tbuckley/cabot-search huggingface dataset:
University of Otago: towards specialisation with a Masters in Physiotherapy, endorsed in Sports Physiotherapy (continuing professional development series)
Authors: Gisela Sole
Journal: British Journal of Sports Medicine (2017)

School of Physiotherapy, University of Otago, Dunedin, New Zealand 

Masters in Physiotherapy endorsed in Sports Physiotherapy: MPhty (Sports Physiotherapy)

The role of sports physiotherapists extends beyond the acute management of on-field injuries and rehabilitation within the confounds of the physical clinic space; it also includes promotion of health and well-being of individuals living with long-term health conditions, of all abilities and ages.1 Thus, advancing knowledge and skills for facilitating and enhancing participation of individuals at all performance levels is critical for sports physiotherapists.2 This includes gaining advanced skills for networking and working within multidisciplinary teams, in addition to promoting innovative practice and extending current knowledge.1 

The MPhty (Sports Physiotherapy) programme is a course for New Zealand and international registered physiotherapists seeking to advance clinical reasoning and athlete/patient management skills. The programme is flexible with both full-time and part-time study options available, and entails completion of up to six papers, the New Zealand equivalent for modules or course units. The programme allows staircasing from a postgraduate certificate (two papers) to the postgraduate …
Additional Prognostic Impact of Specific Sites of Extramedullary Leukemia in Pediatric AML with MLL-Rearrangements but Not in Core-Binding Factor (CBF) AML.
Authors: Ursula Creutzig, Martin Zimmermann, Michael Dworzak, Jean-Pierre Bourquin, Christine von Neuhoff, Annette Sander, Jan Stary, Dirk Reinhardt
Journal: Blood (2012)
Evolution of skeletal muscle mass (SMM) during palliative systemic treatment in metastatic colorectal cancer (mCRC) patients participating in the randomized phase 3 CAIRO3 study
Authors: S.A. Kurk, P.H.M. Peeters, B. Dorresteijn, M. Jourdan, H.J. Kuijf, C. Punt, M. Koopman, A.M. May
Journal: Annals of Oncology (2016)
Clinical Significance of Apoptosis Is Independent from Proliferation in Acute Myeloid Leukemia (AML).
Authors: Giovanni Del Poeta, Maria Ilaria Del Principe, Adriano Venditti, Luca Maurillo, Francesco Buccisano, Maria Irno Consalvo, Carla Mazzone, Maria Christina Cox, Antonio Bruno, Francesco Lo Coco, Sergio Amadori
Journal: Blood (2004)
An added value to Multidisciplinary Team: does a Tutor help to manage head and neck cancer patients?
Authors: P. Cassini, S. Alfieri, P. Bossi, C. Bergamini, R. Granata, C. Resteghini, D. Galbiati, N.A. Iacovelli, E. Orlandi, F. Favales, C. Villa, P. Pistillo, L. Locati, L. Licitra
Journal: Annals of Oncology (2016)
MUC-1 Regulates MiR34a Expression in Acute Myeloid Leukemia Cells Resulting in an Accumulation of Granulocytic Myeloid-Derived Suppressor Cells
Authors: Athalia Rachel Pyzer, Dina Stroopinsky, Hasan Rajabi, Jacalyn Rosenblatt, Maxwell Douglas Coll, Salvia Jain, Kristen Anna Palmer, Ashujit Tagde, Katarina Luptakova, Malgorzata McMasters, James D. Levine, Robin Joyce, Jon E. Arnason, Myrna Rita Nahas, Rebecca Karp Leaf, Abigail Washington, Michal Bar-Natan, Poorvi Somaiya Dutt, Donald Küfe, David Avigan
Journal: Blood (2015)
Prospective Measurement of BK Virus Blood and Urine Levels, and Associations with Morbidity, in Recipients of Allogeneic Hematopoetic Stem Cell Transplants.
Authors: Peter H. O’Donnell, Kate Swanson, Michelle A. Josephson, Andrew S. Artz, Elizabeth Rich, Wendy Stock, Koen van Besien
Journal: Blood (2007)
The red thread between Piacenza and the Michigan Appropriateness guide for intravenous catheters guidelines
Authors: F. Oleari, P. Mordenti, S. Bontini, S. Carini, S. Castellani, C. Gozzo, O. Grassi, M. Muroni, M.R. Cordani, G. Cremona, L. Cavanna
Journal: Annals of Oncology (2016)
STMC-16. EZH2-MEDIATED ARL13B REGULATE CILIOGENESIS IN GBM
Authors: Fatemeh Atashi, Tanwir Hasan, Gina Lee, Donna Guo, Cheol Park, Maciej Lesniak, C. David James, Atique Ahmed
Journal: Neuro-Oncology (2016)

Glioblastoma stem cells (GSCs) are known to be responsible for GBM therapeutic resistance. Previously we have reported exceptional plasticity within GBM during chemotherapy, which is associated with increases in GSC subpopulations. The Initial investigation indicated that Polycomb group protein EZH2 is critical for therapeutic stress-induced cellular plasticity. Chemical inhibition, as well as shRNA-mediated knockdown of EZH2, suppresses cellular plasticity-mediated increases in GSCs. To elucidate molecular mechanisms of EZH2-mediated therapeutic resistance, gene expression analysis was performed in the presence of the EZH2 inhibitor DZNep. The results indicate that the expression of ARL13B, a member of the ADP-ribosylation factor-like family protein critical for cilia formation and maintenance, was most affected by DZNep (more than 13-fold decreased). Knockdown of EZH2 by shRNA completely abolished the expression of ARL13B. TCGA data analysis revealed that ARL13b expression was inversely correlated with survival of patients with grade III (p=0.03) and IV GBM (p=0.007). Immunofluorescent staining showed that ARL13B co-localizes with cilium in primary GBM cells, as well as in a patient-derived xenograft (PDX) model. Chemotherapeutic stress on PDX models significantly enhanced formation (2 fold, p-value <0.0002) and length of primary cilium (1.5 fold, p-value <0.0001), as well as in post-therapy recurrent GBM PDX GBMs (3 fold, p-value <0.0005). Moreover, Shh activators (ex. Smo, Gli) those are required for Shh signaling were co-localized with the primary cilium. Theses observation suggest that therapeutic stress induced ARL13B expression and formation of primary cilium, which can regulate Shh signaling during chemotherapy, may contribute to promote therapeutic resistance in GBM.
Multidisciplinary management in ovarian cancer
Authors: F. Lancia, M. Marzola, R. Martinello, C. Borghi, G. Bernardi, I. Toma, L. Martella, L. Belluomini, F. Daniel, A. Moretti, L. Da Ros, E. Bannò, C. Nisi, A. Frassoldati
Journal: Annals of Oncology (2016)
Final survival results of a multicenter phase I/II study of TAS-102 with bevacizumab for mCRC (C-TASK FORCE)
Authors: Yasutoshi Kuboki, Tomohiro Nishina, Eiji Shinozaki, Kentaro Yamazaki, Shogo Nomura, Akihiro Sato, Atsushi Ohtsu, Takayuki Yoshino
Journal: Annals of Oncology (2016)
The Bromodomain Inhibitor CPI203 Demonstrates Preclinical Synergistic Activity with Bortezomib in Drug Resistant Myeloma
Authors: Matthew B. Siegel, Monika A. Davare, Selina Qiuying Liu, Stephen E. Spurgeon, Marc M. Loriaux, Brian J. Druker, Emma C. Scott, Jeffrey W. Tyner
Journal: Blood (2014)
The Influence of Age and Gender on the Prognostic Impact of Karytoypic Subgroups in Myelodysplastic Syndromes - a Multicenter Analysis.
Authors: Thomas Noesslinger, Ulrich Germing, Barbara Hildebrandt, Claudia Strupp, Manuel Aivado, Detlef Haase, Julie Schanz, Friedrich Wimazal, Wolfgang Sperr, Valent Peter, Lubbert Michael, Otto Krieger, Norbert Gattermann, Aristoteles Giagounidis, Heinz Tuchler, Rainer Haas, Carlo Aul, Michael Pfeilstocker
Journal: Blood (2004)
A novel combination of serum microRNAs for detecting breast cancer and predicting efficacy of treatment
Authors: Akihiko Shimomura, Sho Shine, Junpei Kawauchi, Stoke Takizawa, Hiromi Sakamoto, Junta Matsuzaki, Shumpei Niida, Chikako Shimizu, Takayuki Kinoshita, Kenji Tamura, Takahiro Ochiya
Journal: Annals of Oncology (2016)
Bendamustine Produces Durable Responses with An Acceptable Long-Term Safety Profile in Patients with Rituximab-Refractory Non-Hodgkin's Lymphoma: A Pooled Analysis.
Authors: Bruce D. Cheson, Jonathan W. Friedberg, Brad S. Kahl, Richard H. van der Jagt, Lothar Tremmel, Tal Zaks
Journal: Blood (2009)
MPTH-34. THE PROGNOSTIC VALUE OF POLYSOMY IN OLIGODENDROGLIAL TUMORS
Authors: Hui Chen, Cheddhi Thomas, Felipe Andres Munoz, Sanda Alexandrescu, Craig Horbinski, Adriana Olar, Declan McGuone, Sandra Camelo-Piragua, Lu Wang, Elena Pentsova, Joanna Phillips, Ken Aldape, A. John Iafrate, John Golfinos, Andrew Chi, David Zagzag, Marc Rosenblum, Pamela Ohman-Strickland, Meera Hameed, Matija Snuderl
Journal: Neuro-Oncology (2016)

Testing for 1p/19q status is the most common molecular test for brain tumors. 1p/19q loss is the hallmark feature of oligodendroglial tumors, associated with response to chemotherapy and favorable prognosis. In addition to simple 1p/19q loss, more complex cytogenetic patterns exist. For example, polysomy in >30% of cells in the setting of 1p/19q co-deletion, so-called superloss, has been associated with shorter progression free survival (PFS) in anaplastic oligodendrogliomas. We evaluated the prognostic significance of polysomy across WHO grades and histologies; both in 1p/19q co-deleted as well as not co-deleted tumors. We retrospectively analyzed 412 oligodendrogliomas and oligoastrocytomas diagnosed between 1996 to 2010 from 8 institutions with fluorescence in situ hybridization for 1p/19q. Polysomy was defined as >2 1q and/or 19p signals in cells. Tumors were divided into groups based on their 1p/19q deletion status and polysomy and compared for PFS and overall survival (OS). In our cohort, 333 tumors (81%) had 1p/19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy. Seventy-nine tumors (19%) had 1p/19q maintenance; of these of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the entire group with 1p/19q loss had significantly better PFS and OS than tumors with 1p/19q maintenance (p<0.0001 each). There was a statistically significant difference in PFS and OS (p<0.0001 each) between the groups of patients with tumors with 1p/19q loss, 1p/19q loss and polysomy and tumors with 1p/19q maintenance. There was no difference in survival of 1p/19q co-deleted tumors with >30% and <30% of polysomic cells. There was no statistically significant difference in PFS or OS between patients with 1p/19q maintenance with or without polysomy. The presence of any polysomy in oligodenroglial tumors with co-deletion of 1p/19q predicts early recurrence and short survival.
Low Molecular Weight Heparin for Prevention of Placenta-Mediated Pregnancy Complications: An Individual Patient Data Meta-Analysis
Authors: Marc Rodger, Johanna IP de Vries, Evelyne Rey, Jean-Christophe JCG Gris, Ida Martinelli, Ekkehard Schleussner, Saskia Middeldorp, Shannon M Bates, Paulien de Jong, Nicole Langlois, Ranjeeta Mallick, Ranjeeta Mallick, Timothy Ramsay, David Petroff, Dick Bezemer, Marion van Hoorn, Carolien Abheiden, Risto Kaaja, Annalisa Perna, Alain Mayhew
Journal: Blood (2015)
Dihydropyrimidine dehydrogenase (DPYD) gene polymorphisms profiling in colon cancer patients treated with adjuvant chemotherapy in the randomized phase III TOSCA trial
Authors: F. Graziano, A. Ruzzo, E. Rulli, F. Galli, F. Galli, M. Menghi, D. Viti, E. Giacomini, S. Lonardi, M. Ronzoni, B. Massidda, N. Pella, C. Mucciarini, R. Labianca, E. Veltri, P. Sozzi, S. Barni, A. Sobrero, L. Frontini, M. Magnani
Journal: Annals of Oncology (2016)
Dissecting the role of tumor-infiltrating lymphocytes (TIL) in patients with high-risk soft-tissue sarcoma (STS) receiving neo-adjuvant chemotherapy (NAC) with regional hyperthermia (RHT)
Authors: R. Issels, V. Büclein, E. Kampmann, T. Knösel, E. Nössner, M. Subklewe, L. Lindner
Journal: Annals of Oncology (2016)
Differential Gene Expression in the Human Brain Is Associated with Conserved, but Not Accelerated, Noncoding Sequences
Authors: Kyle A. Meyer, Tomas Marques-Bonet, Nenad Sestan
Journal: Molecular Biology and Evolution (2017)

Previous studies have found that genes which are differentially expressed within the developing human brain disproportionately neighbor conserved noncoding sequences (CNSs) that have an elevated substitution rate in humans and in other species. One explanation for this general association of differential expression with accelerated CNSs is that genes with pre-existing patterns of differential expression have been preferentially targeted by species-specific regulatory changes. Here we provide support for an alternative explanation: genes that neighbor a greater number of CNSs have a higher probability of differential expression and a higher probability of neighboring a CNS with lineage-specific acceleration. Thus, neighboring an accelerated element from any species signals that a gene likely neighbors many CNSs. We extend the analyses beyond the prenatal time points considered in previous studies to demonstrate that this association persists across developmental and adult periods. Examining differential expression between non-neural tissues suggests that the relationship between the number of CNSs a gene neighbors and its differential expression status may be particularly strong for expression differences among brain regions. In addition, by considering this relationship, we highlight a recently defined set of putative human-specific gain-of-function sequences that, even after adjusting for the number of CNSs neighbored by genes, shows a positive relationship with upregulation in the brain compared with other tissues examined.
MNGO-04. THE COMPARATIVE RESULTS OF ADJUVANT CHEMOTHERAPY WITH HYDROXYUREA VERSUS RADIOTHERAPY AFTER INCOMPLETE RESECTION OF ATYPICAL MENINGIOMAS
Authors: Young Zoon Kim, Jiwook Lee
Journal: Neuro-Oncology (2016)

Atypical meningiomas classified as WHO grade II are more locally aggressive and demonstrate more rapid tumor progression than benign meningiomas of WHO grade I. Immediate adjuvant treatment after surgery for the atypical subtype is still under debate. Therefore, we investigated the clinical results of adjuvant chemotherapy with hydroxyurea versus radiotherapy after incomplete resection of atypical meningiomas. The authors retrospectively reviewed the medical records of 412 patients with meningiomas diagnosed in the period from January 2000 to December 2014 at our hospital. Clinical and radiological data included extent of surgery, use of adjuvant therapy, duration of follow-up, and progression. In terms of the extent of surgical resection, incomplete resection was defined as Simpson Grade II–V. The progression rate and time to progression were assessed using Kaplan-Meier analysis. Of the 84 atypical meningiomas eligible for analysis, 55 (65.5%) patients underwent incomplete resection. Among them, 24 (43.6%) were treated with adjuvant hydroxyurea (group A), and 20 (36.4%) with postoperative radiotherapy (group B), and 11 (20.0%) underwent conservative treatment after surgery (group C). Sixteen (29.1%) patients experienced the progression of tumors during the follow-up period (mean duration 47.7 months, range 12.4–132.1 months). Progression was occurred in 3 of 24 (12.5%) patients in group A, 3 of 20 (15.0%) patients in group B, and 10 of 11 (90.9%) patients in group C. The mean time to progression was 30.4 months (range 8.4–62.6 months); 46.2 months in group A, 36.5 months in group B, and 11.9 months in group C (p=0.041). Multivariate analysis showed that adjuvant treatment after surgery (HR 4.276, p<0.001), and Simpson grade (HR 2.572, p=0.040) predicted the recurrence of atypical meningiomas after incomplete resection. This retrospective case control study suggested that adjuvant treatment should be helpful to prevent the progression of atypical meningiomas after incomplete resection.
Phase II trial of 5-fluorouracil (5FU)/leucovorin (LV), irinotecan, and oxaliplatin (FOLFOXIRI) plus cetuximab in patients with metastatic colorectal cancer (mCRC).
Authors: I. Sougklakos, N. K. Vardakis, E. Kampouraki, I. Kotortsi, N. E. M. Androulakis, L. Vamvakas, K. Kalbakis, D. Hatzidaki, D. Mavroudis, V. Georgoulias
Journal: Journal of Clinical Oncology (2011)

e14027 Background: To evaluate the safety and efficacy of cetuximab combined with 5FU/LV, irinotecan and oxaliplatin (FOLFOXIRI) as initial treatment for patients with unresectable, KRAS wt mCRC. Methods: Primary end point was overall response rate while secondary endpoints were the percentage of R0 secondary resection, time to tumor progression (TTP), median overall survival (mOS) and the safety profile of the combination. From July 2007 to August 2010, thirty patients < 70 years old with PS (ECOG) 0-1 and unresectable, KRAS wt mCRC were enrolled in the study. The patients were treated with cetuximab 500 mg/m2 followed by the administration of FOLFOXIRI (d1: Irinotecan 150 mg/m2; d2 L-OHP 65 mg/m2; d2-3 LV 200 mg/m2; and d3? 5-FU 400 mg/m2 as i.v. bolus and 600 mg/m2as 22 h i.v. continuous infusion). The treatment was administered every 2 weeks. Results: The median age of the patients was 64, 16 (53%) were male and 16 of them had disease limited to the liver. Main toxic effects included grade 3-4 neutropenia (23%), grade 3/4 diarrhea (53%), grade 2-3 skin rash (43%) and grade 2-3 neurotoxicity (18%). One toxic death was observed during the study due to diarrhea and sepsis in a female patient with peritoneal disease. Four (13%) complete and seventeen (57%) partial responses were achieved (ORR: 70%; 95% confidence interval: 55% to 86%), whereas 8 (27%) patients had stable disease. Secondary R0 liver resection was performed in 9 patients (30% of the total population, 57% of the patients with liver limited disease). After a median follow-up of 15.1 months the median TTP was 11 months, the mOS had not yet been reached, and the probability of 1-year survival was 53.4%. Conclusions: The combination of cetuximab plus FOLFOXIRI is highly active with significantly high percentage of R0 secondary resection. Due to the high incidence of diarrhea the treatment should be administered in selective patients and mainly in those with liver limited disease.
Occurrence of Immune Responses Against Foreign Transgenes after Infusion of Suicide Gene-Expressing Donor T-Cells Concurrently to an Allogeneic Bone Marrow Transplantation.
Authors: Patricia Mercier, Marina Deschamps, Jean-Marie Certoux, Delphine Sauce, Christophe Ferrand, Eric Deconinck, Pierre Tiberghien, Eric Robinet
Journal: Blood (2004)
Feasibility of Cyclosporine and Short-Term Methotrexate for Graft-Vs.-Host disease Prophylaxis in T-Cell-Replete, Reduced-Intensity Allogeneic Bone Marrow Transplantation From Unrelated Donors.
Authors: Takahiko Nakane, Hirohisa Nakamae, Hideo Koh, Mika Nakamae, Yoshiki Hayashi, Mitsutaka Nishimoto, Takuro Yoshimura, Eri Inoue, Atsushi Inoue, Ran Aimoto, Mizuki Aimoto, Yoshiki Terada, Ki-Ryang Koh, Takahisa Yamane, Masayuki Hino
Journal: Blood (2009)
Triple-negative breast cancer and BRCA mutation: looking at the future
Authors: Z. Ballatore, M. Pistelli, R. Bracci, F. Bianchi, E. Maccaroni, L. Belvederesi, C. Brugiati, S. Pagliaretta, M. De Lisa, A. Della Mora, L. Cantini, L. Bastianelli, A. Pagliacci, N. Battelli, R. Berardi
Journal: Annals of Oncology (2016)
GENT-07. SUBGROUP SPECIFIC ENHANCERS CONTROL DISTINCT REGULATORY CIRCUITRIES IN EPENDYMAL TUMORS
Authors: Lukas Chavez, Kristian W. Pajtler, Konstantin Okonechnikov, Susanne Gröbner, Serap Erkek, Zhiqin Huang, David T. W. Jones, Hendrik Witt, Volker Hovestadt, Marc Zapatka, Jan O. Korbel, Peter Lichter, Stefan M. Pfister, Marcel Kool
Journal: Neuro-Oncology (2016)

Recent molecular classification efforts using DNA methylation profiles from 500 ependymal tumors have revealed six distinct intracranial molecular subgroups, three in the posterior fossa and three in the supratentorial region. The vast majority of high-risk patients, for whom effective therapeutic concepts are desperately needed, were comprised of posterior fossa Group A ependymomas (PF-EPN-A), and supratentorial tumors harboring fusions to the principal effector of canonical NF-κB signaling ­(ST-EPN-RELA). The current inability to effectively target alterations of the NF-κB pathway in ST-EPN-RELA and the lack of recurrent mutations or alternative distinct driver events in PF-EPN-A have so far hindered the development of novel (subgroup-specific) treatment strategies for these high-risk diseases. To get a better understanding what is driving these tumors, we have used H3K27ac ChIP-Seq, integrated with tissue-matched DNA methylation, DNA- and RNA-sequencing, to analyze the active cis-regulatory landscape across 24 individual tumors from all six intracranial molecular subgroups. Quantitative comparisons of H3K27ac enrichments across subgroups identified common and subgroup-specific enhancers as well as super-enhancers, thereby confirming inter-subgroup heterogeneity. Systematic correlation analyses between enhancer activity and gene expression within topologically associated domains, combined with computational analyses of transcription factor binding sites at enhancer loci, identified regulatory circuitries governing distinct transcriptional landscapes that are likely responsible for subgroup divergence. As an example, runt-related transcription factor 2 (RUNX2) is highly expressed in PF-EPN-A compared to the other subgroups, and RUNX2 binding sites are significantly enriched at PF-EPN-A specific enhancers, implicating FGF signaling as a novel target for PF-EPN-A specific treatment. Our integrated analysis of enhancer elements in primary human tumors reveals novel insights into the genome-wide cis-regulatory architecture of ependymoma subgroups and their potential origins and may have relevant implications for future, possibly lineage-specific, therapeutic targeting approaches.
HO-1-Transduced Mesenchymal Stem Cells Attenuate aGVHD By Inhibiting HIF-1α /ROR-γt and then Down-Regulate Proportion of TH17/Treg
Authors: Jishi Wang, Meisheng Yu, Shuya Chen, Jiangyuan Zhao, Yaming Zhang, Xiaojing Lin, Nana Zhe, Qin Fang
Journal: Blood (2015)
FOCUS4-D: Results from a randomised, placebo controlled trial (RCT) of AZD8931 (an inhibitor of signalling by HER1, 2, and 3) in patients (pts) with advanced or metastatic colorectal cancer (aCRC) in tumours that are wildtype (wt) for BRAF, PIK3CA, KRAS & NRAS
Authors: R.A. Adams, E. Brown, L. Brown, R. Butler, S. Falk, D. Fisher, R. Kaplan, P. Quirke, S. Richman, L. Samuel, J. Seligmann, M. Seymour, K.K. Shiu, H. Wasan, R. Wilson, T. Maughan
Journal: Annals of Oncology (2016)
Changes in serum IL8 levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small cell lung cancer patients
Authors: M.F. Sanmamed, J.L. Perez-Gracia, J.P. Fusco, C. Oñate, G. Perez, C. Alfaro, S. Martín-Algarra, A. González, M.E. Rodriguez-Ruiz, M.P. Andueza, J. Wang, A. Bacchiocchi, R. Halaban, H. Kluger, M. Sznol, I. Melero
Journal: Annals of Oncology (2016)
Sarcopenia associated with a body mass index (BMI) &gt; 25 kg/m2 predicts severe acute toxicity of nivolumab and pembrolizumab in melanoma patients
Authors: V. Heidelberger, N. Kramkimel, O. Huillard, P. Boudou Rouquette, J. Chanal, J. Arrondeau, N. Franck, J. Alexandre, B. Blanchet, N. Dupin, S. Aractingi, F. Goldwasser
Journal: Annals of Oncology (2016)
A novel treatment of radiation induced xerostomia by autologous platelet-rich-plasma and peripheral stem cells
Authors: A. Taghizadeh Kermani, P. Izadpanahi, K. Khazaeni, M. Pezeshki Rad M, R. Asadi, M. Asadi, D. Hamidi Alamdari
Journal: Annals of Oncology (2016)