dataesr/scientific-paragraphs-categorization huggingface dataset:
The inevitable consequence is that patients at the margins of these bands receive either lower or higher weight adjusted dosages. Furthermore, paediatric doses are often extrapolated from adult doses, since detailed pharmacokinetic data in children are frequently unavailable  [15]. Thus, as detailed studies of a newly introduced drug are conducted, reassessment of the original dosing recommendations based on a much larger body of evidence are needed to ensure that the original target doses are optimal for the key target populations, most notably the young children who carry the highest burden of disease in high intensity malaria transmission areas. The Worldwide Antimalarial Resistance Network (WWARN) brings together malaria researchers from across the world. This collaborative resource provides a unique opportunity to conduct a series of individual patient data meta-analyses in which the dosing strategies of the recommended ACTs can be reviewed, to define the spectrum of treatment doses actually administered, and the degree to which these dose variations impact on the therapeutic efficacy  [16].
Data Pooling All published antimalarial clinical trials reported in PubMed were identified through a systematic search of the literature of publications between 1st January 1960 and 15th February 2013. A further search was then made for those studies enrolling patients and treating them with DP. Further information on these literature reviews are available on the WWARN website  [16]. Specific details on the relevant DP studies are presented in Texts S1 and S2  [11] [12] [13]. Since the literature review was conducted, a further three clinical studies enrolling 408 patients treated with DP have been published. All research groups who have contributed to the WWARN data repository were also asked whether they were aware of any unpublished or ongoing clinical trials involving DP. Individual study protocols were available for all trials, either from the publication or as a metafile submitted with the raw data.
The principal investigators of relevant studies were invited to contribute individual patient data to WWARN for a collaborative metaanalysis. A study was deemed eligible for the meta-analysis if patients were recruited and treated with DP and evaluated prospectively for clinical efficacy against P. falciparum (either alone or mixed infections), for a minimum of 28 days. Studies were included only if information was available on the treatment dose administered, the age and weight of the patient, and if genotyping was performed to distinguish between new infections and recrudescent infections. Both randomized and non-randomized studies were included. Data were anonymised, uploaded to the WWARN repository, and standardised using a methodology.
Ethical Approval All data included in this analysis were obtained in accordance with the laws and ethical approvals applicable to the countries in which the studies were conducted, and were obtained with the knowledge and consent of the individual to which they relate. Data were fully anonymised either before or during the process of uploading to the WWARN repository. Ethical approval to conduct individual participant data pooled analyses was granted to WWARN by the Oxford Tropical Research Ethics Committee (OxTREC).
Statistical Analysis All statistical analyses were carried out using R (Version 2. 14. 0, The R Foundation for Statistical Computing), on the basis of an a priori statistical plan  [40]. The full statistical plan is available in Text S5. The primary endpoint used in this analysis was the PCRadjusted risk of P. falciparum recrudescence at the end of study follow-up. Secondary endpoints included the new infections of P. falciparum, parasitological clearance rates, and gametocyte carriage. The incidence risk of these endpoints at day 28, day 42, and day 63 was computed using survival analysis (Kaplan-Meier [K-M] estimates). Definitions of outcome status and censoring are detailed in the WWARN Clinical Module DMSAP v1. 2  [38]. The K-M estimates were generated using all the individual patient data and any comparison of K-M survival curves were performed using log rank tests stratified by study and study site.
The risk remained significant after adjusting for baseline parasitemia, and the mg/kg dose of PIP (AHR = 3. 22 [95% CI 1. 42-7. 33; p = 0. 005]). The population attributable risks of recrudescence are presented in Table  6. Overall, the model accounted for 65. 1% of all treatment failures, with a low dose of PIP accounting for 7. 7% and children from 1 up to 5 years of age for 53. 5%. In    [12, 17, 18, 26, 29, 36]. The results for  Ashley-2004 [19]  and  Ashley-2005 [20]  are presented pooled since the datasets did not distinguish between the studies. doi:10. 1371/journal. pmed. 1001564. g003 In the multivariable model every 5 unit increase in mg/kg dose of PIP was associated with a 13% (95% CI 3-22%) decrease in risk of recrudesecence; p = 0. 013. In a predicted risk model, generated from patients' individual covariates, a dose of 59 mg/kg PIP was sufficient to ensure a day 42 cure rate above 95% (Figure  4 ).
6% (530/4,560) of patients. After controlling for age, parasitemia, and fever at presentation the risks of vomiting or diarrhoea were not correlated with the mg/kg dose of PIP. A total of 21 severe adverse events (SAEs) were reported from five studies (n = 2,873), but in none of the patients in eight other studies (n = 1,120). In the remaining 13 studies, severe adverse events were not reported or the data were unavailable. These severe events included one patient with diarrheal disease, considered unrelated to treatment who died, three patients with severe anaemia, three with recurrent vomiting, two with pyomyositis, two with acute pyelonephritis, two with recurrent P. falciparum infections, and one patient each with one of the following: abnormal skin, a swollen arm, anorexia, aspiration pneumonia, cerebritis, convulsions, high fever, and hyperparasitemia P.
Our study has a number of limitations. Although the clinical data used in the analysis constitute almost 70% of the relevant published literature on this treatment regimen, eight studies (2,100 patients) and 170 patients from targeted studies were not available. No specific reasons were given by the investigators for being unable to join the study group, but the majority of these were from Asia. Comparison of the more complete dataset from Africa showed no regional differences in our analysis suggesting that a systematic attrition bias was unlikely. Another limitation of the study is that only in 23% (1,669/7,072) of patients, could drug doses be calculated from the actual number of tablets administered, the total dose in the remainder being extrapolated from the number of tablets predicted to have been administered according to age and weight criteria defined in the study protocol, assuming complete adherence by the attending clinical staff.
Although errors in drug administration may have occurred these were generally identified and the patients censored from analysis. Reassuringly, a sensitivity analysis of a subgroup of patients in whom the exact number of tablets was recorded generated identical parameters to the models of the complete dataset. Another limitation arose from DP being a fixed dose combination, making it impossible to determine whether the observed treatment effects were attributable to the dose of PIP, DHA, or a combination of both. The initial reduction in parasite biomass is widely regarded as being determined by the artemisinin derivative because of its significantly higher potency and faster action, whereas the parasite biomass remaining after 3 days of artemisinin exposure is dependent on its elimination by the intrinsically less active partner drug with longer half-life.
falciparum malaria in 2010) by undertaking a pooled analysis of individual patient data collected during ACT clinical studies. What Did the Researchers Do and Find? The researchers identified all the studies published between 1960 and February 2013 in which patients were treated with DP and obtained individual patient data for almost 70% of study participants (more than 7,000 patients living in Asia, Africa, and South America) from the principal investigators. These data were pooled and statistical models were used to identify risk factors for parasite recrudescence (parasite genotyping was used to correct for re-infection with a new parasite). Overall, DP treatment was successful (judged by parasitological clearance) in 97. 7% and 97. 2% of patients at day 42 and 63, respectively, after treatment.
Acknowledgments We would like to thank the patients and all the staff that participated in these clinical trials at all the sites. We are grateful to  Claude Faurant ,  Tanilu Grande ,  Louis Goubert , and  Piet A. Kager  who contributed to the data collection. We would like to thank colleagues at  MMV ,  Sigma Tau Industrie Farmaceutiche Riunite  who have shared their data for the purposes of this analysis. The complete author affiliation and contributions are listed in Text  S6. The members of the  WorldWide Antimalarial Resistance Network (WWARN) Study Group  are the authors of this paper:  Jane Achan ,  Uganda Malaria Surveillance Project, Kampala, Uganda; Ishag Adam, Faculty of Medicine, University of Khartoum, Khartoum, Sudan; Emmanuel Arinaitwe, Infectious Diseases Research Collaboration, Kampala, Uganda; Elizabeth A Ashley, Shoklo Malaria Research Unit, Mae Sot, Thailand/Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Ghulam Rahim Awab, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand/Ministry of Public Health, Islamic Republic of Afghanistan, Kabul, Afghanistan ;  Mamadou S Ba ,  Department of Parasitology, Faculty of Medicine, University Cheikh Anta Diop, Dakar, Senegal ;  Karen I Barnes ,  Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa ;  Quique Bassat ,  Centro de Investigacao em Saude de Manhica, Manhica, Mozambique/Centre de Recerca en Salut Internacional de Barcelona (CRESIB) ,  Barcelona, Spain ;  Steffen Borrmann ,  Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya/ Heidelberg University School of Medicine, Dept.
WWARN is funded by a  Bill & Melinda Gates Foundation  grant. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EAA has worked as an investigator on studies of dihydroartemisinin-piperaquine sponsored by both  Holley-Cotec  and  Medicines for Malaria Venture. EAA  and FN have received research funding from  Holley-Cotec. KIB serves as a member of a number of malaria-related World Health Organization committees, including the  Malaria Chemotherapy Technical Expert Group. KIB is a recipient of a research grant from the  Medicines for Malaria Venture  and is a sub-recipient of grants from the  Bill & Melinda Gates Foundation. QB has received speaker fees and travel grants from  Sigma Tau. UDA has received research funding and several travel grants from  Sigma Tau ; UDA has been a consultant for Sigma Tau on dihydroartemisinin-piperaquine.
1% Tween and 5% nonfat milk and incubated overnight at 4°C with anti-β-actin (1:1500). For eNOS and eNOS phosphorylation, the membrane was blocked for 30 minutes at 37°C in Tris-buffered saline buffer containing 0. 1% Tween and 5% bovine serum albumin and then incubated overnight at 4°C with anti-eNOS (1:1000) or anti-eNOS phosphorylation (1:1000). Immunoreactive proteins were revealed by enhanced chemiluminescence after incubation for 2 hours at room temperature with horseradish peroxidase-conjugated secondary antibodies. 22 The intensity of the chemiluminescent spots was estimated semiquantitatively using Kodak Molecular Imaging software and expressed as the ratio between intensity of the spot of interest and intensity of the β-actin bands. 23.
Characterization of nanoparticles The liposomes and PACA were characterized by dynamic laser light scattering, as described elsewhere. 1, 2 The plain liposomes had a mean diameter of 120 ± 10 nm with a negative zeta potential of -25. 5 ± 0. 9 mV, that was slightly smaller in liposomes embedding anionic phospholipids (phosphatidic acid or cardiolipin). The particle size and zeta potential remained constant for up to 72 hours, within the experimental error. The PACA had a mean diameter of 160 ± 3 nm and a negative zeta potential of -24 ± 4 mV, that was decreased slightly for PEG-PACA. These data are very similar to those already reported. 1, 2 The solid lipid nanoparticles had a mean diameter of 250 ± 20 nm and a negative zeta potential of -41 ± 1. 60 mV, that decreased slightly after functionalization with phosphatidic acid (-44 ± 1.
Cell viability after exposure to nanoparticles The viability of HUVECs and RAW264. 7 cells in response to exposure to the different doses of nanoparticles was assessed. Treatment of macrophages with plain liposomes and PA-LIP significantly decreased cell viability in a dosedependent manner (from 6 µg/mL to 120 µg/mL of total lipids), whereas treatment with CL-LIP decreased cell viability by about 30% at all concentrations tested (Figure  1 ). None of the liposomes tested induced a reduction in the viability of HUVECs (data not shown). When using solid lipid nanoparticles or PA-SLN, a dose-dependent decrease in cell viability was found for both HUVECs (Figure  2A ) and macrophages (Figure  2B ). In general, macrophages showed much higher cellular suffering (IC 50 solid lipid nanoparticles, 100 ± 10 µg/mL; IC 50 PA-SLN, 110 ± 9 µg/mL) than HUVECs (IC 50 solid lipid nanoparticles, 7000 ± 510 µg/mL; IC 50 PA-SLN, 3500 ± 210 µg/mL) after exposure to solid lipid nanoparticles or PA-SLN.
Nitric oxide production by cells exposed to nanoparticles Nitric oxide levels in HUVECs and RAW264. 7 cells were measured after exposure to the different doses of nanoparticles. PA-LIP and CL-LIP at the highest dose (120 µg/mL of total lipids) significantly increased nitric oxide production in HUVECs (by approximately 21% and 27%, respectively) compared with nonexposed cells (Figure  4 ). The macrophages did not show an increase in nitric oxide production (data not shown). Increased nitric oxide production was detected when HUVECs were exposed to solid lipid nanoparticles and PA-SLN, starting from 100 µg/mL for solid lipid nanoparticles and from 150 µg/mL for PA-SLN ( Figure  5A ). In macrophages, Notes: Cells were incubated with different concentrations (6-120 µg/mL) of plain LIP, PA-LIP, or CL-LIP for 24 hours, and production of nitric oxide was measured in conditioned medium using the Griess method.
Discussion Engineered nanomaterials are now being shown to be interesting biomedical tools, and are potentially able to resolve concerns about efficacy, cellular uptake, and specific transport of drugs and/or imaging agents to target organs, in particular in the case of neurodegenerative diseases like Alzheimer's Disease. 25, 26 n a series of investigations carried out within the framework of the FP7 EU project known as NAD (Nanoparticles for therapy and diagnosis of Alzheimer's Disease), we designed a series of lipid and polymer-based nanoparticles able to bind with high affinity to aggregate forms of β-amyloid peptide 1,2 and to reduce cytotoxicity  4  or aggregation of the peptide in vitro. 2, 27 n order to evaluate cytotoxicity after administration in vivo, we measured nitric oxide production by cultured primary HUVECs and mouse macrophages (RAW264.
27 e A ˚À3 Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: CORINC (Dra ¨ger & Gattow, 1971); program(s) used to solve structure: SIR97 (Altomare et al. , 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: PLATON.
Refinement Hydrogen atoms attached to carbons were placed at calculated positions with C-H = 0. 95 Å (aromatic) or 0. 98-0. 99 Å (sp 3 C-atom). All H atoms were refined in the riding-model approximation with isotropic displacement parameters set at 1. 2-1. 5 times of the U eq of the parent atom. program(s) used to refine structure: SHELXL97  (Sheldrick, 2008) ; molecular graphics: PLATON  (Spek, 2009) ; software used to prepare material for publication: PLATON  (Spek, 2009). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0. 001 Δρ max = 0. 25 e Å -3 Δρ min = -0. 27 e Å -3.
Introduction and Background: IL-17 pathway is being clinically targeted in immune-mediated diseases, most of which are associated with a significant cardiovascular risk. We investigated the relationship between serum levels of IL-17 and the risk of cardiovascular events in patients with acute myocardial infarction. Patients (or Materials) and Methods: We used data from patients enrolled in the prospective, multicenter French registry of acute ST elevation or non-ST-elevation myocardial Infarction (Fast-MI, NCT00673036). Of the 374 centers in France that treated patients with acute MI, 223 (60%) participated in the registry. Among these, 100 centers recruited 1029 patients who contributed to a serum bank. Their baseline characteristics were comparable to the overall population of the registry.
Patients (or Materials) and Methods: A randomized doubleblind noninferiority clinical trial (NCT01586143) included 38 patients admitted to the Accident and Emergency Department of Clermont-Fd University Hospital, France, for trauma of the upper or lower limb, and with pain intensity between 4 and 6 on a 0 to 10 numerical scale (NS). Patients were injected at t0 over a 15-minute period with placebo (0. 9% saline) or APAP (1 g) and concomitantly, 125 mg of APAP dissolved in 1 mL of an hydroalcoholic solution (HAS) or placebo (HAS only) was applied in the left mucogingival sulcus. Patients were asked not to swallow for 1:30 minutes. NS evaluations were done at t10, t30, t120, and t180 minutes after administration. Primary end point was the pain intensity difference (PID) between t30 min and t0.
Acknowledgments. The authors thank the organizers, panelists and presenters for break out session 3:  Huub-Jan Kleijn  (MSD), Matts Kågedal (AZ),  Chyi-Hung Hsu  (J&J),  Wolfgang Köpcke (EMA) ,  Peter Bauer  ( University of Vienna ),  Martin Posch  (EMA),  Ralf Herold  (EMA),  Trevor Johnson  (Simcyp),  Joe Standing  (GOSH),  Stephanie Läer  ( Heinrich-Heine University ) and  Christophe Male  ( Medical University of Vienna ).
Background: The advent of direct-to-consumer (DTC) genetic testing (GT) has sparked a number of debates regarding the scientific validity of tests, their broad health and ethical implications for society as well as their legal status. To date, relatively few empirical studies have been published regarding this phenomenon. We conducted a survey of European clinical geneticists to gauge their awareness of, experiences with, and attitudes towards DTC GT. Methods: We invited 300 clinical geneticists from 28 European countries to complete an online questionnaire. Statistical analyses of closed-ended questions were performed using the STATISTICA software package. Answers to open-ended questions were analysed for recurring themes. Results: One hundred and thirty-one clinical geneticists answered our survey (response rate, 44%).
The concentration of vitamin E was measured using an HPLC system (Agilent System series 1100, Agilent Technologies, California, USA). The HPLC equipment consisted of a pump, an auto-sampler and a UV/VIS detector. The column used was a LiChrospher RP C18 column (5 µm, 15 cm  0. 46 cm) (Supelco, Bellefonte, USA). The separation was carried out using a mixture of methanol and water (96:4 v/v) as the mobile phase at a flow rate of 1. 6 ml/min. The eluent was monitored at 292 nm and peaks were recorded using the chromatography data system software provided by Agilent. Before the chromatographic data were collected, the column was equilibrated for 30 min with a minimum of 30 column volumes. At the end of the assay, the column was washed using water -acetonitrile mixture (50:50 v/v) for 60 min. This HPLC analytical method was validated (data not shown).
The average GϩC content of the draft genome sequences is 47. 5%. Nucleotide sequence accession numbers. The draft genome sequences for the strains B-7195 and B-7194 have been included in the European Nucleotide Archive at EMBL-EBI (http://www. ebi. ac. uk/ena/data/view/) under the accession numbers CBKR010000001 to CBKR010000261 and CBKS010000001 to CBKS010000240, respectively.
ACKNOWLEDGMENTS This work was supported by the  Centre National de la Recherche Scientifique (CNRS) ,  France  ( PICS  project number  5516 ), and the  Russian Foundation for Basic Research  (project number  10-04-91057 ). This work has benefited from the facilities and expertise of the highthroughput sequencing platform of  IMAGIF (Centre de Recherche de Gif  [http://www. imagif. cnrs. fr]).
Gene expression studies by RT-qPCR and microarrays Total RNA was extracted using TRIzol reagent (Life Technologies, Saint Aubin, France). For real-time quantitative polymerase chain reaction (qPCR), 2 mg of total RNA were reverse transcribed with the High Capacity cDNA reverse transcription kit (Life Technologies, Saint Aubin, France). Amplifications with specific primers (Table  1 ) and SYBR Green fluorescence monitoring (Power SYBR Green PCR Master Mix from Life Technologies, Saint Aubin, France) were performed on a Viia7 instrument (Life Technologies, Saint Aubin, France). qPCR data were normalized by the geometric mean of TATAbox binding protein (Tbp) and RNA polymerase II polypeptide A (Polr2a) mRNA levels and analyzed using the 2-DCt method. Microarray data were obtained from 1 mg of hepatic total RNA labeled with Cy3 using One-Color Quick Amp Labeling kit (Agilent, Massy, France) and hybridized to Agilent Whole Rat Genome microarrays (4x44K) following the manufacturer's instructions.
Statistical analysis Data were analyzed under R (R 1 2. 13. 0, www. r-project. org). Microarray data were analyzed using packages from Bioconductor (www. bioconductor. org). Details of microarray data analysis, together with raw and processed microarray data can be found in GEO entry GSE39378. Differentially expressed probes were identified using the limma and q-value packages. Probes with a qvalue 0. 1 were considered significant. All other data were analyzed by ANOVA with the appropriate factors as fixed effects (depending on the experimental design: treatment, genotype and their interaction) followed by Student's t-test with a pooled variance estimate to compare the group's means. Data are presented as mean AE SEM.
An analysis of our microarray data through the use of IPA (Ingenuity Systems, www. ingenuity. com) also suggested that CAR and PXR were the major upstream regulators of liver gene expression upon fipronil treatment (data not shown). We first evaluated this hypothesis by comparing our gene expression profiles to those obtained by Ren et al. [19, GEO record GSE14712]  in female rats exposed to phenobarbital (CAR and PXR activator) or PCN (PXR activator). Despite a limited overlap between the contents screened by Affymetrix and Agilent rat microarrays, we could show that approximately half of the genes regulated by fipronil in rat liver were also regulated by PB and/or PCN (Fig. 2B ). Finally, we confirmed by qPCR the upregulation by fipronil of several genes involved in the metabolism and transport of xenobiotics and endogenous compounds (Fig.