bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost–utility analysis conducted alongside randomized controlled trials: Are economic end points considered in sample size calculations and does it matter?
Authors: Hollingworth William , McKell-Redwood Denise , Hampson Lisa , Metcalfe Chris 
Published: December 2012

Background Many randomized controlled trials (RCTs) collect cost-effectiveness data. Without appropriate sample size calculations, patient recruitment may cease before the cost-effectiveness of the intervention can be established or continue after the cost-effectiveness of the intervention is established beyond doubt. Purpose We determined the frequency with which cost-effectiveness is considered in sample size calculations and whether RCT-based economic evaluations are likely to come to inconclusive results at odds with the clinical findings. Methods We searched the National Health Service Economic Evaluation Database (NHS EED) to identify RCT-based cost-utility analyses. RCTs that collected individual patient data on costs and quality-adjusted life years (QALYs) were eligible. Studies using models to extrapolate the results of RCTs or with insufficient information on incremental costs and QALYs were excluded. Results In total, 38 trials met eligibility criteria. Only one considered cost-effectiveness in sample size calculations. RCTs were less likely to reach definitive conclusions based on the cost-effectiveness results than the primary clinical outcome (15.8% vs. 42.1%; McNemar; p = 0.01). In trials that provided sufficient data, exploratory analysis indicated that the median power to detect important differences was 29.5% for QALYs, 94.1% for costs, and 78.7% for the primary clinical outcome. In three trials (7.9%), a definitely more effective intervention was found to be expensive and probably not cost-effective. Limitations Our results reflect trials where authors considered within-trial estimates of cost-effectiveness to be meaningful. In focusing on one primary clinical outcome from each RCT, we have simplified the clinical effectiveness results, although the primary outcome will usually be one that policy makers use in judging the ‘success’ of the intervention. Conclusions Economic evaluations conducted alongside RCTs are valuable, but often present inconclusive evidence. Trial results may lead to discordant messages when the most effective intervention is probably not the most cost-effective. Despite methodological advances, trialists rarely assessed the extent to which their trial might resolve the key uncertainties about the cost-effectiveness of interventions. We recommend that grant funders should do more to encourage trialists to include economic end points in sample size calculations, particularly when the majority of costs and benefits of the intervention occur within the time frame of the trial.
Clinical development of two innovative pharmaceutical forms of leuprorelin acetate
Authors: Geiges Goetz , Schapperer Elisabeth , Thyroff-Friesinger Ursula , Engert Zoltán Vendel , Gravel Patricia 
Published: December 2012

Objectives: Two innovative pharmaceutical forms of leuprorelin acetate have been developed as 1-month and 3-month implants for the treatment of advanced hormone-dependent prostate cancer. These products contain active substance dispersed homogeneously in a biodegradable polymer. Here we present the key results from the clinical development of these slow-release implant formulations of leuprorelin. Methods: Two therapeutic studies of the 1-month implant were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Enantone) as the active control; and a single-arm study of the leuprorelin implant. For the 3-month implant, four therapeutic studies were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Trenantone) as the active control; a single-arm study of the leuprorelin implant; and two long-term studies with the 3-month implant administered twice, either 12 or 16 weeks apart. A pooled analysis of data from the comparator-controlled and single-arm studies of the 3-month implant was also conducted. The main inclusion criterion for all studies was histologically confirmed advanced prostate cancer, with primary endpoints based around successful testosterone suppression (≤0.5 ng/ml). Results: In the comparator-controlled studies, both implants were as effective as the microspheres for achieving successful testosterone suppression and normalization of prostate-specific antigen (PSA) levels. Data from the single-arm and long-term studies were consistent with those from the comparator-controlled studies. In the pooled analysis, significantly more patients treated with the 3-month implant achieved successful testosterone suppression compared with the comparator ( p ≤ 0.01). The safety profile of the implants in the comparator-controlled studies was similar to that of the prolonged-release microsphere formulation, and consistent with that of the luteinizing hormone-releasing hormone agonist class. Conclusions: The innovative 1-month and 3-month implants of leuprorelin acetate are at least as effective as leuprorelin acetate prolonged-release microspheres for achieving successful testosterone suppression and normalization of PSA in men with advanced hormone-dependent prostate cancer, with a comparable safety profile.
Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice
Authors: Duerschmied Daniel , Suidan Georgette L. , Demers Melanie , Herr Nadine , Carbo Carla , Brill Alexander , Cifuni Stephen M. , Mauler Maximilian , Cicko Sanja , Bader Michael , Idzko Marco , Bode Christoph , Wagner Denisa D. 
Published: December 2012

Key Points
During inflammation, serotonin released by platelets activates vessel wall promoting leukocyte adhesion and recruitment. Absence of platelet serotonin improves survival after lipopolysaccharide-induced endotoxic shock.
An automatic device for detection and classification of malaria parasite species in thick blood film
Authors: Kaewkamnerd Saowaluck , Uthaipibull Chairat , Intarapanich Apichart , Pannarut Montri , Chaotheing Sastra , Tongsima Sissades 
Published: December 2012

Abstract

Background
Current malaria diagnosis relies primarily on microscopic examination of Giemsa-stained thick and thin blood films. This method requires vigorously trained technicians to efficiently detect and classify the malaria parasite species such as Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) for an appropriate drug administration. However, accurate classification of parasite species is difficult to achieve because of inherent technical limitations and human inconsistency. To improve performance of malaria parasite classification, many researchers have proposed automated malaria detection devices using digital image analysis. These image processing tools, however, focus on detection of parasites on thin blood films, which may not detect the existence of parasites due to the parasite scarcity on the thin blood film. The problem is aggravated with low parasitemia condition. Automated detection and classification of parasites on thick blood films, which contain more numbers of parasite per detection area, would address the previous limitation.

Results
The prototype of an automatic malaria parasite identification system is equipped with mountable motorized units for controlling the movements of objective lens and microscope stage. This unit was tested for its precision to move objective lens (vertical movement, z-axis) and microscope stage (in x- and y-horizontal movements). The average precision of x-, y- and z-axes movements were 71.481 ± 7.266 μm, 40.009 ± 0.000 μm, and 7.540 ± 0.889 nm, respectively. Classification of parasites on 60 Giemsa-stained thick blood films (40 blood films containing infected red blood cells and 20 control blood films of normal red blood cells) was tested using the image analysis module. By comparing our results with the ones verified by trained malaria microscopists, the prototype detected parasite-positive and parasite-negative blood films at the rate of 95% and 68.5% accuracy, respectively. For classification performance, the thick blood films with Pv parasite was correctly classified with the success rate of 75% while the accuracy of Pf classification was 90%.

Conclusions
This work presents an automatic device for both detection and classification of malaria parasite species on thick blood film. The system is based on digital image analysis and featured with motorized stage units, designed to easily be mounted on most conventional light microscopes used in the endemic areas. The constructed motorized module could control the movements of objective lens and microscope stage at high precision for effective acquisition of quality images for analysis. The analysis program could accurately classify parasite species, into Pf or Pv, based on distribution of chromatin size.
Mathematical modeling of the immune system recognition to mammary carcinoma antigen
Authors: Bianca Carlo , Chiacchio Ferdinando , Pappalardo Francesco , Pennisi Marzio 
Published: December 2012

Abstract
The definition of artificial immunity, realized through vaccinations, is nowadays a practice widely developed in order to eliminate cancer disease. The present paper deals with an improved version of a mathematical model recently analyzed and related to the competition between immune system cells and mammary carcinoma cells under the action of a vaccine (Triplex). The model describes in detail both the humoral and cellular response of the immune system to the tumor associate antigen and the recognition process between B cells, T cells and antigen presenting cells. The control of the tumor cells growth occurs through the definition of different vaccine protocols. The performed numerical simulations of the model are in agreement with in vivo experiments on transgenic mice.
N-acetylation and phosphorylation of Sec complex subunits in the ER membrane
Authors: Soromani Christina , Zeng Naiyan , Hollemeyer Klaus , Heinzle Elmar , Klein Marie-Christine , Tretter Thomas , Seaman Matthew N J , Römisch Karin 
Published: December 2012

Abstract

Background
Covalent modifications of proteins provide a mechanism to control protein function. Here, we have investigated modifications of the heptameric Sec complex which is responsible for post-translational protein import into the endoplasmic reticulum (ER). It consists of the Sec61 complex (Sec61p, Sbh1p, Sss1p) which on its own mediates cotranslational protein import into the ER and the Sec63 complex (Sec63p, Sec62p, Sec71p, Sec72p). Little is known about the biogenesis and regulation of individual Sec complex subunits.

Results
We show that Sbh1p when it is part of the Sec61 complex is phosphorylated on T5 which is flanked by proline residues. The phosphorylation site is conserved in mammalian Sec61ß, but only partially in birds, and not in other vertebrates or unicellular eukaryotes, suggesting convergent evolution. Mutation of T5 to A did not affect the ability of mutant Sbh1p to complement the growth defect in a Δsbh1Δsbh2 strain, and did not result in a hypophosphorylated protein which shows that alternate sites can be used by the T5 kinase. A survey of yeast phosphoproteome data shows that Sbh1p can be phosphorylated on multiple sites which are organized in two patches, one at the N-terminus of its cytosolic domain, the other proximal to the transmembrane domain. Surprisingly, although N-acetylation has been shown to interfere with ER targeting, we found that both Sbh1p and Sec62p are cotranslationally N-acetylated by NatA, and N-acetyl-proteome data indicate that Sec61p is modified by the same enzyme. Mutation of the N-acetylation site, however, did not affect Sec62p function in posttranslational protein import into the ER. Disabling NatA resulted in growth retardation, but not in co- or posttranslational translocation defects or instability of Sec62p or Sbh1p.

Conclusions
We conclude that N-acetylation of transmembrane and tail-anchored proteins does not interfere with their ER-targeting, and that Sbh1p phosphorylation on T5, which is not present in Sbh2p, plays a non-essential role specific to the Sec61 complex.
iLOCi: a SNP interaction prioritization technique for detecting epistasis in genome-wide association studies
Authors: Piriyapongsa Jittima , Ngamphiw Chumpol , Intarapanich Apichart , Kulawonganunchai Supasak , Assawamakin Anunchai , Bootchai Chaiwat , Shaw Philip J , Tongsima Sissades 
Published: December 2012

Abstract

Background
Genome-wide association studies (GWAS) do not provide a full account of the heritability of genetic diseases since gene-gene interactions, also known as epistasis are not considered in single locus GWAS. To address this problem, a considerable number of methods have been developed for identifying disease-associated gene-gene interactions. However, these methods typically fail to identify interacting markers explaining more of the disease heritability over single locus GWAS, since many of the interactions significant for disease are obscured by uninformative marker interactions e.g., linkage disequilibrium (LD).

Results
In this study, we present a novel SNP interaction prioritization algorithm, named iLOCi (Interacting Loci). This algorithm accounts for marker dependencies separately in case and control groups. Disease-associated interactions are then prioritized according to a novel ranking score calculated from the difference in marker dependencies for every possible pair between case and control groups. The analysis of a typical GWAS dataset can be completed in less than a day on a standard workstation with parallel processing capability. The proposed framework was validated using simulated data and applied to real GWAS datasets using the Wellcome Trust Case Control Consortium (WTCCC) data. The results from simulated data showed the ability of iLOCi to identify various types of gene-gene interactions, especially for high-order interaction. From the WTCCC data, we found that among the top ranked interacting SNP pairs, several mapped to genes previously known to be associated with disease, and interestingly, other previously unreported genes with biologically related roles.

Conclusion
iLOCi is a powerful tool for uncovering true disease interacting markers and thus can provide a more complete understanding of the genetic basis underlying complex disease. The program is available for download at http://www4a.biotec.or.th/GI/tools/iloci.
Helminth secretome database (HSD): a collection of helminth excretory/secretory proteins predicted from expressed sequence tags (ESTs)
Authors: Garg Gagan , Ranganathan Shoba 
Published: December 2012

Abstract

Background
Helminths are important socio-economic organisms, responsible for causing major parasitic infections in humans, other animals and plants. These infections impose a significant public health and economic burden globally. Exceptionally, some helminth organisms like Caenorhabditis elegans are free-living in nature and serve as model organisms for studying parasitic infections. Excretory/secretory proteins play an important role in parasitic helminth infections which make these proteins attractive targets for therapeutic use. In the case of helminths, large volume of expressed sequence tags (ESTs) has been generated to understand parasitism at molecular level and for predicting excretory/secretory proteins for developing novel strategies to tackle parasitic infections. However, mostly predicted ES proteins are not available for further analysis and there is no repository available for such predicted ES proteins. Furthermore, predictions have, in the main, focussed on classical secretory pathways while it is well established that helminth parasites also utilise non-classical secretory pathways.

Results
We developed a free Helminth Secretome Database (HSD), which serves as a repository for ES proteins predicted using classical and non-classical secretory pathways, from EST data for 78 helminth species (64 nematodes, 7 trematodes and 7 cestodes) ranging from parasitic to free-living organisms. Approximately 0.9 million ESTs compiled from the largest EST database, dbEST were cleaned, assembled and analysed by different computational tools in our bioinformatics pipeline and predicted ES proteins were submitted to HSD.

Conclusion
We report the large-scale prediction and analysis of classically and non-classically secreted ES proteins from diverse helminth organisms. All the Unigenes (contigs and singletons) and excretory/secretory protein datasets generated from this analysis are freely available. A BLAST server is available at http://estexplorer.biolinfo.org/hsd, for checking the sequence similarity of new protein sequences against predicted helminth ES proteins.
Novel missense mutation in the RSPO4 gene in congenital hyponychia and evidence for a polymorphic initiation codon (p.M1I)
Authors: Khan Tahir Naeem , Klar Joakim , Nawaz Sadia , Jameel Muhammad , Tariq Muhammad , Malik Naveed Altaf , Baig Shahid M , Dahl Niklas 
Published: December 2012

Abstract

Background
Anonychia/hyponychia congenita is a rare autosomal recessive developmental disorder characterized by the absence (anonychia) or hypoplasia (hyponuchia) of finger- and/or toenails frequently caused by mutations in the R-spondin 4 (RSPO4) gene.

Methods
Three hypo/anonychia consanguineous Pakistani families were ascertained and genotyped using microsatellite markers spanning the RSPO4 locus on chromosome 20p13. Mutation screening of the RSPO4 gene was carried out by direct sequencing of the entire coding region and all intron-exon boundaries.

Results
Mutations in the RSPO4 gene were identified in all families including a novel missense mutation c.178C>T (p.R60W) and two recurrent variants c.353G>A (p.C118Y) and c.3G>A (p.M1I). The c.3G>A variant was identified in unaffected family members and a control sample in a homozygous state.

Conclusions
This study raises to 17 the number of known RSPO4 mutations and further expands the molecular repertoire causing hypo/anonychia. The c.353G>A emerges as a recurrent change with a possible founder effect in the Pakistani population. Our findings suggest that c.3G>A is not sufficient to cause the disorder and could be considered a polymorphism.
Statins and the risk of gastric cancer in diabetes patients
Authors: Lee Jeeyun , Lee Soo Hyeon , Hur Kyu Yeon , Woo Sook Young , Kim Sun Woo , Kang Won Ki 
Published: December 2012

AbstractBackgroundSeveral studies have suggested a cancer risk reduction in statin users although the evidence remains weak for stomach cancer. The purpose of this study was to use an exact-matching case–control design to examine the risk of gastric cancer associated with the use of statins in a cohort of patients with diabetes.MethodsCases were defined as patients with incident gastric cancer identified by International Classification of Diseases 16.0 ~ 16.9 recorded at Samsung Medical Center database during the period of 1999 to 2008, at least 6 months after the entry date of diabetes code. Each gastric cancer case patient was matched with one control patient from the diabetes patient registry in a 1:1 fashion, blinded to patient outcomes.ResultsA total of 983 cases with gastric cancer and 983 controls without gastric cancer, matched by age and sex, were included in the analysis. The presence of prescription for any statin was inversely associated with gastric cancer risk in the unadjusted conditional logistic regression model (OR: 0.18; 95% CI: 0.14 – 0.24; P < .0001). Multivariate analysis using conditional logistic regression with Bonferroni’s correction against aspirin indicated a significant reduction in the risk of gastric cancer in diabetes patients with statin prescriptions (OR: 0.21; 95% CI: 0.16 – 0.28; P < .0001). After adjustment for aspirin use, a longer duration of statin use was associated with reduced risk of gastric cancer, with statistical significance (P<.0001).ConclusionsA strong inverse association was found between the risk of gastric adenocarcinoma and statin use in diabetic patients.
The allogeneic umbilical cord mesenchymal stem cells regulate the function of T helper 17 cells from patients with rheumatoid arthritis in an in vitro co-culture system
Authors: Wang Qin , Li Xiaofeng , Luo Jing , Zhang Li , Ma Lihui , Lv Zhiqin , Xue Lijin 
Published: December 2012

Abstract

Background
Previous in vivo studies have shown that mesenchymal stem cell (MSC) transplantation significantly improves the condition of a number of autoimmune diseases including autoimmune cerebrospinal meningitis, multiple sclerosis, glomerulonephritis and systemic lupus erythematosus.

Methods
To investigate the immunoregulatory effect of stem cell transplantation, human umbilical cord MSCs were co-cultured with peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA). Orphan nuclear receptor gamma (ROR-γ) mRNA and protein expression was detected with real-time PCR and Western blotting. Interleukin (IL)-17, IL-6 and tumor necrosis factor (TNF-α) in the cell culture supernatant were measured using a flow cytometric bead capture method.

Results
After 72 hours of co-culture, the mRNA and protein expression levels of ROR-γ in co-cultured PBMCs were decreased compared with that in PBMC of RA patients cultured alone (p < 0.05). Moreover, the decrement was positively related to the disease activity of RA (p < 0.05). Decreased secretion of IL-17, TNF-α and IL-6 were also found in co-culture supernatants of PBMCs from patients with severe and moderate disease activity, but not in supernatant from PBMCs cultured alone. The decreased cytokine expression levels were positively correlated to the concentrations of MSCs. In contrast, PBMCs from healthy controls or patients with mild RA did not show significant differences in ROR-γ expression or cytokine secretion following co-culture with MSCs as compared with those cultured alone.

Conclusions

In vitro co-culture with MSCs down-regulated the inflammatory response of PBMCs from RA patients with severe disease activity, but had no significant effect on PBMCs from healthy controls or patients with mild disease activity, suggesting that the immunoregulatory role of MSCs may associate with the occurrence of inflammatory mediators.