dataesr/scientific-paragraphs-categorization huggingface dataset:
In the single arm phase II BELIEF trial in 109 Caucasian EGFRmutant NSCLC patients, combined erlotinib and bevacizumab gave median PFS and OS of 13. 2 and 28. 2 months, respectively. However, the primary endpoint was only met in baseline T790Mpositive tumors with a median PFS of 16 months, whereas in T790M-negative tumors, median PFS was 10. 5 months  (62). In the subgroup of patients with pretreated BM (N = 21), median PFS was 8. 8 months. The efficacy of this combination in the BM population does not appear to be superior to standard EGFR TKI therapy  (37) , however only 21 patients with BM were included in the BELIEF trial. Results from the ongoing randomized phase II BRILLANT trial (NCT0265536), testing bevacizumab plus erlotinib vs. erlotinib in BM EGFR-mutant patients, should reveal the efficacy of this combination in this population.
5 months to 4. 4 months (HR 0. 54, 95% CI: 0. 36-0. 80). Among the 17 patients with measurable BM, ceritinib gave a 35% intracranial RR and median duration of intracranial response of 6. 9 months  (76). Nonetheless, despite these second-generation more potent ALK TKIs, BM remained the main site of progression among patients with BM at baseline  (76). Based on ceritinib efficacy, an international prospective phase II open-label study is ongoing (ASCEND-7, NCT02336451) specifically evaluating the anti-tumor activity of ceritinib in ALK-positive NSCLC patients with BM or leptomeningeal disease (previously treated with radiotherapy or not). Gastrointestinal toxicity by ceritinib may reduce treatment compliance. The ASCEND-8 (NCT02299505) aimed to evaluate whether administering ceritinib, 450 or 600 mg, with a low-fat meal may enhance gastrointestinal tolerability vs.
Lorlatinib Lorlatinib (PF06463922) is a selective, potent, brain-penetrant next-generation ALK and ROS1 TKI, active against most known resistance mutations  (79, 89). Lorlatinib was tested in a phase I trial in 54 pretreated or treatment-naïve ALK-(N = 41) or ROS-1 (N = 12) positive NSCLC patients (11% treatment-naïve, 52% two or more previous TKIs, and 72% with BM). Patients reached a RR of 46% in the ALK-positive population irrespective of the number of prior ALK TKI therapies, and median PFS and DOR of 9. 6 and 12. 4 months, respectively. Lorlatinib was highly active in the CNS, including intracranial responses in 8 of 19 (42%) ALKpositive patients with baseline measurable BM, in over a half of whom two or more previous ALK TKIs had failed (90) (Table  2 ). The recommended dose for the phase II trial was 100 mg/day.
For patients with active BM (N = 34) RRs were similar to those with baseline BM, 47 and 73% in arms A and B, respectively. Median intracranial PFS was 12. 8 and 18. 4 months in arms A and B, respectively  (95). The intracranial efficacy of brigatinib compares favorably with other second-generation ALK TKIs (74, 85) (Table  2 ). Brigatinib is currently being investigated in a randomized phase III ALTA-1L (NCT02737501) trial comparing brigatinib vs. crizotinib in ALK-positive TKI-naïve patients. Asymptomatic and pretreated BM are not exclusion criteria. This trial allows crossover from crizotinib to brigatinib and may help to elucidate whether a sequential strategy is better than upfront brigatinib.
Ensartinib Efficacy of ensartinib (X-396) 225 mg/day in an expansion study has been reported. Forty of the 80 enrolled patients were evaluable for response, achieving 58% partial responses (88% in eight crizotinib-naïve patients, and 64% in 22 crizotinib-resistant)  (96). Updated results among 15 TKI-naïve patients showed an 80% RR and median PFS of 23. 8 months  (97). CNS responses [(60% partial responses) were observed in both crizotinib-naïve and crizotinib-resistant populations, with a median DOR of 5. 8 months  (98) ]. The ongoing phase III XALT3 (NCT02767804) will compare ensartinib with crizotinib as first-line treatment (previous chemotherapy allowed).
Similarly, intracranial responses have been reported with alectinib, one patient responding after escalating alectinib to 900 mg twice daily  (112). The efficacy of alectinib (900-1200 mg/day) as first-line treatment in RET-positive NSCLC patients will be assessed in a multi-cohort phase II/III B-FAST trial (NCT03178552). Treated and asymptomatic BM will be allowed. LOXO-292, another RET TKI has reported tolerability and efficacy in RET-dependent cancers even in progressive BM after alectinib  (113). In a phase I trial, vandetanib and everolimus showed antitumor activity in RET-positive NSCLC patients with BM  (114, 115). The short-term outcomes with multikinase inhibitors with activity against RET compared to EGFR/ALK TKIs in EGFRmutant/ALK-rearranged NSCLC, strongly suggest that there is a need for more selective and potent RET targeted agents as monotherapy or in combination in order to enhance activity  (116).
1 months  (137). Recent studies have reported that ALK-positive NSCLC patients with BM treated with SRS and/or WBRT and TKIs have prolonged survival  (68, 69, 138). Given the extended OS for ALK-positive patients and frequent need for repeated courses of CNS radiotherapy, SRS is the preferred strategy for minimizing cerebral toxicity. Synergistic efficacy of crizotinib and radiotherapy could be explained by increased BBB permeability and decreased P-gp expression following irradiation  (139). These results suggest intracranial interventions and TKIs beyond progression are of value in patients with asymptomatic and limited CNS progression on a TKI. This SRS strategy is being validated in an ongoing phase II clinical trial (NCT02314364) among oncogene-addicted (EGFR-, ALK-, ROS1-positive) NSCLC patients with up to four BM.
Second-or Third-Generation TKis Upfront or Sequentially In EGFR-mutant NSCLC patients, osimertinib has reported higher intracranial activity compared with chemotherapy (51) and first-generation EGFR TKIs  (17) , and longer delay of onset of BM  (51). However, lack of stratification according the presence of BM, no reported survival benefit with osimertinib and no prospective validation of this efficacy, limit interpretation. Nonetheless, preclinical data strongly support the increased intracranial efficacy of osimertinib compared with other EGFR TKIs  (44). The ongoing phase II APPLE trial (NCT02856893) assesses the optimal strategy for delivering osimertinib in EGFRmutant NSCLC patients and will prospectively validate the efficacy of osimertinib among those patients with BM at baseline (stratification criteria and brain MRI will be performed at baseline) and also the time to radiological brain progression respect to with first-generation EGFR TKI (gefitinib)  (140).
Standard protocol approvals, registration, and patient consents The three studies (BIA-2093-301 [NCT00957684]; -302 [NCT00957047]; and -304 [NCT00988429]; registered at ClinicalTrials. gov) were undertaken at centers in 35 countries between 2004 and 2012, in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation guidelines and all national, state, and local laws of the pertinent regulatory authorities. Approval was received from the relevant independent ethics committees/institutional review boards; written informed consent was obtained from all patients.
Assessment of TEAEs Individual patient data from studies 301, 302, and 304 were pooled and analyzed, and patients with psychiatric or cognitive TEAEs were identified; investigators recorded TEAEs and were asked to assess them in terms of severity (mild, moderate, severe) and seriousness (serious, nonserious). A serious AE (SAE) was classified as any TEAE that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a birth defect; or was another medically important condition. TEAEs were categorized using the Medical Dictionary for Regulatory Activities (MedDRA) v13. 1. Psychiatric TEAEs were identified as those within the System Organ Class "Psychiatric Disorders".
Discussion In this pooled analysis of data from 1447 patients in three phase III studies of adjunctive ESL, the incidences of reported cognitive and psychiatric TEAEs (including depression and suicidality) were examined, as well as additional measures of suicidal ideation and behavior. The results from these post-hoc analyses will contribute toward our understanding of the potential psychiatric and cognitive impact of add-on ESL in adults with POS. Psychiatric AEs are relatively common in patients taking AEDs. For example, in an outpatient study at the Columbia Comprehensive Epilepsy Center, chart review identified that AED-related psychiatric/ behavioral side effects were reported for 16% of patients who began taking a 'newer' AED (e. g. , gabapentin, LTG, LEV, vigabatrin, felbamate, OXC, tiagabine, topiramate, or zonisamide) as an add-on or as monotherapy  [13].
Acknowledgements The authors would like to thank  Dr. Rui Sousa , formerly of BIAL -Portela & C a , S. A. , for his advice and input during development of the manuscript. The authors would also like to acknowledge the writing assistance of  Mallory Gough, PhD , of  FireKite , an Ashfield company, part of  UDG Healthcare plc , for support in drafting this manuscript. and other funding from  UCB ,  Sunovion Pharmaceuticals Inc. , and  Lundbeck. M. Carreño  received financial support for research from  Eisai, Bial , and  UCB ; and consultancy funds from  Eisai, Bial ,  UCB , and  Shire. E. Trinka  received speaker's honoraria from  UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc. , and Novartis; consultancy funds from  UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc.
Search strategy and selection criteria Studies were identified by searching electronic databases PubMed and Scopus. Pubmed was searched using the following terms: (« hemorrhagic fever, ebola » [MeSH Terms] OR « ebola » [All fields] OR « ebolavirus » [MeSH Terms] OR « ebolavirus » [All fields]) AND (« vaccines » [MeSH Terms] OR « vaccines » [All fields] OR « vaccine » [All Fields]). Scopus was searched using the following terms TITLE-ABS-KEY (ebola) AND TITLE-ABS-KEY (vaccine). Additionally, the Clinicaltrials. gov website was searched to identify unpublished and ongoing studies. Several experts in the field were contacted to find papers which could be not indexed in databases. Reference lists of relevant papers and reviews were examined to identify further articles. The search was performed on March 23, 2016 and updated as of February 24, 2018 with a publication date limit of the same date in order to identify all published studies which met the inclusion criteria and without restriction on language.
Data extraction A first step of selection was performed on the title and abstract, and then a second step was performed after reading the full article. Two authors independently assessed each full article to include papers matching the review's inclusion criteria. Disagreements between reviewers were resolved by consensus. Data were extracted by two independent reviewers, with differences reconciled by consensus. The following variables were extracted: paper identification (title, first author, publication year), study design, inclusion and exclusion criteria, characteristics of the population (number of subjects; human or nonhuman primates; proportion of women, average age and study site for clinical trials; and animal species for pre-clinical studies using nonhuman primates), characteristics of vaccine (vaccine platform in terms of delivery technology used, specific vector for recombinant vaccines, Ebola viral insert, dosage, route of administration, vaccination schedule), characteristics of measurement techniques (time interval between last injection and measure, strain and nature of antigen used to detect antibody response, measurement method), antibody response after vaccination (geometric mean titre and its variance).
Regarding the antibody response after vaccination, geometric mean titre was extracted from the text or estimated from figures. If a single vaccination group had more than one measure of antibody response, data from measurement after each injection were extracted. Therefore, if available, measurement post-prime and measurement post-boost from a same vaccination group were both included in our meta-analysis. If several measurements post-prime or if several measurements post-boost were available, for each injection we extracted the one closest to 28 days after injection, which is a standard time point in Ebola vaccine trials. Variance of titre (within-group variance) was extracted directly from the text or calculated from confidence interval or from individual values. The present study was registered in  PROSPERO (no.
Data analysis For all analyses, the statistical unit used was the vaccination group (one or several groups for a single study), i. e. a protocoldefined group undergoing the same intervention and follow-up procedures (such as a randomized arm of a clinical trial or an animal group in NHP studies). First descriptive analyses were performed among all groups, separately for nonhuman primates and for humans. Then, a random-effect meta-regression analysis was performed including only human groups with 8 individuals or more. This threshold allowed both to have sufficient inter-individual variability in each group and to avoid excluding too many groups. Thus, it was not possible to perform the regression analysis with NHP studies because of the usual small sample size of the groups. The effect of every potential determinant of antibody response was assessed through fixed effects.
Conclusion Our findings show that there are still significant uncertainties in the determinants of the antibody response after preventive vaccination against Ebola virus disease. This emphasises the interest of harmonizing measurement methods and study designs. Furthermore, it indicates the impossibility to directly compare results from one published study to another or to extrapolate results, due to considerable variations in studies features. Assessment of immunogenicity between Ebola vaccines needs randomised controlled multi-arm trials, as performed in PREVAIL study (NCT02344407) and PREVAC study (NCT02876328).
Funding source This project has received funding from the  Innovative Medicines Initiative 2 Joint Undertaking  under grant agreement No  115861. This Joint Undertaking receives support from the  European Union 's  Horizon 2020 research and innovation programme and EFPIA. The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Conflict of interest This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 115861 This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. Laura Richert and Rodolphe Thiebaut are also involved in the ongoing PREVAC (NCT02876328) and Ebovac2 (NCT02564523, NCT02416453) trials. Edouard Lhomme is involved in the PREVAC trial (NCT02876328).
The U. S. National Center for Health Statistics describes a chronic disease as one that last for three months or more, but the literature uses the term "chronic disease" variably and it depends on the data used for the research and the discipline of the lead authors  (32). There were some members of the working group that agreed that a period of persistent pathologic response for greater than 6 months after AP or RAP was a reasonable and pragmatic threshold for the diagnosis of Early CP while others advocated for at least 12 months. Some also argued that within that time frame (6 or 12 months) there should be detection of "at least some" morphological features diagnostic of Established CP but not enough for definitive diagnosis of CP.
RMD Open RMD Open RMD Open the rate of radiographic progression of structural joint damage. 4 aricitinib is an oral, selective, inhibitor of JAK1 and JAK2 and has demonstrated clinical benefit, including reducing the rate of structural joint damage, in several studies in patients with RA. [5] [6] [7] [8]  In the 24-week phase III RA-BUILD study (NCT01721057), baricitinib significantly reduced radiographic progression of joint damage in patients with active RA who had an inadequate response to or were intolerant of previous conventional synthetic DMARDs (csDMARDs). 8 On completion of the 24-week RA-BUILD study, patients could enrol in the long-term extension study, RA-BEYOND (NCT01885078). This report describes the effect of treatment with baricitinib 2 or 4 mg over 48 weeks on radiographic progression of structural joint damage in patients who completed RA-BUILD and enrolled in RA-BEYOND.
8 atients who completed the RA-BUILD study were eligible to enter the long-term extension study, RA-BE-YOND. Rescue in RA-BUILD did not preclude enrolment in RA-BEYOND. Patients were not eligible for participation in RA-BEYOND if they demonstrated significant uncontrolled laboratory abnormalities, had a known hypersensitivity to baricitinib, or if they permanently discontinued baricitinib during the RA-BUILD study. Radiographs from RA-BUILD baseline, and weeks 24 and 48 in RA-BEYOND were scored in the reading campaign used to generate the data for these analyses. study protocol and oversight RA-BEYOND is a phase III, multicentre, extension study evaluating the long-term efficacy and safety of baricitinib (2 mg once daily (QD) and 4 mg QD) in patients with RA. Patients who completed RA-BUILD and entered RA-BEYOND continued to receive the dose of baricitinib they were receiving at the end of RA-BUILD (baricitinib 2 or 4 mg).
All authors participated in data analysis and interpretation, reviewed drafts and final manuscript, and provided critical comments. The authors vouch for the veracity and completeness of the data and data analyses. efficacy Radiographic joint damage was measured using the van der Heijde modified Total Sharp Score (mTSS). 9 10 This methodology quantifies the extent of bone erosions and joint space narrowing for 44 and 42 joints, respectively, within the hands and feet with higher scores representing greater damage. Radiographs were scored by two primary readers separately and independently, blinded to chronological order, patient identity and treatment group. The mean score obtained between the two readers was used in the analyses. 5 6 Radiographic progression was determined by the change from baseline in mTSS, bone erosion and joint space narrowing.
statistical analyses Analysis of structural progression was conducted on the modified intent-to-treat population using patients with available baseline (from RA-BUILD study) and at least one radiographic assessment at any time after baseline. Analysis of covariance (ANCOVA) was used to analyse radiographic progression, and a logistic regression model was used to analyse percentage of patients with no progression of structural joint damage, with baseline value (for ANCOVA model only), treatment, region and centrally confirmed presence of baseline joint erosions in the model. The Fisher exact test was used for categorical safety data or when sample size requirements for the aforementioned logistic regression model were not met. Analyses were assessed with a significance level of 0. 05 (two-sided).
4 These data provide further support that baricitinib is an effective DMARD for treating RA in csDMARD-inadequate response patients. Data from an open label LTE describing the long-term effects of tofacitinib on progression of radiographic structural damage were recently reported. 13 Slightly over 1000 patients were followed for up to 48 months; the patients were receiving either 5 or 10 mg two times Although it is dangerous to compare data across trials, the baricitinib data reported in patients who all had an inadequate response to csDMARDS were similar. This study had limitations. Patients who completed the RA-BUILD study were included in this analysis whether or not they entered the long-term extension study, RA-BEYOND; however, 85% of the randomised and 95% of the completed patients of RA-BUILD entered RA-BEYOND, thereby limiting the influence of dropouts.
Data were imputed for patients who did not enter the extension study or those with missing radiographs. The extension study was open-label in that all patients were aware that they were receiving baricitinib. However, the original treatment assignment as well as the actual dose of baricitinib remained blinded to the patient and investigator, and the readers scored all images blinded to all clinical information. Finally, the focus of the present manuscript is radiographic progression of joint damage from a single Phase three study and associated long-term extension data -limited conclusions can be drawn from the safety analyses, as evaluations from larger datasets that integrate information across multiple studies are better suited for this purpose. 14 n summary, these data provide evidence that the positive structural efficacy response in csDMARD-IR patients initially observed at 24 weeks was maintained over 48 weeks of treatment with baricitinib.
Acknowledgements the authors would like to thank the patients who participated in this study. they also thank  Stephanie colvin, PhD , employee of eli lilly and company, for creating the tables and figures and for assisting with manuscript preparation and process support. Contributors all authors participated in the analyses and interpretation of data, provided critical comments and input, and reviewed and approved the final manuscript. Funding this study was funded by eli lilly and company and incyte corporation. Competing interests DvdH has received consulting fees from abbVie, amgen, astellas, astraZeneca,  BMS , Boehringer ingelheim, celgene, Daiichi, eli-lilly, galapagos, gilead,  Janssen ,  Merck , novartis,  Pfizer , regeneron, roche,  Sanofi ,  UcB  and is director of imaging rheumatology bv.
Methods The Multidomain Alzheimer Preventive Trial, ethics and approval Data were obtained from a [ 18 F]-florbetapir positron emission tomography (PET) study carried out as an ancillary project to the Multidomain Alzheimer Preventive Trial (MAPT)  [32]  (ClinicalTrials. gov, NCT00672685), a large multicentre, phase III, randomized, placebo-controlled trial. The MAPT was designed to assess the effects of omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation alone or in combination with a multidomain intervention (involving nutritional and exercise counselling and cognitive training), compared to placebo, in slowing cognitive decline in older adults with subjective memory complaints (n = 1680). Both the MAPT and the ancillary [ 18 F]-florbetapir PET study were approved by the ethics committee in Toulouse (CPP SOOM II) and written consent was obtained from all participants.
Participants At inclusion, subjects were community-dwelling men and women without dementia, aged ≥ 70 years, who met at least one of the following criteria: spontaneous memory complaints, limitation in executing ≥ 1 Instrumental Activity of Daily Living, or slow gait speed (≤ 0. 8 m/s). Participants of this study were 180 individuals who had data on plasma 25(OH)D and cerebral Aβ load. However, two participants were excluded from the present analysis because they had CDR ≥ 1 (suggestive of dementia) at the clinical visit closest to PET-scan assessment. Thus, a total of 178 participants were included in the study described here. [ 18 F]-Florbetapir positron emission tomography PET scans as a measure of cerebral Aβ load were performed using [ 18 F]-florbetapir as described previously  [32, 33].