tbuckley/cabot-search huggingface dataset:
Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations
Authors: Jake A. Gertie, Biyan Zhang, Elise G. Liu, Laura R. Hoyt, Xiangyun Yin, Lan Xu, Lauren L. Long, Arielle Soldatenko, Uthaman Gowthaman, Adam Williams, Stephanie C. Eisenbarth
Journal: Journal of Allergy and Clinical Immunology (2021)
AB0174 FATIGUE IN RHEUMATOID ARTHRITIS: A CASE-CONTROL STUDY
Authors: A. Fazaa, H. Boussaa, K. Ouenniche, S. Miladi, M. Sellami, L. Souabni, S. Kassab, S. Chekili, K. Ben Abdelghani, A. Laatar
Journal: Annals of the Rheumatic Diseases (2021)

Background: Fatigue is a common symptom in many chronic inflammatory diseases, including rheumatoid arthritis (RA). It is considered one of the most frustrating, uncontrollable, and overwhelming symptoms. However, most of rheumatologists do not assess fatigue despite its clinical significance and its impact on patients’ lives. Objectives: The aims of this study were to determine whether RA patients express more fatigue than healthy controls, and to analyze its correlation with disease activity. Methods: We conducted a cross-sectional study including patients with RA (ACR/EULAR 2010) and healthy controls matched for sex and age. Patients with other acute or chronic diseases that may induce fatigue (such as cancer, infection or depression) were excluded. Demographic data and the following clinical parameters were collected: pain Visual Analog Scale (VAS), Global Patient Assessment (GPA), tender joint count (TJC) and swollen joint count (SJC), Erythrocyte Sedimentation Rate (ESR), C Protein Reactive (CRP), Disease Activity Score 28 (DAS28), and Health Assessment Questionnaire (HAQ). Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) which is a short 13-item questionnaire validated in RA. The score FACIT-F ranges between 0 and 52. Fatigue was considered mild if the FACIT-F score was ≥40, moderate if 20≤FACIT-F&lt;40 and severe if 0≤FACIT-F&lt;20. A p value inferior to 0.05 was considered significant. Results: We included 100 RA patients (84 women and 16 men) with a mean age of 49.5±10 years old [18-65]. The mean disease duration was 87.3 months [1-360]. The mean pain VAS was 49 cm [0-100] and the mean GPA was 47.8 cm [0-100]. The mean TJC and SJC were 5.3 [0-36] and 1 [0-9] respectively. The mean levels of ESR and CRP were 38.1 mm [10-120] and 10.8 mg/l [2-61] respectively. The mean DAS28 ESR was 3.68 [1.90-8.33] and the mean HAQ score was 0.90 [0-2.75]. Thirty-nine healthy controls were enrolled including 35 women and 4 men with a mean age of 51.2 years old [30-64]. The mean FACIT-F score was 27.1 [0-51] in RA patients versus 46.2 [0-52] in healthy controls (p&lt;0.001). Among RA patients, 57% had moderate fatigue and 26% had severe fatigue. A significant negative correlation was noted between the FACIT-F score and the following parameters in RA patients: TJC ( r =-0.568, p &lt;0.001), SJC ( r =-0.274, p &lt;0.001), pain VAS ( r =-0.605, p &lt;0.001), GPA ( r =-0.658, p &lt;0.001), ESR ( r =-0.405, p &lt;0.001), CRP ( r =-0.149, p &lt;0.001), DAS28 ( r =-0.837, p &lt;0.001) and HAQ ( r =-0.634, p &lt;0.001). Conclusion: Fatigue was significantly more observed in RA patients. This symptom was correlated with disease activity and disability. It is important to recognize and manage fatigue in order to improve patients’ quality of life. Disclosure of Interests: None declared
Comparison of Frontline Induction Therapy Using Idarubicin in Combination with High-Dose (HDAC3) Versus Intermediate-Dose Cytarabine (IDAC3) in Adult Acute Myeloid Leukemia
Authors: Ing Soo S Tiong, Katherine Fielding, Chun Y Fong, Hadley Bortz, Sharon Avery, Andrew P Grigg, Andrew Wei
Journal: Blood (2017)
BCR Unresponsiveness and 13q14 Duplication Underpin Spontaneous Disease Regression in Chronic Lymphocytic Leukemia
Authors: Marwan Kwok, Andy Rawstron, Angelo Agathanggelou, Anshita Goel, Ceri Oldreive, Rhiannon E Jones, Samantha Drennan, Archana Sharma-Oates, Paul Evans, Edward Smith, Jingwen Mao, Jamie Beaumont, Jusveen Rai, Mayumi Hamada, Surita Dalal, Naheema Gordon, Nicholas Davies, Helen Parry, Andrew Beggs, Talha Munir, Paul Moreton, Shankara Paneesha, Guy Pratt, Malcolm Taylor, Francesco Forconi, Duncan M Baird, Jean-Baptiste Cazier, Paul Moss, Peter Hillmen, Tatjana Stankovic
Journal: Blood (2017)
NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis
Authors: Zhenjun Zhao, Helge Gad, Carlos Benitez-Buelga, Kumar Sanjiv, Hua Xiangwei, He Kang, Mingxuan Feng, Zhicong Zhao, Ulrika Warpman Berglund, Qiang Xia, Thomas Helleday
Journal: Cancer Research (2021)

Abstract Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC. Significance: This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.
Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
Authors: David Planchard, Benjamin Besse, Harry J M Groen, Pierre-Jean Souquet, Elisabeth Quoix, Christina S Baik, Fabrice Barlesi, Tae Min Kim, Julien Mazieres, Silvia Novello, James R Rigas, Allison Upalawanna, Anthony M D'Amelio, Pingkuan Zhang, Bijoyesh Mookerjee, Bruce E Johnson
Journal: The Lancet Oncology (2016)
Abstract 198: Metabolic Stress Causes Mitochondrial Dysfunction and Vascular Senescence via Angiotensin II Type I Receptor Signal / Rho Kinase Induced Mitochondrial Fission
Authors: Yoshihiro Uchikado, Yoshiyuki Ikeda, Yuichi Sasaki, Yuichi Akasaki, Mitsuru Ohishi
Journal: Circulation (2019)

Introduction: Metabolic stress, such as oxidized low density lipoprotein (ox-LDL) and advanced glycation end products (AGE) cause mitochondrial dysfunction and evoke vascular senescence and atherosclerosis. Mitochondria are highly dynamic organelles that constantly change their morphology to fusion or fission. This study aims to clarify whether mitochondrial dynamics is involved in the etiology of vascular senescence. Methods: We used C57BL6 (WT), apolipoprotein E deficient (ApoE KO) and db/db mice. We also conducted in vitro experiments using VSMC and HUVEC. Results: The degree of arterial senescence, arterial protein level of Drp1 in mitochondrial fraction and mitochondrial oxidative stress were higher and the number of fused mitochondria and mitochondrial function were lower in either ApoE KO or db/db mice than those of WT mice. Treatment with Drp1-specific inhibitor, mdivi-1, to these mice reduced excessive mitochondrial fission, oxidative stress and attenuated vascular senescence. Administration of either ox-LDL or AGE to cells also induced excessive mitochondrial fission though phosphorylation of Drp1 at Ser616, mitochondrial dysfunction, reactive oxygen species production and cellular senescence. Treatment with mdivi-1 to these cells restored imbalance of mitochondrial dynamics and these detrimental alterations. These results suggest that metabolic stress-induced mitochondrial dysfunction and cellular senescence were derived from Drp1-dependent mitochondrial fission. Treatment with angiotensin II type1 receptor (AT1R) blocker (ARB) to either Apo E KO mice or db/db in in vivo experiments and administration of ARB to cells with ox-LDL or AGE stimulation in in vitro experiments inactivated Drp1 and improved imbalance of mitochondrial dynamics, mitochondrial dysfunction and cellular senescence, suggesting that AT1R signal is involved in regulating metabolic stress-induced mitochondrial fission. Finally, inhibition of Rho kinase ROCK1 successfully attenuated Drp1-mediated mitochondrial fission and cellular senescence derived from metabolic stress. Conclusion: Metabolic stress causes cellular and vascular senescence through AT1R signal/Rho kinase-mediated mitochondrial fission.
Abstract 12967: Inhibition of GATA4 Dimerization Suppresses Hypertrophic Responses in Cardiomyocytes
Authors: Satoshi Shimizu, Yoichi Sunagawa, Kodai Hara, Asami Hishiki, Yasufumi Katanasaka, Yusuke Miyazaki, Masafumi Funamoto, Nurmila Sari, Kana Shimizu, Hiromichi Wada, Koji Hasegawa, Hiroshi Hashimoto, Tatsuya Morimoto
Journal: Circulation (2018)

Introduction: In the development of heart failure, hypertrophic signals, such as hemodynamic overload, eventually reach the nuclei of cardiomyocytes, change patterns of gene expression, and cause t...
AB0520 PUBIC SYMPHYSIS INVOLVEMENT IN NON-RADIOGRAPHIC SPONDYLARTHRITIS
Authors: H. Ferjani, M. Moalla, K. Maatallah, D. Ben Nessib, W. Triki, D. Kaffel, W. Hamdi
Journal: Annals of the Rheumatic Diseases (2021)

Background: Structural change within pubic symphysis (PS) occurs in 20–25% of patients with spondylarthritis (SpA). It occurs in all developmental stages, even in the early stages of the disease. Changes in the symphysis can sometimes precede spine and sacroiliac involvement. Radiological findings in PS were poorly described in the SpA, especially on its non-radiographic form (nr-axSpA). Objectives: We aimed in this study to evaluate pubic symphyseal features in patients with a confirmed diagnosis of nr-axSpA and to assess the correlation of these changes with clinical and imaging features of nr-axSpA in these patients. We also focused on the relationship between parity and radiographic changes in pubic symphysis (PS). Methods: We retrospectively reviewed the data of 40 patients diagnosed with nr-axSpA according to the ASAS criteria. Radiological-morphological changes of PS were assessed in pelvic radiography by two distinct rheumatologists. Grading symphysial involvement was made as follow: scores ranged from 0-4 per reading: grade 0 = normal; grade 1 = subtle irregularity and/or subchondral sclerosis, grade 2 = clear erosions, 3 = marked sclerosis, grade 4 = ankylosis. For all patients, we calculated the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the BASRI (Bath Ankylosing Spondylitis Radiology Index). For all patients, we recorded the sacroiliac changes showed by the previous pelvic radiography and/or the pelvic scanner and/or by magnetic resonance imaging (MRI). Results: We enrolled forty patients with a sex-ratio H/F=1/3. Mean age of patients at diagnosis was 39,9 +/- 10,8 [17-59]. Forty percent of patients had peripheral enthesitis, and 45% had peripheral arthritis. BASDAI mean score was 4,63 +/- 0,9 [0-8,6]. HLA B-27 was present in 32,3% of cases. We noted radiographic changes in PS in 37,5% (15 patients): grade 1 (n=1), grade 2 (n=10), grade 3 (n=3) and grade 4 (n=1). There was not a significant difference between the sex group (p=0,85). A comparison of 2 groups (women with 3 children or more and women with less than 3 children) concluded that childbirth did not modify PS changes (p=0,9). Also, PS changes did not differ with age (p=0,5). There was no correlation between the BASRI value with the presence of PS changes nor with its grades (p=0,5 and p=0,89, respectively). Also, disease activity did not influence the PS involvement (p=0,4). Radiological findings in PS was not correlated with the sacroiliac features found on MRI or pelvic CT scan (p=0,59 and p=0,1). Conclusion: In SpA criteria, PS changes were not considered. It can be an additional help in making the diagnosis. Interestingly, pubic symphysis may exist without sacroiliitis. Disclosure of Interests: None declared.
Mapping biopsy for bile duct cancer using a novel device delivery system
Authors: Tomoaki Matsumori, Norimitsu Uza, Masahiro Shiokawa, Takahisa Maruno, Takeshi Kuwada, Saiko Marui, Hiroshi Seno
Journal: Endoscopy (2021)

A 56-year-old man presented to our department with abnormal liver function tests. Imaging studies showed a distal biliary stricture with dilated intrahepatic bile ducts ([Fig. 1]). An endoscopic ultrasound (EUS) revealed that there was continuous mild thickening of the wall of the upstream bile duct ([Fig. 2 a, b]). Cholangiocarcinoma was suspected; therefore, an endoscopic retrograde cholangiography (ERC) and an intraductal ultrasound were performed, which showed circumferential thickening of the biliary wall ([Fig. 2 c, d]). Mapping biopsies up to the hilar bile duct and targeted biopsies of the biliary stricture were taken using a novel device delivery system (EndoSheather; Piolax, Japan) ([Fig. 3]; [Video 1]). As cancer cells were observed in both mapping and targeted biopsy samples ([Fig. 4 a]), additional mapping biopsies were performed on the right and left hepatic ducts ([Fig. 5]), but no malignant cells were detected ([Fig. 4 b]). Based on these imaging and pathological findings, a left hepatopancreatoduodenectomy was performed, and a negative surgical margin was confirmed.
POS1146 NONCODING RNA CONTRIBUTE TO PATHOGENESIS IN PRIMARY GOUTY ARTHRITIS
Authors: Q. B. Zhang, Y. Q. Huang, F. N. Xiao, G. L. Jian, Y. P. Tang, F. Dai, J. X. Zheng, Y. F. Qing
Journal: Annals of the Rheumatic Diseases (2021)

Background: Gout is an arthritic disease caused by the deposition of monosodium urate crystal (MSU) in the joints, which can lead to acute inflammation and damage adjacent tissue [1].Over the past decade, noncoding RNAs (ncRNAs) have been shown to have crucial importance in health and disease[2,3]. However, studies evaluating the function of ncRNAs in gout are scarce, and current knowledge of the role of ncRNAs in gout is still limited. Objectives: To assess the contribution of noncoding RNAs to gout and the clinical importance of these genes in primary gouty arthritis (GA). Methods: The mRNA expression levels of noncoding RNAs (LINC00173, LINC00963, LINC01330 and miRNA-182-5p) were measured in peripheral blood mononuclear cells (PBMCs) from 60 gout patients(including 30 acute gout patients, 30 intercritical gout patients) and 40 healthy subjects. The relationship between noncoding RNA expression levels and laboratory features was analyzed in GA patients. Results: The expression levels of LINC00173, LINC00963 and miRNA-182-5p were much lower in the AG and IG group than in the HC groups (p&lt;0.05), and no significant difference was detected between AG and IG groups(P&gt;0.05). The expression levels of LINC01330 were much lower in the AG group than in the IG and HC groups (p&lt;0.05), and no significant difference was detected between AG and IG groups(P&gt;0.05). In GA patients, the levels of noncoding RNAs mRNA correlated with laboratory inflammatory and metabolic indexes. Conclusion: Altered noncoding RNAs expression suggests that noncoding RNAs is involved in the pathogenesis of GA and participates in regulating inflammation and metabolism. References: [1]Xu Yi-Ting,Leng Ying-Rong,Liu Ming-Ming et al. MicroRNA and long noncoding RNA involvement in gout and prospects for treatment.[J].Int Immunopharmacol, 2020, 87: 106842.doi:10.1016/j.intimp.2020.106842 [2]Yu Yunfang,Zhang Wenda,Li Anlin et al. Association of Long Noncoding RNA Biomarkers With Clinical Immune Subtype and Prediction of Immunotherapy Response in Patients With Cancer.[J].JAMA Netw Open, 2020, 3: e202149.doi:10.1001/jamanetworkopen.2020.2149 [3]Zou Yaoyao,Xu Siqi,Xiao Youjun et al. Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation.[J].J Clin Invest, 2018, 128: 4510-4524.doi:10.1172/JCI97965 Figure 1. Relative Expression of noncoding RNAs in the PBMCs of Patients. Disclosure of Interests: Quan-Bo Zhang Grant/research support from: the National Natural Science Foundation of China(General Program) (no.81974250) and Science and Technology Plan Project of Sichuan Province (no.2018JY0257), Yu-Qin Huang: None declared, Fan-Ni Xiao: None declared, gui-lin jian: None declared, Yi-Ping Tang: None declared, Fei Dai: None declared, Jian-Xiong Zheng: None declared, Yu-Feng Qing Grant/research support from: Science and Technology Project of Nanchong City (no.18SXHZ0522).
Prevalence and outcome of patients with acute myocarditis and positive viral search on nasopharyngeal swab
Authors: Enrico Ammirati, Marisa Varrenti, Giacomo Veronese, Diana Fanti, Alice Nava, Manlio Cipriani, Patrizia Pedrotti, Andrea Garascia, Maurizio Bottiroli, Fabrizio Oliva, Manuela Bramerio, Silvio Veronese, Cristina Giannattasio, Emanuela Bonoldi, Carlo F. Perno, Paolo G. Camici, Maria Frigerio
Journal: European Journal of Heart Failure (2021)
Ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis in France: a retrospective multicentre study
Authors: Thomas Bettuzzi, Aurélie Jourdes, Olivier Robineau, Isabelle Alcaraz, Victoria Manda, Jean Michel Molina, Maxime Mehlen, Charles Cazanave, Pierre Tattevin, Sami Mensi, Benjamin Terrier, Alexis Régent, Jade Ghosn, Caroline Charlier, Guillaume Martin-Blondel, Nicolas Dupin
Journal: The Lancet Infectious Diseases (2021)
Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial
Authors: Ingo K. Mellinghoff, Marta Penas-Prado, Katherine B. Peters, Howard A. Burris, Elizabeth A. Maher, Filip Janku, Gregory M. Cote, Macarena I. de la Fuente, Jennifer L. Clarke, Benjamin M. Ellingson, Saewon Chun, Robert J. Young, Hua Liu, Sung Choe, Min Lu, Kha Le, Islam Hassan, Lori Steelman, Shuchi S. Pandya, Timothy F. Cloughesy, Patrick Y. Wen
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Patients and Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2–40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8–6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.
AB0489 CORRELATION BETWEEN DISEASE ACTIVITY AND SERUM TNF-ALPHA LEVELS IN PATIENTS WITH ANKYLOSING SPONDYLITIS
Authors: K. Kraev, M. Geneva-Popova, S. Popova
Journal: Annals of the Rheumatic Diseases (2021)

Background: Ankylosing spondylitis (AS) is an immune-mediated rheumatic disease, it belongs to the spectrum of the axial spondyloarthritis. Several elements are important for the pathogenesis of AS - they include interactions in the context of a specific genetic origin between the intestinal microbiome, innate immunity, lymphoid cells and anatomical structures, which are the entheses of the axial skeleton and peripheral joints. The main mediators of the inflammatory process are TNF - α, IL-17 and IL-17A. Objectives: To study the level of TNF-alpha in the serum of patients with ankylosing spondylitis and to assess its relationship with the indices of disease activity before starting therapy with TNF-alpha blockers and in the dynamics after initiation of treatment. Methods: The present study included 50 patients with ankylosing spondylitis and 31 healthy controls similar in age, sex, and BMI. Clinical and non-clinical methods of examination and evaluation were used for proper assessment and follow-up of patients. The disease activity indices that were used were BASDAI and ASDAS. Statistical analysis was performed with the IBM SPSS program, v.24., To prove the relationship between the level of TNF-alpha in the serum of patients and disease activity, a correlation analysis of Spearman Rho was used. Results: The level of TNF-α in patients with AS was highest before treatment initiation with biologics, 89.77 ± 36.89 pg / ml, and was significantly higher than that of healthy controls. At the next visit, the TNF-α level decreased to 27.59 ± 23.88 pg / ml, the difference being significant from baseline. 24 months after initiation of treatment with biological therapy average level of TNF-α in patients with AS did not differ reliably from its levels in 6 and 12 month after initiation of treatment, respectively, 22.36 ± 22.38 pg/ml, 19,29 ± 21.07 pg/ml. The level of this cytokine significantly correlates with the activity of the disease, measured by the activity indices BASDAI, ASDAS. Conclusion: The level of the pro-inflammatory cytokine TNF-alpha is significantly higher in patients with ankylosing spondylitis and significantly correlates with the disease activity in them, measured by the respective indices (BASDAI, ASDAS). References: [1]Arends S., N. Lebbink, A. Spoorenberg et al., “The formation of autoantibodies and antibodies to TNF-α blocking agents in relation to clinical response in patients with ankylosing spondylitis”, Clin Exp Rheumatol, 2010, 28: 661- 668. [2]Bal A., E. Unlu, G. Bahar et al., “Comparison of serum IL-1 beta, sIL-2R, IL-6, and TNF-alpha levels with disease activity parameters in ankylosing spondylitis.” Clin Rheumatol, 2007, 26: 211–215. Disclosure of Interests: None declared.
Structural racism hide and seek: only one of five official UK reports on health has found structural racism
Authors: Raj S Bhopal
Journal: BMJ (2021)

Gopal and Rao’s editorial made me reflect on five important UK reports published in the past year, generating controversy about institutional and structural racism.1

The UK government commissioned Public Health England (PHE) to report on inequalities in covid-19, including ethnicity.2 The report was criticised for having no recommendations and no reference to extensive public consultations by PHE. A second report including the consultations with more than …