dataesr/scientific-paragraphs-categorization huggingface dataset:
In addition to effectiveness of ICS it is important to assess side effects. 1  Confirmed pneumonia was infrequent and comparable with both ICS treatments, recorded for three patients in each initiation cohort and one in each step-up cohort. However, the incidence of pneumonia may have been underestimated in this study, as some cases of pneumonia may have been coded as lower respiratory tract infection and treated in the home setting. Moreover, it is possible that some hospitalizations for pneumonia were not captured in the database. The post-study all-cause mortality rates did not differ between cohorts. Observational research provides important insights into the realities of real-life practice. For instance, although extrafine beclomethasone is not approved for use in COPD, this analysis shows that it is widely prescribed for patients with COPD in general practice.
In addition, we followed patients for 2 years, allowing us to describe the course of therapy over this time period. A high percentage of patients in this study, $55% in each treatment cohort, also had a diagnosis of asthma recorded in the database (after the age of 40, per inclusion criteria). This may reflect the fact that a subgroup of patients with asthma develops persistent airway obstruction over time, particularly when they smoke. 31 We believe that the COPD diagnosis was valid for most patients under study for several reasons: 1) all patients had a recorded post-bronchodilator FEV 1 /FVC ratio of ,0. 7; 2) all were smokers or ex-smokers; 3) the mean age was 67 years, and the cohorts included a preponderance of men (60%); 4) among those with an FEV 1 reading at baseline (87% of the full population studied), the mean %predicted FEV 1 in the four cohorts ranged from 52% to 55% (depending on cohort); and from 60% to 69% of patients in each cohort had a %predicted FEV 1 of ,60%; 5) moreover, of the patients with an asthma codiagnosis, most also had substantial FEV 1 impairment (mean FEV 1 %predicted, 53%; data not shown); 6) finally, the COPD diagnosis was recorded at or close to the time of the asthma diagnosis for most patients, and, importantly, the COPD diagnosis was confirmed (via FEV 1 / FVC ratio ,0.
7) for most patients after the asthma diagnosis was recorded (Figure  S3 ). This suggests that the asthma codiagnosis was often an initial misdiagnosis that was later superseded by a diagnosis of COPD. Retrospective studies such as this one are limited by the available data. All included patients had a database-recorded post-bronchodilator FEV 1 /FVC ,0. 7; however, we were unable to track lung function during the outcome period because spirometry is not performed routinely in primary care. Moreover, not all potential matching criteria were available for all patients at baseline, including the FEV 1 value (hence GOLD grade) and scores for the modified Medical Research Council or COPD Assessment Test, which would have enabled patient categorization according to recent GOLD guidelines. 1  Nonetheless, patients appeared to be well-matched for physical characteristics and disease severity, and the analyses incorporated adjustments for residual confounding (although we cannot rule out unidentified confounding factors).
Acknowledgments We thank  Professor Neil Barnes  for his contributions in the early stages of the analyses, and we gratefully acknowledge  Victoria Thomas  for her assistance with the statistical analyses and production of figures. Merck Sharp & Dohme ,  Mundipharma ,  Novartis ,  Pfizer ,  Teva ; and research funds from  Boehringer Ingelheim ,  Pfizer ,  Novartis ,  Nycomed. GC is speaker/advisor/consultant for  Teva, MedImmune, Alitair, Dey ,  Mylan ,  Novartis. EI reports receiving consulting fees from  Cowen & Co, Infinity Pharmaceuticals, Merck, Regeneron Pharmaceuticals, Teva Specialty Pharmaceuticals ; fees for expert testimony from  Campbell ,  Campbell ,  Edwards and Conroy, Ficksman and Conley, Ryan Ryan Deluca LLP ; lecturing fees from  Merck ; travel grant support from  TEVA Specialty Pharmaceuticals , and having grant support paid to his institution from  Amgen, i3 Research (Biota).
-Figure S1 ---Figure S2 S1S2 Figure S1Patient selection and matching for the initiation sample. Note: Patients in the two treatment cohorts were matched on clinically and demographically significant characteristics. Abbreviations: BAI, breath-actuated inhaler; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; FDC, fixed-dose combination; FEV 1 , forced expiratory volume in 1 second; FVC, forced vital capacity; gPrD, general Practice research Database; ICs, inhaled corticosteroid; laBa, long-acting β 2 -agonist; laMa, long-acting muscarinic antagonist; OPCrD, Optimum Patient Care research Database; rx, therapy; saBa, short-acting β 2 -agonist; saMa, short-acting muscarinic antagonist.
18 Note that d relates to the drug/placebo effect but has not been explicitly linked to actual doses or concentrations in this publication. ( ) = + - ( ) ⋅ -⋅ ⋅ 0 1 (7) The term "-1" is used to ensure that at time 0, tumor size y(0) = y 0. Here, tumor size is assumed to increase and decrease exponentially, with d and g being the rate constants for the drug-induced decay and the net growth of the tumor size, respectively. Note that in the original article, this formula, even if proposed for the analysis of tumor size measurements, was applied to the analysis of the time course of prostate-specific antigen data. However, the same model was successfully used in ref. 16 ( ) = + ⋅ + ⋅ ⋅ -⋅ 0 2 (8) Analytical models present some advantages for implementation: because of their mathematical simplicity, they are easy to implement in classical statistical software programs such as SAS, and computations are very quick.
Models for the analysis of preclinical data Preclinical experiments comprise an important stage in the process of understanding drug effects. A multitude of different techniques, animals, and processes can be used to Slide calipers are used to periodically measure tumor size over a predefined period of time. A standard measurement approach is to measure three tumor diameters and to calculate the corresponding geometric mean, which is then an approximation of the tumor volume. 40 n the section that follows, we present several preclinical models whose mathematical representations are similar to those presented in the previous section. One modeling framework often used for the analysis of tumor size dynamics in mice is presented in ref. 38. This framework relies on a general model for time-dependent transduction systems.
The European Medicines Agency's Policy 070 on publication and access to clinical trial data will definitively help in that regard by creating the opportunity for scientists to access pools of individual-level data from clinical trials (http://www. ema. europa. eu/docs/en_GB/document_library/ Other/2013/06/WC500144730. pdf). Similar initiatives are already available for other therapeutic indications, such as stroke, through the Vista repository (http://www. vista. gla. ac. uk). We believe that access to appropriate data is the most problematic issue for further mechanistic developments and relevant applications of models. In oncology, in addition to the significant costs of evaluating tumor size response through imaging techniques, the method itself of evaluating treatment efficacy in clinical trials with an end point assessed at a specific time point resulted in forgetting the potential interest in evaluating the dynamic aspect of the response.
Acknowledgments. The research leading to these results has received support from the  Innovative Medicines Initiative Joint Undertaking  under grant agreement no. 115156 , resources of which are composed of financial contribution from the  European Union 's  Seventh Framework Program  ( FP7/2007-2013 ) and The  European Federation of Pharmaceutical Industries and Associations (EFPIA)  companies' in-kind contribution. The  Drug Disease Model Resources (DDMoRe)  project is also financially supported by contributions from the academic and small-and-medium enterprise partners. This work does not necessarily represent the views of all DDMoRe partners.
In a prospective study of over 15 years using both Southern blot and PCR analyses, 3 cases of MoMN have been detected on a cohort encompassing 220 male carriers of a full mutation (D Glaeser's data). Some individuals carry in their lymphocytes alleles 4200 repeats that are completely or partially unmethylated (methylation mosaic: MoMe). Some of them have been reported to show a moderate or normal phenotype ('high-functioning' fragile X males). 38, 39 ther rare loss-of-function variations, such as substitutions  40, 41  or deletions of all or part of FMR1 have also been reported to cause the FXS, including a hot spot for deletions that occurred in the context of an expanded allele in FMR1 exon 1. [42] [43] [44] [45] [46] [47] [48] [49] [50]  There are gene variant public databases for the disease, in which it is important to share gene variants: the Human Gene Mutation Database (HGMD) and the locus-specific database (LOVD).
INTERPRETATION AND REPORTING The reasons for referral should be restated with a clear distinction between diagnostic testing (FXS, FXTAS, or FXPOI), carrier testing (FXS), and prenatal diagnosis (FXS). The title of the report should reflect the reason for referral. The report should indicate the gene (FMR1 and Accession number) and give data about the relevant allele's range classes with reference source. Nomenclature: HGVS' nomenclature can be used but this must be in addition to an essential worded explanation describing the number of CGGs (eg, premutation, full mutation, etc) taking into account that fragile-X tri-nucleotide repeat is known as the CGG repeat, but based on the HGVS' rule that for all descriptions the most 3' position possible should be arbitrarily assigned the repeat has to be described as a GGC repeat.
On the basis of the coding DNA reference sequence (GenBank NM_002024. 4), c. -128GGC(79) describes the presence of an extended GGC-repeat of exactly 79 units and c. -128GGC(1000) describes the presence of an extended GGC-repeat of about 1000 units (the '()' is used to indicate uncertainties). The technique used should be clearly indicated (Southern blot, PCR, TP-PCR, etc) with the reference of the publication which described it and the reference of the kit and the provider in such case. A statement of the limitations/sensitivity of the technique(s) used should appear clearly in the conclusion section of the molecular diagnosis report. Whenever an exact number of the CGGs is reported it should be accompanied by a statement of the testing laboratory's accuracy of sizing. Some laboratories perform 'pre-screening' tests with a method which is not able to detect the whole range of expansions.
ACKNOWLEDGEMENTS The first version of the guidelines was established at the EMQN Best Practice Meeting, held 23-24 November 2001 in Strasbourg, France, and updated again in January 2006. This new update occurred in December 2013 after distribution of the revised version to participants of the FRAX EQA. We would like to acknowledge following people for carefully reading the manuscript and providing useful comments and additional information: D Barton, D Bodmer, N Canson, C Clabby, S Ceylaner on behalf of the Turkish Medical Genetic Association, I Delon, A DeSandre, A Ferlini on behalf of the Italian Molecular Genetics working group (SIGU-A Murgia, A Mesoraca, C Gervasini, C Lapucci, MC Patrosso, F Gualandi, F Brancati, G Police, G Merla, G Sabbatini, I Sani, M Seia, M Neri, MA Melis, M Grasso, P Primignani, R Stuppia, S Russo, V Bizzarri), L Jenkins, W Just, P Johnels, P Jorge, T Kahre, J MacPherson, M Milà Recasens on behalf of the Spanish expert groups working on Fragile X-associated Disorders, belonging to the AEGH-GIRMOGEN-CIBERER, A Murray, M.
© 2014 de Graeff et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4. 0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons. org/publicdomain/zero/1. 0/) applies to the data made available in this article, unless otherwise stated.
Approximately 70% of the 5 0 genomic region of the PKD1 gene (exons 1-33) is duplicated six times on chromosome 16p within six pseudogenes (PKD1P1 to PKD1P6), which share a 97. 7% sequence identity with the genuine gene  (Bogdanova et al. 2001; Rossetti et al. 2012 ). This, together with a high GC content, the presence of many missense variants, the absence of mutation hot spots, and the high allelic heterogeneity of ADPKD, makes the molecular diagnostics of ADPKD challenging. In addition, most mutations are private variants, with a total of 1272 pathogenic PKD1 and 202 pathogenic PKD2 mutations reported to date (March 2014, ADPKD Database [PKDB], http://pkdb. mayo. edu). Thus, genetic diagnosis by conventional techniques of a new ADPKD family requires longrange polymerase chain reaction (LR-PCR) of the repeated region of PKD1 followed by nested PCRs  (Rossetti et al.
No probe redundancy was allowed in the final capture design for the rest of target regions. The Browser Extensible Data file of captured regions is available on request to the authors. Libraries were prepared with the TruSeq DNA Sample Preparation Kits (Illumina, Inc. , San Diego, CA). Genomic capture from pooled libraries was carried out using NimbleGen SeqCap EZ Library (Roche, Inc. ) following User's Guide v3. 0 instructions, as previously described  (Trujillano et al. 2013). The libraries of the patients of the validation cohort and the five controls were prepared and sequenced together with seven samples of other diseases using the same capture design and enrichment pro-tocol in two pools of 24 samples, for a total of 48 samples multiplexed in two HiSeq 2000 (Illumina, Inc. ) lanes to generate 2 9 100 bp paired-end reads.
Bioinformatics analysis and mutation identification and classification The resulting fastq files were analyzed with an in-house developed pipeline previously described  (Trujillano et al. 2013). All the bioinformatics tools used in this study were run using default settings unless stated otherwise. For the patients included in this study, only the sequencing data produced for PKD1 and PKD2 were analyzed, as stated in the signed informed consent. The reference sequences used were NM_001009944. 2 for PKD1 and NM_000297. 2 for PKD2. In order to identify pathogenic mutations that could cause ADPKD, we applied the following cascade of filtering steps  (Walsh et al. 2010 ): 1 We required all candidate variants on both sequenced DNA strands and to account for ≥20% of total reads at that site in order to filter out spurious variant calls caused by misaligned reads in the duplicated region of PKD1.
2 Common polymorphisms (≥5% in the general population) were discarded by comparison with dbSNP 137, the 1000G, the Exome Variant Server (http://evs. gs. washington. edu), and an in-house exome variant database to filter out both common benign variants and recurrent artifact variant calls, especially in the duplicated PKD1 regions. However, since these databases also contain known disease-associated mutations, all detected variants were compared to gene mutation databases (The Human Gene Mutation Database [HGMD], www. hgmd. cf. ac. uk and ADPKD Database [PKDB], http://pkdb. mayo. edu). 3 Mutations that could give rise to premature truncated proteins, that is, stop mutations, exonic deletions/insertions, and large genomic rearrangements were classified as definitely pathogenic. 4 Missense and noncanonical splicing variants were considered a priori Unclassified Sequence Variants (UCV) and their potential pathogenicity was evaluated using an in silico scoring system developed for PKD1 and PKD2 genes as previously described  (Rossetti et al.
2154344-2186386del (Fig. 2A ), and patient 11-571-P2 presented PKD2 g. 88952828-89050618del (Fig. 2B ). For the unique patient with a previously known mutation not identified by our NGS assay, 03-393-P3, manual inspection of the sequence alignment files revealed that the missing p. (Met1fs) was localized in a region of exon 1 of PKD1 for which no NGS reads were available due to problems with the genomic capture. We included in this study five control individuals without personal or family history of ADPKD to determine the clinical specificity of our assay. These controls had been previously genotyped with a HumanOmni 2. 5-8 BeadChip (Illumina, Inc. ) and were also used to determine the analytic sensitivity of our assay to detect heterozygous and homozygous SNVs. Genotype data were available for a total of 80 and 269 sites within the targeted regions of PKD1 and PKD2, respectively.
Acknowledgments We thank the patients and referring physicians who participated in this study. We thank  Justo Gonzalez ,  Sheila Sant ın ,  Laia Ejarque ,  Estefania Eugui , and  Patricia Ruiz  for technical support,  Cristian Tornador  and  Georgia Escaramis  for bioinformatics assistance, and IIB Sant Pau-Fundaci o  Puigvert Biobank  for kindly providing some of the ADPKD samples, ReTBioH ( Spanish Biobank Network )  RD09/76/00064. This project was funded by the  Spanish Plan Nacional   SAF2008-00357  (NOVADIS); the  Instituto de Salud Carlos III  ( FIS/FEDER PI11/00733 ;  PI12/01523  and  PI13/01731 ); the  European Commission   7th Framework Program , Project N. 261123 (GEUVA-DIS), and Project N. 262055 (ESGI);  Spanish Renal Network for Research   16/06 ,  RETICS, Instituto de Investigaci on Carlos III :  REDinREN/RD06/0016  and  RD012/ 0021 FEDER  funds; the  Catalan Government  ( AGAUR 2009/SGR-1116 ); and the  Fundaci on Renal Iñigo Alvarez de Toledo in Spain.
Methods Patients from 3 melanoma cohorts treated with Pembrolizumab 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W in the Phase I KEYNOTE-001 trial served as the source population. Tumor imaging was performed every 12 weeks. Response was assessed by irRC and RECIST v1. 1 by independent central review. Patients were managed by irRC by investigator. Early and delayed pseudoprogression were identified using centrally assessed irRC data among patients treated with Pembrolizumab who were followed by imaging for ≥28 weeks as of May 2014. Early pseudo-progression was defined as unconfirmed PD at assessment 1 (ie, week 12) and non-PD at assessment 2. Delayed pseudo-progression was defined as PD at any time point followed by non-PD at the next assessment. Survival data as of May 2014 were analyzed in all 411 patients enrolled in KEYNOTE-001.
© 2014 Hodi et al. ; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4. 0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons. org/publicdomain/zero/1. 0/) applies to the data made available in this article, unless otherwise stated.
The Markov order of the underlying process is here somewhat arbitrarily set to k = 2, following on  [22]  where we extensively checked its effect on the reconstructions: in our previous study, k = 2 resulted to be the lowest dimensionality in the probability distribution allowing to separate actual interactions from signal artifacts like light scattering. Note that we did not perform any delay embedding of the time-series, because we did not find it here necessary to reach satisfying performance levels, or leading to noticeable improvements. Methodological developments along the lines of  [38, 39]  would be however desirable for future applications to real experimental data. Code for our Generalized Transfer Entropy method is publicly available at https://github. com/olavolav/TE-Causality.
Combining two reconstruction results To distinguish between excitatory and inhibitory neurons, we combined the information of the reconstructions obtained from the "E+I" and "E-only" data, namely M E+I and M Eonly. We assumed that excitatory links are present in both datasets, while inhibitory ones appear only in the "E+I" reconstruction, and proceeded by defining new matrices of putative excitatory M exc and putative inhibitory influences M inh , of the form: M exc = M E+I + M Eonly , (15) M inh = M E+I -M Eonly. (16) To obtain the effective connectivity reconstruction only the rank ordering of GTE values is relevant. Therefore no rescaling of these matrices is necessary, and the final set of links could be obtained by thresholding the matrices as described above. To label the neurons as either excitatory or inhibitory, we first removed all links that were present in both reconstructions, and then ranked the neurons according to the difference between excitatory and inhibitory links, l i = j T exc jij T inh ji.
Acknowledgments JO and JS received financial support from  Ministerio de Ciencia e Innovación (Spain)  under projects  FIS2009-07523 , and  FIS2010-21924-C02-02 ,  FIS2011-28820-C02-01  and from the  Generalitat de Catalunya  under project  2009-SGR-00014. OS, TG and DB were supported by the  German Ministry for Education and Science (BMBF)  via the  Bernstein Center for Computational Neuroscience (BCCN) Göttingen  (Grant No. 01GQ0430 ). OS and DB acknowledge in addition, respectively, the  Minerva Foundation (München, Germany)  and funding from the  FP7 Marie Curie career development fellowship IEF 330792  (DynViB).
2012). Unfortunately, there is a general lack of suitable experimental data to validate these theoretical predictions over a range of situations. Such experimental data would be best collected in situations (i) favoring metapopulation dynamics (geographically close but distinct sites with frequent local extinction) and (ii) with different dominant host genotypes between sites. This conjunction is well met in the potato late blight pathosystem close to the English Channel. This pathosystem is indeed characterized by the following:.
Different dominant cultivars in Jersey and on the continent In the French potato production area considered, cultivar Europa was dominant but not exclusive. By contrast, potato production on Jersey has been dedicated almost exclusively since the early 1900s to cv. Jersey Royal, a selection of the early cultivar International Kidney. Jersey Royal is grown year round in Jersey and is not produced anywhere else. Jersey therefore represents a unique situation in Europe, because of its island location, the extensive monoculture of a single potato cultivar for more than a century, and strict controls on movement of seed tubers of this cultivar into and out of Jersey  (Deahl et al. 2009 ). Both cultivars are susceptible to P. infestans, according to the European Potato Database (www. europotato. org).
Searching the European Potato Database (www. europotato. org) reveals that cv. Europa has cv. Bintje among its progenitors, through cvs. Climax and Edzina. It is therefore understandable that adaptation to cv. Bintje, previously shown in French populations  (Montarry et al. 2008) , might also confer adaptation to some of its offspring. This then favors the persistence of a large population with the same core adaptive features and thus limits the possibility for emergence of local adaptation patterns and metapopulation dynamics with divergent selection histories. Our finding that P. infestans populations cluster into two distinct genetic groups is consistent with previous data from French isolates collected in 2004 and 2005  (Montarry et al. 2010b ) revealing that the admixture pattern was stable over at least three successive years  (from 2004 to 2006).