tbuckley/cabot-search huggingface dataset:
A Phase I/Randomized Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nintedanib versus Sorafenib in Asian Patients with Advanced Hepatocellular Carcinoma
Authors: Chia-Jui Yen, Tae-You Kim, Yin-Hsun Feng, Yee Chao, Deng-Yn Lin, Baek-Yeol Ryoo, Dennis Chin-Lun Huang, David Schnell, Julia Hocke, Arsène-Bienvenu Loembé, Ann-Lii Cheng
Journal: Liver Cancer (2018)

Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC).For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5-6, an Eastern Cooperative Oncology Group performance score ≤2, and an ALT/AST ≤2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory.The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib (n = 63) or sorafenib (n = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73-2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59-1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome.Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.
P131 Study of urate transporters in primary gout and hyperuricemia
Authors: K Pavelcova, L Petru, J Zavada, K Pavelka, B Stiburkova
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> The urate transporters are one of the main genetic determinants of serum uric acid concentrations. Primarily nonsynonymous polymorphisms in <i>ABCG2</i> and <i>SLC2A9</i> are clinically important for the development of primary gout and hyperuricemia. In this study we investigated the effects of allelic variants of urate transporters in a cohort with primary gout and/or hyperuricemia. <h3>Methods</h3> The cohort was recruited in the Institute of Rheumatology, gout was diagnosed in 165 subjects (151 men/14 women) and hyperuricemia in 58 subjects (39 men/19 women). Coding regions of <i>ABCG2</i>, <i>SLC2A9</i>, <i>SLC22A11</i>, <i>SLC22A8</i>, <i>SLC17A3</i>, and <i>SLC17A1</i> genes were amplified and sequenced directly. <h3>Results</h3> In <i>ABCG2</i> gene, we detected nine non-synonymous variants: p.V12M, p.Q141K, p.R147W, p.T153M, p.K360del, p.F373C, p.T434M, p.S476P and p.D620N. The minor allelic frequency of p.Q141K is 0.23, whereas for the European population it is 0.09. In addition, this variant is associated with early onset of the gout.<sup>1</sup> We identified novel intron variant c.689+1G&gt;A which is associated with two abnormal splicing variants, leading to premature introduction of the stop codon.<sup>2</sup> In <i>SLC2A9</i> gene, seven missense variants were identified: p.A17T, p.G25R, p.T275M, p.D281H, p.V282I, p.R294H, and p.P350L. In <i>SLC17A3</i> gene, the analysis revealed allelic variants p.A100T and p.G279R. Non-synonymous variants p.V202M and p.R343L were found in <i>SLC22A11</i>. Only one missense variant (p.T269I) was identified in <i>SLC17A1</i>. In <i>SLC22A8</i> gene, sequencing revealed three non-synonymous variants p.R149C, p.V448I and p.R513G. <h3>Conclusions</h3> Genetic variants of <i>ABCG2</i>, common and rare, increased the risk of gout. The precise impact of <i>SLC22A11</i>, <i>SLC22A8</i>, <i>SLC17A3</i>, and <i>SLC17A1</i> in the context of hyperuricemia and gout in our cohort is unclear. Although knowledge of renal urate handling has been increased, current evidence is insufficient to fully understand the precise mechanism governing the bi-directional transport of urate. <h3>References</h3> . Stiburkova B, et al. Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology (Oxford)2017November 1;56(11):1982–1992. . Stiburkova B, et al. Novel dysfunctional variant in ABCG2 as a cause of severe tophaceous gout: Biochemical, molecular genetics and functional analysis. Rheumatology (Oxford)2016January;55(1):191–4. <h3>Acknowledgements</h3> This study was supported by the grant from the Czech Republic Ministry of Health AZV 15-26693A. <h3>Disclosure of interest</h3> None declared
GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis
Authors: Ayalew Tefferi, Paola Guglielmelli, Maura Nicolosi, Francesco Mannelli, Mythri Mudireddy, Niccolo Bartalucci, Christy M. Finke, Terra L. Lasho, Curtis A. Hanson, Rhett P. Ketterling, Kebede H. Begna, None Naseema Gangat, Animesh Pardanani, Alessandro M. Vannucchi
Journal: Leukemia (2018)

International collaborations over the years have produced a series of prognostic models for primary myelofibrosis (PMF), including the recently unveiled mutation-enhanced international prognostic scoring systems for transplant-age patients (MIPSS70 and MIPSS70-plus). In the current study, we considered the feasibility of a genetically inspired prognostic scoring system (GIPSS) that is exclusively based on genetic markers. Among 641 cytogenetically annotated patients with PMF and informative for previously recognized adverse mutations, multivariable analysis identified “VHR” karyotype, “unfavorable” karyotype, absence of type 1/like CALR mutation and presence of ASXL1, SRSF2, or U2AF1Q157 mutation, as inter-independent predictors of inferior survival; the respective HRs (95% CI) were 3.1 (2.1–4.3), 2.1 (1.6–2.7), 2.1 (1.6–2.9), 1.8 (1.5–2.3), 2.4 (1.9–3.2), and 2.4 (1.7–3.3). Based on HR-weighted risk points, a four-tiered GIPSS model was devised: low (zero points; n = 58), intermediate-1 (1 point; n = 260), intermediate-2 (2 points; n = 192), and high (≥3 points; n = 131); the respective median (5-year) survivals were 26.4 (94%), 8.0 (73%), 4.2 (40%), and 2 (14%) years; the model was internally validated by bootstrapping and its predictive accuracy was shown to be comparable to that of MIPSS70-plus. GIPPS offers a low-complexity prognostic tool for PMF that is solely dependent on genetic risk factors and, thus, forward-looking in its essence.
FRACTIONAL FLOW RESERVE DERIVED FROM COMPUTED TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH COMPLEX CORONARY ARTERY DISEASE: FEASIBILITY AND VALIDATION OF THE NON-INVASIVE FUNCTIONAL SYNTAX SCORE
Authors: Carlos A. Collet, Yosuke Miyazaki, Nicola Ryan, Jeroen Sonck, Bernard Cosyns, Taku Asano, Javier Escaned, Adrian Banning, Vasim Farooq, Giovanni Luigi De Maria, Yoshinobu Onuma, Antonio Bartorelli, Daniele Andreini, Patrick Serruys
Journal: Journal of the American College of Cardiology (2018)
BMA deems “completely unacceptable” plans to allow Welsh consultants’ contracts to be locally negotiated
Authors: Abi Rimmer
Journal: BMJ (2014)

The BMA has spoken out against a move by the Welsh government to allow health boards in Wales to negotiate consultants’ contracts at a local level.

BMA Wales said that one of the Welsh government’s lead negotiators had written to health boards across the country advising them that they could set terms and conditions for consultants’ contracts locally.

Trevor Pickersgill, deputy chairman of the BMA Wales consultants’ committee, told BMJ Careers that the letter was sent after the BMA’s withdrawal from the Welsh government’s strategic pay taskforce and its refusal to enter negotiations on changes to consultants’ contracts.

The negotiations, Pickersgill said, would have …
BMA seeks evidence from doctors affected by immigration rule changes
Authors: Helen Jaques
Journal: BMJ (2013)

The BMA is seeking evidence from doctors who have not been able to bring their elderly relatives to settle with them in the UK, in a bid to convince the government to rethink its changes to the family immigration rules

In June 2012 the Home Office changed a number of elements of its family immigration policy, including the rules on whether immigrants who have become British citizens can bring elderly dependants from outside the European Economic Area (EEA) to live with them in the UK.1

Under the changes to the visa category of adult dependent relatives, UK citizens can bring an adult or elderly dependant to settle …
Abstract 13008: No Effect of the Type of Sugar on Changes in Traditional Risk Factors for Cardiovascular Disease when Consumed at Typical Levels
Authors: Joshua Lowndes, Nan Lu, Stephanie Sinnett, James Rippe
Journal: Circulation (2013)

The American Heart Association recommends that women and men should not consume more than 100 or 150 kcal/day, respectively, from added sugars. As the most common sources of added sugar, sucrose and high fructose corn syrup (HFCS) have been singled out for particular concern. However, the majority of the cited studies have compared glucose to fructose with effects often extrapolated to commonly consumed sugars. Few data exist on the effects of the most commonly used sugars when consumption is at typical population levels.  268 individuals aged 20-60 years old were required to drink sugar sweetened, low fat milk every day for 10 weeks as part of their usual diet. All participants had been at a stable weight (± 3%) for 30 days prior to enrollment and were given recommendations on how to account for calories in the milk, but were given no further dietary guidance. The amount of milk consumed was individualized for each participant based on the estimated number of calories required to maintain body weight (via Miflin St Joer equation ) and random group assignment: Groups 1 and 2 - 9% estimated caloric intake from fructose or glucose respectively added to milk. Groups 3 and 4 - 18% of estimated caloric intake from HFCS or sucrose respectively added to the milk (50th percentile population consumption levels of fructose).  There was a small change (p≤0.001) in body mass (162.2 ± 27.8 vs 164.2 ± 28.1lbs) and BMI (26.3 ± 3.3 vs 26.6 ± 3.4) in the entire cohort, as well as in total cholesterol (177.4 ± 39.4 vs 180.1 ± 40.0mg/dl, p≤0.05), but both systolic (109.2 ± 10.2 vs 106.1 ± 10.4 mmHg) and diastolic blood pressure (69.8 ± 8.7 vs 68.1 ± 9.7mmHg) decreased (p≤0.01). There were no changes in HDL (52.5 ± 12.8 vs 52.4mg/dl ±12.9), LDL (104.3 ± 34.2 vs 105.4 ± 34.6mg/dl) or glucose (90.0 ± 6.5 vs 90.7 ± 7.9mg/dl, all p>0.05). The type of sugar consumed had no effect on the response of any measure (interaction p>0.05).  These data suggest that when consumed as part of normal diet at typical levels the effects of commonly consumed sugars on traditional cardiovascular risk factors are small and mixed. More importantly, the often cited negative effects of fructose compared to glucose do not seem to be applicable to the commonly consumed sugars (HFCS and sucrose) when consumed at typical population consumption levels.
Review: Adding a DPP-4 inhibitor to an SGLT-2 inhibitor reduces genital, but not genitourinary, tract infections
Authors: René Rodriguez-Gutierrez, Victor M. Montori
Journal: Annals of Internal Medicine (2018)

Source Citation Fadini GP, Bonora BM, Mayur S, Rigato M, Avogaro A. Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab. 2018;20:740-4.29053207
Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer
Authors: Jennifer Haynes, Trevor D. McKee, Andrew Haller, Yadong Wang, Cherry Leung, Deena M.A. Gendoo, Evelyne Lima-Fernandes, Antonija Kreso, Robin Wolman, Eva Szentgyorgyi, Douglass C. Vines, Benjamin Haibe-Kains, Bradly G. Wouters, Ur Metser, David A. Jaffray, Myles Smith, Catherine A. O'Brien
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Cancer-initiating cells (C-IC) have been described in multiple cancer types, including colorectal cancer. C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities; however, recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then therapeutic targeting of hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived colorectal cancer xenografts were treated with evofosfamide, a hypoxia-activated prodrug (HAP), in combination with 5-fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a noninvasive method to assess intratumoral hypoxia. Results: Hypoxia was sufficient to drive the formation of CC-ICs and colorectal cancer cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by evofosfamide not only inhibits tumor growth of xenografts compared with 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, noninvasive FAZA-PET hypoxia imaging was predictive of a tumor's response to evofosfamide. Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach. Clin Cancer Res; 24(9); 2116–27. ©2018 AACR.
The ketogenic diet for patients with brain tumours: Two parallel randomised trials
Authors: Matt Williams, Helen Cross, Michael D Jenkinson, Kirsty Martin, Susan Wood, Adrienne C Scheck, Nelofer Syed, Kevin O’Neill, Katie Sheen, Catherine Zabilowicz, Kieran Breen, Kathy Oliver, Emma Williams, Mike Johnson, Wendy Fulcher
Journal: Neuro-Oncology (2018)

The ketogenic diet (KD) has attracted considerable interest from the brain tumour community. There is evidence for synergy with radiotherapy in animal models, and improved seizure control in children with epilepsy due to structural abnormalities. However, there is little data on mechanism or effect in brain tumour patients, and different options for implementing the ketogenic diet. In November 2016 we assembled multiple stakeholders, including the James Lind PSP in neuro-oncology and several charities to develop a trial outline. We addressed mechanistic, clinical and practical factors to develop a trial protocol. Based on the meeting, we are planning two parallel open-label phase 2 randomised trials of the Modified Ketogenic Diet (MKD) in patients with high grade gliomas (HGG) receiving chemoradiotherapy, and in patients with low- grade gliomas (LGG). Patients will be enrolled following a histological diagnosis and informed consent. They will receive training on a Modified Ketogenic Diet (MKD) and dietetic support throughout the trial. Patients will be aged 18+, performance score <=2, with adequate baseline blood parameters and will not have received previous treatment (except surgery). Patients will receive standard clinical care as usual. The primary endpoint will be overall survival (not powered for comparison) (HGG) and symptom levels (LGG), with secondary endpoints including the degree and length of ketosis, disease progression and quality of life measures, including seizures. Translational assessments will include blood ketone (BHB) levels, changes in specific miRNA levels in plasma, tumour sample analysis and MRI/ MRS-based assessment of ketosis and tumour response. There is an embedded psychological component to explore patient experience, explore reasons for participation and the psychological impact of the trial. Given the nature of the trial, we are intending to open the trial in 3 - 5 centres to concentrate dietetic support.
Effect of genetic variation on overall survival in a clinical trial of metastatic colorectal cancer (mCRC).
Authors: Heinz-Josef Lenz, Fredrick Schumacher, Fotios Loupakis, Chiara Cremolini, Yan Ning, Stefan Stremitzer, Yu Sunakawa, Satoshi Matsusaka, Satoshi Okazaki, Wu Zhang, Alfredo Falcone
Journal: Journal of Clinical Oncology (2015)

3562 Background: TRIBE, a phase III randomized trial comparing FOLFIRI + BEV (Arm A) vs FOLFOXIRI + BEV (Arm B) as first-line treatment for mCRC, were recently published in the NEJM. No known predictive biomarkers for BEV-based chemotherapy exist. Here we assess the impact of genetic variation with overall survival (OS). Methods: The Illumina HumanExome array (248,538 SNPs) was genotyped on 418 genomic DNA samples from TRIBE. The analysis included 385 pts and 37,043 coding SNPs (MAF > 1%) following quality control. An additive genetic model in a Cox proportional hazard framework was utilized to identify associations with OS adjusting for relevant confounders. A subgroup analysis by study arm, sex, and primary location was performed. A Bonferroni correction was applied to minimize false positives. Results: Arm A (N = 163) had a mean age of 59.9 years, median OS of 26.2 mos while Arm B (N = 222) had a mean age of 59.9 years, median OS of 31.0 mos. We identified 12 statistically significant associations (P< 1.35x10-6) with OS; yielding six statistically significant subgroup interactions (P< 4.4x10-4). In all patients group, VEGFR2 rs10008360 is significantly associated with OS (HR = 5.76; 95%CI: 2.66-12.46; P= 8.8x10-6); significant in Arm B (HR = 9.81; 95%CI: 3.59-26.81; P= 8.52x10-6) and left-sided CRCs(HR = 10.48; 95%CI: 3.73-29.49; P= 8.4x10-6), The strongest association was detected in Arm B with the missense variant rs3750025 in DSPP (HR = 22.7; 95%CI: 7.4-69.5; P= 4.2x10-8), including a significant statistical interaction by study arm (P= 2.0x10-5). The median OS in Arm B for rs3750025 AA and AG/GG genotypes were 31.0 (95%CI: 28.4-36.1) and 3.9 (1.6-7.2) mos. Among right-sided CRCs, ZNF749 rs2240038 yielded a statistically significant association (HR = 40.3, P= 2.27x10-7) with a median OS of 24.8 (20.5-30.9) and 4.4 (4.0-5.9) mos for the GG and GA/AA genotypes. Conclusions: This is the first study to identify novel biomarkers for OS among clinically relevant subgroups defined by study arm, tumor location and sex. These results demonstrate the clinical potential for novel biomarker discovery using genetic variation. Further validation of our findings in FIRE3 trial is ongoing.
DEVELOPING A TARGETED APPROACH TO 30-DAY CHF READMISSIONS
Authors: Chukwudi Obiagwu, Sarah Rabice, Paurush Ambesh, Olaoluwatomi Lamikanra, Chiemeziem Nwanyanwu, Samson Alliu, Parul Kakar, Abhinav Saxena, Aleksandar Adzic, Norbert Moskovits, Melvyn Hecht, Vijay Shetty
Journal: Journal of the American College of Cardiology (2018)
Genomic variations associated with prostate cancer in large cohort of African American men.
Authors: Rayford Walter, Jennifer Jordan, Mandeep Takhar, Mohammed Alshalalfa, Darlene Dai, Nicholas Erho, Mark Greenberger, Randy Bradley, Elai Davicioni
Journal: Journal of Clinical Oncology (2018)

20 Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well known. PCa is known to be more aggressive in African American men (AAM) in terms of higher incidence and mortality rates. Here we validate a tumor gene expression pan-cancer race model in men with PCa and further characterize genomic differences that may contribute to disparate clinical outcomes Methods: We obtained de-identified genome-wide expression profiles from clinical use of the Decipher RP test in 9,953 men from the GRID registry database. A subset of men (n = 313) had known race status. A pan-cancer race model, developed to predict patient AAM race from analysis of gene expression patterns in 4,162 tumors from retrospective cohorts with known race status was applied to the prospective cohort for race prediction. Gene expression data was used to define genomic differences. Results: The race model has an AUC of 0.98 discriminating EAM from AAM in independent PCa cohort. The model was then applied to the 9,640 GRID patients with unknown race status and classified 6,831 as EAM, 1,058 as AAM with 1,751 as having indeterminate race. Characterizing the molecular subtypes, we found known and predicted AAM to be enriched with SPINK1+ tumors (21% and 24%, respectively) compared to predicted EAM (8%). In contrast, while ERG+ was found 22% and 19% in known and predicted AAM, respectively compared to 46% in predicted EAM. Based on PAM50 prostate cancer classifier, 61% of AAM were classified as basal-like tumors, whereas 41% were basal-like in EAM. Similarly, 28% of AAM had low AR-A while only 11% of EAM had low AR-A. AAM tumors had higher levels of immune infiltration signatures as well as higher scores for inflammatory and interferon gamma responses, and Interleukin 6 (IL6) signaling activity scores. AAM had lower DNA repair and glycolysis pathway activity compared to EAM Conclusions: Known and predicted AAM, were enriched with SPINK1+ tumors, higher immune infiltration and activation but lower ERG+, DNA repair and AR activity tumors. Using such large GRID data with known race, we will further understand the underlying causes associated with prostate cancer racial disparities which could lead to personalized diagnosis and treatment.
An Adolescent With Desquamation of Both Feet
Authors: Yu Seok Jung, Gyong Moon Kim, Jung Min Bae
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation
Authors: Qian Xiao, Jibo Wu, Wei-Jia Wang, Shiyang Chen, Yingxia Zheng, Xiaoqing Yu, Katrina Meeth, Mahnaz Sahraei, Alfred L M Bothwell, Lieping Chen, Marcus Bosenberg, Jianfeng Chen, Veronika Sexl, Le Sun, Lin Li, Wenwen Tang, Dianqing Wu
Journal: Nature Medicine (2018)