dataesr/scientific-paragraphs-categorization huggingface dataset:
Data The following data were collected from the RespiRare® database and analysed: age at diagnosis; gender; DS status; familial history of pulmonary hemosiderosis and/or autoimmune disease; initial symptoms; biological parameters, including hemoglobin (Hb), reticulocytes, autoantibodies (antinuclear antibodies [ANA], anti-cytoplasmic antibodies [ANCA], anti-smooth muscle, anti-cyclic citrullinated peptide [CCP], anti-proteinase-3 [PR-3], anti-myeloperoxidase [MPO], anti-DNA, anti-endomysium, anti-transglutaminase, anti-SSA, anti-cardiolipin) and rheumatoid factor (RF); lung imaging results, including chest X-ray and thoracic high-resolution computed tomography (HRCT); pulmonary function tests (PFT); BAL and histological results; type and durations of treatments; and evolution of the disease with a specific attention to the presence or absence of pulmonary arterial hypertension (PAH) and relapses.
Acknowledgments We thank the  Assistance Publique Hôpitaux de Paris, Sorbonne Université, Paris, France , and the national networks for rare lung diseases:  Centre de référence des maladies respiratoires rares (RespiRare) ,  Centre de référence des maladies pulmonaires rares (OphaLung)  and Filière de soins pour les maladies respiratoires rares (RespiFIL). We also thank the  Jerôme Lejeune Institute for Down syndrome. The ILD cohort is developed in collaboration with the Rare Cohort Disease (RaDiCo)- ILD  project ( ANR-10-COHO-0003 ), the  FP7-305653-child-EU  project and the  COST Action European network  for translational research in children's and adult interstitial lung disease ( COST-ILD ) project ( CA16125 ).
Background: Standard treatment options for patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) are associated with limited efficacy and some toxicity. Recently, immunotherapy with antibodies that inhibit the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interaction has emerged as a new treatment option. This manuscript reviews early-phase and late-phase trials of immunotherapy in advanced GC/GEJC. Methods: Searches for studies of immunotherapy in GC/GEJC were performed using PubMed, ClinicalTrials. gov, and abstract databases for select annual congresses. Findings were interpreted based on expert opinion. Results: Monotherapy with anti-PD-1/PD-L1 antibodies, including pembrolizumab, nivolumab, avelumab, durvalumab, and atezolizumab, has shown interesting objective response rates (ORRs; 7-26%) across varying GC/GEJC populations, with ORRs potentially higher in PD-L1 + vs PD-L1tumors.
2 months. Grade 3/4 TRAEs occurred in 17% of patients. Nivolumab monotherapy is also being assessed in an ongoing open-label phase 1/2 study that is recruiting a subgroup of patients with EBV+ advanced GC (NCT02488759). Data from 2 studies of avelumab, an anti-PD-L1 antibody, in patients with GC/GEJC, have been reported to date. In the JAVELIN Solid Tumor trial, avelumab was administered to a large phase 1b cohort of patients with locally advanced or metastatic GC/GEJC unselected for PD-L1 expression  [63]. A total of 151 patients were enrolled, including a subgroup of 62 patients who received avelumab as 2L or later treatment. In an interim analysis from this subgroup, the unconfirmed ORR was 10%, and clinical activity was seen irrespective of PD-L1 expression status (based on a ≥ 5% tumor cell cutoff; 73-10 assay).
Avelumab was associated with an acceptable safety profile, including grade ≥3 TRAEs in 10% of patients. OS data were not mature at the time of reporting  [63]. Avelumab has also been studied in a phase 1 expansion cohort of Japanese patients with advanced GC/GEJC that progressed after chemotherapy (JAVELIN Solid Tumor JPN)  [64]. In the first 20 patients enrolled, the ORR was 15% based on partial responses in 3 patients, and there was 1 grade 3 TRAE (5%). Data have been reported following durvalumab (anti-PD-L1) treatment in 28 patients with previously treated gastroesophageal cancer within a phase 1 trial. The ORR was 7%, and grade ≥3 TRAEs occurred in 17%  [65]. Durvalumab is also being evaluated in a phase 1/ 2 study as monotherapy in patients with advanced GC/GEJC (NCT02340975), but no data have been reported to date.
Combination therapy In cohort 2 of KEYNOTE-059, 25 patients with advanced HER2-GC/GEJC received 1L treatment with pembrolizumab in combination with 5-FU/cisplatin chemotherapy  [61]. The ORR was 60%, and there was a potential association between PD-L1+ tumors (≥1% combined positive score based on tumor or immune cells; 22C3 assay) and higher ORR (69% and 38% in patients with PD-L1+ vs PD-L1-tumors, respectively). Median OS was 13. 8 months. The incidence of grade 3/4 TRAEs was 76%, which was notably higher than that seen with 1L pembrolizumab monotherapy (23%). Durvalumab is being evaluated in combination with tremelimumab in a phase 1/2 study in patients with advanced GC/GEJC (NCT02658214), although no data have been reported to date.
Phase 1 and 2 trials of checkpoint inhibitors as 1L maintenance treatment Based on the encouraging antitumor activity and safety profiles of checkpoint inhibitors in GC/GEJC, there has been considerable interest in assessing whether these agents could provide a clinical benefit as maintenance treatment in patients without disease progression after 1L induction chemotherapy. CA184-162 (NCT01585987) was a phase 2 trial comparing the efficacy of maintenance ipilimumab vs best supportive care (BSC) following 1L chemotherapy in 114 patients with unresectable locally advanced/metastatic GC/GEJC  [67]. In the BSC arm, 79% of patients received continued fluoropyrimidine chemotherapy. Ipilimumab did not improve efficacy compared with fluoropyrimidine/BSC (median OS, 12. 7 vs 12. 1 months, respectively), and grade ≥3 TRAEs occurred in 23% with ipilimumab vs 9% with fluoropyrimidine/BSC, respectively  [67].
Monotherapy JAVELIN Gastric 100 (NCT02625610) is the only phase 3 trial assessing switch-maintenance treatment with immunotherapy. This study is comparing avelumab vs continuation of leucovorin + 5-FU + oxaliplatin (FOLFOX) or capecitabine + oxaliplatin (XELOX) in patients with advanced GC/GEJC and without disease progression after 1L induction chemotherapy. The hypothesis for this trial is that avelumab may provide durable antitumor activity following immunogenic priming and tumor shrinkage induced by 1L chemotherapy, with the added benefit of avoiding the toxicity burden of additional chemotherapy or combination therapy. The primary endpoints are PFS and OS, and recruitment is now complete. Two phase 3 trials were designed to compare 2L pembrolizumab monotherapy vs paclitaxel in non-Asian (KEYNOTE-061; NCT02370498) or Asian (KEYNOTE-063; NCT03019588) patients with advanced PD-L1+ GC/GEJC that progressed after 1L platinum/fluoropyrimidine doublet therapy.
A recent press release reported that KEYNOTE-061 did not meet its primary endpoints of superior OS and PFS for pembrolizumab vs paclitaxel  [68] ; data for KEYNOTE-063, which has completed enrollment, are expected in the near future. Two other phase 3 trials were performed to assess later-line treatment with an anti-PD-1/PD-L1 antibody in patients with GC/GEJC. ATTRACT-ION-02 (ONO-4538-12; NCT02267343) is a completed phase 3 trial of 3L or later nivolumab vs placebo in 493 Asian patients with unresectable advanced or recurrent GC/GEJC that had positive findings  [69]. Prior treatment (including in the adjuvant setting) included 2 lines in 20%, 3 lines in 40%, and ≥4 lines in 40%. In the nivolumab vs placebo arm, median OS (primary endpoint) was 5. 3 vs 4. 1 months (HR = 0. 63; p < 0. 0001), and ORR was 11% vs 0% (P < 0.
0001). Nivolumab efficacy was seen irrespective of PD-L1 status (based on a ≥ 1% cutoff in tumor cells; 28-8 assay). Grade 3/4 TRAEs occurred in 10% of patients treated with nivolumab compared with 4% in the placebo arm. Based on this trial, the Japanese Ministry of Health, Labour, and Welfare approved nivolumab in September 2017 for the treatment of unresectable advanced or recurrent GC progressed after chemotherapy  [29]. JAVELIN Gastric 300 (NCT02625623) is a global randomized trial of 3L avelumab compared with investigator choice of chemotherapy (either paclitaxel or irinotecan) performed in 371 patients with advanced GC/GEJC progressed or relapsed after 2 prior lines of treatment, unselected for PD-L1 expression and stratified by region (Asia vs non-Asia), with all patients receiving BSC as background therapy.
Combination therapy Ongoing phase 3 trials assessing checkpoint inhibitor-based combination therapy in the 1L setting are KEYNOTE-062 (NCT02494583), a trial of pembrolizumab alone or in combination with cisplatin/5-FU vs cisplatin/5-FU alone in patients with PD-L1+/HER2-advanced GC/ GEJC, and CheckMate 649 (NCT02872116), a 3-arm trial of nivolumab plus ipilimumab, nivolumab plus investigator choice of chemotherapy (XELOX or FOLFOX), or XELOX/FOLFOX alone in patients with previously untreated advanced or metastatic GC/GEJC. The primary endpoint in both studies is OS in patients with PD-L1+ tumors. Enrollment in KEYNOTE-062 is complete. In addition, ATTRACTION-04 (ONO-4538-37; NCT02746796) is a phase 2/3 trial evaluating the safety and efficacy of 1L nivolumab plus S-1 (tegafur/gimeracil/oteracil potassium) plus oxaliplatin (SOX) therapy or capecitabine plus oxaliplatin (CAPOX) therapy in Asian patients with unresectable advanced or recurrent GC/GEJC.
nivolumab/SOX and nivolumab/CAPOX was 67% and 71%, respectively. Grade ≥3 TRAEs, most of which were common side effects of chemotherapy, occurred in 52% and 67% of patients, respectively, and there was no difference in activity and safety between the 2 regimens. Part 2 of this study, a randomized comparison of nivolumab vs placebo in combination with SOX/CAPOX, is ongoing, and results are awaited. Ongoing phase 3 trials in the neoadjuvant/adjuvant setting are ONO-4538-38 (NCT03006705), a trial of nivolumab in combination with S-1 or CAPOX vs S-1 or CAPOX alone in patients with resected GC/ GEJC; CheckMate 577 (NCT02743494), a trial of nivolumab vs placebo in patients with esophageal cancer or GEJC after chemoradiotherapy and surgery; and KEYNOTE-585 (NCT03221426), a trial comparing pembrolizumab plus chemotherapy vs chemotherapy alone as neoadjuvant or adjuvant treatment for untreated patients with GC/GEJC.
In a phase 1 study of pembrolizumab plus ramucirumab in 69 patients with advanced GC/GEJC receiving 1L or later treatment, ORR in the 1L and 2L or later subgroups was 14% and 7%, and grade ≥3 TRAEs occurred in 39% and 27%, respectively  [74]. Thus, these 2 studies suggest no additive activity for ramucirumab combined with a checkpoint inhibitor. Other ongoing trials of checkpoint inhibitors plus antiangiogenic agents include trials of atezolizumab plus bevacizumab with or without chemotherapy (NCT01633970) and nivolumab plus ramucirumab (NCT02999295). In addition to CTLA-4 and PD-1/PD-L1, other suppressive immune checkpoint proteins include LAG-3 (a lymphocyte surface protein) and IDO (an enzyme that catabolizes tryptophan, creating an immunosuppressive tumor microenvironment), and inhibitors of these proteins may work in synergy with anti-PD-1/PD-L1 antibodies to produce a more robust antitumor immune response (Fig.
2 )  [75]. Trials examining this strategy in which enrollment of patients with GC is specified in the trial record include nivolumab plus BMS-986016 (anti-LAG-3; NCT01968109) and pembrolizumab plus epacadostat (IDO inhibitor; NCT02178722; NCT03196232), and other similar trials are ongoing in patients with various advanced tumors. In addition, FRAC-TION-GC (NCT02935634) is assessing nivolumab plus BMS-986016 (LAG-3 inhibitor) or ipilimumab specifically in patients with advanced GC. An alternate strategy to enhance antitumor responses would be to combine a checkpoint inhibitor with an agonist antibody that activates a co-stimulatory receptor expressed on T cells. For example, the combination of INCAGN01876 (anti-glucocorticoid-induced tumor necrosis factor receptor-related protein) and nivolumab with or without ipilimumab (vs ipilimumab alone) is being tested in patients with advanced or metastatic tumors, including a cohort of patients with advanced GC/ GEJC (NCT03126110).
Combining checkpoint inhibitors with antibodies targeted to proteins overexpressed on tumors is another rational treatment strategy; for example, combining anti-HER2 antibodies with immunotherapy may enhance antibody-dependent cell-mediated cytotoxicity against tumor cells by natural killer cells  [76]. Studies investigating this approach are combining treatment with pembrolizumab and trastuzumab (NCT02901301) or margetuximab (NCT02689284) in patients with HER2+ advanced GC/GEJC or combining nivolumab and andecaliximab (anti-matrix metallopeptidase-9; NCT02864381). Finally, another trial (NCT03122548) is investigating a combination of pembrolizumab and CRS-207, a live attenuated Listeria monocytogenes vaccine genetically engineered to overexpress mesothelin, in patients with advanced GC/GEJC.
014)  [78]. Separate studies have shown the T-cell-inflamed phenotype includes tumors within all GC genomic subtypes  [80]. Helicobacter pylori and EBV infections induce a T-cell response in gastric tissues and increase PD-L1 expression, suggesting another subset of cancers that may preferentially respond to checkpoint inhibitor therapy  [81, 82] ; however, clinical data to confirm this hypothesis are lacking. Finally, a phase 2 trial has been initiated that will analyze pembrolizumab treatment in relation to gene expression profiling, copy number variations, Lauren classification, EBV/TP53 status, and integrative genomic analysis (NCT02589496); this hypothesis-generating approach will hopefully lead to better understanding of the predictive value of these biomarkers.
6 6. 2 KEYNOTE-098 GEJC: 25 (NCT02443324) I4T-MC-JVDJ 1 Ramucirumab + durvalumab GC: 19 Unselected 2L: 19 15 Not reported Not reported (NCT02572687) GEJC: 7 3L: 6 CheckMate 032 1/2 N3: nivolumab 3 mg/kg; N1I3: nivolumab GC, N3: 19 Unselected 1L, N3: 0 N3 overall: 12 N3: 1. 4 N3: 6. 2 (NCT01928394) 1 mg/kg + ipilimumab 3 mg/kg; N3I1: N1I3: 22 N1I3: 1 PD-L1+: 19 N1I3: 1. 4 N1I3: 6. 9 nivolumab 3 mg/kg + ipilimumab 1 mg/ N3I1: 18 N3I1: 0 PD-L1-: 12 N3I1: 1. 6 N3I1: 4. 8 kg GEJC, N3: 2L, N3: 10 N1I3 overall: 24 40 N1I3: 6 PD-L1+:40 N1I3: 27 N3I1: 16 PD-L1-: 22 N3I1: 34 3L+, N3: 49 N3I1 overall: 8 N1I3: 42 PD-L1+: 23 N3I1: 36 PD-L1-: 0 No identifier reported 2 Tremelimumab GC: 6 Unselected 2L: 18 6 2. 8 4. 8 GEJC: 6 EC: 6 KEYNOTE-059 2 Pembrolizumab GC: 124 Unselected 3L+: 259 Overall: 12 2. 0 5.
5 cohort 1 GEJC: 134 PD-L1+: 16 (NCT02335411) PD-L1-: 6 1L therapy I4T-MC-JVDF/ 1 Ramucirumab + pembrolizumab GC: 18 Unselected 1L: 28 14 5. 6 Not reported KEYNOTE-098 GEJC: 10 (NCT02443324) KEYNOTE-059 cohort 2 2 Pembrolizumab + cisplatin + GC: 20 Unselected 1L: 25 60 6. 6 13. 8 (NCT02335411) 5-FU or capecitabine GEJC: 5 PD-L1+: 69 PD-L1-: 38 KEYNOTE-059 cohort 3 2 Pembrolizumab GC: 19 PD-L1+ 1L: 31 26 3. 3 20. 7 (NCT02335411) GEJC: 12 1L maintenance therapy JAVELIN Solid Tumor 1b Avelumab GC or Unselected 1L Mn: 89 Overall: 9 Overall: 12. 0 Not reported (NCT01772004) GEJC: 89 PD-L1+: 9 wks PD-L1-: 5 PD-L1+: 17. 6 wks PD-L1-: 11. 6 wks CA184-162 2 Ipilimumab vs GC: 95 Unselected 1L Mn, Ipilimumab: 2 Ipilimumab: 2. 7 Ipilimumab: (NCT01585987) BSC GEJC: 19 Ipilimumab: 57 BSC: 7 BSC: 4. 9 12.
Study population Given the current activity in our clinic, we estimate that the study will involve 150-170 consecutive patients who attend a Consultation for Suffering at Work between 1 January and 31 December 2018. All Francophone patients attending a Consultation for Suffering at Work will be eligible for inclusion, whether or not they present with an associated somatic problem. Participants will be contacted 3 months (M3) and 12 months (M12) after the consultation. Patients will be considered lost to follow-up if their M12 data is unobtainable. With regards to similar studies in other countries, the percentage of patients who will be lost to follow-up at M12 is estimated to be between 20% and 40%  [23]. Refusal to participate in the study or an inability to fill in the written questionnaires will also constitute reasons for non-inclusion.
Data collection The patient attends the Consultation for Suffering at Work at M0. The consulting physician collects any data on the patient's antecedent problems and his current socio-professional situation. The patient completes the five questionnaires mentioned previously: the GHQ-28, WHOQOL-BREF, IPDE, SSQ6 and WCC. After the Consultation for Suffering at Work (M0′), both the patient and the consulting physician evaluate the dynamic perceived in the consultation using ad hoc questionnaires that were designed for the needs of this protocol (Annexes 5 and 6). The physician notes the recommendations and advice given to the patient on a form that is attached to the patient's medical record. At M3 and M12, information on whether those recommendations were adhered to is noted on the same form during a follow-up telephone interview with the patient.
For the M12 evaluations, patients will be contacted in sub-groups of approximately 15 subjects at a time. This means that the average follow-up length for each patient will equal one year ± 15 days. The end of the data collection period should, therefore, be in December 2019. Data input should be completed by June 2020. Data analysis should be finished in November 2020. Table  1  is a summary of all these procedures.
Quantitative data An initial descriptive analysis will describe the population's characteristics. Statistical analysis will be structured around the two principal evaluation criteria and the protocol's formulated hypotheses. The first evaluation criterion-employment status at 12 months-is a qualitative variable, collected once. Analysis will be by multiple logistic regression. The potential effects of the consultation on the patient's return to work will be evaluated using an "adherence to recommendations" variable at M3 and by an estimation of the perceptions of the consultation's dynamic. These regressions will systematically take into account the patient's age and sex. The other potential confounding factors will be included one by one if their statistical significance is characterised by a p <.
20. The second evaluation criterion is the patient's change in health status, as estimated using the scores from the repeated use of the WHOQOL-BREF and GHQ questionnaires. Each one of the scores will be analysed using a mixed linear model with a random effect and with the moment of data collection as the fixed effect. The normality of the random effects and the normality of the baseline residuals of both scores will be checked. If necessary, transformation of the scores (e. g. logarithmic) will be done. If none leads to acceptable normality, the scores will be discretized in low/high scores and logistic mixed models will be applied. The effect of the consultation itself on return to work will be estimated partially by the differential change in the patient's health status, partially by the differences between the subjects who followed the recommendations and advice given and those who did not, and partially by the perceived dynamics in the consultations.
Qualitative data Thirty of the telephone interviews carried out to collect information on patients' adherence to medical recommendations will become extended interviews on the effects of the Consultation for Suffering at Work itself. Subjects for these 30 extended interviews will be selected so as to cover all the profile types in the study population. These interviews will be recorded, transcribed, anonymised, analysed and coded using independent double coding. The transcriptions will be subjected to a contents analysis (theme occurrence analysis) as part of a comprehensive approach (intuitive iterative reading, identification of invariables in different scenarios and interpretation). The use of specialist software is not foreseen for this part of the study.
Taxonomic diversifications A number of studies are focused on important taxonomic groups. Ernst (2018)  provides a new, detailed biodiversity curve for bryozoans through the Ordovician Period. The highest diversities of bryozoan taxa were achieved in the Late Ordovician, possibly mirroring sea-level patterns. Esteve et al. (2018)  in an analysis of trilobite enrolment using kinematics, clarify and illustrate that although a few structures appeared for the first time during the Ordovician, the majority had already evolved during the Cambrian. The CHITDB, the Chitinozoan Database, has captured detailed range data for these Ordovician and Silurian microfossils from the Baltic region  (Hints et al. 2018) ; analysis of the database demonstrates a diversity hike during the Darriwilian to middle Katian and subsequently during the Telychian.
Acknowledgements. We are enormously grateful to our group of reviewers who responded promptly (in most cases) to our requests:  Mike Benton ,  Anthony Butcher ,  Caroline Buttler ,  Jason Dunlop ,  Cole Edwards ,  Lars Holmer ,  Jin Jisuo ,  Jörg Maletz ,  Ronald Martin ,  Mike Melchin ,  Stewart Molyneux ,  Claude Monnet ,  Ian Percival ,  Elena Raevskaya ,  Christian Rasmussen ,  John Repetski ,  Cristiana Ribecai ,  Shen Shuzhong ,  Martin Smith ,  Alycia Stigall ,  Enrique Villas ,  Wang Wenhui ,  Patrick Wyse Jackson ,  Seth Young , as well as a number of anonymous referees. We thank  Alan Owen  and especially  Peter Doyle  (editor-in-chief) for their huge input in turning this issue into reality. David Harper  acknowledges receipt of a  Leverhulme Fellowship  and support from the  Wenner Gren Foundation (Sweden).
In order to compare relative isotope ratios, we reported here the helium isotopic ratios from the measurements of intensities of the helium isotopes. Regarding data processing, the normalized helium isotopic ratio of each sample aliquot is calculated by dividing the 3 He/ 4 He ratio of the sample aliquot by the mean of the ratios of the internal standard measured directly before and after the sample  (Mabry et al. , 2013) Â Ã =2 ð1Þ For each complete analysis, the mean composition of all individual R a,n measurements, is determined  (Mabry et al. , 2013) as: R m;N ¼ X n 1 R a;n ! 0 n ð2Þ where ''n" corresponds to the number of R a measured and thus, to the number of sample aliquot measured. Then we report the average of the ratios R m,N measured for the repeated complete analyses executed on the same air sample: R M;S ¼ X N 1 R m;N ! 0 N ð3Þ where ''N" corresponds to the number of complete analyses performed on the same air sample.
N is the number of sample/standard bracketing analyses performed for each sample. We detected a significant decrease in the R M,BB * ratios from November 2015 onwards with a confidence level of 95% (Table  3 ; Fig. 1 ). The mean of the R m,BB ratios measured before November 2015 was 1. 0331 ± 0. 0024 (N = 95), while the mean of all sample/standard bracketing analyses carried out after this period was 1. 0291 ± 0. 0024 (N = 26). Thus, the long-term stability of our secondary standard BB, before and after the replacement of the mass spectrometer filament, has a standard deviation of about 2. 4‰ (1 SD). Note that only air samples from Antarctica, Ethiopia and the Atlantic Ocean were analysed after November 2015. The respective data were calibrated against BB standards measured during the same period.