization and efficiency by implementation of innovative management and communication tools. Based on findings of both our review of scholar`s perspective as well insights from experts we will provide – in the sense of synthesis – a more clear understanding of what does professionalization mean that can be useful in terms of further studies. References: Dowling, M., Edwards, J. & Washington, M. (2014). Understanding the concept of professionalisation in sport management research. Sport Management Review, 17 (4), 520–529. Shilbury, D., Ferkins, L. & Smythe, L. (2013). Sport governance encounters: Insights from lived experiences. Sport Management Review, 16,349–363. Shilbury, D., & Ferkins, L. (2011). Professionalisation, sport governance and strategic capability. Managing Leisure, 16, 108–127.

Individual predictors of adolescents' vocational interest stabilities

The study investigated the predictive utility of interest profile differentiation, coherence, elevation, congruence, and vocational identity commitment and career maturity (career planning and exploration) on the 10-month interest stability of 292 Swiss eighth-grade students: profile, rank, and level stabilities were assessed. Controlling for socio-demographic and vocational interest type variables, measures of differentiated and coherent vocational interests were significant predictors of profile stability. Interest elevation predicted more rank and level stability. The career development variables explained only a non-significant additional amount of variance in the different stability measures.

Liquid–Vapor Interface of Formic Acid Solutions in Salt Water: A Comparison of Macroscopic Surface Tension and Microscopic in Situ X-ray Photoelectron Spectroscopy Measurements

The liquid–vapor interface is difficult to access experimentally but is of interest from a theoretical and applied point of view and has particular importance in atmospheric aerosol chemistry. Here we examine the liquid–vapor interface for mixtures of water, sodium chloride, and formic acid, an abundant chemical in the atmosphere. We compare the results of surface tension and X-ray photoelectron spectroscopy (XPS) measurements over a wide range of formic acid concentrations. Surface tension measurements provide a macroscopic characterization of solutions ranging from 0 to 3 M sodium chloride and from 0 to over 0.5 mole fraction formic acid. Sodium chloride was found to be a weak salting out agent for formic acid with surface excess depending only slightly on salt concentration. In situ XPS provides a complementary molecular level description about the liquid–vapor interface. XPS measurements over an experimental probe depth of 51 Å gave the C 1s to O 1s ratio for both total oxygen and oxygen from water. XPS also provides detailed electronic structure information that is inaccessible by surface tension. Density functional theory calculations were performed to understand the observed shift in C 1s binding energies to lower values with increasing formic acid concentration. Part of the experimental −0.2 eV shift can be assigned to the solution composition changing from predominantly monomers of formic acid to a combination of monomers and dimers; however, the lack of an appropriate reference to calibrate the absolute BE scale at high formic acid mole fraction complicates the interpretation. Our data are consistent with surface tension measurements yielding a significantly more surface sensitive measurement than XPS due to the relatively weak propensity of formic acid for the interface. A simple model allowed us to replicate the XPS results under the assumption that the surface excess was contained in the top four angstroms of solution.

Loss of Sirt1 function improves intestinal anti-bacterial defense and protects from colitis-induced colorectal cancer

Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int-/-) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC.

A systematic review of glomerular hyperfiltration assessment and definition in the medical literature.

BACKGROUND AND OBJECTIVES Evaluation of glomerular hyperfiltration (GH) is difficult; the variable reported definitions impede comparisons between studies. A clear and universal definition of GH would help in comparing results of trials aimed at reducing GH. This study assessed how GH is measured and defined in the literature. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Three databases (Embase, MEDLINE, CINAHL) were systematically searched using the terms "hyperfiltration" or "glomerular hyperfiltration". All studies reporting a GH threshold or studying the effect of a high GFR in a continuous manner against another outcome of interest were included. RESULTS The literature search was performed from November 2012 to February 2013 and updated in August 2014. From 2013 retrieved studies, 405 studies were included. Threshold use to define GH was reported in 55.6% of studies. Of these, 88.4% used a single threshold and 11.6% used numerous thresholds adapted to participant sex or age. In 29.8% of the studies, the choice of a GH threshold was not based on a control group or literature references. After 2004, the use of GH threshold use increased (P<0.001), but the use of a control group to precisely define that GH threshold decreased significantly (P<0.001); the threshold did not differ among pediatric, adult, or mixed-age studies. The GH threshold ranged from 90.7 to 175 ml/min per 1.73 m(2) (median, 135 ml/min per 1.73 m(2)). CONCLUSION Thirty percent of studies did not justify the choice of threshold values. The decrease of GFR in the elderly was rarely considered in defining GH. From a methodologic point of view, an age- and sex-matched control group should be used to define a GH threshold.

Evaluating minimal important differences for the FACT-Melanoma quality of life questionnaire

Objectives. Minimal Important Differences (MIDs) establish benchmarks for interpreting mean differences in clinical trials involving quality of life outcomes and inform discussions of clinically meaningful change in patient status. As such, the purpose of this study was to assess MIDs for the Functional Assessment of Cancer Therapy–Melanoma (FACT-M). ^ Methods. A prospective validation study of the FACT-M was performed with 273 patients with stage I to IV melanoma. FACT-M, Karnofsky Performance Status (KPS), and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scores were obtained at baseline and 3 months following enrollment. Anchor- and distribution-based methods were used to assess MIDs, and the correspondence between MID ranges derived from each method was evaluated. ^ Results. This study indicates that an approximate range for MIDs of the FACT-M subscales is between 5 to 8 points for the Trial Outcome Index, 4 to 5 points for the Melanoma Combined Subscale, 2 to 4 points for the Melanoma Subscale, and 1 to 2 points for the Melanoma Surgery Subscale. Each method produced similar but not identical ranges of MIDs. ^ Conclusions. The properties of the anchor instrument employed to derive MIDs directly affect resulting MID ranges and point values. When MIDs are offered as supportive evidence of a clinically meaningful change, the anchor instrument used to derive thresholds should be clearly stated along with evidence supporting the choice of anchor instrument as the most appropriate for the domain of interest. In this analysis, the KPS was a more appropriate measure than the ECOG-PS for assessing MIDs. ^

Incidence of breast cancer in first-degree female relatives of men with newly diagnosed prostate cancer

Prostate cancer is the most common incident cancer and the second leading cause of death in men in the United States. Although numerous attempts have been made to identify risk factors associated with prostate cancer, the results have been inconsistent and conflicting. The only established risk factors are age and ethnicity. A positive family history of prostate cancer has also been shown to increase the risk two- to three-fold among close relatives.^ There are several similarities between breast and prostate cancer that make the relationship between the two of interest. (1) Histologically, both cancers are predominantly adenocarcinomas, (2) both organs have a sexual and/or reproductive role, (3) both cancers occur in hormone-responsive tissue, (4) therapy often consists of hormonal manipulation, (5) worldwide distribution patterns of prostate and breast cancer are positively correlated.^ A family history study was conducted to evaluate the aggregation of prostate cancer and co-aggregation of breast cancer in 149 patients referred to The University of Texas, M.D. Anderson Cancer Center with newly diagnosed prostate cancer. All patients were white, less than 75 years of age at diagnosis and permanent residents of the United States. Through a personal interview with the proband, family histories were collected on 1,128 first-degree relatives. Cancer diagnoses were verified through medical records or death certificate. Standardized incidence ratios were calculated using a computer program by Monson incorporating data from Connecticut Tumor Registry.^ In this study, familial aggregation of prostate cancer was verified only among the brothers, not among fathers. Although a statistically significant excess of breast cancer was not found, the increased point estimates in mothers, sisters and daughters are consistent with a co-aggregation hypothesis. Rather surprising was the finding of a seven-fold increased risk of prostate cancer and a three-fold increased risk of breast cancer among siblings in the presence of a maternal history of any cancer. Larger family history studies including high risk (African-Americans) and lower-risk groups (Hispanics) and incorporating molecular genetic evaluations should be conducted to determine if genetic differences play a role in the differential incidence rates across ethnic groups. ^

Rabies control in the developing world: Results of a cross-sectional study in Bohol, Philippines

Rabies remains a significant problem in much of the developed world, where canine rabies is not well controlled, and the bite of an infected dog is the most common means of transmission. The Philippines continues to report several hundred cases of human rabies every year, and many more cases go undetected. In recent years, the province of Bohol has been targeted by the Philippine government and the World Health Organization for a rabies eradication program. ^ The primary objective of this dissertation research was to describe factors associated with dog vaccination coverage and knowledge, attitudes, and practices regarding rabies among households in Bohol, Philippines. Utilizing a cross-sectional cluster survey design, we sampled 460 households and 541 dogs residing within dog-owning households. ^ Multivariate linear regression was used to examine potential associations between knowledge, attitudes, and practices (KAPs) and variables of interest. Forty-six percent of households knew that rabies was spread through the bite of an infected dog. The mean knowledge score was 8.36 (SD: ± 3.4; range: 1–24). We found that having known someone with rabies was significantly associated with an almost one point increase in the knowledge score (β = 0.88; p = 0.02). The mean attitudes score was 5.65 (SD: ± 0.63; range: 2–6), and the mean practices score was 7.07 (SD: ± 1.7; range: 2–9). Both the attitudes score and the practices score were positively and significantly associated with only the knowledge score and no other covariates. ^ Multivariate logistic regression was used to examine associations between dog vaccination coverage and variables of interest. Approximately 71% of owned dogs in Bohol were reported as vaccinated at some time during their lives. We found that a dog's age was significantly associated with vaccination, and the odds of vaccination increased in a linear fashion with age. We also found that dogs had approximately twice the odds of being vaccinated if they were confined both day and night to the household premises or if the owner was employed; however, these results were only marginally significant (p = 0.07) in the multivariate model. ^ Finally, a systematic review was conducted on canine rabies vaccination and dog population demographics in the developing world. We found few studies on this topic, especially in countries where the burden of rabies is greatest. Overall, dog ownership is high. Dogs are quite young and do not live very long due to disease and accidents. The biggest deterrent to vaccination is the rapid dog population turnover. ^ It is our hope that this work will be used to improve dog rabies vaccination programs around the world and save lives, both human and canine.^

INTERACTION OF BACILLUS ANTHRACIS EXOSPORIUM PROTEIN BCLA WITH COMPLEMENT FACTOR H AND SPORE PERSISTENCE IN THE LUNG

Anthrax outbreaks in the United States and Europe and its potential use as a bioweapon have made Bacillus anthracis an interest of study. Anthrax infections are caused by the entry of B. anthracis spores into the host via the respiratory system, the gastrointestinal tract, cuts or wounds in the skin, and injection. Among these four forms, inhalational anthrax has the highest lethality rate and persistence of spores in the lungs of animals following pulmonary exposure has been noted for decades. However, details or mechanisms of spore persistence were not known. In this study, we investigated spore persistence in a mouse model. The results suggest that B. anthracis spores have special properties that promote persistence in the lung, and that there may be multiple mechanisms contributing to spore persistence. Moreover, recent discoveries from our laboratory suggest that spores evolved a sophisticated mechanism to interact with the host complement system. The complement system is a crucial part of the host defense mechanism against foreign microorganisms. Knowledge of the specific interactions that occur between the complement system and B. anthracis was limited. Studies performed in our laboratory have suggested that spores of B. anthracis can target specific proteins, such as Factor H (fH) of the complement system. Spores of B. anthracis are enclosed by an exosporium, which consists of a basal layer surrounded by a nap of hair-like filaments. The major structural component of the filaments is called Bacillus collagen-like protein of anthracis (BclA), which comprises a central collagen-like region and a globular C-terminal domain. BclA is the first point of contact with the innate system of an infected host. In this study, we investigated the molecular details of BclA-fH interaction with respect to the specific binding mechanism and the functional significance of this interaction in a murine model of anthrax infection. We hypothesized that the recruitment of fH to the spore surface by BclA limits the extent of complement activation and promotes pathogen survival and persistence in the infected host. Findings from this study are significant to understanding how to treat post-exposure prophylaxis and improve our knowledge of spores with the host immune system.

Improving disclosure of medical errors: Including patients and family members in the disclosure process

Over the last decade, adverse events and medical errors have become a main focus of interest for the standards of quality and safety in the U.S. healthcare system (Weinstein & Henderson, 2009). Particularly when a medical error occurs, the disclosure of medical errors and its practices have become a focal point of the healthcare process. Patients and family members who have experienced a medical error might be able to provide knowledge and insight on how to improve the disclose process. However, patient and family member are not typically involved in the disclosure process, thus their experiences go unnoticed. ^ The purpose of this research was to explore how best to include patients and family members in the disclosure process regarding a medical error. The research consisted of 28 qualitative interviews from three stakeholder groups: Hospital Administrators, Clinical Service Providers, and Patients and Family Members. They were asked for their ideas and suggestions on how best to include patients and family members in the disclosure process. Framework Analysis was used to analyze this data and find prevalent themes based on the primary research question. A secondary aim was to index categories created based on the interviews that were collected. Data was used from the Texas Disclosure and Compensation Study with Dr. Eric Thomas as the Principal Investigator. Full acknowledgement of access to this data is given to Dr. Thomas. ^ The themes from the research revealed that each stakeholder group was interested and open to including patients and family members in the disclosure process and that the disclosure process should not be a "one-way" avenue. The themes gave many suggestions regarding how to best include patients and family members in the disclosure process of a medical error. Secondary aims revealed several ways to assess the ideas and suggestion given by the stakeholders. Overall, acceptability of getting the perspective of patients and family members was the most common theme. Comparison of each stakeholder group revealed that including patients and family members would be beneficial to improving hospital disclosure practices. ^ Conclusions included a list of recommendations and measureable appropriate strategies that could provide hospital with key stakeholders insights on how to improve their disclosure process. Sharing patients and family members experience with healthcare providers can encourage a shift in culture where patients are valued and active in participating in hospital practices. To my knowledge, this research is the very first of its kind and moves the disclosure process conversation forward in a patient-family member inclusion direction that will assist in improving disclosure practices. Future research should implement and evaluate the success of the various inclusion strategies.^