dataesr/scientific-paragraphs-categorization huggingface dataset:
2 with a significance level of 5%, a power of 80%, and a sample size of 8 (G*Power software version 3. 1. 9. 7, Heinrich Heine University, Germany). In addition, to evaluate the association between independent variables (recording time points, temperature, and Poly I:C injection) and each outcome variable (respiratory frequency, heart rate and mean arterial pressure), mixed models were used (SAS Institute Inc. , version 9. 3, Cary, NC). Since multiple measurements were made in each lamb, a random effect on intercept and a first-order autoregressive structure of the residuals were specified in the covariance structure of the mixed models (PROC MIXED in SAS). Linear, quadratic and cubic associations were studied for time and temperature, considering each day separately, and included in the multivariable models if significant.
Z1scanner, Carl Zeiss, Zaventem, Belgium) showing the location of quantified areas from the rostral ventrolateral areas of the medulla (RVLM) and the nucleus tractus solitarius (NTS) in both control and Poly I:C injected lambs. B-I 3D confocal stack representative images with full-cell segmentation automatically generated by 3DMorph MATLAB-based script showing how quantitative morphological analysis of microglial cells (Iba1-positive cells in green and GFAP-positive in red) is performed. The full-cell segmentation column shows complete quantified microglial cells remaining after exclusion of partial cells and small processes not related to a cell body. Individual cells were identified, reconstructed, and stained with the colorimetric scale from the largest cell (red) to the smallest (blue).
This approach has been widely used to estimate the conditional VaR. For instance  [7, 19]  find GARCH-EVT to give accurate VaR estimates for standard and extreme quantiles compared with GARCH-type models and unconditional EVT methods on stock market data collected across the US, Latin America, Europe and Asia. Being a two-step procedure based on GARCH-type filtering, the accuracy of the GARCH-EVT approach has been debated. [9]  points out that estimates of the conditional VaR via the GARCH-EVT approach are sensitive to the fitting of a GARCH-type model to the dataset in the first step. On the other hand,  [22, 27]  have concluded that there is no evidence of any difference in the conditional VaR estimates, regardless of the particular GARCH model selected to filter financial data. Since the debate on filtering, several modifications of the conventional GARCH-EVT method have been suggested in the literature to provide a more accurate calculation of the residuals before applying the EVT method in the second step.
Empirical analysis of four financial time series We consider historical daily negative log-returns of three financial indices and an exchange rate, all made of n = 4000 observations: • The Dow Jones Industrial Average (DJ) from 23 December 1993 to 9 November 2009; • The Nasdaq Stock Market Index (NASDAQ) from 30 August 1993 to 16 July 2009; • The Nikkei 225 (NIKKEI) from 14 May 1993 to 12 August 2009; • The Japanese Yen-British Pound exchange rate (JPY/GBP) from 2 January 2000 to 14 December 2010. The data have been taken from the R package qrmdata  [26]  and are represented in Figure  1. The graphs show that these negative log-returns are extremely volatile around the 2007-2008 financial crisis, which created a succession of extreme positive and negative returns over short time horizons. A noticeable degree of volatility clustering is also detected from a visual inspection of Figure  1 , revealing the presence of the heteroskedasticity.
Summary of descriptive statistics and basic statistical tests for daily negative log-returns on DJ, NASDAQ, NIKKEI and JPY/GBP. Notes: A kurtosis greater than 3 indicates that the dataset has heavier tails than a normal distribution. J-B stands for the Jarque-Bera test, Q(n) and Q 2 (n) are the Ljung-Box tests for autocorrelation at lags n in the negative log-return series and squared negative log-returns, respectively. The ADF test is the augmented Dickey-Fuller stationarity test statistic without trend. The p-values are given between brackets.
Acknowledgments The first author gratefully acknowledges the financial support from the  SOKENDAI (Graduate University for Advanced Studies)  under  SOKENDAI Student Dispatch Program  grant, and the  Research Fellowships of Japan Society for the Promotion of Science for Young Scientists  (Project number:  20J15188 ). Y. Kawasaki is supported by  JSPS   Grantin-Aid for Scientific Research  ( 18H00836 ,  19K01597 ,  20H01502 ) and by the  ISM Cooperative Research Program   2020-ISMCRP-2038. G. Stupfler is supported by the  French National Research Agency  under the grant  ANR-19-CE40-0013 / ExtremReg  project, and he also acknowledges support from an  AXA Research Fund  Award on "Mitigating risk in the wake of the  COVID-19 pandemic ".
For M. longulum, genomic HiFi reads were generated by circular consensus sequencing (CCS) from the subreads. bam files provided by the   (Li et al. , 2009). We used flye v2. 8. 2  (Kolmogorov et al. , 2019)  with the -pacbio-hifi option to assemble the M. longulum genome. Assembly quality was evaluated based on continuity [QUAST v5. 0. 2  (Gurevich et al. , 2013) ] and completeness of Benchmarking Universal Single-Copy Orthologs (BUSCOs) with BUSCO 5. 2. 2  (Simão et al. , 2015; Waterhouse et al. , 2018)  using the lineage dataset endopterygota_odb10 in genome mode.
, 2000)  as an outgroup. We used Expasy ProtParam (https://web. expasy. org/protparam/) to compute the molecular weight of each sequence. For each species, we used custom-made scripts to split the silk gene into repeat modules (https://github. com/AshlynPowell/silk-gene-visualization/tree/main). For schematic visualization of the primary structure, we generated a consensus sequence of all representative sequences of each repeat module by aligning these in Geneious using the Muscle 3. 8. 425 plugin with a maximum of 1,000 iterations.
Discussion In this study, we report new genomic resources for the order Trichoptera. This is important since aquatic insects have been underrepresented in genomics research  (Hotaling et al. , 2020 (Hotaling et al. , , 2021a (Hotaling et al. , , 2021b)). For the first time, we provide long high-fidelity sequences of a fixed retreat-making caddisfly species. In addition, we report seven new full-length h-fibroins from de novo assembled HiFi data. This data was either provided by the authors of this study or large genome sequencing initiatives (e. g. Darwin Tree of Life, European Reference Genome Atlas) showing the importance of these projects for the scientific community. The new full-length h-fibroins represent a substantial increase in the number of genomic resources available for the study of caddisfly silk and allowed us to compare the major silk gene across the main clades of Trichoptera, which are represented by species with different silk usage.
Acknowledgements We thank  Brigham Young University  and  LOEWE-Centre for Translational Biodiversity Genomics (TBG)  for providing the computational resources needed to complete this study. The Leptonema lineaticorne specimen was collected in Ecuador under the " Genetic Resources Access Contract " No. MAAE-DBI-CM-2021-0161 , and the support of project  AMB. BRT. 19. 02  (" Mountain Freshwater Diversity , from  Taxonomy to Functional Genomics , and Approximation from  Trichoptera "). We appreciate help from  Sacha Lodge  for field logistics.
Data Availability Raw sequence data, genome assembly (SUB10837191) and sample information (SAMN25408291) of L. lineaticorne has been submitted to NCBI under Bioproject PRJNA802365. Raw sequence data (SRR15840268) and sample information (SAMN20982427) of M. longulum are available from NCBI under Bioproject PRJNA558902. Full-length H-fibroin gene sequences including introns, h-fibroin protein coding sequences and h-fibroin protein sequences newly identified in this paper are available at Figshare Project: https://doi. org/10. 6084/m9. figshare. 20407101. v1.
Objective To compare the risk of malignancy between patients with rheumatoid arthritis (RA) initiating their first biological disease-modifying antirheumatic drug (bDMARD) and those continuing conventional synthetic DMARDs (csDMARDs). Methods Nine-year historical Propensity Score (PS) matched cohort study within the French national healthcare database (87% of the French population; ~57 million people), including adults RA without malignancy. Exposures started with the first use of any systemic treatment (csDMARDs and/or bDMARDs). Incident users of bDMARDs were matched on a dynamic PS to patients continuing csDMARDs. Their risk of malignancy was compared by Cox model. Results From 1 January 2007 to 31 December 2014, 83 706 patients with RA started their first systemic treatment (63 837 remained on csDMARDs and 19 869 initiated a bDMARD during follow-up).
After dynamic PS matching, 19 727 bDMARD initiators were compared with 19 727 RA remaining on csDMARDs. They did not statistically differ in risk of overall malignancies (HR 0. 99 (95% CI 0. 86 to 1. 14)), solid cancer (HR 0. 95 (95% CI 0. 82 to 1. 11)), nor lymphoma (HR 1. 35 (95% CI 0. 72 to 2. 53)). Results were similar when bDMARDs were given as monotherapy or in association with csDMARDs. Analyses restricted to patients starting TNF inhibitor as first bDMARD compared with matched RA remaining on csDMARDs, provided similar results (HR for overall malignancy 1. 03 (95% CI 0. 88 to 1. 21)). Sensitivity analyses, varying carry-over periods (up to 5 years) to define risk periods, provided similar results. Conclusions In this historical cohort study within the French nationwide healthcare database, the risk of overall, solid or haematological malignancies did not significantly differ between patients with RA initiating bDMARD and those continuing csDMARDs.
WHAT THIS STUDY ADDS ⇒ Among patients with RA included in the French national healthcare database (87% of the French population; ~57 million people), we run a propensity score matched cohort study using very stringent methodology to handle the risk of bias and analysed a large variety of malignancies. ⇒ No significant increased risk of overall malignancies, solid cancers, nor haematological malignancies, including lymphoma, was observed in patients initiating bDMARDs compared with those remaining on conventional synthetic DMARDs (csDMARDs). ⇒ Restricting the analysis to RA exposed patients initiating a first TNF inhibitor matched to unexposed patient with RA remaining on csDMARDs, provided similar results. on September 11, 2022 by guest. Protected by copyright. RMD Open RMD Open RMD Open have also been suspected to increase the risk of malignancy.
16 18 21 31 32 Nationwide healthcare databases may provide sufficient power to detect differences in risk of malignancy in an unselected population. 33 Nevertheless, such studies are prone to potential biases (particularly selection bias, indication bias, attrition bias, channelling bias, immortal time bias) inherent to their observational nature that are not always adequately handled. The aim of this study was to compare the risk of malignancy in patients witn RA initiating a bDMARD and those continuing conventional synthetic DMARDs (csDMARDs) within the French nationwide health insurance claims database, using an incident user cohort with dynamic Propensity Score (PS) matching design to adequate handle methodological issues.
Data source The 'système national des données de santé' (SNDS) is the French nationwide healthcare database and contains individual claims and hospital discharge summary prospectively recorded since 2005 for every subject covered by French Health Insurance and pseudonymised. The general insurance plan covers both private and public sector employees, thus accounts for approximately 87% of the French population (~57 million people). The SNDS includes sociodemographic data, out-hospital health resource use including outpatient consultations and procedures, drugs and devices dispensation covered by the insurance, sick days, inpatient data and vital status. Inpatient data include discharge summaries including reason of admission and relevant patients' comorbidities described through International Classification of Diseases, 10th Revision (ICD-10) codes, procedures and highly expensive drugs dispensed during the stay (such as biologics).
Study design We conducted a 9-year historical cohort study within the General Scheme of the (SNDS (see online supplemental file). 34 35 The period of inclusion was from 1 January 2007 to 31 December 2014 (online supplemental figure  1 ). The data extraction period was 1 January 2006 to 31 December 2015, for having a 1-year 'look-back' period and at least 1 year of follow-up. Under optimal epidemiological conditions (new incident users of DMARDs with known exposures over time), we tested the hypothesis of an association between incident exposure to bDMARDs and risk of malignancies. Thus, to compare the risk of malignancy associated with initiating bDMARDs or continuing csDMARDs, we first identified all patients with RA ≥18 years old initiating their first csDMARD or bDMARD during the inclusion period (ie, did not receive any csDMARD or bDMARD during the 1-year look-back period).
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY ⇒ Our study provided an important reassuring message for patients with RA and physicians treating them regarding the risk of malignancies associated with the use of bDMARDs. ⇒ Even in a national healthcare database (87% of the French population), some malignancies, such as lymphoma, remained rare events that deserve to be analysed in future studies including more recently treated patients. on September.
Study population Adults (≥18 years old) with RA were identified from longterm disability status and/or hospital discharge summaries (main, related or an associated diagnosis) with ICD-10 codes M05 or M06. The date of RA diagnosis was defined as the first occurrence of RA diagnosis in the database (ie, the earliest date between the first hospital discharge diagnosis of RA available and the date of declaration of long-term disability for RA). To be included, RA adults had to be affiliated to the General Scheme of the French health insurance for more than 1 year, live in mainland France and have no history of organ transplantation, HIV infection or malignancy before the index date and initiate their first DMARD during the inclusion period.
RA patient population Between 2007 and 2015, 238 083 patients with RA were identified, including 169 600 received any DMARD during this period (figure  1 ). Considering the 90-day lag period and after excluding patients who had received a csDMARD or bDMARD in the 1-year look back period, 83 706 patients with RA initiated their first DMARD during the inclusion period. Among them, 63 837 received only csDMARDs and 19 869 initiated a bDMARD. Among the 83 706 DMARDs incident users, the median follow-up in the database since first DMARD initiation was 4. 64 range (0. 25-8. 99) years.
DISCUSSION In this historical PS matched cohort study within the French nationwide healthcare database, covering 87% of the French population (~57 million people), the risk of overall malignancies, organ-specific cancers and haematological malignancies did not significantly differ between patients continuing csDMARDs and those initiating bDMARDs. Likewise, the risk of overall malignancies, organ-specific cancers and haematological malignancies did not differ between patients initiating TNF inhibitors and matched patients remaining on csDMARDs. Sensitivity analyses hypothesising a persistent risk after bDMARD withdrawal up to 5 years, and subgroup analysis in patients >65 years provided similar results. This study aimed to investigate the risk of malignancy associated with bDMARDs. Thus, we compared, in incident users of any DMARD, the risk of malignancy in patients initiating bDMARDs to that those, having the same duration on csDMARD, but continuing csDMARDs, which allow to account for the recommendation to start bDMARD after inefficacy or intolerance of csDMARDs.
] [18] [19] [20] [21]  Considering the use of bDMARDs in association or not with csDMARDs did not change the results. By contrast, in a previous study on the same database involving patients with inflammatory bowel disease (IBD), the use of conventional immunomodulating agents in adjunction to TNF inhibitors increased the risk of lymphoma. However, there are major differences between these two studies. First, the main csDMARD used in IBD is azathioprine and not methotrexate. 5] [46]  Also, this study included both incident and prevalent users making difficult the analysis of the impact of previous therapeutic lines. Finally, analyses considered only 'on-treatment' period, thus not accounting for the potential delayed effect of treatment on the risk of malignancy. Effectively, when analysing the risk of malignancy associated with treatments, an 'on-treatment' analysis is not appropriate, since such risk might appear with some delay but also may persist after treatment discontinuation.
Effectively, to define risk periods, our analyses implemented lag and carry-over periods. The lag period avoids including malignancies that appear in the database immediately after treatment initiation and are unlikely to be related to this treatment. In addition, the carry over period is useful to account for the delay of cancer registering in the database and for the persistent treatment effect after its discontinuation. Here, sensitivity analyses hypothesising a persistent risk after bDMARD withdrawal up to 5 years accounted for this potential risk. Regarding the risk of melanoma, results are conflicting in the literature, with a trend to an increased risk of melanoma with bDMARDs only in northern countries  23 26 31 47 48  We did not find an increased risk of invasive melanoma in any of our analyses.
77 (95% CI 0. 42 to 1. 43)). Also, in analyses with a 2-year carry over effect, we observed a variation of the bDMARD effect over time with a possible increased risk of lymphoma in patients exposed to bDMARDs between 1 and 2 years after bDMARD initiation. However, due to the relatively small number of events at each time period, we cannot definitely conclude on theses time variations. This point will be investigated in further analyses, planned integrating the most recent years of the SNDS database, when available. The risk of bias in observational studies may be high, particularly in complex situations in which exposure and confounding factors are time-dependent, with a channelling phenomenon, and a long-term outcome (cancer) for which cumulative immunosuppressant exposure is an issue. As compared with previous studies, to adequately handle these methodological issues, we used a cohort of csDMARD incident users to eliminate the potential impact of previous therapeutic lines.
Nevertheless, the SDNS database account for nearly 90% of the French population which ensure a high representativeness of the whole population and a limited risk of selection bias. Also, the definition of RA cases, mainly based on ICD-10 codes, may be subject to misclassification. However, with a similar definition, previous work with a representative sample of the SNDS found the RA prevalence within the expected range. 50 In addition, our analyses included only patients receiving DMARDs, which strengthened the confidence regarding RA diagnoses. Finally, the use of a healthcare claim database has some pitfalls, particularly regarding the phenotyping of the RA cases with no data available on ACPA status and disease activity. Nevertheless, ACPA status has not been shown to be associated with the overall risk of malignancy, even though it remains uncertain regarding.
CONCLUSIONS AND RELEVANCE In this large 9-year cohort study within the French nationwide healthcare database, including almost all, thus representative of, the French population, the risk of overall malignancies and organ-specific cancers and haematological malignancies in adults with RA initiating bDMARDs did not significantly differ from that of matched patients with RA continuing on csDMARDs. The results were similar when considering the use of bDMARDs alone or in association with csDMARDs, when comparing patients initiating TNF inhibitors to patients continuing on csDMARDs, or in sensitivity analyses hypothesising a persistent risk after treatment withdrawal of up to 5 years.
Acknowledgements We acknowledge  Pr Eric Solary  for his support in initiating this project. We also acknowledge  Sofia Zemouri ,  Marie-Laure Specq ,  Nessima Yelles ,  Sylvie Guillo  and  Ouissem Saiah  for their inestimable help in administrative, technical and regulatory process. Contributors RS and FT had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, they are responsible of the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. RS and FT are acting as guarantor. XM and FT contributed equally. Concept and design: RS, XM, YDR and FT. Statistical analysis plan design, acquisition, analysis: FT, YDR, AL, SP, JS. Interpretation of data: All authors. Drafting of the manuscript: RS.
| Study of the variant functional impact In order to confirm our hypothesis that LTBP4 is the disease-causing gene in our patient, we performed a RNA analysis of this gene. Because of the proximity of the deletion with the exonic-intronic junction, we hypothesized that exon 30 splicing was affected. A high probability of exon skipping was predicted by in silico prediction tools. Indeed, according to the Ex-Skip software (https://ex-skip. img. cas. cz/ ), the variant carrying allele was more likely to being subjected to an exon skipping than the wild type allele. RT-PCR on RNA was performed with two exonic primer pairs (amplifying exons 28-32 and exons 29-31) and showed no impact on splicing, particularly no exon.
| Analysis of the variation pathogenicity following ACMG guidelines This variant is absent from the gnomAD database (Pathogenic Moderate 2, PM2). The predicted protein length is shorter than the wild protein and indeed, lacks three amino acids (PM4). The deletion affects the functional EGF-like 14 domain (PM1). The three deleted amino acids are highly conserved through species (Pathogenic Supporting 3, PP3, Figure  2d ). Finally, the patient's phenotype is quite specific to the LTBP4 gene, for which pathogenic variations are pretty rare (PP4). Our variant, has therefore, two "PP" criteria and three "PM" criteria, which allows its classification as "likely pathogenic," that is, class 4 according to ACMG classification.
4. 1. Spades software  (Bankevich et al. , 2012)  was used to assemble the Illumina generated sequencing data and also for the assembly of the mixed Nanopore-Illumina data. Genome annotation, antibiotic resistance gene, and plasmid screening were performed with RAST  (Aziz et al. , 2008 ), Resfinder (Bortolaia et al. , 2020)  and PlasmidFinder  (Carattoli et al. , 2014) , respectively. The CPE sequence type (ST) was performed in silico using multilocus sequence typing (MLST) analysis on the Center for Genomic Epidemiology website (https://www. genomicepidemiology. org/). The genetic environment of the bla OXA-48 genes was reconstructed by comparing the sequences of the genes surrounding this gene to the NCBI database using the blastX parameter. The complete plasmid sequences of strains P7697, P7699, P7536 and P7538 carrying bla OXA-48 genes were compared with the reference plasmid CP027039.