dataesr/scientific-paragraphs-categorization huggingface dataset:
77, gap size: 600 bps, E value for identification of candidate islands that exhibit clustering: 1000, false discovery rate controlling significance: 1E-2. Fragment size was set according to the value assessed by Homer v4. 7. 2 makeTagDirectory. Peaks were annotated using Homer v4. 7. 2 with annotation extracted from Ensembl v75. For mouse samples, the ChipSeq analysis was described in  (Achour et al. , 2015). Global clustering of the ChIP-seq data and quantitative comparisons were performed using seqMINER software. We used the core gene coordinates as reference coordinates, defined as the region between TSS À5kb and TSS +5kb; gene lists used as a reference were reduced according to the results of the cell-specificity or differential expression RNA-seq analysis in the mouse. The k-means linear method was used to group genes in six clusters called A-F.
Differential binding analysis We detected differential regions by generating a meta-peak list composed of the union of all H3K27ac peaks detected by SICER in all patients and control samples with bedtools merge v2. 21. 0  (Quinlan and Hall, 2010). Striatal meta-peak list was composed of 58,635 non-overlapping H3K27ac peaks. We then counted the number of reads falling into the genomic coordinates of the meta-peaks using bedtools intersect. The meta-peak list was annotated with Homer v4. 7. 2, associating one meta-peak to a single gene. We summed up read counts of all meta-peaks of a given gene using a custom R script to have one read count value per gene (number of different genes n = 25,808). Read counts were then normalized across samples with the method proposed by  Anders and Huber (2010).
ACKNOWLEDGMENTS We gratefully acknowledge  Dr. Florence D. Morgenthaler-Grand  ( CIF, Lausanne University ) and  Dr. Georg Kienzel  ( Arcturus, Basel ) for LCM technical support. We thank  Dr. Keith Harshman  and the  Genomic Technologies Facility team at the Center for Integrative Genomics (Lausanne University ) for RNAseq and miRNA microarray experiments. We thank  Virginie Zimmer  ( LCMN, Lausanne University Hospital ) for animal breeding and genotyping. We gratefully acknowledge  Sylvain Pradervand  ( CIG, Lausanne University ),  Leonore Wieger  ( CIG, Lausanne University ), and the Bioconductor support team for help in bioinformatics. This work was supported by  Swiss National Science Foundation  grant  31003A-140945 ,  Joint Programming Neurodegenerative Disease (JPND)  grant  31ND30-166947 , the  European Huntington's Disease Network  (EHDN; project  599 ), and funds from  Centre National de la Recherche Scientifique (CNRS).
Collected data Information on age, sex and stage at diagnosis was routinely collected. The period of diagnosis was divided into four periods  : 1976-1983, 1984-1991, 1992-1999 and 2000-2006. Patients were categorized into three age groups: under 65 years, 65-74 years and over 75 years. Stage at diagnosis was classified according to the TNM classification  [8]  : stage I (T1/2, N0, M0), stage II (T3/4, N0, M0), and stage III (all T, N1/3, M0). For stage II cases, the number of harvested lymph nodes was categorized into two groups: <12 nodes and ≥12 nodes. For stage III cases, the number of involved nodes was categorized as <4 nodes (N1) and ≥4 nodes (N2/N3). Clinical presentation was separated into emergency (obstruction or perforation) or scheduled resection. According to macroscopic gross features, tumors were classified as fungating or ulcero-infiltrative.
Five-year net survival conditional on the absence of recurrence (CNS-RF) was defined as the (x+5)-year net survival of recurrence-free survivors x years after diagnosis. This expanded definition of conditional survival could not be directly calculated from net survival estimates because recurrence was neither considered as an event nor censored in the net survival analysis. As proposed by Zamboni et al  [14] , the condition relied on the "conditioning set of patients", in our study alive and free of recurrence. CNS-RF was estimated six times by allowing x to vary from t0=0 to t0=5 years after diagnosis. For each t0, patients who had undergone death or recurrence prior to t0 were removed from the dataset. For each t0, the follow-up was censored at t0+5 years, 5-year net survival was estimated through a net survival model and factors associated with CNS-RF were assessed using a multivariate net survival model.
Only one publication estimated overall survival conditional to recurrence. It concerned colon cancer and relied on data from clinical trials  [14]. Estimations from hospital databases or clinical trials cannot be regarded as a reference because of unavoidable selection bias. Population-based studies provide unbiased indicators, but detailed information on cancer recurrence at the population level is rarely available. This study demonstrated the feasibility of estimating CNS-RF at the population level. The active clinical follow-up, the large size of the cohort and the use of a flexible parametric model of net survival strengthened the reliability and widened the scope of our results. There is increasing interest in cancer registries for this type of information, and, in the future, highresolution studies may provide data on recurrence, making CNS-RF comparisons possible.
There are some limitations of this study. As time elapsed from diagnosis, an increasing number of patients developed recurrences or died. Those patients were removed from the dataset at each t0, decreasing the size of the iterative datasets. As a consequence, some analyses relied on small numbers of individuals. This limitation may have resulted in a failure to detect some associations over time. Moreover, extensive and long-standing observational population-based studies cannot include detailed data, such as comorbidities and lifestyle characteristics, throughout the follow-up of patients. In conclusion, this study shows that conditional net survival of recurrence-free patients with colon cancer increases dramatically with the time since diagnosis. These results will help clinicians to provide potentially reassuring information to cancer survivors.
All colon cancers diagnosed in a French administrative area (Côte-d'Or, Burgundy) have been recorded since 1976 by a population-based digestive cancer registry. Data were actively collected from multiple sources: public and private pathology laboratories, university hospitals (including the cancer centers), general hospitals, private specialists (gastroenterologists, surgeons, medical oncologists, and radiotherapists), hospital administrative databases, the Regional Health Service database and death certificates. Patients treated outside the area were identified through the National Health Service database. Registration quality and exhaustiveness are certified every four years by an audit performed through the Registries Evaluation Committee by the National Cancer Institute (INCa), the National Institute for Health and Medical Research (INSERM) and the National Public Health Institute (SpF).
Exclusion criteria were severe mental retardation, age <18 years, a preoperative language deficit making cortical mapping impossible and a quality control of fMRI data showing unusable data, for example, with head movements ≥3 mm in one of the axes during their acquisition. Fifty patients identified in accordance with inclusion criterion were included in this study. Details of the population are presented in Table  1. A T1-weighted anatomical three-dimensional dataset was also obtained, covering the whole brain to coregister and normalize EPI images, with the following parameters: 192 contiguous sagittal slices, in-plane matrix 256 × 256, yielding a voxel size of 1 × 1 × 1 mm 3.
Beforehand, all subjects received detailed instruction and were trained to perform the task overtly and then covertly. Before fMRI acquisitions, the subjects were asked to grade their anxiety score and after acquisition their estimated performance for the task fMRI. The visual analog scales were converted in a value on a scale from 0 to 10. These results were compared to data from 33 healthy volunteers that underwent the same fMRI protocol and enrolled in a previous study and were used to compare clinical data, anxiety, and success scores after fMRI acquisitions  (Dinomais et al. , 2016). All patients enrolled did not have language impairment at the moment of the fMRI acquisition and during the surgical procedure.
| Analysis of imaging data The first three acquisition volumes in each functional series were discarded, to allow the longitudinal magnetization to stabilize. Preprocessing was carried out using SPM8 For rsfMRI data analysis, a spatial independent component analysis (sICA) approach was used, employing a customized version of the Infomax algorithm running under MATLAB, for the identification of large-scale networks  (Marrelec et al. , 2006). Fifty-five spatial independent components (ICs) were computed on preprocessed images of each individual run. Individual spatial components were thresholded at z = 2.
In a second step, further TA B L E 1 (Continued) | 5 of 17 LEMÉE Et aL. 2006); middle temporal gyrus (MTG) with a peak of activity in its mid-posterior part (MTG) in the vicinity of superior temporal sulcus  (Devlin, Jamison, Matthews, & Gonnerman, 2004; Dronkers & Ogar, 2004) ; temporal poles  (Binder et al. , 2011) ; caudate nucleus  (Crosson et al. , 2003) ; cerebellum  (Jansen et al. , 2005) ; and dorsomedial prefrontal cortex  (Alario, Chainay, Lehericy, & Cohen, 2006). However, we retained the presence of MTG, inferior frontal gyrus, and ANG, either unilaterally or bilaterally, as the main criteria for the identification of LANGrest. The distinction between LANGrest and the ventral attention network (VAN) was also critical for a proper identification of the language network in rsfMRI, especially in left-handed patients.
Indeed, the VAN presents topographical similarities with the language, with specific activations in the ventrolateral prefrontal cortex, inferior frontal cortex, and temporal gyrus in the right hemisphere in right-handed subjects  (Corbetta, Patel, & Shulman, 2008). The main difference between these two networks lies in the different activation of the inferior parietal lobule. The activity of the parietal lobule in VAN involves the supramarginal gyrus and the temporo-parietal junction in adults  (Corbetta et al. , 2008) , and also in children  (Sylvester et al. , 2013) , whereas the angular gyrus is preferentially activated in the language network  (Vigneau et al. , 2006). VAN is also mainly located in the nondominant hemisphere, mirroring the language network. Thus, the presence of a specific activation in the angular gyrus was a major criterion for the identification of LANGrest in left-handed patients.
Statistical significance threshold was FWE p <. 05 corrected for multiple comparisons at the voxel level for the mean language networks identified in task fMRI, rs-fMRI, and also for task fMRI > rsfMRI contrast (Figure  2 ). Statistical significance threshold was defined at FDR p <. 05 corrected for multiple comparisons at the cluster level using a statistical threshold p <. 001 uncorrected at the voxel level for the rsfMRI > task fMRI contrast. Anatomical labels were ascribed to the activation or peak component maxima using the anatomy toolbox for SPM (http://www. fzjueli ch. de/inm/inm-1/DE/Forsc hung/_docs/SPMAn atomy Toolb ox/ SPMAn atomy Toolb ox_node. html). Lateralization index (LI) was calculated for each patient from neuroimaging data, using the LI toolbox for SPM  (Wilke & Lidzba, 2007; Wilke & Schmithorst, 2006).
| Comparison of cortical mapping to fMRI data The location of area with speech impairment during cortical mapping was recorded using the neuronavigation and manually reported on the fMRI activation maps. Optical recording shows that ECS maps eloquent areas in a volume of brain tissue up to more than three hundred of mm 3 and can act on BOLD signal as far as 20 mm of the stimulation site  (Borchers, Himmelbach, Logothetis, & Karnath, 2011; Suh, Bahar, Mehta, & Schwartz, 2006). Thus, in our sensitivity analysis we did not consider widespread activation around BOLD peak but the distance around the peaks: We considered the existence of a peak of activity (for task fMRI) or peak of component (for rsfMRI) within 10 mm of the site of ECS.
| Identification of the language network in rsfMRI and task fMRI This study has shown the possibility to isolate the language network in resting-state fMRI, even in patients with atypical lateralization or brain lesions. In healthy volunteers, LANGrest was identified as a left lateralized network in right-handed subjects. Indeed, 82%-96% of righthanded individuals use their left hemisphere for language processing  (Knecht, Deppe, et al. , 2000; Knecht, Dräger, et al. , 2000; Springer et al. , 1999). This criterion remains true in left-handed people but is weaker. Moreover, the incidence of right hemisphere dominance is linearly correlated with the degree of handedness on EHI, ranging from 4% when EHI = 100%-27% when EHI = -100  (Knecht, Deppe, et al. , 2000). As the correlation between LI indexes from the Edinburgh Handedness Inventory Score, task fMRI, and rsfMRI Thus, we suggest that when attempting to identify LANGrest by sICA, identification of VAN should also be performed in such a way to discriminate these two networks by their different activity in the inferior parietal lobule, with the involvement of the angular gyrus for language network  (Vigneau et al.
Current findings of distinct networks identified by sICA linked to these areas are in line with the results of Farrant et al. , and in our study,  VAN and SN are  distinct spatial components. In this study, a coactivation of the main nodes of SN together with the language network was observed during task fMRI. The presence of SN nodes in task fMRI may be linked to the experimental block design of the task-based acquisition and is not surprising according to the difficult acoustic condition inherent to MRI. Indeed, coactivation of the SN during a linguistic task supports word identification in difficult acoustic conditions  (Vaden et al. , 2013). The presence of SN nodes in fMRI may also explain the stronger right lateralization observed in language network in fMRI compared to LANGrest, since the SN is slightly right lateralized.
All datasets were acquired on a 3. 0 Tesla MR Scanner (Magnetom ® Skyra Medical Systems™). During image acquisition, patients laid supine with the head immobilized by foam pads and straps, with earphones, and kept in darkness. Patients watched a black screen with a red fixation cross in the center through a prism. Echo planar imaging (EPI) sequence was used for each fMRI with the following parameters TR = 2,280 ms, TE = 30 ms, flip angle = 90°, 42 axial interleaved slice of 4 mm slice thickness, in-plane matrix = 64 × 64 with a field of view = 168 × 187 mm, yielding a voxel size of 3 × 3 × 4 mm 3 , covering the whole brain including the cerebellum. During task fMRI, we acquired 270 functional volumes per session over two sessions, and for rsfMRI, we acquired 270 functional volumes over one session.
Renal involvement was defined as hematuria (> 5 RBC in the field of vision), macroscopic hematuria or proteinuria (> 300 mg/24 h). 43 healthy children were included in the control group, selected in terms of age and gender (Table  2 ). Children from the control group attended the outpatient pediatric clinic for non-immunological, non-inflammatory health problems and needed venous puncture. A blood sample for laboratory tests was collected at the time of the patient's admission to the hospital (before the start of treatment) and tested in the central laboratory within the first hour after collection. Standard tubes with ethylenediaminetetraacetic acid (EDTA) were used. The following laboratory data were recorded:.
Objective. Regulatory agencies require the assessment of cardiovascular (CV) safety for new type 2 diabetes (T2D) therapies through CV outcome trials (CVOTs). However, patients included in CVOTs assessing sodium-glucose cotransporter-2 inhibitors (SGLT2i) might not be representative of those seen in clinical practice. This study examined the proportion of patients that would have been enrolled into three main SGLT2i CVOTs to determine whether these trials' eligibility criteria can be applied to a real-world Mediterranean T2D population. Methods. Cross-sectional, retrospective, cohort study of T2D patients registered in primary care centres of the Catalan Institute of Health using medical records from a population database (SIDIAP) that includes approximately 74% of the population in Catalonia (Spain).
Eligibility criteria were according to those of three SGLT2i CVOTs: EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin). Results. By the end of 2016, the database included 373,185 patients with T2D with a mean age of 70 ± 12 years, 54. 9% male, with a mean duration of T2D of 9 ± 6 years, and a mean glycated haemoglobin (HbA1c) of 7:12% ± 1:32 (59% with HbA1c < 7%). Of these, 86,534 (23%) had established CV disease and 28% chronic renal failure (estimated glomerular filtration < 60 ml/min/1:73m 2 ). Among all included patients, only 8. 2% would have qualified for enrolment into the EMPA-REG OUTCOME trial, 29. 6% into the CANVAS program, and 38% into the DECLARE-TIMI 58 trial. The main limiting factors for inclusion would have been a previous history of CV disease and the baseline HbA1c value.
Materials and Methods 2. 1. Design. This was a cross-sectional retrospective study of the T2D population attended at primary care centres of Catalonia, an autonomous region located in the northeast of Spain, corresponding to 12% of the total Spanish population. We compared the potential eligibility of patients to those included in publications describing three completed SLGT2i CVOTs  [15] [16] [17]. The study was approved by the Ethics Committee of the Primary Health Care University Research Institute (IDIAP) Jordi Gol in accordance with the Spanish regulations on observational studies. This retrospective study using anonymised data did not require obtaining informed consent from the patients. 2. 2. Data Source. Data from patients were extracted from the SIDIAP database, which contains anonymised longitudinal patient information obtained from electronic clinical records; it incorporates available information from 288 primary care teams of the Catalonian Health Institute (ICS), which serves around 5.
Study Variables. The following variables from the SIDIAP database at the end of December 2016 were analysed: age and gender; duration of T2D; the most recent value (closest to 31 December 2016) of glycated haemoglobin (HbA1c); and presence of risk factors, including hypertension (ICD-10 codes I10 and I15, or systolic blood pressure ðSBPÞ ≥ 140 and/or diastolic blood pressure ðDBPÞ ≥ 90 mmHg, or use of antihypertensive medications), dyslipidemia (ICD-10 codes E780 to E785, or LDL cholesterol ðLDLcÞ ≥ 160 mg/dl, or use of lipid-lowering drugs), smoking status, body mass index (BMI), estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, albumin-to-creatinine ratio (UACR), and history of CVD (stroke, peripheral artery disease, ischaemic heart disease, and heart failure) (Supplementary Table  2 ).
Results A total of 373,185 patients with T2D were registered in the SIDIAP database as of 31 December 2016 (Table  1 ). The mean age was 70:1 ± 12:3 years, and 54. 9% were male. The mean T2D duration was 9:3 ± 6:2 years, and the mean HbA1c was 7:12% ± 1:32. More than half (59%) of the patients had good glycaemic control (HbA1c ≤ 7%), about one-third (28%) had chronic kidney disease (eGFR < 60 ml/min/1:73m 2 ), and 4% had severe renal insufficiency (eGFR < 30 ml/min/1:73m 2 ). Overall, 77% of patients (n = 286,651) did not have any ICD-10 code of established CVD recorded, thus considered primary prevention cases; 23% (n = 86,534) had an ICD-10 code of an established CVD, so they were considered secondary prevention cases. Patients with established CVD were more often men, older, and with a longer T2D duration and had more CV risk factors (Table  1 ).
Applying the EMPA-REG OUTCOME eligibility criteria, only 8. 2% (n = 30,559) of the patients included in the SIDIAP database would have qualified for entry in the trial (Table  2 ), while 29. 6% (n = 110,551) could have   4 ). In Figure  1 , these results are shown in comparison to those reported by two studies conducted in the US and Northern Europe  [18, 19]. Compared with the characteristics of the patients enrolled in the three studied CVOTs (Table  5 ), the main limiting factors for inclusion would have been the absence of a history of CVD and the value of HbA1c. Specifically, only 23% of patients in our T2D population had a preexisting CVD and only 41% had HbA1c values ≥ 7%. Finally, chronic renal failure (present in 28% of our T2D patients) was a restrictive criterion in DECLARE, while in EMPAREG and CANVAS, only patients with severe renal failure (eGFR < 30 ml/min/1:73m 2 ) were excluded (4% in SIDIAP).
73m 2 (HR 0. 52; 95% CI, 0. 38-0. 72) [38]. Indeed, a recent systematic review and trial-level metaanalysis of SGLT2i CVOT trials concludes that SGLT2i reduce the risk of worsening eGFR in a broad spectrum of T2D patients  [39]. Considering the facts mentioned above, if SGLT2i were allowed to be prescribed to patients with eGFR>30 ml/min/1. 73 m 2 , the proportion of patients eligible for inclusion in the DECLARE TIMI 58 in the SIDIAP database would have increased. The results of the present study show that the patterns of external validity of SGLT2i CVOTs were limited, in line with the studies conducted in Northern Europe or the US  [18, 19]. However, the proportion of eligible patients would have been less in our population than in Northern Europe for all three trials but higher than that in the US for the CANVAS and EMPAREG studies as shown in Figure  1.
This could be explained by differences in the prevalence of CVD between regions and countries. Indeed, the prevalence of CVD is higher in countries from the north of Europe than from the south of Europe  [21] , but it is also probable that differences in the prevalence of specific CV risk factors by country and region have impacted our results. The low eligibility for CANVAS and EMPA-REG OUTCOME in the US study is striking, although the percentage of patients having CVD was similar to ours (23. 7 and 23%, respectively). One explanation for this discordance could be related to the different methodologies used in the US study, which is an estimation was higher in our database (23%) and produced higher percentages of inclusion in the CANVAS and EMPA-REG OUTCOME trials  [18]. On the other hand, the applicability of SGLT2i is certainly much wider than the strict entry criteria of CVOTs, as shown in several of studies and subanalyses reporting the additional benefits of SGLT2i, particularly in chronic kidney disease and heart failure  [40].
For instance, real-world evidence (RWE) studies have confirmed reductions in mortality (43% to 49%) and hospitalization for heart failure (40% to 51%) in hundreds of thousands of patients  [40]. So far, the main RWE studies published are CVD-Real, CVD-Real 2, EASEL, and EMPRISE; these studies compared SGLT2i with other antidiabetic drugs, especially against DPP-4 inhibitors (CVD-Real 2 and EMPRISE). However, our study aimed at determining how many patients from our Mediterranean database would be eligible to enter in each CVOT, but not the applicability of SGLT2i in the whole diabetic population. Thus, even though we found a low percentage of patients that would have been enrolled in each of the cardiovascular outcome trials, we should not dismiss the additional benefits of using SGLT2i in the whole diabetic population in terms of heart failure benefit.