bluuebunny/crossref_metadata_2025 huggingface dataset:
Monotonic and Cyclic Deformation Behavior of MIG‐CMT Welded and Heat‐Treated Joints of Aluminum Cast and Wrought Alloys
Authors: Kantehm Matthias , Söker Marcus , Krupp Ulrich , Michels Wilhelm
Published: July 2012

While the fatigue behavior of die cast aluminum as well as welded aluminum wrought alloys have been subject of several studies, no systematic work has been carried out on hybrid structures made as a combination of welded sand castings and wrought alloys. Aim of the present study is to correlate the monotonic and cyclic deformation behavior of thin sheet welded joints with the microstructure in the heat affected zone of the material combination sand cast EN AC‐Al Si7Mg0.3 and wrought alloy EN AW‐Al Si1MgMn (EN AW‐6082). The metal sheets were welded using a metal inert gas cold metal transfer process under variation of the welding gap, the heat treatment parameters, as well as the surface finishes. It was demonstrated by Wöhler diagrams based on bending fatigue tests that the fatigue life could be increased for the welded and heat treated specimens as compared to the as‐received cast specimens. By means of optical microscopy this effect was attributed to microstructural changes due to the optimized welding and heat treatment process. A detailed analysis of the mechanical tests was possible by the application of an optical 3D strain analysis.
CdTe Quantum Dots/Layered Double Hydroxide Ultrathin Films with Multicolor Light Emission via Layer‐by‐Layer Assembly
Authors: Liang Ruizheng , Xu Simin , Yan Dongpeng , Shi Wenying , Tian Rui , Yan Hong , Wei Min , Evans David G. , Duan Xue
Published: July 2012

Quantum dots (QDs) luminescent films have broad applications in optoelectronics, solid‐state light‐emitting diodes (LEDs), and optical devices. This work reports the fabrication of multicolor‐light‐emitting ultrathin films (UTFs) with 2D architecture based on CdTe QDs and MgAl layered double hydroxide (LDH) nanosheets via the layer‐by‐layer deposition technique. The hybrid UTFs possess periodic layered structure, which is verified by X‐ray diffraction. Tunable light emission in the red‐green region is obtained by changing the particle size of QDs (CdTe‐535 QDs and CdTe‐635 QDs with green and red emision respectively), assembly cycle number, and sequence. Moreover, energy transfer between CdTe‐535 QDs and CdTe‐635 QDs occurs based on the fluorescence resonance energy transfer (FRET), which greatly enhances the fluorescence efficiency of CdTe‐635 QDs. In addition, a theoretical study based on the Förster theory and molecular dynamics (MD) simulations demonstrates that CdTe QDs/LDH UTFs exhibit superior capability of energy transfer owing to the ordered dispersion of QDs in the 2D LDH matrix, which agrees well with the experimental results. Therefore, this provides a facile approach for the design and fabrication of inorganic‐inorganic luminescent UTFs with largely enhanced luminescence efficiency as well as stability, which can be potentially applied in multicolor optical and optoelectronic devices.
Ideal Energy‐Level Alignment at the ZnO/P3HT Photovoltaic Interface
Authors: Noori Keian , Giustino Feliciano
Published: July 2012

Hybrid semiconductor‐polymer nanostructured solar cells hold the promise of photovoltaic energy conversion based on abundant and nontoxic materials and scalable manufacturing processes. After a decade of intense research activity, hybrid solar cells still exhibit low short‐circuit currents and moderate open‐circuit voltages. These bottlenecks call for a detailed understanding of the physics underlying the device operation at the nanoscale. Using first‐principles calculations the ideal energy‐level alignment of hybrid solar cell interfaces based on the wide bandgap semiconductor ZnO and the polymer poly(3‐hexylthiophene) (P3HT) is investigated. The interfacial charge transfer is quantified and it is shown that this effect increases the ideal open‐circuit voltage with respect to the electron‐affinity rule by as much as 0.5 V. The results of this work suggests that there is significant room for optimizing this class of excitonic solar cells by tailoring the semiconductor/polymer interface at the nanoscale.
Effect of DISC1 SNPs on brain structure in healthy controls and patients with a history of psychosis
Authors: Kähler Anna K. , Rimol Lars M. , Brown Andrew Anand , Djurovic Srdjan , Hartberg Cecilie B. , Melle Ingrid , Dale Anders M. , Andreassen Ole A. , Agartz Ingrid
Published: July 2012

Disrupted‐in‐Schizophrenia‐1 (DISC1) has been suggested as a susceptibility locus for a broad spectrum of psychiatric disorders. Risk variants have been associated with brain structural changes, which overlap alterations reported in schizophrenia and bipolar disorder patients. We used genome‐wide genotyping data for a Norwegian sample of healthy controls (n = 171) and patients with a history of psychosis (n = 184), to investigate 61 SNPs in the DISC1 region for putative association with structural magnetic resonance imaging (sMRI) measures (hippocampal volume; mean cortical thickness; and total surface area, as well as cortical thickness and area divided into four lobar measures). SNP rs821589 was associated with mean temporal and total brain cortical thickness in controls (Padjusted = 0.009 and 0.02, respectively), but not in patients. SNPs rs11122319 and rs1417584 were associated with mean temporal cortical thickness in patients (Padjusted = 0.04 and 0.03, respectively), but not in controls, and both SNPs have previously been highly associated with DISC1 gene expression. There were significant genotype ×  case–control interactions. There was no significant association between SNPs and cortical area or hippocampal volume in controls, or with any of the structural measures in cases, after correction for multiple comparisons. In conclusion, DISC1 SNPs might impact brain structural variation, possibly differently in psychosis patients versus controls, but independent replication will be needed to confirm our findings. © 2012 Wiley Periodicals, Inc.
A systematic review and meta‐analysis on the association between BDNF val66met and hippocampal volume—A genuine effect or a winners curse?
Authors: Molendijk Marc L. , Bus Boudewijn A.A. , Spinhoven Philip , Kaimatzoglou Anna , Voshaar Richard C. Oude , Penninx Brenda W.J.H. , van IJzendoorn Marinus H. , Elzinga Bernet M.
Published: July 2012

Inconsistenties have been reported with regard to an association between val66met, a polymorphism on the BDNF gene, and hippocampal volume. We performed a systematic review and a meta‐analysis to determine the magnitude and direction of this putative association and estimated the potential influence of demographic, clinical, and methodological characteristics of studies. Tests of publication bias and time‐related trends were performed and statistical power of the included studies was calculated. The literature search for MRI studies on differences in total hippocampal volume as a function of BDNF val66met returned 25 records that fulfilled our criteria (total N = 3,620). Meta‐analysis showed that carriers of a met allele had lower hippocampal volumes relative to val/val homozygotes (d = 0.13, P = 0.02). Between‐study heterogeneity in effect size estimates was substantial (Q = 54.47, P < .001) and this could not be explained by demographic, clinical, and methodological differences across studies. Funnel plot inspection and trim‐and‐fill estimations suggested evidence for publication bias and effect sizes decreased substantially over the years (Pearson's r = −0.54, P < .01). All included studies were underpowered. This meta‐analysis shows that carriers of a met allele have lower total hippocampal volumes relative to val/val homozygotes. However, effect sizes converged closer to null with virtually each attempt at replication and were based on underpowered studies. Altogether, this may call into question whether the observed effect is a genuine biological effect of the met allele or whether it is subject to a winners curse, with large effect sizes found in a few early studies and increasingly smaller effect sizes in later studies. © 2012 Wiley Periodicals, Inc.
Revolutionizing medicine in the 21st century through systems approaches
Authors: Hood Leroy , Balling Rudi , Auffray Charles
Published: July 2012

Personalized medicine is a term for a revolution in medicine that envisions the individual patient as the central focus of healthcare in the future. The term “personalized medicine”, however, fails to reflect the enormous dimensionality of this new medicine that will be predictive, preventive, personalized, and participatory‐a vision of medicine we have termed P4 medicine. This reflects a paradigm change in how medicine will be practiced that is revolutionary rather than evolutionary. P4 medicine arises from the confluence of a systems approach to medicine and from the digitalization of medicine that creates the large data sets necessary to deal with the complexities of disease. We predict that systems approaches will empower the transition from conventional reactive medical practice to a more proactive P4 medicine focused on wellness, and will reverse the escalating costs of drug development an will have enormous social and economic benefits. Our vision for P4 medicine in 10 years is that each patient will be associated with a virtual data cloud of billions of data points and that we will have the information technology for healthcare to reduce this enormous data dimensionality to simple hypotheses about health and/or disease for each individual. These data will be multi‐scale across all levels of biological organization and extremely heterogeneous in type – this enormous amount of data represents a striking signal‐to‐noise (S/N) challenge. The key to dealing with this S/N challenge is to take a “holistic systems approach” to disease as we will discuss in this article.
Chiral analytical method development of liquiritigenin with application to a pharmacokinetic study
Authors: Sayre Casey L. , Hopkins Mandi , Takemoto Jody K. , Davies Neal M.
Published: July 2012

Pharmacometric characterization studies of liquiritigenin have historically overlooked its chiral nature. To achieve complete characterization, an analytical method enabling the detection and quantification of the individual enantiomers of racemic (±) liquiritigenin is necessary. Resolution of the enantiomers of liquiritigenin was achieved using a simple high‐performance liquid chromatographic method. A Chiralpak® ADRH column was employed to perform baseline separation with UV detection at 210 nm.The standard curves were linear ranging from 0.5 to 100 µg/mL for each enantiomer. Limit of quantification was 0.5 µg/mL. The assay was applied successfully to stereoselective serum disposition of liquiritigenin enantiomers in rats. Liquiritigenin enantiomers were detected in serum as both aglycones and glucuronidated conjugates. Both unconjugated enantiomers had a serum half‐life of ~15 min in rats. The volume of distribution (Vd) for S‐ and R‐liquiritigenin was 1.49 and 2.21 L/kg, respectively. Total clearance (Cltotal) was 5.12 L/h/kg for S‐liquiritigenin and 4.79 L/h/kg for R‐liquiritigenin, and area under the curve (AUC0‐inf) was 3.95 µg h/mL for S‐liquiritigenin and 4.23 µg h/mL for R‐liquiritigenin. The large volume of distribution coupled with the short serum half‐life suggests extensive distribution of liquiritigenin into tissues. Copyright © 2012 John Wiley & Sons, Ltd.
Differential expression of miRNAs in the serum of patients with high‐risk oral lesions
Authors: MacLellan Sara Ann , Lawson James , Baik Jonathan , Guillaud Martial , Poh Catherine Fang‐Yeu , Garnis Cathie
Published: July 2012

Oral cancer is one of the most commonly diagnosed cancers worldwide. Disease is often diagnosed at later stages, which is associated with a poor 5‐year survival rate and a high rate of local recurrence. MicroRNAs (miRNAs), a group of small, noncoding RNAs, can be isolated from blood serum samples and have demonstrated utility as biomarkers in multiple cancer types. The aim of this study was to examine the expression profiles of circulating miRNAs in the serum of patients with high‐risk oral lesions (HRLs; oral cancer or carcinoma in situ) and to explore their utility as potential oral cancer biomarkers. Global serum miRNA profiles were generated using quantitative PCR method from 1) patients diagnosed with HRLs and undergoing intent‐to‐cure surgical treatment (N = 30) and 2) a demographically matched, noncancer control group (N = 26). We next honed our list of serum miRNAs associated with disease by reducing the effects of interpatient variability; we compared serum miRNA profiles from samples taken both before and after tumor resections (N = 10). Based on these analyses, fifteen miRNAs were significantly upregulated and five were significantly downregulated based on presence of disease (minimum fold‐change >2 in at least 50% of samples, P < 0.05, permutation). Five of these miRNAs (miR‐16, let‐7b, miR‐338‐3p, miR‐223, and miR‐29a) yielded an area under the ROC curve (AUC) >0.8, suggesting utility as noninvasive biomarkers for detection of oral cancer or high‐grade lesions. Combining these serum miRNA profiles with other screening techniques could greatly improve the sensitivity in oral cancer detection.
Intravascular ultrasound assessment of optimal stent area to prevent in‐stent restenosis after zotarolimus‐, everolimus‐, and sirolimus‐eluting stent implantation
Authors: Song Hae‐Geun , Kang Soo‐Jin , Ahn Jung‐Min , Kim Won‐Jang , Lee Jong‐Young , Park Duk‐Woo , Lee Seung‐Whan , Kim Young‐Hak , Lee Cheol Whan , Park Seong‐Wook , Park Seung‐Jung
Published: July 2012

Objectives and background

The impact of underexpansion and minimal stent area (MSA) criteria in the second generation drug‐eluting stents (DES) has not been addressed yet.

Methods

Using intravascular ultrasound (IVUS), we assessed the optimal cut‐off values of post‐stenting MSA to prevent in‐stent restenosis (ISR). Poststenting IVUS data and 9‐month follow‐up angiography were available in 912 patients with 990 lesions: 541 sirolimus‐eluting stents (SES), 220 zotarolimus‐eluting stents (ZES) and 229 everolimus‐eluting stents (EES).

Results

For the prediction of angiographic ISR, the MSA of each DES was measured. The poststenting MSA was 6.4 ± 1.8 mm2 in SES, 6.2 ± 2.1 mm2 in ZES and 6.2 ± 2.1 mm2 in EES. At the 9‐months follow‐up, the incidence of angiographic ISR was similar between SES (3.3%) vs. ZES (4.5%) vs. EES. (4.4%), (P = 0.53). Multivariable logistic regression analysis identified the post‐stenting MSA as the only independent predictor of angiographic ISR in ZES (Odds ratio 0.722, 95% confidence interval 0.581–0.897, P = 0.001) and in EES (Odds ratio 0.595, 95% confidence interval 0.392–0.904, P = 0.015). The best MSA cut‐off value was 5.5 mm2 for the prediction of SES restenosis (sensitivity 72.2% and specificity 66.3%). For ZES, the optimal MSA predicting ISR was 5.3 mm2 (sensitivity 56.7% and specificity 61.8%). For EES, the MSA <5.4 mm2 predicted ISR (sensitivity 60.0% and specificity 60.0%).

Conclusions

As a preventable mechanism of ISR, smaller stent area predicted angiographic restenosis of the second generation DES as well as the first generation. The optimal cut‐off values of post‐stenting MSA for preventing restenosis were similar between ZES vs. EES vs. SES. © 2012 Wiley Periodicals, Inc.
Multivalent, Sulfur‐Rich PyBox Asterisk Ligands in Asymmetric Metal Catalysis
Authors: Aubert Catherine , Dallaire Carol , Pèpe Gérard , Levillain E. , Félix Guy , Gingras Marc
Published: July 2012

Multivalent PyBox asterisk ligand 1 and monovalent ligand 2 are reported. The innovative feature in 1 is a sulfur‐rich persulfurated benzene core as a template joining six PyBox units in close proximity. An efficient persulfuration of C6Cl6 with p‐methoxybenzenethiol (95 %, >99 % per C–S bond) and deprotection led to hexaphenol 4. Six O‐arylations of 4 with Cl‐PyBox 3 (94 %, >99 % per C–O bond) provided 1. The electronic delocalization of 1 and 2 was analyzed by UV/Vis spectroscopy and cyclic voltammetry. PyBox ligands 1 and 2 were successfully used for Rh‐catalyzed hydrosilylation of acetophenone, in spite of competitive bindings from six proximal sulfur atoms. The concept of multivalency and the presence of donating and oxidizable sulfur atoms in asymmetric metal catalysis were tested. The reactivities and the enantiocatalytic behavior of 1 and 2 with varying rhodium content were determined. Lability of the Rh complexes under certain conditions, was demonstrated by some crossover experiments with other PyBox ligands. Conformational and competitive metal binding studies of 1 with the aid of molecular modeling (GenMol™) helped to explain the results. This work suggests new directions for simple multivalent ligands in metal‐mediated catalysis.
Probiotic fermented foods for health benefits
Authors: Beena Divya Jayakumar , Kulangara Varsha Kontham , Madhavan Nampoothiri Kesavan , Ismail Bindhumol , Pandey Ashok
Published: July 2012

The history of fermented foods used by humans can be traced back to centuries. The medicinal as well as flavor enhancing properties of fermented foods are mainly due to the presence of bacteria known as probiotics. Probiotics aid in digestion and nutrient assimilation. These bacteria are also known for their beneficial effects for the immune system and health. Many of them produce antimicrobial bioactive molecules that make them effective biopreservatives and produce nutraceuticals to create functional foods with increased bioavailability of nutrients. Thus, these lactic acid bacteria have undeniable favorable effects. This review will summarize the health benefits of probiotic fermented foods.
Gasteromycetation in Agaricaceae s. l. (Basidiomycota): Morphological and ecological implementations
Authors: Gube Matthias , Dörfelt Heinrich
Published: July 2012

In this study, a review of the morphological features of gasteroid members of Agaricaceae is provided. Consideration of their ecological background and phylogenetic relationships allows for interpretation of the underlying process of gasteromycetation. The main dispersal strategies of gasterothecia are outlined. With lycoperdoids, tulostomatoids and the secotioid species, three functional groups of agaricoid gasterothecia are defined. Whereas the first two are phylogenetic units as well, the latter are united exclusively by their close systematic and anatomical relationships to hymenothecia and their habitat. Semiarid open land habitats are proposed as likely origin of gasteromycetation for this group, as they incorporate the highest diversity of morphological adaptations and are inhabited by members of all analysed gasteroid taxa. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The impact of cognitive deficit on self‐reported car crashes in ultra‐octogenarian population: data of an Italian population‐based study
Authors: Rozzini Luca , Riva Maddalena , Zanetti Marina , Gottardi Federica , Caratozzolo Salvatore , Vicini Chilovi Barbara , Trabucchi Marco , Padovani Alessandro
Published: July 2012

Objective

To examine the usefulness of specific neurocognitive tests for predicting the crash involvement in ultra‐octogenarian population.

Methods

A total of 800 subjects (mean age 82.4 + 3.1 years) underwent a battery of neuropsychological tests. Global intellectual functioning was assessed using the Mini Mental State Examination, mental flexibility and information processing speed were assessed using the Trail Making Test parts A and B (TMT‐A and TMT‐B), long‐term memory was evaluated with the short story, and visuo‐spatial skills were tested with Clock Drawing Test. One year after this evaluation, 343 (43%) participants have been interviewed by a telephone call to know if they were currently driving and if they had a car crash during this period.

Results

Two hundred ninety‐seven subjects had their driving license renewed and completed the follow‐up 1 year after. Data shows that less than 11% of this group had a car crash during the first year of observation (Crash Involved). Older subjects involved in a car crash showed significant worse performances on TMT‐B (TMT‐B pathological Crash Involved vs. Noncrash Involved 47% vs. 27%; p = 0.02) and on short story (short story pathological Crash Involved vs. Noncrash Involved 19% vs. 5%; p = 0.02).

Conclusions

Trail Making test B and short story have been demonstrated to provide a predictive value of driving performance of older people. Therefore, we suggest that a simple and standardized battery of neuropsychological tests, lasting about 30 min and administered by an experienced staff, is a good diagnostic instrument for risk prevention of driving activity of older drivers. Copyright © 2012 John Wiley & Sons, Ltd.
Loss in connectivity among regions of the brain reward system in alcohol dependence
Authors: Kuceyeski Amy , Meyerhoff Dieter J. , Durazzo Timothy C. , Raj Ashish
Published: July 2012

A recently developed measure of structural brain connectivity disruption, the loss in connectivity (LoCo), is adapted for studies in alcohol dependence. LoCo uses independent tractography information from young healthy controls to project the location of white matter (WM) microstructure abnormalities in alcohol‐dependent versus nondependent individuals onto connected gray matter (GM) regions. LoCo scores are computed from WM abnormality masks derived at two levels: (1) groupwise differences of alcohol‐dependent individuals (ALC) versus light‐drinking (LD) controls and (2) differences of each ALC individual versus the LD control group. LoCo scores based on groupwise WM differences show that GM regions belonging to the extended brain reward system (BRS) network have significantly higher LoCo (i.e., disconnectivity) than those not in this network (t = 2.18, P = 0.016). LoCo scores based on individuals' WM differences are also higher in BRS versus non‐BRS (t = 5.26, P = 3.92 × 10−6) of ALC. These results suggest that WM alterations in alcohol dependence, although subtle and spatially heterogeneous across the population, are nonetheless preferentially localized to the BRS. LoCo is shown to provide a more sensitive estimate of GM involvement than conventional volumetric GM measures by better differentiating between brains of ALC and LD controls (rates of 89.3% vs. 69.6%). However, just as volumetric measures, LoCo is not significantly correlated with standard metrics of drinking severity. LoCo is a sensitive WM measure of regional cortical disconnectivity that uniquely characterizes anatomical network disruptions in alcohol dependence. Hum Brain Mapp 34:3129–3142, 2013. © 2012 Wiley Periodicals, Inc.
DIAGNOSIS RELATED GROUPS AND VARIATIONS IN RESOURCE USE FOR CHILD DELIVERY ACROSS 10 EUROPEAN COUNTRIES
Authors: Or Zeynep , Renaud Thomas , Thuilliez Josselin , Lebreton Cora ,   on behalf of the EuroDRG group
Published: July 2012

Childbirth is one of the main causes of hospitalisation for women, accounting for about 5% of hospital activity in most Organisation for Economic Co‐operation and Development countries. We analysed the factors that explain variations in resource use for child delivery in ten European countries. We compared the performance of three models for explaining the variations in resource use (log cost or length of inpatient stay) at patient and hospital level. The first model used only the DRGs to which child deliveries were coded (MD), the second used a set of ‘patient‐level’ and delivery specific explanatory variables (MP), and the third model combined both sets of variables (MF). Countries vary both in the number of DRGs and the criteria used to classify cases of child delivery (range: 3–8) and in the percentage of deliveries classified as ‘delivery without complication’ (range: 53–90%). The capacity of DRGs and patient level variables to explain cost variation for child birth ranges from 48% in Sweden to over 70% in Spain. There is room for improving current DRG classification in most countries, but this does not necessary imply multiplying the groups and/or complicating criteria. Countries with a higher number of DRGs do not always perform better. Copyright © 2012 John Wiley & Sons, Ltd.
HOW WELL DO DIAGNOSIS‐RELATED GROUPS FOR APPENDECTOMY EXPLAIN VARIATIONS IN RESOURCE USE? AN ANALYSIS OF PATIENT‐LEVEL DATA FROM 10 EUROPEAN COUNTRIES
Authors: Mason Anne , Or Zeynep , Renaud Thomas , Street Andrew , Thuilliez Josselin , Ward Padraic ,   ON BEHALF OF THE EURODRG GROUP
Published: July 2012

Appendectomy is a common and relatively simple procedure to remove an inflamed appendix, but the rate of appendectomy varies widely across Europe. This paper investigates factors that explain differences in resource use for appendectomy.

We analysed 106 929 appendectomy patients treated in 939 hospitals in 10 European countries. In stage 1, we tested the performance of three models in explaining variation in the (log of) cost of the inpatient stay (seven countries) or length of stay (three countries). The first model used only the diagnosis‐related groups (DRGs) to which patients were coded, the second model used a core set of general patient‐level and appendectomy‐specific variables, and the third model combined both sets of variables. In stage two, we investigated hospital‐level variation.

In classifying appendectomy patients, most DRG systems take account of complex diagnoses and comorbidities but use different numbers of DRGs (range: 2 to 8). The capacity of DRGs and patient‐level variables to explain patient‐level cost variation ranges from 34% in Spain to over 60% in England and France. All DRG systems can make better use of administrative data such as the patient's age, diagnoses and procedures, and all countries have outlying hospitals that could improve their management of resources for appendectomy. Copyright © 2012 John Wiley & Sons, Ltd.
PATIENT CLASSIFICATION AND HOSPITAL COSTS OF CARE FOR STROKE IN 10 EUROPEAN COUNTRIES
Authors: Peltola Mikko ,   on behalf of the EuroDRG group
Published: July 2012

Stroke is a major cause of death and disability around the world, and the care of stroke patients ties up a great amount of resources in healthcare systems. Stroke severity and the given care may vary substantially between patients, and there is remarkable variation in both the costs and length of stay (LoS) of stroke patients.

Using patient level data from 10 European countries on costs and LoS, we explored the ability of the diagnosis‐related group (DRG) systems to explain variance in the costs and length of stay of stroke patients. In addition, we evaluated whether the existing DRGs for stroke patients would benefit from additional patient‐related and treatment‐related factors that are commonly found in the administrative databases across countries. Cost analyses were run using OLS fixed effects models, and LoS analyses with negative binomial models.

The descriptive statistics showed that the stroke patients differ remarkably across countries. Large variations in the classification of stroke patients raise concerns about whether all systems rely on the most appropriate classification variables. In all the countries, the DRG classifications' performance could be improved with the introduction of the patient characteristics analysed here. Copyright © 2012 John Wiley & Sons, Ltd.
DO DIAGNOSIS‐RELATED GROUPS APPROPRIATELY EXPLAIN VARIATIONS IN COSTS AND LENGTH OF STAY OF HIP REPLACEMENT? A COMPARATIVE ASSESSMENT OF DRG SYSTEMS ACROSS 10 EUROPEAN COUNTRIES
Authors: Geissler Alexander , Scheller‐Kreinsen David , Quentin Wilm ,   on behalf of the EuroDRG group
Published: July 2012

This paper assesses the variations in costs and length of stay for hip replacement cases in Austria, England, Estonia, Finland, France, Germany, Ireland, Poland, Spain and Sweden and examines the ability of national diagnosis‐related group (DRG) systems to explain the variation in resource use against a set of patient characteristic and treatment specific variables. In total, 195 810 cases clustered in 712 hospitals were analyzed using OLS fixed effects models for cost data (n = 125 698) and negative binominal models for length‐of‐stay data (n = 70 112). The number of DRGs differs widely across the 10 European countries (range: 2–14). Underlying this wide range is a different use of classification variables, especially secondary diagnoses and treatment options are considered to a different extent. In six countries, a standard set of patient characteristics and treatment variables explain the variation in costs or length of stay better than the DRG variables. This raises questions about the adequacy of the countries' DRG system or the lack of specific criteria, which could be used as classification variables. Copyright © 2012 John Wiley & Sons, Ltd.
Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation
Authors: Martel Cecile , Allouche Maya , Esposti Davide Degli , Fanelli Elena , Boursier Céline , Henry Céline , Chopineau Joel , Calamita Giuseppe , Kroemer Guido , Lemoine Antoinette , Brenner Catherine
Published: July 2012

Nonalcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of nonalcoholic steatosis, i.e., livers from patients with fatty liver disease, ob/ob mice, mice fed a high-fat diet, and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and identified a posttranslational modification of voltage-dependent anion channel (VDAC), a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in nonalcoholic steatosis VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization, and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover, lipid accumulation triggers a rapid lack of VDAC phosphorylation by glycogen synthase kinase 3 (GSK3). Pharmacological and genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. Conclusion: VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis. (Hepatology 2013)
Increased functional connectivity within medial temporal lobe in mild cognitive impairment
Authors: Das Sandhitsu R. , Pluta John , Mancuso Lauren , Kliot Dasha , Orozco Sylvia , Dickerson Bradford C. , Yushkevich Paul A. , Wolk David A.
Published: July 2012

Pathology at preclinical and prodromal stages of Alzheimer's disease (AD) may manifest itself as measurable functional change in neuronal networks earlier than detectable structural change. Functional connectivity as measured using resting‐state functional magnetic resonance imaging has emerged as a useful tool for studying disease effects on baseline states of neuronal networks. In this study, we use high resolution MRI to label subregions within the medial temporal lobe (MTL), a site of early pathology in AD, and report an increase in functional connectivity in amnestic mild cognitive impairment between entorhinal cortex and subregions of the MTL, with the strongest effect in the anterior hippocampus. However, our data also replicated the effects of decreased connectivity of the MTL to other nodes of the default mode network reported by other researchers. This dissociation of changes in functional connectivity within the MTL versus the MTL's connection with other neocortical structures can help enrich the characterization of early stages of disease progression in AD. © 2012 Wiley Periodicals, Inc.
Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+‐permeable TRPC6 channels
Authors: Leuner Kristina , Li Wei , Amaral Michelle D. , Rudolph Stephanie , Calfa Gaston , Schuwald Anita M. , Harteneck Christian , Inoue Takafumi , Pozzo‐Miller Lucas
Published: July 2012

The standardized extract of the St. John's wort plant (Hypericum perforatum) is commonly used to treat mild to moderate depression. Its active constituent is hyperforin, a phloroglucinol derivative that reduces the reuptake of serotonin and norepinephrine by increasing intracellular Na+ concentration through the activation of nonselective cationic TRPC6 channels. TRPC6 channels are also Ca2+‐permeable, resulting in intracellular Ca2+ elevations. Indeed, hyperforin activates TRPC6‐mediated currents and Ca2+ transients in rat PC12 cells, which induce their differentiation, mimicking the neurotrophic effect of nerve growth factor. Here, we show that hyperforin modulates dendritic spine morphology in CA1 and CA3 pyramidal neurons of hippocampal slice cultures through the activation of TRPC6 channels. Hyperforin also evoked intracellular Ca2+ transients and depolarizing inward currents sensitive to the TRPC channel blocker La3+, thus resembling the actions of the neurotrophin brain‐derived neurotrophic factor (BDNF) in hippocampal pyramidal neurons. These results suggest that the antidepressant actions of St. John's wort are mediated by a mechanism similar to that engaged by BDNF. © 2012 Wiley Periodicals, Inc.
Preoperative serum tissue polypeptide‐specific antigen is a valuable prognostic marker in breast cancer
Authors: Ahn Soo Kyung , Moon Hyeong‐Gon , Ko Eunyoung , Kim Han Suk , Shin Hee‐Chul , Kim Jisun , You Jee Man , Han Wonshik , Noh Dong‐Young
Published: July 2012

Tissue polypeptide‐specific antigen (TPS), a specific epitope structure of a peptide in serum associated with human cytokeratin 18, is linked to the proliferative activity of tumors. Here, we aimed to identify the association between the preoperative serum TPS level and outcome in breast cancer patients. We assayed preoperative serum TPS levels in 1,477 breast cancer patients treated between June 2000 and December 2006. The TPS level was measured with a one‐step solid phase radiometric sandwich assay detecting the M3 epitope on cytokeratin 18 fragments. The cutoff value was 80 U/L. Among the 1,477 breast cancer patients examined, preoperative serum TPS level was elevated (>80 U/L) in 290 patients (19.6%). Age (>45 years), tumor size (>2 cm), nodal metastasis, negative progesterone receptor and human epidermal growth factor receptor 2 were associated with elevated TPS. Evidence of recurrence was observed in 229 patients (15.6%). Elevated TPS was associated with poor disease‐free survival (p < 0.001) and overall survival (p < 0.001). In a multivariate analysis using the Cox proportional regression model, elevated TPS was an independent prognostic factor for disease‐free survival (p = 0.001) and overall survival (p = 0.026). Furthermore, in subgroup analysis based on molecular subtype, the prognostic effect of preoperative TPS on survival (OS: HR 2.614, p = 0.003; DFS: HR 1.895, p = 0.001) was identified only in the luminal A subtype. Elevated preoperative serum TPS level is associated with poor breast cancer outcomes. Based on these findings, we conclude that preoperative TPS is a valuable biomarker for clinical use in predicting outcomes in breast cancer patients.
Prognostic value of arginase‐II expression and regulatory T‐cell infiltration in head and neck squamous cell carcinoma
Authors: Bron Luc , Jandus Camilla , Andrejevic‐Blant Snezana , Speiser Daniel E. , Monnier Philippe , Romero Pedro , Rivals Jean‐Paul
Published: July 2012

Tumor‐infiltrating lymphocytes are present in a variety of tumors and play a central role in antitumor immune responses. Nevertheless, most cancers progress probably because tumors are only weakly immunogenic and develop multiple immunosuppressive mechanisms. In the present study, on head and neck squamous cell carcinoma, we found high intraepithelial infiltration of regulatory FOXP3+T cells, and relatively high levels of BDCA2+and FOXP3+cells in stromal (peripheral) regions of the tumors. Tumor‐infiltrating (intraepithelial) FOXP3+T cells were significantly more frequent in patients with oropharynx and oral cavity squamous cell carcinoma and in patients without lymph node metastasis. Furthermore, arginase‐II (ARG2) was expressed by 60%, inducible nitric oxide synthetase by 9%, cyclooxygenase‐2 by 43%, and B‐cell lymphoma 2 (BCL2) by 26% of tumors. Interestingly, the absence of ARG2 expression, enhanced stromal infiltration of CD11c+myeloid dendritic cells, and high numbers of FOXP3+T cells were each significantly associated with prolonged overall survival, and the latter two parameters were also confirmed by multivariate analysis. For disease‐free survival, multivariate analysis revealed significant negative correlations with BCL2 and ARG2 expression by tumor cells. These findings shed new light on mechanisms of cancer progression, and provide rationales for therapeutic inhibition of immunosuppressive mechanisms in head and neck squamous cell carcinoma.
Early childhood infection of Kaposi's sarcoma‐associated herpesvirus in Zambian households: A molecular analysis
Authors: Olp Landon N. , Shea Danielle M. , White Maxine K. , Gondwe Clement , Kankasa Chipepo , Wood Charles
Published: July 2012

Sub‐Saharan Africa is endemic for Kaposi's sarcoma‐associated herpesvirus (KSHV) and there is a high rate of early childhood infection; however, the transmission sources are not well characterized. We examined household members as potential KSHV transmission sources to young children in the KSHV‐endemic country of Zambia. To this end, we enrolled and followed Zambian households with at least one KSHV‐seropositive child and collected longitudinal buccal swab samples. KSHV burden was evaluated and K1 sequences from the children were determined and analyzed for differences to K1 sequences from household members. The K1 sequences were also analyzed for evolution over time. We generated K1 sequences from 31 individuals across 16 households. Nine households contained multiple KSHV‐positive members, including at least one child. In six out of the nine households, the child had 100% sequence identity to all household members. However, in two households the child and mother had distinct K1 sequences. In the remaining household, the children were the only KSHV‐infected individuals. Furthermore, we report that 1 out of 18 individuals had K1 sequence variation within the timespan analyzed. In our study, we provide evidence that (i) early childhood KSHV transmission occurs from both within and outside the household, (ii) intrahousehold transmission can occur via nonmaternal sources, (iii) viral shedding in the buccal cavity is highly variable and (iv) the dominant K1 sequence within an individual did not rapidly evolve over time. These results are important for developing KSHV intervention strategies.
Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors
Authors: Chadalapaka Gayathri , Jutooru Indira , Sreevalsan Sandeep , Pathi Satya , Kim Kyounghyun , Chen Candy , Crose Lisa , Linardic Corinne , Safe Stephen
Published: July 2012

Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are highly expressed in rhabdomyosarcoma (RMS) cells. In tissue arrays of RMS tumor cores from 71 patients, 80% of RMS patients expressed high levels of Sp1 protein, whereas low expression of Sp1 was detected in normal muscle tissue. The non‐steroidal anti‐inflammatory drug (NSAID) tolfenamic acid (TA) inhibited growth and migration of RD and RH30 RMS cell lines and also inhibited tumor growth in vivo using a mouse xenograft (RH30 cells) model. The effects of TA were accompanied by downregulation of Sp1, Sp3, Sp4 and Sp‐regulated genes in RMS cells and tumors, and the role of Sp protein downregulation in mediating inhibition of RD and RH30 cell growth and migration was confirmed by individual and combined knockdown of Sp1, Sp3 and Sp4 proteins by RNA interference. TA treatment and Sp knockdown in RD and RH30 cells also showed that four genes that are emerging as individual drug targets for treating RMS, namely c‐MET, insulin‐like growth factor receptor (IGFR), PDGFRα and CXCR4, are also Sp‐regulated genes. These results suggest that NSAIDs such as TA may have potential clinical efficacy in drug combinations for treating RMS patients.
Vibrational frequency scale factors for density functional theory and the polarization consistent basis sets
Authors: Laury Marie L. , Carlson Matthew J. , Wilson Angela K.
Published: July 2012

Calculated harmonic vibrational frequencies systematically deviate from experimental vibrational frequencies. The observed deviation can be corrected by applying a scale factor. Scale factors for: (i) harmonic vibrational frequencies [categorized into low (<1000 cm−1) and high (>1000 cm−1)], (ii) vibrational contributions to enthalpy and entropy, and (iii) zero‐point vibrational energies (ZPVEs) have been determined for widely used density functionals in combination with polarization consistent basis sets (pc‐n, n = 0,1,2,3,4). The density functionals include pure functionals (BP86, BPW91, BLYP, HCTH93, PBEPBE), hybrid functionals with Hartree‐Fock exchange (B3LYP, B3P86, B3PW91, PBE1PBE, mPW1K, BH&HLYP), hybrid meta functionals with the kinetic energy density gradient (M05, M06, M05‐2X, M06‐2X), a double hybrid functional with Møller‐Plesset correlation (B2GP‐PLYP), and a dispersion corrected functional (B97‐D). The experimental frequencies for calibration were from 41 organic molecules and the ZPVEs for comparison were from 24 small molecules (diatomics, triatomics). For this family of basis sets, the scale factors for each property are more dependent on the functional selection than on basis set level, and thus allow for a suggested scale factor for each density functional when employing polarization consistent basis sets (pc‐n, n = 1,2,3,4). A separate scale factor is recommended when the un‐polarized basis set, pc‐0, is used in combination with the density functionals. © 2012 Wiley Periodicals, Inc.
Calculating pKa values for substituted phenols and hydration energies for other compounds with the first‐order fuzzy‐border continuum solvation model
Authors: Sharma Ity , Kaminski George A.
Published: July 2012

We have computed pKa values for 11 substituted phenol compounds using the continuum Fuzzy‐Border (FB) solvation model. Hydration energies for 40 other compounds, including alkanes, alkenes, alkynes, ketones, amines, alcohols, ethers, aromatics, amides, heterocycles, thiols, sulfides, and acids have been calculated. The overall average unsigned error in the calculated acidity constant values was equal to 0.41 pH units and the average error in the solvation energies was 0.076 kcal/mol. We have also reproduced pKa values of propanoic and butanoic acids within about 0.1 pH units from the experimental values by fitting the solvation parameters for carboxylate ion carbon and oxygen atoms. The FB model combines two distinguishing features. First, it limits the amount of noise which is common in numerical treatment of continuum solvation models by using fixed‐position grid points. Second, it uses either second‐ or first‐order approximation for the solvent polarization, depending on a particular implementation. These approximations are similar to those used for solute and explicit solvent fast polarization treatment which we developed previously. This article describes results of using the first‐order technique. This approximation places the presented methodology between the Generalized Born and Poisson‐Boltzmann continuum solvation models with respect to their accuracy of reproducing the many‐body effects in modeling a continuum solvent. © 2012 Wiley Periodicals, Inc.
Observed changes and trends in numbers of summer and tropical days, and the 2010 hot summer in Turkey
Authors: Erlat Ecmel , Türkeş Murat
Published: July 2012

Long‐term variability and trends of the annual numbers of summer and tropical days were investigated by using nonlinear (monotonic) and linear trend detection tests for the period 1950–2010 for 97 meteorological stations of Turkey. The results suggest that the numbers of both summer and tropical days indicate a general increasing tendency in Turkey. For the study period, statistically significant increasing trends for summer (tropical) days are detected at 64 (71) stations, of which 51 (58) of these positive trends are significant at the 0.01 significance level. Two periods of changes in summer and tropical days are identified: in the 1950–1975 sub‐period with an episode of slight cooling, the annual number of summer and tropical days decreases, whereas in the sub‐period of 1976–2010 with an episode of significant increasing trend, the annual number of summer and tropical days increases. The summer of 2010 was exceptional for the number of summer and tropical days at most of the stations in Turkey. Normalized anomalies of summer (tropical) days at 2010 were larger than three standard deviations with respect to 1961–1990 normal at 27 (43) stations. The largest positive anomalies are observed in the northeastern Anatolia sub‐region. This increasing trend has significant impacts on agriculture, energy, tourism and natural ecosystems (e.g., forest fires) in Turkey. Copyright © 2012 Royal Meteorological Society
Consistency and inconsistency in network meta‐analysis: concepts and models for multi‐arm studies
Authors: Higgins J. P. T. , Jackson D , Barrett J. K. , Lu G , Ades A. E. , White I. R.
Published: July 2012

Meta‐analyses that simultaneously compare multiple treatments (usually referred to as network meta‐analyses or mixed treatment comparisons) are becoming increasingly common. An important component of a network meta‐analysis is an assessment of the extent to which different sources of evidence are compatible, both substantively and statistically. A simple indirect comparison may be confounded if the studies involving one of the treatments of interest are fundamentally different from the studies involving the other treatment of interest. Here, we discuss methods for addressing inconsistency of evidence from comparative studies of different treatments. We define and review basic concepts of heterogeneity and inconsistency, and attempt to introduce a distinction between ‘loop inconsistency’ and ‘design inconsistency’. We then propose that the notion of design‐by‐treatment interaction provides a useful general framework for investigating inconsistency. In particular, using design‐by‐treatment interactions successfully addresses complications that arise from the presence of multi‐arm trials in an evidence network. We show how the inconsistency model proposed by Lu and Ades is a restricted version of our full design‐by‐treatment interaction model and that there may be several distinct Lu–Ades models for any particular data set. We introduce novel graphical methods for depicting networks of evidence, clearly depicting multi‐arm trials and illustrating where there is potential for inconsistency to arise. We apply various inconsistency models to data from trials of different comparisons among four smoking cessation interventions and show that models seeking to address loop inconsistency alone can run into problems. Copyright © 2012 John Wiley & Sons, Ltd.
Consistency and inconsistency in network meta‐analysis: model estimation using multivariate meta‐regression
Authors: White Ian R. , Barrett Jessica K. , Jackson Dan , Higgins Julian P. T.
Published: July 2012

Network meta‐analysis (multiple treatments meta‐analysis, mixed treatment comparisons) attempts to make the best use of a set of studies comparing more than two treatments. However, it is important to assess whether a body of evidence is consistent or inconsistent. Previous work on models for network meta‐analysis that allow for heterogeneity between studies has either been restricted to two‐arm trials or followed a Bayesian framework. We propose two new frequentist ways to estimate consistency and inconsistency models by expressing them as multivariate random‐effects meta‐regressions, which can be implemented in some standard software packages. We illustrate the approach using the mvmeta package in Stata. Copyright © 2012 John Wiley & Sons, Ltd.