dataesr/scientific-paragraphs-categorization huggingface dataset:
1 serious cardiovascular events per 100,000 patient-years. The authors concluded that there was no evidence that the use of ADHD drugs was associated with an increased risk of serious cardiovascular events. The methods and conclusions of this study are at odds with those of the study by  Gould et al. (2009)  showing an association between use of psychostimulants and risk of sudden death in children and adolescents, hence the call from the FDA to adhere strictly to prescription recommendations. Through its amphetamine-like properties, methylphenidate also exerts anorexigenic effects. In the UK pharmacovigilance database, anorexia is the most frequently reported side effect in children treated for ADHD, representing 34% of all reports  (Tobaiqy et al. 2011). These findings confirm reports from the WHO's Vigibase database indicating that in the 2-11 year age group, ADHD drugs account for 14% of reports, with anorexia cited most often  (Star et al.
Conclusion Despite restricted conditions for the prescription of methylphenidate in France, we observed a progressive increase in the number of spontaneous reports of ADRs, with a high proportion of off-label use, in a national pharmacovigilance database. In half the reports where the use was considered to be off-label, the ADR was classed as serious. The widespread use of methylphenidate in adults is a cause for concern. The diagnosis of adult ADHD remains imprecise, and methylphenidate is not indicated in this context at the present time. The profile of side effects appears to differ between adult and paediatric populations, with greater risk of misuse, increased doses, probable cardiovascular effects and disinhibition in adult users. The use of methylphenidate in women aged >18 years incurs a risk of exposition during pregnancy, with potential teratogenic effects.
Nevertheless, this method is strongly limited by the number of ions  [6, 7]  and when the density of the trapped ion cloud increases, space charge effects get stronger, leading to frequency shifts, peak broadening and screening effects which makes the selective re-centering inefficient. First simulations have been performed with the SIMBUCA program  [12] , which directly calculates the Coulomb interaction between the particles and therefore is well suited for the investigation of space charge effects. In these simulations, an ion ensemble with 10% of 136 Sb and 90% of 136 Te are first excited for 4 ms at the magnetron frequency. Then a quadrupolar excitation is applied for 300 ms at ω c of 136 Sb, using helium as a buffer gas at a pressure of 10 -4 mbar. Figure  2  shows the efficiency of the selective re-centering as a function of the total number of ions.
Methods Our methodology is based on a study by  Vogeli et al. (2007 [11] ), presented as a semi-structured literature review consisting in a two-step bibliographic search: an initial search targeting the heart of the subject (for Vogeli, articles identified in PubMed with the MeSH terms ''chronic diseases'' and ''comorbidity''), and then a second search based on the articles identified in the first step, this time targeting more specific characteristics (for Vogeli, for example: prevalence, access to care, mortality rate, and healthcare expenditures). In order to collect material for analysis, we did a primary search on the PubMed database on July 16, 2013, using the following search string: ''multipathology'' [Title/Abstract] or That primary search was supplemented by a second literature search in three other databases -Embase, CINAHL, and Scopus -using the same search criteria.
The aim of the second search was basically to verify whether the results found in PubMed were representative of the problem, and if not, to fill in any references missing from the first selection. Note that, to the best of our knowledge, there are currently no MeSH terms dedicated to multiple chronic conditions. In addition, we tested the same search string with the prefix ''comorbid*'' added. We applied secondary criteria to choose articles for a full reading, to cover the following four areas: the definitions of, or if lacking, the measures used to identify people with, multimorbidity; the epidemiological data regarding multimorbidity (prevalence and determinants); the factors associated with it (mortality, functional capacity, and quality of life); and the organization-of-care targeting multimorbidity.
We can also note that one definition of multimorbidity is based on the risk of high future healthcare utilization  [16]. Conversely, the 2012 Brilleman and Salisbury study  [36]  compared the usefulness of different measures of multimorbidity in terms of the primary outcome to be measured. It turns out that the number of drugs prescribed was the best predictor of future outpatient visits, and the second-best predictor of mortality. However, most of the indices were good predictors of 3-year mortality. Another important aspect of the epidemiological approach of multimorbidity relies on novel and expanding ways to harvest and analyze personal and population data. The information and healthcare systems are increasingly developing in hospitals and many healthcare or health-related databases are already available (e.
g. , claims databases). In France, the Programme de medicalisation du systeme d'information (PMSI) is both a medical and administrative database. The main medical data available in the PMSI are the primary diagnosis (the primary motive for being in the hospital at this time) and the secondary or associated diagnoses (co-occurring diseases or complications of the primary motive, for example). From this point of view, approaches and measures of multimorbidity are obviously limited or biased. The structure and composition of medical databases can thus be an important obstacle to the development of appropriate or novel approaches  [37, 38]. Nonetheless, the integration of data of diverse types (e. g. social habits or lifestyle) may address these issues. This is the purpose of so-called big data  [39].
Thermal, mechanical and metallurgical models A residual stress model has to integrate thermal, mechanical and metallurgical models which play important roles in the generation and evolution of residual stresses. Each model has a strong interaction with others (Fig. 2 ). The thermal conditions during heat treatment and notably during quenching are parameters of first order. For vapourisable media like water, quenching trials with thermocouples are necessary due to the complexity of the liquid flow and phase transformation  [3]. Nowadays, these data are completed by evident progress made in Computational Fluid Dynamics (CFD). In the case of a disk cooled by blown air, the software THOST R codeveloped by Aubert&Duval can be used to study the air flow (Fig. 3 ). A constitutive law specifically developed for residual stresses is required.
As the growth is epitaxial, the lattice spacing in the in-plane (xdirection) does not change. However, in the growth (z-direction) the lattice parameter is expanded relative to the unstrained substrate due to the presence of Ge and it is this relative expansion which is measured. The dark holography experiments were performed using a probe corrected FEI Titan operated at 200 kV, the precession NBED (PED) and the HAADF STEM experiments were performed using a double corrected FEI Titan operated at 200 kV. All of the data was processed using software written at CEA.
Measurements of CO 2 , CO, NO x and selected Volatile Organic Compounds (VOCs) concentrations have been performed continuously during ten days in the Guy Môquet tunnel in Thiais, in a peri-urban area about 15 km south from the centre of Paris, between 28 September and 8 October 2012. This dataset is used here to identify the characteristics of traffic-emitted CO 2 by evaluating its ratios to co-emitted species, for the first time in the Paris region. High coefficients of determination (r 2 > 0. 7) are observed between CO 2 and some compounds which are characteristic of the traffic source (CO, NO x , benzene, xylenes and acetylene). Weak correlations (r 2 < 0. 2) are found with species such as propane, n-butane, i-butane, that are associated with fuel evapora-ACPD 14, 20197.
Most of the regional CO 2 emissions are concentrated in the Paris metropolitan area. They are attributed essentially to the residential and tertiary sectors (43 %) and to traffic (29 %). As is quite common for emission inventories, there is no independent quantitative assessment of the Airparif database, and its uncertainties are poorly constrained. Moreover, Airparif emission estimates are based on activity proxies, calibrated from benchmark situations that may significantly differ from real ones. For instance, chassis dynamometer tests  (Bosteels et al. , 2006)  characterized the vehicle emissions under controlled conditions and fuel composition, but cannot represent the diversity of real driving conditions well and fleet composition. Therefore independent evaluations of the inventory are needed and atmospheric Figures measurement programs around the Paris megacity such as the CO 2 -Megaparis project that sample the actual emission plume  (Xueref-Remy et al.
Back Close Full Laboratory, Teddington, UK). Mean response factors of these three injections were used to calibrate NMHC during the campaign. NMHC concentrations in ambient air were estimated on 2 October 2012 between 13:50 and 16:30 LT. The total uncertainty on the data was estimated better than 15 %. A chemiluminescent analyser (API TELEDYNE, model T200UP) continuously measured Nitrogen Oxides (NO and NO 2 ) concentrations with a time resolution of 1 min. Calibration of the instrument is regularly checked at the laboratory by injecting 30 ppb from a 10 ppm NO calibration gas mixture (Air Liquide, France). In order to check the calibration parameters within the range of values expected in the tunnel, 500 ppb of NO from the Air Liquide standard were injected in the instrument prior to the campaign.
In most cases, it indicated that the inventory overestimates the ratios to CO 2 , even though satisfactory agreement is found for the CO to CO 2 , n-pentane to CO 2 , n-propylbenzene to CO 2 and xylenes to CO 2 ratios. VOC emissions for the traffic sector are the most overestimated, suggesting that the VOCs speciation matrix should be updated in the inventory, in order to account for the latest regulations about fuel composition. The evaluation of the mean ratios for the whole regional inventory indicated significant spatial variability in the inventory data. The fact that the best fit to our measurements is seen when the inventory data for the tunnel road is isolated, suggests some skill in this inventory variability. The satisfactory agreement found for several ratios to CO 2 suggests that data from the inventory are representative of low speed regimes.
of the measurement. Thus for each compound measured by the other instruments, data were averaged on the same 10 min interval. Doing so, all the final data have a time step of 30 min with a resolution of 10 min. NO and NO 2 data were screened because of the characteristics of the analyser. Since the instrument saturated when NO concentrations reach 2300 ppb, a filter was applied to remove the NO and NO 2 data when the NO concentration exceeds 2200 ppb. Figures Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper |.
ACPD ACPD ACPD ACPD ACPD ACPD ACPD ACPD ACPD ACPD ACPD ACPD Acknowledgements. We thank  Tiphaine Le Priol  and  Jean-François Petit  from the  DRIEA-CETE-IF  for the logistics and technical preparation of the Thiais tunnel experiment and for providing us data about vehicle density and speed during our experiment. INERIS is gratefully thanked for its logistical help in the field. We thank  Irena Jesek  and  Grisa Mocnik  for their help during the campaign and for the fruitful discussions. We thank the  PRIMEQUAL  " PREQUALIF " and  ANR-CO 2 -MegaParis  projects for allowing us to carry out this measurement campaign. This work was supported partly by  CNRS  and  CEA. We thank the  ICOS-France team  for the calibration of the CO 2 tanks to the  NOAA  scale.
Because sensitive and specific laboratory tests are largely unavailable, the burden of disease and epidemiological data are often unreliable and do not allow informed disease prioritization and efficient control. We report the use of serum spotted on filter paper to improve the surveillance of leptospirosis in remote and resource-limited settings. Methods: A total of 172 acute-phase serum samples collected from patients with suspected dengue at Yap State Hospital, Federated States of Micronesia, were spotted on filter paper and sent by regular mail to the Institut Louis Malarde, French Polynesia. Real-time PCR protocols for dengue and leptospirosis confirmation were performed on all specimens. Results: A total of five leptospirosis infections were detected amongst the patients with suspected dengue.
Introduction: The MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions? Methods: Using high-resolution melt curve analysis followed by Sanger sequencing, we mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls.
Rare variants in the three genes were pooled using bioinformatics methods similar to those previously applied to ATM, BRCA1, BRCA2, and CHEK2, and then assessed by logistic regression. Results: Re-analysis of our ATM, BRCA1, and BRCA2 mutation screening data revealed that these genes do not harbor pathogenic alleles (other than modest-risk SNPs) with minor allele frequencies >0. 1% in Caucasian Americans, African Americans, or East Asians. Limiting our MRN analyses to variants with allele frequencies of <0. 1% and combining protein-truncating variants, likely spliceogenic variants, and key functional domain rare missense substitutions, we found significant evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes (odds ratio (OR) = 2. 88, P = 0. 0090). Key domain missense substitutions were more frequent than the truncating variants (24 versus 12 observations) and conferred a slightly higher OR (3.
Alignments and scoring of missense substitutions We used M-Coffee  [29] , which is part of the Tree-based consistency objective function for alignment evaluation (T-Coffee) software suite of alignment tools  [30]  to prepare a protein multiple sequence alignment for each of the three MRN proteins (MRE11A, RAD50 and NBN) in order to predict the effect of missense substitutions on the proteins and on the activity of the MRN complex. Each alignment consisted of sequences from 16 species: Homo sapiens, Macaca mulatta, Callithrix jacchus, Mus musculus, either Sus scrofa or Bos Taurus, Loxodonta africana, Dasypus novemcinctus, Monodelphis domestica, Ornithorhynchus anatinus, Gallus gallus, Anolis carolinensis, either Xenopus tropicalis or Xenopus laevis, Latimeria chalumnae, either Fugu rubripes or Danio rerio, Branchiostoma lanceolatum, and Strongylocentrotus purpuratus.
The alignments were characterized using the Protpars routine of Phylogeny Inference Package version 3. 2 software (PHYLIP)  [31]  to make a maximum parsimony estimate of the number of substitutions that occurred along each clade of the underlying phylogeny. The sequence alignment, or updated versions thereof, is available at the Align Grantham variation Grantham deviation (Align-GVGD) website  [32]. Missense substitutions observed during our mutation screening of the three MRN genes were scored using the Align-GVGD and Sorting Intolerant from Tolerant (SIFT) software programs with our curated alignments, and with polymorphism phenotyper (PolyPhen-2. 1) software using its precompiled alignments  [33] [34] [35]. In brief, Align-GVGD grades missense substitutions against a protein multiple sequence alignment based on a combination of Grantham Variation (GV), which measures the amount of physicochemical variation at a particular position in the alignment, and Grantham Deviation (GD), which measures the physicochemical difference between the missense residue and the range of variation observed at its position in the protein.
, manuscript in preparation. Thus these MES-based rules were used to identify rare sequence variants that are likely to alter MRN gene mRNA splicing. Analysis of rare variant threshold frequency from ATM, BRCA1, BRCA2, and CHEK2 data For ATM, we examined the relationship between sequence variant frequency and breast cancer risk as follows. Frequencies for all of the variants included in our 2009 ATM case-control mutation screening meta-analysis  [19]  were extracted from the EVS (for Caucasian American and African American frequencies) or UK National Genetics Reference Laboratory Manchester (NGRL Manchester) summary of 1000G data (for East Asian allele frequencies)  [40]. T + SJV (as defined in  [19] ) plus missense substitutions and in-frame indels falling from position 1960 through the end of the protein were then grouped into the following allele frequency bins: 1% to 0.
32%, 0. 32% to 0. 10%, 0. 10% to 0. 032%, <0. 032%. ORs for each bin were then estimated by logistic regression, adjusting for study, ethnicity and mutation-screening method employed, using Stata version 11 software (StataCorp, College Station, TX, USA). CHEK2 sequence variants included in our 2011 CHEK2 case-control mutation screening study  [20]  were evaluated in the same way except that (a) position in the protein was not considered, and (b) logistic regressions were adjusted for study center and race/ethnicity. For BRCA1 and BRCA2, we examined the relationship between frequency and risk as follows. First we defined 'pseudo-cases' and 'pseudo-controls' from the tested population at Myriad Genetics in the data set we used to evaluate more than 1,000 BRCA1/2 sequence variants in 2007  [38].
The data set included results from approximately 68,000 full-sequence tests. Pseudo-cases for BRCA1 were defined to be all tested individuals who were affected with breast cancer and were not found to carry a pathogenic variant in either BRCA1 or BRCA2; pseudo-controls were taken to be affected individuals who were found to carry pathogenic mutations in BRCA2 (thus explaining their personal and family history of cancer). A similar approach was taken for BRCA2 variants, with carriers of BRCA1 pathogenic variants serving as pseudo-controls. For each gene, variants were categorized into frequency bins as described above. Logistic regression was then used to estimate ORs for each frequency bin. Note that, because carriage of clearly pathogenic variants was used to differentiate between pseudocases and pseudo-controls, the BRCA1 and BRCA2 ORs were estimated from the distributions of unclassified variants.
Statistical analyses of MRN case-control mutation screening data To assess the relationship between MRN variants and breast cancer risk, analyses were performed using the chi-square test and multivariable unconditional logistic regression using Stata version 11 software (StataCorp). Differences in the case-control ratio between racial/ethnic groups and study center were accounted for by including categorical variables for each racial/ethnic group and each study center. Adjustment for racial/ethnic group should also capture confounding of genetic and social factors with interaction terms, allowing that this confounding effect may be different for the broadly labeled racial/ethnic groups in different centers. P values reported from analyses of the MRN case-control data are from the likelihood ratio test, adjusted for racial/ethnic group and study center, unless otherwise noted.
In the 0. 32% to 0. 10% allele frequency bin, there was significant evidence of pathogenic variants in CHEK2; indeed, the known pathogenic CHEK2 variants c. 1100delC (Chr22:29091856delG) and p. Ile157Thr (rs17879961) both have allele frequencies between 0. 32% and 0. 10% in the EVS 'Caucasian American' sample. But there was no evidence for pathogenic variants in the other three genes in this allele frequency range. In the 0. 10 to 0. 032% bin, BRCA2 had an OR of 1. 60 (P = 0. 078). Although just shy of significant, an elevated BRCA2 OR in this EVS frequency bin is supported by the presence of known pathogenic BRCA2 variants with multiple reports in the Breast Information Core (BIC) database such as c. 2806_2809delAAAC (rs80359351) and c. 3847_3848delGT (rs80359405)  [41]. While the OR for ATM in this frequency bin was very near 1.
In our case-control mutation screening analysis of ATM, we also found that evidence for rMS that predispose to breast cancer was limited to rMS with Align-GVGD severity scores of greater than Boldface within the table indicates P <0. 05. ¥ Underlying data from  [19]. Analyses were performed on data from the nine bona fide case-control studies. Missense substitutions were only included if they fell after position 1960 in the protein sequence. Odds ratios adjusted for study, ethnicity and mutation-screening method employed. ¢ This grouping included just one missense substitution carried by just one control subject. § Underlying data from  [33]. † Underlying data from  [20] ; odds ratios adjusted for study center and race/ethnicity. In these binary logistic regressions, the regression coefficient = ln(OR).
43, 1. 00, and 0. 53, respectively (Table  7 ). Similarly, looking at the genes individually, neither truncating variants, nor key domain missense substitutions, nor a combination of the two reached statistical significance from single gene data (Table  9 ). Thus evidence from this study in favor of the MRN genes as intermediate-risk breast cancer susceptibility genes emerges from the ensemble analysis of the three genes. Although MRN gene T + SJV were not by themselves a significant breast cancer risk factor, we note that our OR point estimate of 2. 61 is both very close to the metaanalysis point estimate of 2. 63 that Zhang et al. obtained for NBN c. 657del5  [13] , and close to the point estimate of 2. 32 that we obtained in our meta-analysis of ATM T + SJV  [19]. Thus, while we cannot exclude that our nonsignificant finding is actually indicative of little or no risk of breast cancer conferred by MRN gene proteintruncating variants, our data are more strongly in accord with the hypothesis that they confer an intermediate risk of magnitude similar to the risk conferred by truncating variants in ATM.