bluuebunny/crossref_metadata_2025 huggingface dataset:
Status- and Stigma-related Consequences of Military Service and PTSD
Authors: Hipes Crosby , Lucas Jeffrey W. , Kleykamp Meredith
Published: June 2014

This article describes an experimental study that investigates the status- and stigma-related consequences of military service and of experiences in war resulting in posttraumatic stress disorder (PTSD). In the study, participants interacted with fictitious partners whom they believed were real in four conditions: a control condition, a condition in which the “partner” was in the military, a condition in which the “partner” was a war veteran who had been deployed to Iraq or Afghanistan, and a condition in which the partner was a military veteran with PTSD who had been deployed. Results support predictions that military experience would advantage partners with respect to influence over participants, but that PTSD would be disadvantaging. Previous contact with veterans moderated this relationship, mitigating the loss of influence associated with PTSD. A prediction that PTSD would significantly increase social distance was not supported.
Multidimensional Item Response Model for Nominal Variables
Authors: Revuelta Javier
Published: June 2014

This article describes a multidimensional generalization of the nominal categories model that serves to estimate factorial models from nominal and ordinal observed responses, and includes a structural model for latent variables that distinguishes between endogenous and exogenous factors. The model includes a scale parameter for each response category in each factor. Item parameters relate the logit between categories to the vector of latent variables. The inferential framework is marginal maximum likelihood, implemented via static and adaptive Gauss–Hermite quadrature and Monte Carlo EM. The properties of estimators are investigated in a simulation study. An example with real data illustrates the utility of the model in analyzing local dependencies in testlets composed of multiple-choice items that are clustered in several groups around a common theme.
Impact of feedstock properties and operating conditions on sewage sludge gasification in a fixed bed gasifier
Authors: Werle Sebastian
Published: June 2014

This work presents results of experimental studies on the gasification process of granulated sewage sludge in a laboratory fixed bed gasifier. Nowadays, there is a large and pressing need for the development of thermal methods for sewage sludge disposal. Gasification is an example of thermal method that has several advantages over the traditional combustion. Gasification leads to a combustible gas, which can be used for the generation of useful forms of final energy. It can also be used in processes, such as the drying of sewage sludge directly in waste treatment plant. In the present work, the operating parameters were varied over a wide range. Parameters, such as air ratio λ = 0.12 to 0.27 and the temperature of air preheating t = 50 °C to 250 °C, were found to influence temperature distribution and syngas properties. The results indicate that the syngas heating value decreases with rising air ratio for all analysed cases: i.e. for both cold and preheated air. The increase in the concentration of the main combustible components was accompanied by a decrease in the concentration of carbon dioxide. Preheating of the gasification agent supports the endothermic gasification and increases hydrogen and carbon monoxide production.
Gaseous fuels production from dried sewage sludge via air gasification
Authors: Werle Sebastian , Dudziak Mariusz
Published: June 2014

Gasification is a perspective alternative method of dried sewage sludge thermal treatment. For the purpose of experimental investigations, a laboratory fixed-bed gasifier installation was designed and built. Two sewage sludge (SS) feedstocks, taken from two typical Polish wastewater treatment systems, were analysed: SS1, from a mechanical-biological wastewater treatment system with anaerobic stabilization (fermentation) and high temperature drying; and (SS2) from a mechanical-biological-chemical wastewater treatment system with fermentation and low temperature drying. The gasification results show that greater oxygen content in sewage sludge has a strong influence on the properties of the produced gas. Increasing the air flow caused a decrease in the heating value of the produced gas. Higher hydrogen content in the sewage sludge (from SS1) affected the produced gas composition, which was characterized by high concentrations of combustible components. In the case of the SS1 gasification, ash, charcoal, and tar were produced as byproducts. In the case of SS2 gasification, only ash and tar were produced. SS1 and solid byproducts from its gasification (ash and charcoal) were characterized by lower toxicity in comparison to SS2. However, in all analysed cases, tar samples were toxic.
Growth Hormone Deficiency in a Dopa-Responsive Dystonia Patient With a Novel Mutation of Guanosine Triphosphate Cyclohydrolase 1 Gene
Authors: Lin Yu , Wang Dan-Ni , Chen Wan-Jin , Lin Xiang , Lin Min-Ting , Wang Ning
Published: June 2014

Dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 ( GCH1) gene. This disease typically manifests in dystonia, with marked diurnal fluctuation and a dramatic response to levodopa. However, growth retardation in dopa-responsive dystonia has rarely been reported, and the etiology of short stature is not clarified. Here, we report a 14-year-old patient with extremities dystonia and short stature. Treatment with levodopa relieved his symptoms and resulted in a height increase. We also investigated the mutation in GCH1 and the etiology of short stature in this case. Sequence analysis of GCH1 revealed a novel mutation (c.695G>T). Laboratory examinations and imaging confirmed the diagnosis of growth hormone deficiency. We conclude that our case reveals a rare feature for dopa-responsive dystonia and suggests a possible pathogenic link between growth hormone deficiency and dopa-responsive dystonia. We recommend levodopa as the first choice for treating dopa-responsive dystonia in children with growth hormone deficiency.
Two Paths Diverged
Authors: Shumate Michelle , Atouba Yannick , Cooper Katherine R. , Pilny Andrew
Published: June 2014

This research examines the antecedents that motivate and prepare social entrepreneurs to begin social ventures. Drawing from in-depth interviews with 20 social entrepreneurs, this research reveals that there are two paths to social entrepreneurship: the activist path and the business path. Both activist and business social entrepreneurs were motivated by a family legacy or a transformative early adulthood experience as the moral basis for forming a social venture, and both suggested that prior work experience was instrumental in helping them launch their social venture. However, activist social entrepreneurs were likely to form their social venture as a continuation of their ongoing work on a social issue. In contrast, business social entrepreneurs’ first activity on a social issue was to form a social venture. This research suggests that these two different paths to social entrepreneurship result in different types of social ventures.
Fixed-Dose Rasburicase in Overweight and Obese Patients Versus Normal-Weight Patients
Authors: Clemmons Amber B. , Ensley Elizabeth , Hoge Stephanie , Clark Stephen
Published: June 2014

Background: Fixed-dose rasburicase (FDR) is common practice in treating hyperuricemia associated with tumor lysis syndrome in adults; however, there is a lack of data regarding the effectiveness of this dosing strategy specifically in the overweight and obese patient populations. Objective: To determine if patient weight per body mass index (BMI) category is associated with failure of initial FDR as defined by the need for additional dose(s) based on a uric acid level (UAL) ≥7.5 mg/dL within 10 days of previous rasburicase administration. Method: Adults who received FDR per institutional guidelines from October 2008 to August 2013 were reviewed. Patients had either a baseline UAL ≥7.5 mg/dL or were considered high risk (leukemia or lymphoma diagnosis with white blood cell count >50 000/mm3 or lactate dehydrogenase level greater than 2 times the upper limit of normal). Patients were stratified by BMI as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), or obese (30+). Result: Overall, 12 out of 151 patients who received FDR required a repeat dose of rasburicase. The percentage of patients requiring a repeat rasburicase dose was not different between obese/overweight versus normal/underweight patients (8.7% vs 6.4%, P = 0.75). Similarly, there was no difference between obese alone versus normal/underweight patients (12.3% vs 6.4%; P = 0.51). Conclusion: In this retrospective analysis, patient BMI did not correlate with failure of FDR in adults, suggesting that this dosing strategy is efficacious in the adult population.
It’s all about the six-pack
Authors: Drummond Murray , Drummond Claire
Published: June 2014

This is an article about boys and their construction of masculinities. It draws on 5 years of qualitative research data from the same group of boys from early childhood through to 10 years of age in an attempt to articulate the way in which boys come to view their bodies, and other male bodies, in contemporary Western culture. The research is based on focus groups and is a part of a longitudinal study with the same cohort of boys, at a school in Adelaide, Australia. The data were analysed using inductive thematic analysis to identify key emergent themes. The results indicate that there is an emerging trend among boys from early childhood through to middle primary school surrounding the acknowledgement of male body aesthetics as a signifier of being male. The use of terminology such as ‘six-pack’ is now commonplace among all of the groups. The consistency around muscularity as a signifier of being a man was very high among the boys of all ages. It is clear that greater emphasis needs to be placed on younger males’ and boys’ awareness of the meaning of the male body in contemporary Western society.
Trends in referred patient profiles in a memory clinic over 20 years
Authors: Azam Bushra , Whitfield Tim J , Radford Darren , Dontham Santhosh G , Stevens Tim , Dannhauser Thomas , Walker Zuzana
Published: June 2014

The increasing numbers of people with dementia in the UK, as well as the associated costs have led to an effort to improve dementia services for the benefit of patients, caregivers and the taxpayer. These efforts have frequently emphasised the importance of early diagnosis in dementia care. We sought to test the hypotheses that the mean cognitive score of new referrals to a secondary care memory assessment service increased while mean age decreased over a period of 20 years. We retrospectively analysed the data of 1476 patients. The passage of time was associated with a significant increase in mean cognitive scores, while there was no association between time and age after controlling for other factors. We suggest that memory services need to be designed to meet the needs of less cognitively impaired patients. In practice this means that using simple screening tests is not sufficient in this group of patients.
Solving the puzzle of Parkinson’s disease using induced pluripotent stem cells
Authors: Zhao Ping , Luo Zhiwei , Tian Weihua , Yang Jiayin , Ibáñez David P , Huang Zhijian , Tortorella Micky D , Esteban Miguel A , Fan Wenxia
Published: June 2014

The prevalence and incidence of Parkinson’s disease (PD) is increasing due to a prolonged life expectancy. This highlights the need for a better mechanistic understanding and new therapeutic approaches. However, traditional in vitro and in vivo experimental models to study PD are suboptimal, thus hampering the progress in the field. The epigenetic reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) offers a unique way to overcome this problem, as these cells share many properties of embryonic stem cells (ESCs) including the potential to be transformed into different lineages. PD modeling with iPSCs is nowadays facilitated by the growing availability of high-efficiency neural-specific differentiation protocols and the possibility to correct or induce mutations as well as creating marker cell lines using designer nucleases. These technologies, together with steady advances in human genetics, will likely introduce profound changes in the way we interpret PD and develop new treatments. Here, we summarize the different PD iPSCs reported so far and discuss the challenges for disease modeling using these cell lines.
Dynamics of cocaine- and amphetamine-regulated transcript containing cell changes in the adrenal glands of two kidney, one clip rats
Authors: Kasacka Irena , Piotrowska Zaneta , Janiuk Izabela , Zbucki Robert
Published: June 2014

Taking into consideration the homeostatic disorders resulting from renal hypertension and the essential role of cocaine- and amphetamine-regulated transcript (CART) in maintaining homeostasis by regulating many functions of the body, the question arises as to what extent the renovascular hypertension affects the morphology and dynamics of changes of CART-containing cells in the adrenal glands. The aim of the present study was to examine the distribution, morphology, and dynamics of changes of CART-containing cells in the adrenal glands of “two kidney, one clip” (2K1C) renovascular hypertension model in rats. The studies were carried out on the adrenal glands of rats after 3, 14, 28, 42, and 91 days from the renal artery clipping procedure. To identify neuroendocrine cells, immunohistochemical reaction was performed with the use of a specific antibody against CART. It was revealed that renovascular hypertension causes changes in the endocrine cells containing CART in the adrenal glands of rats. The changes observed in the endocrine cells depend on the time when the rats with experimentally induced hypertension were examined. In the first period of hypertension, the number and immunoreactivity of CART-containing cells were decreased, while from the 28-day test, it significantly increased, as compared to the control rats. CART is relevant to the regulation of homeostasis in the cardiovascular system and seems to be involved in renovascular hypertension. The results of the present work open the possibility of new therapeutic perspectives for the treatment of arterial hypertension, since CART function is involved in their pathophysiology.
Health Benefits of Exercise for People Living With HIV
Authors: Jaggers Jason R. , Hand Gregory A.
Published: June 2014

With life expectancy increasing and the symptomatology of HIV being altered since the advent of antiretroviral therapy (ART), we now have begun to see metabolic changes with negative implications among people living with HIV/AIDS (PLWHA). Some of these changes include increased blood lipids, central fat accumulation, lipodystrophy, and decreased aerobic capacity. All of which are known risk factors for cardiovascular disease, cancer, and all-cause mortality. A common practice among healthy and other clinical populations to help modify these risk factors is some form of aerobic exercise, resistance exercise, or a combination of both. It has been demonstrated that PLWHA could respond in a similar manner, which in turn may enhance life expectancy and/or quality of life. The purpose of this literature review was to examine the evidence of health benefits of routine exercise training among PLWHA since the advent of ART. Although limited in strength because of small sample sizes and limited intervention durations, there is overall consistency in the general findings. An overview of the findings would indicate that physical activity and exercise are both safe and effective in improving cardiorespiratory fitness, metabolic profile, and quality of life among PLWHA.
Implementing research in professional higher education
Authors: Griffioen Didi ME , de Jong Uulkje
Published: June 2014

Higher professional education in Europe has changed from teaching-only institutes to hybrids of teaching and research. The purpose of this study was to examine factors that influence the judgements of lecturers about new organisational goals and perceptions of their new research-related competencies. Lecturers’ judgements of new organisational goals and self-efficacy related to newly expected competencies were modelled in a bio-ecological model. Findings show that lecturers’ perceptions of self-efficacy can be influenced by an open organisational culture, while lecturers’ judgements of new organisational goals can be influenced by decision-making systems. The professional development of lecturers through formal education and participation in research influences both self-efficacy and judgements. Hence, direct executive managers have three steering mechanisms by which they can influence lecturers’ perceptions during the implementation of new organisational activities: a) Educational Policy, b) Management Policy and c) Developmental Policy. Implications are discussed.
Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide
Authors: Yu Siegfried W.B. , Rao Satish S.C.
Published: June 2014

Constipation-predominant irritable bowel syndrome (IBS-C) is a commonly prevalent and clinically challenging disorder to treat. Until recently, most therapeutic agents had limited ability to address the complexity of symptoms inherent to the syndrome. The development of linaclotide provides a physiologically sound approach to treatment of the multiple symptoms of IBS-C. Clinical trials demonstrate the efficacy of linaclotide, and a platform to better understand the symptomatology of IBS-C. Based on recent clinical evidence, linaclotide should be considered for patients with IBS-C because it improves abdominal pain and bowel symptoms. In phase III trials, linaclotide met the US Food and Drug Administration responder endpoint with a number needed to treat (NNT) of 5.1–7.9, and European Medicines Agency coprimary endpoints at 12 weeks with a NNT of 4.39–7.69, and at 26 weeks with a NNT of 4.93–5.68. It is safe and effective, with diarrhea reported as the most common adverse effect, which leads to discontinuation of the medication in approximately 5% of patients.
FDA-Approved Biosimilar Insulin
Authors: Carter Alan W.
Published: June 2014

If a biosimilar insulin is discovered postmarketing to be subpotent, superpotent, or contaminated or the contents mislabeled, it is an adulterated product and must be quarantined for removal including from a patient’s home. Adulterated products could be considered “counterfeit” since they do not meet the original standards established by the FDA. The FDA must establish a method of regularly assaying samples of biosimilar insulin drawn directly from the supply pipeline to help ensure patient safety and evaluate clinical performance. Independent groups without conflict of interest would perform confidential comparison assay. For less than 5 cents per vial/pen, manufacturers could easily support an independent, FDA-recognized, random sample program and create a functional postmarket surveillance system that better protects the public and the manufacturer from undesired outcomes.
Comparison of Danish dichotomous and BI-RADS classifications of mammographic density
Authors: Hodge Rebecca , Hellmann Sophie Sell , Euler-Chelpin My von , Vejborg Ilse , Andersen Zorana Jovanovic
Published: June 2014

Background

In the Copenhagen mammography screening program from 1991 to 2001, mammographic density was classified either as fatty or mixed/dense. This dichotomous mammographic density classification system is unique internationally, and has not been validated before.

Purpose

To compare the Danish dichotomous mammographic density classification system from 1991 to 2001 with the density BI-RADS classifications, in an attempt to validate the Danish classification system.

Material and Methods

The study sample consisted of 120 mammograms taken in Copenhagen in 1991–2001, which tested false positive, and which were in 2012 re-assessed and classified according to the BI-RADS classification system. We calculated inter-rater agreement between the Danish dichotomous mammographic classification as fatty or mixed/dense and the four-level BI-RADS classification by the linear weighted Kappa statistic.

Results

Of the 120 women, 32 (26.7%) were classified as having fatty and 88 (73.3%) as mixed/dense mammographic density, according to Danish dichotomous classification. According to BI-RADS density classification, 12 (10.0%) women were classified as having predominantly fatty (BI-RADS code 1), 46 (38.3%) as having scattered fibroglandular (BI-RADS code 2), 57 (47.5%) as having heterogeneously dense (BI-RADS 3), and five (4.2%) as having extremely dense (BI-RADS code 4) mammographic density. The inter-rater variability assessed by weighted kappa statistic showed a substantial agreement (0.75).

Conclusion

The dichotomous mammographic density classification system utilized in early years of Copenhagen’s mammographic screening program (1991–2001) agreed well with the BI-RADS density classification system.
Delhi’s Meatscapes: Cultural Politics of Meat in a Globalizing City
Authors: Ahmad Zarin
Published: June 2014

This article is located at the intersection of two distinct entry points—one, the development of Delhi as a global or world class city and two, the contested social location of meat in the city. Delhi is developing and is being projected as a world-class city with all the trappings of globalization which includes among other things state of art infrastructure, technologies, services and experiences. This development discourse is indeed a contested one and it is well-argued that urban transformations are beset with its own baggage of contradictions often resulting in marginalizing segments of its population. This article analyzes the construction of urban margins in contemporary globalizing Delhi through the lens of meat. Historical evidence shows that meat has been considered marginal to city spaces politically, spatially and socially. However, in the last two decades, the consumption, production, presentation and packaging of meat in India are in the throes of critical changes: in terms of technologies, geographies and actors. However, meat as a site is still beset with many tensions and contradictions which are located at the juncture between old and new forms of margin-making. Based on social and political contradictions regarding meat in India and specifically focusing on legal contestations and local activism around the relocation of the abattoir in Delhi, I argue that meat is a site around which margins are construed, transmitted and contested. Drawing from Appadurai, the article uses the concept of ‘meatscapes’ as a conceptual and linguistic tool to unravel the entangled reality of meat in Delhi.
Flowback or the End of Globalization
Authors: Smith Paul
Published: June 2014

The processes of globalization have often been described by way of the metaphor of ‘flows’—flows of people, goods, capital or ideas. Since the recent worldwide economic recession the nature, direction and vectors of those flows have altered, such that it is time to talk about ‘flowback’ or even the end of globalization. Looking at flows of people and capital in particular, the article proposes that the changes brought about by the recession were always immanent in the processes of globalization itself and that the recession is best seen as a crisis of globalization. Even if a recovery is underway, the processes of globalization will have been altered forever.
The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation
Authors: Taur Ying , Jenq Robert R. , Perales Miguel-Angel , Littmann Eric R. , Morjaria Sejal , Ling Lilan , No Daniel , Gobourne Asia , Viale Agnes , Dahi Parastoo B. , Ponce Doris M. , Barker Juliet N. , Giralt Sergio , van den Brink Marcel , Pamer Eric G.
Published: June 2014

Key Points

Intestinal diversity is predictive of mortality in allo-HSCT.
Outcome prediction in plasmacytoma of bone: a risk model utilizing bone marrow flow cytometry and light-chain analysis
Authors: Hill Quentin A. , Rawstron Andy C. , de Tute Ruth M. , Owen Roger G.
Published: June 2014

Key Points

Occult marrow disease is demonstrable in 68% of patients with solitary plasmacytoma of bone and is predictive of progression. Trials of adjuvant systemic therapy are warranted in high-risk patients.
Quality of cardiovascular disease care in Ontario’s primary care practices: a cross sectional study examining differences in guideline adherence by patient sex
Authors: Naicker Kiyuri , Liddy Clare , Singh Jatinderpreet , Taljaard Monica , Hogg William
Published: June 2014

Background

Women are disproportionately affected by cardiovascular disease, often experiencing poorer outcomes following a cardiovascular event. Evidence points to inequities in processes of care as a potential contributing factor. This study sought to determine whether any sex differences exist in adherence to process of care guidelines for cardiovascular disease within primary care practices in Ontario, Canada.

Methods

This is a secondary analysis of pooled cross-sectional baseline data collected through a larger quality improvement initiative known as the Improved Delivery of Cardiovascular Care (IDOCC). Chart abstraction was performed for 4,931 patients from 84 primary care practices in Eastern Ontario who had, or were at high risk of, cardiovascular disease. Measures examining adherence to guidelines associated with nine areas of cardiovascular care (coronary artery disease, peripheral vascular disease (PVD), stroke/transient ischemic attack, chronic kidney disease, diabetes, dyslipidemia, hypertension, smoking cessation, and weight management) were collected. Multivariable logistic regression analysis was performed to evaluate sex differences, adjusting for age, physician remuneration, and rurality.

Results

Women were significantly less likely to have their lipid profiles taken (OR = 1.17, 95% CI 1.03-1.33), be prescribed lipid lowering medication for dyslipidemia (OR = 1.54, 95% CI 1.20-1.97), and to be prescribed ASA following stroke (OR = 1.56, 95% CI 1.39-1.75). Women with PVD were significantly less likely to be prescribed ACE inhibitors and/or angiotensin receptor blockers (OR = 1.74, 95% CI 1.25-2.41) and lipid lowering medications (OR = 1.95, 95% CI 1.46-2.62) or ASA (OR = 1.59, 95% CI 1.43-1.78). However, women were more likely to have two blood pressure measurements taken and to be referred to a dietician or weight loss program. Male patients with diabetes were less likely to be prescribed glycemic control medication (OR = 0.84, 95% CI 0.74-0.86).

Conclusions

Sex disparities exist in the quality of cardiovascular care in Canadian primary care practices, which tend to favour men. Women with PVD have a particularly high risk of not receiving appropriate medications. Our findings indicate that improvements in care delivery should be made to address these issues, particularly with regard to the prescribing of recommended medications for women, and preventive measures for men.
Whole genome sequencing reveals potential targets for therapy in patients with refractory KRASmutated metastatic colorectal cancer
Authors: Shanmugam Vijayalakshmi , Ramanathan Ramesh K , Lavender Nicole A , Sinari Shripad , Chadha Manpreet , Liang Winnie S , Kurdoglu Ahmet , Izatt Tyler , Christoforides Alexis , Benson Hollie , Phillips Lori , Baker Angela , Murray Christopher , Hostetter Galen , Von Hoff Daniel D , Craig David W , Carpten John D
Published: June 2014

Background

The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy is poor, with median survival of less than one year. The purpose of this study was to identify candidate therapeutically targetable somatic events in mCRC patient samples by whole genome sequencing (WGS), so as to obtain targeted treatment strategies for individual patients.

Methods

Four patients were recruited, all of whom had received > 2 prior therapy regimens. Percutaneous needle biopsies of metastases were performed with whole blood collection for the extraction of constitutional DNA. One tumor was not included in this study as the quality of tumor tissue was not sufficient for further analysis. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing systems, which yielded coverage of greater than 30X for all samples. NGS data were processed and analyzed to detect somatic genomic alterations including point mutations, indels, copy number alterations, translocations and rearrangements.

Results

All 3 tumor samples had KRAS mutations, while 2 tumors contained mutations in the APC gene and the PIK3CA gene. Although we did not identify a TCF7L2-VTI1A translocation, we did detect a TCF7L2 mutation in one tumor. Among the other interesting mutated genes was INPPL1, an important gene involved in PI3 kinase signaling. Functional studies demonstrated that inhibition of INPPL1 reduced growth of CRC cells, suggesting that INPPL1 may promote growth in CRC.

Conclusions

Our study further supports potential molecularly defined therapeutic contexts that might provide insights into treatment strategies for refractory mCRC. New insights into the role of INPPL1 in colon tumor cell growth have also been identified. Continued development of appropriate targeted agents towards specific events may be warranted to help improve outcomes in CRC.
In Silicotarget fishing: addressing a “Big Data” problem by ligand-based similarity rankings with data fusion
Authors: Liu Xian , Xu Yuan , Li Shanshan , Wang Yulan , Peng Jianlong , Luo Cheng , Luo Xiaomin , Zheng Mingyue , Chen Kaixian , Jiang Hualiang
Published: June 2014

Background

Ligand-based in silico target fishing can be used to identify the potential interacting target of bioactive ligands, which is useful for understanding the polypharmacology and safety profile of existing drugs. The underlying principle of the approach is that known bioactive ligands can be used as reference to predict the targets for a new compound.

Results

We tested a pipeline enabling large-scale target fishing and drug repositioning, based on simple fingerprint similarity rankings with data fusion. A large library containing 533 drug relevant targets with 179,807 active ligands was compiled, where each target was defined by its ligand set. For a given query molecule, its target profile is generated by similarity searching against the ligand sets assigned to each target, for which individual searches utilizing multiple reference structures are then fused into a single ranking list representing the potential target interaction profile of the query compound. The proposed approach was validated by 10-fold cross validation and two external tests using data from DrugBank and Therapeutic Target Database (TTD). The use of the approach was further demonstrated with some examples concerning the drug repositioning and drug side-effects prediction. The promising results suggest that the proposed method is useful for not only finding promiscuous drugs for their new usages, but also predicting some important toxic liabilities.

Conclusions

With the rapid increasing volume and diversity of data concerning drug related targets and their ligands, the simple ligand-based target fishing approach would play an important role in assisting future drug design and discovery.
The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study
Authors: Ljung Lotta , Askling Johan , Rantapää-Dahlqvist Solbritt , Jacobsson Lennart ,   for the ARTIS Study Group
Published: June 2014

Introduction

The elevated risk of ischaemic heart disease in patients with rheumatoid arthritis (RA) has been linked to inflammation and disease severity. Treatment with tumour necrosis factor inhibitors (TNFis) is often effective in reducing disease activity and could possibly modify cardiovascular risk. Our objective in the study was to evaluate the risk of acute coronary syndrome (ACS) in patients with RA treated with TNFis compared with the risk among biologic-naïve RA patients and the general population.

Methods

By linkage of the Swedish National Patient Register and the Swedish Biologics Register, we identified a cohort of patients who were started on their first biologic, a TNFi, between 2001 and 2010 (N = 7,704), and a cohort comprising matched biologic-naïve RA patient referents at a 3:1 ratio. Furthermore, a matched comparator cohort (5:1 ratio) was extracted from the Swedish population register. The incidence rates of a first ACS event were calculated and compared between cohorts using Cox proportional hazards regression in three different risk windows: ‘ever-exposed’, ‘actively on TNFi’ and ‘short-term exposure’ (active treatment maximized to 2 years). The models were adjusted for disease duration, joint surgery, comorbidity and socioeconomic factors, and, in a sensitivity analysis including a subpopulation started on therapy beginning 1 January 2006 or later, for dispensed drugs.

Results

Based on 221 events in 7,704 patients (comprising 32,621 person-years) treated with TNFi biologics, the hazard ratio ((HR); ever-exposed) for ACS among the TNFi-exposed RA patients compared with biologic-naïve RA patients was 0.8 (95% confidence interval (CI) = 0.7 to 0.95). In comparison with the general population referents, statistical analysis using fully adjusted models resulted in a HR of 2.0 (95% CI = 1.8 to 2.3) for biologic-naïve RA patients and a HR of 1.6 (95% CI = 1.4 to 1.9) for the TNFi-exposed group. Similar risk estimates were obtained using the other two risk windows. A sensitivity analysis in which we compared the TNFi-exposed patients included from 1 January 2006 onward with biologic-naïve patients resulted in a HR (ever-exposed) of 0.7 (95% CI = 0.5 to 1.0).

Conclusions

RA patients treated with TNFi had a lower risk of ACS compared with biologic-naïve RA patients. Compared with the general population, the risk among patients with RA was elevated, although the difference was less pronounced among the TNFi-exposed patients. This finding could be attributable to the TNFi as such, or it could correspond to a lower degree of inflammation in the TNFi-treated group.
Credibly reaching a reliability target using a model initially constructed by expert elicitation
Authors: Pado Lawrence E
Published: June 2014

The Defense Advanced Research Projects Agency Defense Science Office (DARPA/DSO) is sponsoring Open Manufacturing (OM), an initiative to develop new technologies, new computational tools, and rapid qualification to accelerate the manufacturing innovation timeline. Certification Methodology to Transition Innovation (CMTI), an OM program, has developed a methodology to quantify the effect of manufacturing variability on product performance to address the risk to cost and performance associated with failure to take manufacturing capability and material and fabrication/assembly variation into account early in the design process. An important aspect of this program is the use of Bayesian networks (BN) to evaluate risk. The BN is used as a graphical representation of the contributing factors that lead to manufacturing defects. The reliability of the final product is then analyzed using the contributing factors. There are many types of programs where there is little relevant data to support the probabilities needed to populate the BN model. This is very likely the case for new programs or at the end of long programs when obsolescence challenges servicing a product when original vendors are no longer in business. In these cases, probabilities must be obtained from expert opinion using a technique called expert elicitation. Even under objective ‘Good Faith’ opinions, the expert himself has a lot of uncertainty in that opinion. This paper details an approach to obtaining credible model output based on the idea of having a hypothetical expert whose unconscious bias influences the model output and discovering and using countermeasures to find and prevent these biases. Countermeasures include replacing point probabilities with beta distributions to incorporate uncertainty, 95% confidence levels, and using a multitude of different types of sensitivity analyses to draw attention to potential trouble spots. Finally, this paper uses a new technique named ‘confidence level shifting’ to optimally reduce epistemic uncertainty in the model. Taken together, the set of tools described in this paper will allow an engineer to cost effectively determine which areas of the manufacturing process are most responsible for performance variance and to determine the most effective approach to reducing that variance in order to reach a target reliability.
Stoichiometry of scaffold complexes in living neurons - DLC2 as a dimerization engine for GKAP
Authors: Moutin Enora , Compan Vincent , Raynaud Fabrice , Clerté Caroline , Bouquier Nathalie , Labesse Gilles , Ferguson Matthew L. , Fagni Laurent , Royer Catherine A. , Perroy Julie
Published: June 2014

Quantitative spatio-temporal characterization of protein interactions in living cells remains a major challenge facing modern biology. We have investigated in living neurons the spatial dependence of the stoichiometry of interactions between two core proteins of the NMDA receptor-associated scaffolding complex, GKAP and DLC2, using a novel variation of Fluorescence Fluctuation Microscopy called two-photon scanning Number and Brightness (sN&B). We found that dimerization of DLC2 was required for its interaction with GKAP, which in turn potentiated GKAP self-association. In dendritic shaft, the DLC2-GKAP hetero-oligomeric complexes were composed mainly of 2 DLC2 and 2 GKAP monomers, while in spines, the hetero-complexes were much larger, with an average of ∼16 DLC2 and ∼13 GKAP. Disruption of the GKAP-DLC2 interaction strongly destabilized the oligomers, decreasing the spine-preferential localization of GKAP and inhibiting NMDA receptor activity. Hence, DLC2 serves a hub function in the control of glutamatergic transmission via ordering of GKAP-containing complexes in dendritic spines. Beyond illuminating the role of DLC2–GKAP interactions in glutamergic signalling, these data underscore the power of the sN&B approach for quantitative spatio-temporal imaging of other important protein complexes.
The Changing Role of Government in Financing Health Care: An International Perspective
Authors: Stabile Mark , Thomson Sarah
Published: June 2014

This paper explores the changing role of government involvement in health care financing policy outside the United States. It provides a review of the economics literature in this area to elucidate the implications of recent policy changes on efficiency, costs, and quality. Our review reveals that there has been some convergence in policies adopted across countries to improve financing incentives and encourage efficient use of health services. In the case of risk pooling, all countries with competing pools experience similar difficulties with selection and are adopting more sophisticated forms of risk adjustment. In the case of hospital competition, the key drivers of success appear to be what is competed on and measurable, rather than whether the system is public or private. In the case of both the success of performance-related pay for providers and issues resulting from wait times, evidence differs within and across jurisdictions. However, the evidence does suggest that some governments have effectively reduced wait times when they have chosen explicitly to focus on achieving this goal. Many countries are exploring new ways of generating revenues for health care to enable them to cope with significant cost growth, but there is little evidence to suggest that collection mechanisms alone are effective in managing the cost or quality of care. (JEL H51, I11, I18)
Modelling The Fire Performance of Structural Timber-Concrete Composite Floors
Authors: O'Neill James , Abu Anthony , Carradine David , Moss Peter , Buchanan Andrew
Published: June 2014

This paper describes numerical modelling to predict the fire resistance of engineered timber-concrete composite floor systems. The paper describes 3D numerical modelling of the floor systems using finite element software, carried out as a sequential thermo-mechanical analysis. Experimental testing of these floor assemblies has also been undertaken to validate the models, with multiple full scale tests conducted to determine the failure mechanisms and assess fire damage to the system components. The final outcome of this research is the development of simplified design methods for calculating the fire resistance of a wide range of engineered timber floor systems, as part of a larger research project on multi-storey timber buildings.
Limitations in Simulation of Building Pounding in Earthquakes
Authors: Khatiwada Sushil , Chouw Nawawi
Published: June 2014

Several methods have been proposed for the analysis of building pounding. In previous studies some of these models have been considered in isolation, while others have been studied as a specific configuration of buildings. Although the pounding force predicted by each model varies significantly, results from the evaluation of these models have been inconclusive. This leads to uncertainties in the practical applications of pounding force models. This study addresses the limitations in numerical and experimental simulations of building pounding. The Sears impact model is suggested to overcome some of these limitations. It is concluded that contact stiffness and coefficient of restitution are the main reason for the diverse numerical results, while differences observed in the experiments could be due to sampling rate and instrumental constraints.
Evaluation of the Effect of Sand Pack Coverings on Rockfall Protection Fences Using Numerical Approach
Authors: Ho Tam Sy , Masuya Hiroshi , Nishita Youichi
Published: June 2014

Flexible fences have been used widely for protection against rockfall impact and have garnered considerable attention from engineers and researchers due to their effectiveness and adaptability to various types of topography and impact energy magnitude. Generally, friction braking devices are widely used for absorbing impact energy and external support cables are added to enhance structure stability. The utilization of sand packs as impact absorbing components in the fence structure is considered a new and rational idea. This research was conducted to gain better understanding of the structural behavior of a fence without any braking device or external support cable, and the absorption performance of sand pack to cushion rockfall impact. The fence studied in this research consist of three spans of cable net covered by 14 sand packs, and was subjected to impact load by a vertical free fall of weight. The sand packs covering the fence were considered for a numerical study using the finite element method of LS-DYNA to simulate the behavior of the complete fence structure, including the sand pack cushion. The numerical model was adequately validated through a comparison between the results of the model analysis and those of the fundamental experiment. The examination and discussion of the structural dynamic behavior of fences by applying the validated model clearly revealed the effects of the sand pack and impact energy magnitudes on the structural characteristics of the fence. These effects led to the revelation that the absorption performance of the sand pack coverings to absorb the impact and redistribute its load are expected to result in the practical application of sand packs as absorbing elements in rockfall protection fences.
A Study on the Effectiveness of Energy Absorbing Rubber in Pin-Fixed Cable Restrainer of a Bridge
Authors: Tamai Hiroki , Uno Mariko , Yuki Yoichi , Sonoda Yoshimi , Kasugai Toshihiro
Published: June 2014

The Japanese specifications for highway bridges require unseating prevention devices to be installed on bridges as necessary. Recently, a new type of cable restrainer was developed where the assembly allows the cable to rotate without restriction on the brackets' mounting angle. Cylindrical rubber pieces are inserted around pins to absorb impact forces. However, no standard design method has been established for the shock absorbers so far. This paper presents the impact-resisting characteristics of a pin-fixed cable device; design indications for shock absorbers were acquired based on the results of impact tests on bracket models of actual restrainers. The results showed that the pin-fixed restrainers had sufficient impact resistance for all tested sizes and that the maximum impact load showed consistent trends. Finite element analysis was also performed on the device assuming hyper-elastic bodies for rubber pieces. The numerical results sufficiently represented the impact response trend obtained from the experimental results.
Study on Steel Railings Installed on Concave- and Convex-Curved Bridge Parapet
Authors: Itoh Yoshito , Thanh Le
Published: June 2014

This paper reports performance results for steel bridge railings installed on concave- and convex-curved bridge parapet based on new-type posts. Preliminary experimental tests are first conducted to examine the behaviours of these posts when subjected to a collision from a heavy steel ball. The values thus verified are then fed into the LS-DYNA 3D analysis tool to generate improved simulations for the performances of new-type curved steel railings subjected to truck collisions. For some concave road curvatures, it is found that the impact angles between the vehicle and the railings are larger than assumed in the current Japanese specifications. Some researchers and engineers suspect that a curved railing is less effective than a straight one in the same collision conditions. The purposes of this study, in addition to contributing to the further improvement of curved steel railings, are accordingly to test the validity of the said suspicion, and to investigate the performances of these new-type concave-curved steel railings under larger collision impact angles. The performance results for concave- and convex-curved railings are compared against each other as well as with the results for straight railings.
Case Report: A case of hypertrophic lupus erythematosus with negative CD123 staining and absence of transepidermal elimination of elastin
Authors: Hughes Matthew , Gardner Jerad M. , Gao Ling
Published: June 2014

We report the case of a 49-year-old male with clinical and histological findings consistent with hypertrophic lupus erythematosus (HLE). HLE must be clinically and histologically differentiated from keratoacanthoma, hypertrophic lichen planus, squamous cell carcinoma and plaque type psoriasis. CD123 positivity and transepidermal elimination of elastin have recently been reported as tools to distinguish HLE. Interestingly, in this case, biopsies of two separate lesions failed to reveal these two features. The etiology of this discrepancy is unknown and further studies are needed to clarify the utility of CD123 positivity and transepidermal elimination of elastin in the diagnosis of hypertrophic lupus erythematosus.