Herbivores that have recently expanded their host plant ranges provide opportunities to test hypotheses about the evolution of host plant specialization. Here, we take advantage of the contemporary global range expansion of the monarch butterfly (Danaus plexippus) and conduct a reciprocal rearing experiment involving monarch populations with divergent host plant assemblages. Specifically, we ask the following questions: (1) Do geographically disparate populations of monarch butterflies show evidence for local adaptation to their host plants? If so, what processes contribute to this pattern? (2) How is dietary breadth related to performance across multiple host species in monarch populations? (3) Does the coefficient of variation in performance vary across sympatric versus allopatric hosts? We find evidence for local adaptation in larval growth rate and survival based on sympatric/allopatric contrasts. Migratory North American monarchs, which have comparatively broad host breadth, have higher mean performance than derived nonmigratory populations across all host plant species. Monarchs reared on their sympatric host plants show lower coefficient of variation in performance than monarchs reared on allopatric hosts. We focus our discussion on possible mechanisms contributing to local adaptation to novel host plants and potential explanations for the reduction in performance that we observed in derived monarch populations.
The U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell therapy, tisagenlecleucel, in August 2017. We sought to describe adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS) for tisagenlecleucel in the post-marketing period. We searched FAERS reports to identify U.S. patients treated with tisagenlecleucel between August 30, 2017-August 31, 2019.We reviewed individual reports, calculated AE frequencies and reporting rates (RRs), and used Empirical Bayesian Geometric Mean methods to identify disproportionate reporting. We identified 646 de-duplicated reports with a median age at AE of 18 (interquartile range: 11-56) years. The overall RR was 81.0%, and more than 95% of reports described a serious outcome. Cytokine release syndrome (CRS) was the most frequently reported AE (51.1%) with a RR of 41.4%; neurotoxicity was reported less frequently (21.2%), with a RR of 17.2%. Most disproportionately reported AEs were listed on the package insert or confounded by indication. We identified 13 subsequent neoplasms (SPN), the majority occurring within 6 months of tisagenlecleucel administration, and none reporting evidence of insertional mutagenesis. A total of 165 reports (26%) described a death outcome; most deaths occurred >30 days after treatment. The majority of deaths (64%) were due to progression of the underlying lymphoid neoplasm, and few (<5%) were attributed to CRS or neurotoxicity. We did not identify new safety concerns reported for tisagenlecleucel in the post-marketing period. Reporting rates for CRS and neurotoxicity were lower than identified in the prelicensure clinical trials. 1 | INTRODUCTION On August 30, 2017, the U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy. 1 Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals Corporation) is a CD19-directed genetically modified immunotherapy that is comprised of genetically modified autologous T-cells using a lentiviral vector to encode an anti-CD19 chimeric antigen receptor. 2 Administered as a single infusion, the initial indication was treatment of B-cell precursor acute lymphoblastic leukemia (ALL) refractory to treatment or in second or later relapse among individuals up to 25 years of age. On May 1, 2018, the indication expanded to treatment of adults with relapsed/refractory (r/r) large B-cell lymphoma (including diffuse large B-cell lymphoma [DLBCL] not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma) after two or more lines of systemic therapy. Because of the increased risk for cytokine release syndrome (CRS) and neurotoxicity identified in the pre-licensure clinical trials, tisagenlecleucel is available through a Risk Evaluation and Mitigation Strategy (REMS) program to ensure that the benefits of treatment outweigh the risks. 3-5 As part of the REMS
The advancement of the construction sector has made the complexity of a project increase in line with the increasing demands on construction engineers to complete a project on time, in accordance with cost, and prioritize quality. From that statement, a cost overrun problem shows in the process of running the project. Several techniques have been espoused by innovative organizational and managerial practices to reduce the risk of cost overrun from the construction project, but cost overrun in project construction remain as a one of the problem. This study aims to identify the factors that cause cost overrun in residential projects. The process of data collection was carried out using a questionnaire as the instrument. The data from the questionnaire is primary data that will be processed with the help of IBM SPSS 25 software. The identification of the factors causing the cost overrun using the relative important index (RII) method to determine the level of importance of each variable. The results of this study indicate that the project data and information are incomplete (when aanwijzing) and the erroneous estimation of material costs and wages are the main factors causing cost overrun with an RII value ≥ 0,9. ABSTRAK Majunya sektor pekerjaan konstruksi membuat kompleksitas suatu proyek semakin meningkat sejalan dengan meningkatnya tuntutan kepada pelaku konstruksi untuk menyelesaikan proyek secara tepat waktu, sesuai dengan biaya, dan mengendepankan kualitas. Dari tuntutan tersebut, timbul suatu masalah cost overrun (pembengkakan biaya) dalam proses berjalannya proyek. Berbagai upaya telah dilakukan oleh berbagai organisasi mandiri dan praktisi manajemen untuk mengurangi risiko dari adanya cost overrun (pembengkakan biaya) pada suatu proyek, namun masalah cost overrun tetap menjadi salah satu problema dalam proyek konstruksi. Penelitian ini bertujuan untuk mengidentifikasi faktor-faktor penyebab terjadinya cost overrun (pembengkakan biaya) pada proyek rumah tinggal. Proses pengumpulan data dilakukan dengan menggunakan kuesioner sebagai instrumennya. Data dari kuesioner tersebut merupakan data primer yang akan diolah dengan bantuan software IBM SPSS 25. Pengidentifikasian faktor-faktor penyebab terjadinya cost overrun menggunakan metode relative importance index (RII) untuk menentukan tingkat kepentingan setiap variabel. Hasil dari penelitian ini menunjukaan bahwa data dan informasi proyek kurang lengkap (saat aanwijzing) dan perencanaan estimasi biaya material dan upah yang keliru menjadi faktor paling utama penyebab cost overrun dengan nilai RII ≥ 0,9.
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