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De la Giclais, Bertrand, François Duforez, Damien Leger, Nathalie De Premorel, Alexandre Dubois e Maxime Elbaz. "Particularité du sommeil polyphasique d’après l’EEG de sommeil en mer chez 7 navigateurs de la route du Rhum". Médecine du Sommeil 12, n.º 1 (janeiro de 2015): 44. http://dx.doi.org/10.1016/j.msom.2015.01.070.
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de La Giclais, B., F. Duforez, N. de Prémorel, A. Dubois, M. Elbaz e D. Léger. "Particularités du sommeil polyphasique d’après la polysomnographie en mer chez 7 navigateurs de la route du Rhum 2014". Médecine du Sommeil 13, n.º 3 (setembro de 2016): 122–27. http://dx.doi.org/10.1016/j.msom.2016.07.003.
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Chen, BD. "In vivo administration of recombinant human interleukin-1 and macrophage colony-stimulating factor (M-CSF) induce a rapid loss of M- CSF receptors in mouse bone marrow cells and peritoneal macrophages: effect of administration route". Blood 77, n.º 9 (1 de maio de 1991): 1923–28. http://dx.doi.org/10.1182/blood.v77.9.1923.1923.
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Abstract Earlier studies suggested the existence of a blood-bone marrow barrier that significantly inhibits the transfer of plasma macrophage colony- stimulating factor (M-CSF) to responsive hematopoietic cells in vivo as indicated by its failure to induce a receptor downregulation in bone marrow cells. In this study, the effect of recombinant human interleukin-1 (rhuIL-1) was investigated. In vivo administration of rhuIL-1, either intraperitoneally (IP) or intravenously (IV), induced a rapid transient loss of M-CSF receptor binding activity in bone marrow cells, with a nadir occurring between 2 to 4 hours while loss of M-CSF receptors by cells in the peritoneal cavity occurred only in animals receiving rhuIL-1 via IP administration. The loss of M-CSF receptor activity after rhuIL-1 treatment was correlated with an elevated level of circulating M-CSF. However, the loss of M-CSF receptors in marrow cells was prevented by dexamethasone (Dex) treatment before rhuIL-1 administration. The fact that Dex treatment also reduced the level of circulating M-CSF after rhuIL-1 administration suggests that the inhibitory effects of IL-1 are mediated through locally produced M-CSF. Administration of rhuM-CSF at higher doses, either IV or IP, also induced a loss of M-CSF receptor of lesser degree in the marrow cells. However, the loss of M-CSF receptors by the peritoneal cells was induced only in mice receiving rhuM-CSF through IP administration. Taken together, these results indicate the existence of a unidirectional barrier that prevents the transfer of blood M-CSF and IL- 1 to peritoneal cavity but not vice versa.
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Chen, BD. "In vivo administration of recombinant human interleukin-1 and macrophage colony-stimulating factor (M-CSF) induce a rapid loss of M- CSF receptors in mouse bone marrow cells and peritoneal macrophages: effect of administration route". Blood 77, n.º 9 (1 de maio de 1991): 1923–28. http://dx.doi.org/10.1182/blood.v77.9.1923.bloodjournal7791923.
Texto completo da fonteResumo:
Earlier studies suggested the existence of a blood-bone marrow barrier that significantly inhibits the transfer of plasma macrophage colony- stimulating factor (M-CSF) to responsive hematopoietic cells in vivo as indicated by its failure to induce a receptor downregulation in bone marrow cells. In this study, the effect of recombinant human interleukin-1 (rhuIL-1) was investigated. In vivo administration of rhuIL-1, either intraperitoneally (IP) or intravenously (IV), induced a rapid transient loss of M-CSF receptor binding activity in bone marrow cells, with a nadir occurring between 2 to 4 hours while loss of M-CSF receptors by cells in the peritoneal cavity occurred only in animals receiving rhuIL-1 via IP administration. The loss of M-CSF receptor activity after rhuIL-1 treatment was correlated with an elevated level of circulating M-CSF. However, the loss of M-CSF receptors in marrow cells was prevented by dexamethasone (Dex) treatment before rhuIL-1 administration. The fact that Dex treatment also reduced the level of circulating M-CSF after rhuIL-1 administration suggests that the inhibitory effects of IL-1 are mediated through locally produced M-CSF. Administration of rhuM-CSF at higher doses, either IV or IP, also induced a loss of M-CSF receptor of lesser degree in the marrow cells. However, the loss of M-CSF receptors by the peritoneal cells was induced only in mice receiving rhuM-CSF through IP administration. Taken together, these results indicate the existence of a unidirectional barrier that prevents the transfer of blood M-CSF and IL- 1 to peritoneal cavity but not vice versa.
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Jie, Junwu, e Congjin Miao. "Analysis and Selection of Shipping Route in Ocean". Journal of Physics: Conference Series 2029, n.º 1 (1 de setembro de 2021): 012151. http://dx.doi.org/10.1088/1742-6596/2029/1/012151.
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Abstract This electronic document is a “live” template. Ocean navigation is a long-distance cross ocean navigation. There are three kinds of ocean routes in common use: great circle route, rhumb line route and mixed route. The great circle route is usually used when ships are sailing in the ocean, but sometimes in the mid latitude sea area, the rhumb line route is a choice in the mid latitude sea area. Combined with the calculation of a navigation example, this paper makes some analysis on the selection of ocean routes in mid latitude sea area, illustrates the advantages and disadvantages of these three ocean routes with data, and draws a conclusion on how to choose the routes.
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O'Day, SJ, SN Rabinowe, D. Neuberg, AS Freedman, RJ Soiffer, NA Spector, MJ Robertson, K. Anderson, M. Whelan e K. Pesek. "A phase II study of continuous infusion recombinant human granulocyte- macrophage colony-stimulating factor as an adjunct to autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma in first remission". Blood 83, n.º 9 (1 de maio de 1994): 2707–14. http://dx.doi.org/10.1182/blood.v83.9.2707.2707.
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Abstract Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.
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O'Day, SJ, SN Rabinowe, D. Neuberg, AS Freedman, RJ Soiffer, NA Spector, MJ Robertson, K. Anderson, M. Whelan e K. Pesek. "A phase II study of continuous infusion recombinant human granulocyte- macrophage colony-stimulating factor as an adjunct to autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma in first remission". Blood 83, n.º 9 (1 de maio de 1994): 2707–14. http://dx.doi.org/10.1182/blood.v83.9.2707.bloodjournal8392707.
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Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.
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Renaut, Didier. "Nouveau rapport du GIEC. La convention-cadre sur les changements climatiques. ATLAS 3 a étudié le soleil et l'atmosphère. Quand un avion en renifle d'autres. Chaos, régimes de temps et prévisibilité. Jean-Pierre Beysson nommé directeur général de MÉTÉO-FRANCE. La route du rhum 1994, ou la météorologie médiatisée". La Météorologie 8, n.º 9 (1995): 88. http://dx.doi.org/10.4267/2042/51946.
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Saparbayeva, Nurzipa Abubakirovna. "Biological features of Rheum wittrockii Lundstr. in the natural population of the Ketpen ridge". Bulletin of the Karaganda University. “Biology, medicine, geography Series” 103, n.º 3 (29 de setembro de 2021): 125–33. http://dx.doi.org/10.31489/2021bmg3/125-133.
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The article presents data on the biological characteristics of Rheum wittrockii Lundstr. on the Ketpen ridge. The aim of the study was to research the biological characteristics of the natural growth of Rh. wittrockii. Study objects are Rh. wittrockii in natural populations of the Ketpen Ridge. In June-July 2015–2017 the route-reconnaissance method of research was carried out in the northern gorges of the Ketpen ridge of the Uygur district of the Almaty region. Determination of the morphological characteristics of plant seeds was carried out according to the methodological instructions of N.L. Udolskaya (1976). Systematic monitoring of structural changes in plant organs in a large development cycle, determination of biological characteristics and structure was carried out in accordance with the instructions of A. Zhukov (2012b), Program and methodology..., (1986). The study revealed that in the gorges Ketpen Rh. wittrockii is found at altitudes above sea level (1900–3200 m). In the first year of growth, only vegetative organs develop. The development of generative shoots begins in the 2–3rd year of plant growth. The rapid growth of reproductive generative shoots is accompanied by the growth of vegetative shoots. The flowering phase lasts 7–10 days. Flowering of one individual lasts 3–5 days. The generative phase lasts 7–8 (10) years. The fruiting process lasts from midJuly to the third decade of August. The fruiting phase is 12–14 days. The growing season of the plant is 60–75 days. The seed is a triangular nutlet. Germination is underground. Sprouts have two true leaves. The underground perennial shoot system consists of a multidisciplinary caudex formed as a result of infinitely long monopodial growth due to the activity of the apical bud of the main underground shoots. Roots Rh. wittrockii are composed of basic taproots. In the underground part, tender young roots develop in the surface layer of the soil. The duration of the generative period from germination to aging is 15–16 years.
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Hsieh, Tsung-Hsuan, Qian Meng, Bing Han, Shengzheng Wang e Xuezhen Wu. "Optimization of Waypoints on the Great Circle Route Based on Genetic Algorithm and Fuzzy Logic". Journal of Marine Science and Engineering 11, n.º 2 (5 de fevereiro de 2023): 358. http://dx.doi.org/10.3390/jmse11020358.
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Determining the appropriate number and position of waypoints on a great circle route (GCR) helps to shorten the sailing distance, reduce the number of course changes, and well-approximate the GCR through a small number of rhumb line (RL) legs. In this study, a genetic algorithm-based method (i.e., the GA method) is proposed to optimize the positions of waypoints on the GCR when the number of waypoints is given. Furthermore, a fuzzy logic-based evaluation method for the number of waypoints (i.e., the FL method) is proposed to judge whether to add a new waypoint or stop the process by using the non-fixed values while considering both the number of waypoints and the remaining benefit of the GCR. According to the example demonstration results, the two methods proposed in this study can well-determine the number and position of waypoints and provide effective support for ocean route planning.
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Sharma, Deepika, Naveen Kumar, Tarang Mehrotra, Naveed Pervaiz, Lokesh Agrawal, Shalini Tripathi, Abhishek Jha, Thanasis Poullikkas, Ravinder Kumar e Lalita Ledwani. "In vitro and in silico molecular docking studies of Rheum emodi-derived diamagnetic SnO2 nanoparticles and their cytotoxic effects against breast cancer". New Journal of Chemistry 45, n.º 3 (2021): 1695–711. http://dx.doi.org/10.1039/d0nj04670a.
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Green-route-bioengineered nanoparticles have received significant attention for diagnosis and treatment of cancer in the medical technology era due to their non-toxic nature, cost-friendliness, and energy efficiency.
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Zhang, Wenping, Jian Wang, Chen Zhang, Qiang Fang, Jianhong Shu, Si Li, Jia Jin et al. "Synergetic Protein Factors That Improve rhGM-CSF Absorption via an Oral Route Exist in Silkworm Pupae". Molecular Pharmaceutics 12, n.º 5 (30 de março de 2015): 1347–55. http://dx.doi.org/10.1021/mp500371g.
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Grundhöfer, Petra, e Georg G. Gross. "Purification of Tetragalloylglucose 4-O-Galloyltransferase and Preparation of Antibodies against This Key Enzyme in the Biosynthesis of Hydrolyzable Tannins". Zeitschrift für Naturforschung C 55, n.º 7-8 (1 de agosto de 2000): 582–87. http://dx.doi.org/10.1515/znc-2000-7-817.
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Abstract The enzyme, β-glucogallin: 1,2,3,6-tetra-O-galloyl- β-ᴅ-glucose 4-O-galloyltransferase, which catalyzes the last common step in the biosynthesis of the two subclasses of hydrolyzable tannins, i.e. gallotannins and ellagitannins, was purified 868-fold from leaves of pedunculate oak ( Quercus robur, syn. Q. pedunculata) to apparent homogeneity. Polyclonal antibodies against this pivotal enzyme were raised in rabbits and purified by protein-A chromatography, gel-filtration and affinity complexation. They were found to react specifically with acyltransferase from oak, displaying no cross-reactivity towards analogous enzymes from other plants synthesizing hydrolyzable tannins along the same biogenetic route, e.g. Rhus typhina or Tellima grandiflora.
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Teste, Iliana Sosa, Yuneidys Mengana Tamos, Yamila Rodríguez Cruz, Adriana Muñoz Cernada, Janette Cruz Rodríguez, Nelvis Subirós Martínez, Rosa Maria Coro Antich, Alina González-Quevedo e Julio Cesar García Rodríguez. "Dose Effect Evaluation and Therapeutic Window of the Neuro-EPO Nasal Application for the Treatment of the Focal Ischemia Model in the Mongolian Gerbil". Scientific World Journal 2012 (2012): 1–12. http://dx.doi.org/10.1100/2012/607498.
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Cerebrovascular disease is the third leading cause of death and the leading cause of disability in Cuba and in several developed countries. A possible neuroprotective agent is the rHu-EPO, whose effects have been demonstrated in models of brain ischemia. The Neuro-EPO is a derivative of the rHu-EPO that avoids the stimulation of erythropoiesis. The aim of this study was to determine the Neuro-EPO delivery into the central nervous system (CNS) to exert a neuroprotective effect in cerebral ischemia model of the Mongolian gerbil. The Neuro-EPO in a rate of 249.4 UI every 8 hours for 4 days showed 25% higher viability efficacy (), improving neurological score and behavior of the spontaneous exploratory activity, the preservation of CA3 areas of the hippocampus, the cortex, and thalamic nuclei in the focal ischemia model of the Mongolian gerbil. In summary, this study, the average dose-used Neuro-EPO (249.4 UI/10 μL/every 8 hours for 4 days), proved to be valid indicators of viability, neurological status, and spontaneous exploratory activity, being significantly lower than that reported for the systemically use of the rHu-EPO as a neuroprotectant. Indeed, up to 12 h after brain ischemia is very positive Neuro-EPO administration by the nasal route as a candidate for neuroprotection.
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UPADHYAY, SUDHAKER, e BHABANI PRASAD MANDAL. "NONCOMMUTATIVE GAUGE THEORIES: MODEL FOR HODGE THEORY". International Journal of Modern Physics A 28, n.º 25 (8 de outubro de 2013): 1350122. http://dx.doi.org/10.1142/s0217751x13501224.
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The nilpotent Becchi–Rouet–Stora–Tyutin (BRST), anti-BRST, dual-BRST and anti-dual-BRST symmetry transformations are constructed in the context of noncommutative (NC) 1-form as well as 2-form gauge theories. The corresponding Noether's charges for these symmetries on the Moyal plane are shown to satisfy the same algebra, as by the de Rham cohomological operators of differential geometry. The Hodge decomposition theorem on compact manifold is also studied. We show that noncommutative gauge theories are field theoretic models for Hodge theory.
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Picciariello, L., F. Ceccarelli, F. Natalucci, G. Olivieri, C. Pirone, V. Orefice, C. Garufi et al. "AB0436 EFFECTIVENESS OF BELIMUMAB IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS: A REAL-LIFE ANALYSIS". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 1346.1–1346. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3040.
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BackgroundEfficacy and safety of belimumab (BLM) in Systemic Lupus Erythematosus (SLE) patients with active disease have been demonstrated by RCTs [1,2] and confirmed by several observational studies [3-8]. Most of these data have been obtained by the use of BLM intravenous formulation (IV); on the contrary, very few findings are available on the use of the drug subcutaneous formulation (SC).ObjectivesEfficacy and drug survival of BLM have been assessed in a monocentric cohort of SLE patients, exploring any difference between the two routes of administration, IV or SC.MethodsA longitudinal study on SLE patients (according to ACR 1997 classification criteria [9]) candidates for treatment with BLM has been performed. Demographic, clinical-laboratory and therapeutic data - including glucocorticoid dosage in prednisone-equivalent - have been collected. Disease activity has been assessed by SLEDAI-2k [10]; in patients with inflammatory articular involvement, DAS28-PCR [11] has been used. In compliance with the study protocol, patients were assessed at baseline and at 3 and 12 months after starting treatment.ResultsA total of 85 patients treated with BLM were enrolled, most of whom were female (male/female 2/83), with a median age of 48 years (IQR 13) and a median disease duration of 127 months (IQR 151). Fifty-one patients (60%) were treated with IV formulation and the remaining 34 (40%) with SC route. BLM was prescribed due to the following clinical manifestations: joint involvement (61.2%), cutaneous manifestations (20.0%), renal involvement (for residual proteinuria, 5.9%), haematological modifications (5.9%), constitutional involvement (3.5%), pericarditis (1.2%), headache (1.2%). In both the formulations, joint involvement was the most frequent indication of BLM (IV: 64.7%, SC: 58.8%). Median treatment duration was 15 months (IQR 24). Moving on drug efficacy, after 3 and 12 months of follow-up BLM has determined a significant reduction of SLEDAI-2k median values (p=0.001, p<0.001 respectively, Figure 1A) as well as of daily prednisone dose (p=0.009, p<0.0001 respectively, Figure 1B). In patients treated because of musculoskeletal manifestations, DAS28-PCR reduced significantly at 3 and 12 months after treatment (p<0.0001). Drug survival at 12 months was 70% in the total cohort (Figure 1C) and was higher in patients treated with SC formulation than with IV route (75.8% versus 66.5%, p=ns). During the period of follow-up, 39 patients (45.9%) discontinued BLM: 38.4% of patients due to adverse events, 41% for primary or secondary inefficacy, 15% lost to follow-up, 5.1% for pregnancy. BLM withdrawal for adverse events was more frequent in the group of patients treated with IV formulation than SC one (25.9% versus 5.9%, p=0,0001). 11 patients switched from IV formulation to SC one after a median period of 40 months (IQR 20) without loss of efficacy or adverse events.ConclusionOur results confirm BLM efficacy also in a real-life setting. Notably, our data highlight a better drug survival in patients treated with SC formulation, mainly secondary to a less frequency of adverse events.References[1]Furie R et al. Arthritis Rheum. 2011;63(12):3918-3930.[2]Navarra SV et al. Lancet. 2011;377(9767):721-731.[3]Andreoli L et al. Isr Med Assoc J. 2014;16(10):651-653.[4]Hui-Yuen JS et al. J Rheumatol. 2015;42(12):2288-2295.[5]Collins CE et al. Lupus Sci Med. 2016;3(1):e000118.[6]Touma Z et al. Rheumatol Int. 2017;37(6):865-873.[7]Iaccarino L et al. Arthritis Care Res (Hoboken). 2017;69(1):115-123.[8]Gatto M et al. Arthritis Rheumatol. 2020;72(8):1314-1324.[9]Hochberg M.C. Arthritis Rheum. 1997;40:1725.[10]Gladman DD et al. J Rheumatol. 2002;29(2):288-291.[11]Prevoo ML et al. Arthritis Rheum. 1995;38(1):44-48.Disclosure of InterestsNone declared
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Sanchez-Bilbao, L., J. Loricera, S. Castañeda, C. Moriano, J. Narváez, V. Aldasoro, O. Maiz et al. "POS0272 INTRAVENOUS VERSUS SUBCUTANEOUS TOCILIZUMAB IN A SERIES OF 471 PATIENTS WITH GIANT CELL ARTERITIS". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 379.2–380. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3260.
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BackgroundTocilizumab (TCZ) has shown efficacy in large-vessel vasculitis, including Giant Cell Arteritis (GCA) (1-3). Clinical trials with TCZ in GCA was performed with intravenous (iv) TCZ in a phase 2 trial (3), and with subcutaneous (sc) TCZ in the phase 3 GiACTA (4). However, in GCA there are no studies comparing IV vs SC TCZ.ObjectivesTo compare the efficacy of TCZ in GCA patients according to the route of administration IV-TCZ vs SC-TCZ.MethodsMulticentre study of 471 patients diagnosed with GCA and treated with TCZ. They were divided into 2 groups according to the route of administration: a) IV, and b) SC. GCA was diagnosed by: a) ACR criteria, and/or b) temporal artery biopsy, and/or c) imaging techniques. Sustained remission was established according to EULAR definitions (5).ResultsWe studied 471 patients (mean age, 74±9 years) treated with TCZ, 238 with IV-TCZ and 233 with SC-TCZ (Table 1). The time between diagnosis of GCA and TCZ onset was shorter in the SC TCZ group. Regarding acute phase reactants at the beginning of TCZ, no differences were found between both groups. There were no significant differences in sustained remission or in glucocorticoid-sparing effect of TCZ (Figure 1). Patients on IV TCZ treatment suffered more relevant adverse effects during follow-up.Table 1.Main characteristics of GCA patients treated with intravenous and subcutaneous tocilizumabIV TCZ (n= 238)SC TCZ (n=233)PBaseline characteristics at TCZ onsetAge(years), mean±SD73.3±8.773.7±9.30.63Sex, female/male (% female)175/63 (73)167/66 (72)0.65Time from GCA diagnosis to TCZ onset (months), median [IQR]8 [3-23.5]5 [2-15]0.016ESR, mm 1st hour, median [IQR]30.5 [12.5-53]28 [10-56.5]0.66CRP, mg/dL, median [IQR]1.4 [0.5-2.8]1.4 [0.4-4]0.92Prednisone dose, mg/day, median [IQR]20 [10-40]20 [10-36.2]0.69Safety after TCZ onsetFollow-up, (months), median [IQR]27 [16-44]14 [6-26.7]<0.001Relevant adverse events, n (%)80 (34)46 (19)<0.001Relevant adverse events per 100 patients-year12.715.2NSSerious infections, n (%)44 (18)21 (9)0.44Serious infections per 100 patients-year6.77.2NSMACEs, n (%)/1 (0.4)0 (0)-MACEs per 100 patients-year0.10NSMalignancies, n (%)4 (1.7)1 (0.4)0.20Malignancies per 100 patients-year0.60.3NSAbbreviations: CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; GCA: giant cell arteritis; IQR: interquartile range; IV: intravenous; MACEs: major adverse cardiovascular events; NS: non significant; SC: subcutaneous; SD: standard deviationConclusionIn GCA, TCZ seems equally effective and safe regardless of the route of administration IV or SC.References[1]Calderón-Goercke M, et al. Semin Arthritis Rheum. 2019; 49: 126-135. PMID: 30655091[2]Prieto-Peña D, et al. Ther Adv Musculoskelet Dis. 2021; 13: 1759720X211020917. PMID: 34211589[3]Villiger PM, et al. Lancet. 2016; 387:1921-1927. PMID: 26952547[4]Stone JH, et al. N Engl J Med. 2017; 377:317-328. PMID: 28745999Hellmich B, et al. Ann Rheum Dis. 2020; 79: 19-30. PMID: 31270110Disclosure of InterestsNone declared
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Wallick, S. C., I. S. Figari, R. E. Morris, A. D. Levinson e M. A. Palladino. "Immunoregulatory role of transforming growth factor beta (TGF-beta) in development of killer cells: comparison of active and latent TGF-beta 1." Journal of Experimental Medicine 172, n.º 6 (1 de dezembro de 1990): 1777–84. http://dx.doi.org/10.1084/jem.172.6.1777.
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Using recombinant DNA technology, we have generated Chinese hamster ovary (CHO) cell lines that synthesize latent transforming growth factor beta 1 (TGF-beta 1) to study immune regulation by TGF-beta 1. In vitro, latent TGF-beta 1 synthesized by transfectants or added exogenously as a purified complex after activation inhibited CTL generation to a similar extent as seen with acid-activated recombinant human (rHu) TGF-beta 1. In vivo, serum from nu/nu mice bearing CHO/TGF-beta 1 tumors contained significant levels of latent TGF-beta 1 in addition to depressed natural killer (NK) activity in spleens which paralleled that seen in C3H/HeJ mice treated with acid-activated rHuTGF-beta 1. rHuTGF-beta 1 treatment of mice receiving heart allografts resulted in significant enhancement of organ graft survival. Because of possible regulated tissue-specific activation, administration of latent rather than active TGF-beta may provide a better route to deliver this powerful immunosuppressive agent in vivo.
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Looijen, A., E. Van Mulligen, A. Van der Helm-van Mil e P. De Jong. "POS0669 TAPERING SUBCUTANEOUS METHOTREXATE CAUSES MORE DISEASE FLARES COMPARED TO ORAL ADMINISTRATION IN ESTABLISHED RHEUMATOID ARTHRITIS PATIENTS." Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 608.1–608. http://dx.doi.org/10.1136/annrheumdis-2022-eular.571.
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BackgroundThanks to improved treatment strategies, disease remission in rheumatoid arthritis(RA) patients has become more common. Therefore, current guidelines recommend to consider tapering DMARDs, including methotrexate(MTX), in patients who are in sustained remission. Previous research has shown that subcutaneous methotrexate(MTXsc) has a better bioavailability, efficacy and tolerability in active RA than oral MTX[1]. However, these advantages might be a disadvantage when tapering of MTXsc is considered.ObjectivesTo compare the 1-year cumulative flare rates between established RA patients who taper subcutaneous and oral MTX.MethodsData from the TApering strategies in Rheumatoid Arthritis(TARA) trial were used[2]. In this trial, established RA patients with a well-controlled disease, defined as Disease Activity Score(DAS)≤2.4 and swollen joint count(SJC)≤1, using ≥1 csDMARD and TNF-inhibitor(TNFi) were included. Participants were randomized into two groups which gradually tapered their csDMARD first followed by the TNFi, or vice versa. The csDMARD was tapered by reducing the dosage by a half at baseline, by a quarter at 3 months and was stopped at 6 months. Patients who tapered MTX were included in this analysis. If a disease flare(DAS>2.4 or SJC>1) occurred, the last effective therapy was restarted and intensified every 3 months, until DAS≤2.4 and SJC≤1.Following an intention-to-treat principle, flare rates were compared between patients who tapered subcutaneous and oral MTX, using a chi-square test. Two sensitivity analyses were performed were we 1) only included patients with a complete follow-up; and 2) assumed that patients developed a flare at the moment of drop-out.ResultsA total of 71 and 17 patients respectively used oral and subcutaneous MTX. The median disease duration was 5.9 years and 70% was female. The median MTX dosage for both administration routes was 20 milligrams per week.After 12 months, 53% of patients who tapered MTXsc developed a flare compared to 27% who tapered oral MTX (OR 3.1(1.0-9.1, 95%CI), p=0.037)(Figure 1). Respectively 68% and 67% of the patients who developed a flare and were using oral and subcutaneous MTX had a well-controlled disease 3 months after restarting their treatment(p=0.93). Both sensitivity analyses showed similar results.Figure 1.Flare development and resolution over time for different administration routes of methotrexate.The first part on the X-axis illustrates the cumulative % of patients that develop a disease flare during follow up, the second part illustrates the cumulative % of patients that still has active disease (DAS>2.4 +/ SJC44>1) from point of flare development and after restarting the last effective treatment.Abbreviations: DAS, Disease Activity Score; MTX, methotrexate; SJC44, swollen joint count measured in 44 joints.ConclusionPatients who tapered MTXsc have a higher chance at developing a disease flare compared to those who tapered oral MTX. This could be explained by a higher efficacy of MTXsc when similar dosages are used[1]. Alternatively, the better tolerability of MTXsc, especially regarding gastro-intestinal side effects[1], may lead to a difference in adherence.When deciding to taper MTX, the administration route should be taken into account. Because of the increased risk of flare after tapering MTXsc, these patients could be monitored more closely than those tapering oral MTX.References[1]Li D, Yang Z, Kang P, Xie X. Subcutaneous administration of methotrexate at high doses makes a better performance in the treatment of rheumatoid arthritis compared with oral administration of methotrexate: A systematic review and meta-analysis. Semin Arthritis Rheum. 2016 Jun; 45(6):656-662.[2]van Mulligen E, de Jong PHP, Kuijper TM, van der Ven M, Appels C, Bijkerk C, et al. Gradual tapering TNF inhibitors versus conventional synthetic DMARDs after achieving controlled disease in patients with rheumatoid arthritis: first-year results of the randomised controlled TARA study. Ann Rheum Dis. 2019 Jun; 78(6):746-753.Disclosure of InterestsNone declared
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KRISHNA, S., A. SHUKLA e R. P. MALIK. "COMMENTS ON THE DUAL-BRST SYMMETRY". Modern Physics Letters A 26, n.º 36 (30 de novembro de 2011): 2739–44. http://dx.doi.org/10.1142/s0217732311036899.
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In view of a raging controversy on the topic of dual-Becchi–Rouet–Stora–Tyutin (dual-BRST/co-BRST) and anti-co-BRST symmetry transformations in the context of four (3+1)-dimensional (4D) Abelian two-form and 2D (non-)Abelian one-form gauge theories, we attempt, in our present short note, to settle the dust by taking the help of mathematics of differential geometry, connected with the Hodge theory, which was the original motivation for the nomenclature of "dual-BRST symmetry" in our earlier set of works. It has been claimed, in a recent set of papers, that the co-BRST symmetries are not independent of the BRST symmetries. We show that the BRST and co-BRST symmetries are independent symmetries in the same fashion as the exterior and co-exterior derivatives are independent entities belonging to the set of de Rham cohomological operators of differential geometry.
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García-Rodríguez, Julio Cesar, e Iliana Sosa Teste. "The Nasal Route as a Potential Pathway for Delivery of Erythropoietin in the Treatment of Acute Ischemic Stroke in Humans". Scientific World JOURNAL 9 (2009): 970–81. http://dx.doi.org/10.1100/tsw.2009.103.
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Intranasal delivery provides a practical, noninvasive method of bypassing the blood-brain barrier (BBB) in order to deliver therapeutic agents to the brain. This method allows drugs that do not cross the BBB to be delivered to the central nervous system in a few minutes. With this technology, it will be possible to eliminate systemic administration and its potential side effects. Using the intranasal delivery system, researchers have demonstrated neuroprotective effects in different animal models of stroke using erythropoietin (EPO) as a neuroprotector or other different types of EPO without erythropoiesis-stimulating activity. These new molecules retain their ability to protect neural tissue against injury and they include Asialoerythropoietin (asialoEPO) carbamylated EPO (CEPO), and rHu-EPO with low sialic acid content (Neuro-EPO). Contrary to the other EPO variants, Neuro-EPO is not chemically modified, making it biologically similar to endogenous EPO, with the advantage of less adverse reactions when this molecule is applied chronically. This constitutes a potential benefit of Neuro-EPO over other variants of EPO for the chronic treatment of neurodegenerative illnesses. Nasal administration of EPO is a potential, novel, neurotherapeutic approach. However, it will be necessary to initiate clinical trials in stroke patients using intranasal delivery in order to obtain the clinical evidence of its neuroprotectant capacity in the treatment of patients with acute stroke and other neurodegenerative disorders. This new therapeutic approach could revolutionize the treatment of neurodegenerative disorders in the 21stcentury.
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Shukla, A., S. Krishna e R. P. Malik. "Augmented Superfield Approach to Nilpotent Symmetries of the Modified Version of 2D Proca Theory". Advances in High Energy Physics 2015 (2015): 1–21. http://dx.doi.org/10.1155/2015/258536.
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We derive the complete set of off-shell nilpotent and absolutely anticommuting Becchi-Rouet-Stora-Tyutin (BRST), anti-BRST, and (anti-)co-BRST symmetry transformations forallthe fields of the modified version of two(1+1)-dimensional (2D) Proca theory by exploiting the “augmented” superfield formalism where the (dual-)horizontality conditions and (dual-)gauge invariant restrictions are exploitedtogether. We capture the (anti-)BRST and (anti-)co-BRST invariance of the Lagrangian density in the language of superfield approach. We also express the nilpotency and absolute anticommutativity of the (anti-)BRST and (anti-)co-BRST charges within the framework of augmented superfield formalism. This exercise leads to somenovelobservations which have, hitherto, not been pointed out in the literature within the framework of superfield approach to BRST formalism. For the sake of completeness, we also mention, very briefly, a unique bosonic symmetry, the ghost-scale symmetry, and discrete symmetries of the theory and show that the algebra of conserved charges provides a physical realization of the Hodge algebra (satisfied by the de Rham cohomological operators of differential geometry).
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De la Torre Rubio, N., M. Pavía Pascual, J. Campos, J. Sanz, M. Machattou, P. Navarro Palomo, M. Alonso de Francisco et al. "AB1833-HPR STUDY OF THE DEMAND FOR REFERRALS FROM PRIMARY CARE TO THE RHEUMATOLOGY DEPARTMENT OF A TERTIARY HOSPITAL". Annals of the Rheumatic Diseases 82, Suppl 1 (30 de maio de 2023): 2148.1–2149. http://dx.doi.org/10.1136/annrheumdis-2023-eular.3995.
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BackgroundEPISER study has confirmed the great burden of rheumatic diseases, which represent almost 30% of primary care medical consultations in Spain[1,2]. Electronic consultation could be an alternative response[3]as well as rheumatologist-led update programmes and joint case discussion with primary care physicians have shown to reduce the burden of care and waiting times in rheumatology units[4].ObjectivesTo analyze the demand from primary care to the rheumatology service of a tertiary hospital.MethodsRetrospective descriptive study of the data consecutively collected from 15 to 30 May 2022 from new rheumatology consultations at the reference hospital requested from primary care (PC) health centers in the area. The following variables were collected: waiting time (median and range in days), referral route (ordinary, preferential or e-consultation), reason for derivation, type of visit (discharge or follow-up), suspicion of inflammatory disease by the specialist in Family and Community Medicine (Yes/No), confirmation diagnosis of inflammatory disease by the specialist in Rheumatology (Yes/No), time from onset of inflammatory symptoms to rheumatology consultation (median and range in months), referral with analytical tests (Yes/No/With acute phase reactants) and with musculoskeletal image requested by the PC physician (Yes/No); those provided by patients in private centers were excluded. Descriptive statistics were used for the presentation of results and Cohen’s Kappa coefficient was calculated to quantify the degree of agreement in the diagnosis of inflammatory disease between primary care physicians and rheumatologists.ResultsA total of 116 new consultations were registered in the system referring to 100 patients, 16 did not attend their appointment. Results are shown inTable 1. The degree of agreement according to Cohen’s Kappa index was 0.53, representing 80% of agreement (moderate degree). No differences were found between health care centers in the referral rate according to the population assisted by each health care center.ConclusionMain reasons for consultation were ‘osteoporosis assessment’ and ‘polyarthralgias’. Ordinary route was the most frequently used with a median waiting time of 80 days and 50 days for preferential route. Thirty percent of patients were referred with analysis and 75% with some musculoskeletal image. The degree of agreement was moderate in the diagnosis of inflammatory disease between primary care physicians and rheumatologists.References[1] Carmona L et al. The burden of musculoskeletal diseases in the general population of Spain: results from a national survey. Ann Rheum Dis 2001 -11;60(11):1040-1045.[2] Seoane-Mato D et al. Frequency of medical visits due to osteoarticular problems of the adult general population in Spain. EPISER2016 Study. Gac Sanit 2020 Sep - Oct;34(5):514-517.[3] Pego-Reigosa JM et al. Analysis of the implementation of an innovative IT solution to improve waiting times, communication with primary care and efficiency in Rheumatology. BMC Health Serv Res 2022 -01-12;22(1):60.[4] Surís X et al. A rheumatology consultancy program with general practitioners in Catalonia, Spain. J Rheumatol. 2007 Jun;34(6):1328-31.Table 1.Description of variablesWaiting time in days (median (range))OrdinaryPreferentiale-consultation79 (159)50 (150)35 (58)Referral route (%)OrdinaryPreferentiale-consultation73234Reason for derivation (%)OsteoporosisPolyarthralgiaArthrosisRheumatoid arthritisSpondyloarthritisFibromyalgiaGoutLow back painPolymyalgia rheumaticaPsoriatic arthritisRaynaud’s phenomenonOther221798854432119Type of visit (%)DsichargeFollow-up1882Suspicion of inflammatory disease by the specialist in Family and Community Medicine (%)38Confirmation diagnosis of inflammatory disease by the specialist in Rheumatology (%)20Time from onset of inflammatory symptoms to Rheumatology consultation in months (median (range))13 (44)Additional tests (%)Analysis (with PCR and VSG)Musculoskeletal image3175Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Albert, J., T. Hosey e B. Lamoreaux. "THU0431 PEGLOTICASE RESPONSE RATE IN UNCONTROLLED GOUT PATIENTS CO-TREATED WITH METHOTREXATE: EXPERIENCE IN A COMMUNITY RHEUMATOLOGY PRACTICE". Annals of the Rheumatic Diseases 79, Suppl 1 (junho de 2020): 453.2–454. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2076.
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Background:Pegloticase is an infused biologic approved to treat uncontrolled gout. The drug is highly effective, but patients can develop anti-drug antibodies that interfere with efficacy.1Randomized clinical trials have shown that 42% of patients treated with bi-weekly pegloticase had a serum uric acid (sUA) below 6.0 mg/dl at 3 and 6 months.2Mild-to-moderate immunomodulation has been shown to lower the prevalence of anti-drug antibody formation in patients with other autoimmune diseases (rheumatoid arthritis, Crohn’s disease, juvenile idiopathic arthritis).3Cases published in the literature suggest that low-to-moderate doses of methotrexate4,5or azathioprine6may also attenuate anti-pegloticase antibody formation in uncontrolled gout patients. Therefore, immunomodulation may allow patients to remain on pegloticase therapy longer and achieve a more complete therapeutic response.Objectives:To examine pegloticase treatment response in patients co-treated with methotrexate.Methods:This retrospective chart review included patients from a single community rheumatology practice who began pegloticase (8 mg every 2 weeks) therapy between January 2017 and September 2019 and were co-treated with methotrexate. Unless contraindicated, methotrexate co-treatment with pegloticase is now standard in this practice and all patients undergo close monitoring of laboratory parameters including serum uric acid level (sUA), blood counts, and liver function tests (LFTs). To maximize the number of cases, patients administered methotrexate in any form were included. Collected data included demographic information, laboratory values, methotrexate treatment parameters (timing with respect to pegloticase therapy, dose, route), pegloticase response parameters (number of infusions, duration of therapy), and adverse events. Main outcome measures included the number of pegloticase infusions administered (responder defined as ≥12 infusions administered) and therapy duration.Results:Ten patients (9 male) were included. All patients had visible tophi and average patient age was 52.3 ± 13.5 years. Nine patients began subcutaneous methotrexate (25 mg weekly) an average of 19.9 ± 7.0 days (range: 14 to 35 days) before the first pegloticase infusion. The remaining patient began oral methotrexate (12.5 mg weekly) 14 days after the first pegloticase infusion. Eight of 10 patients (80%) were considered responders, receiving an average of 15.5 ± 3.8 pegloticase infusions (range: 12-21 infusions) over 31.8 ± 9.5 weeks (range: 22.1 to 48.3 weeks). In these 8 responders, mean sUA was 0.2 ± 0.0 mg/dL immediately prior to the last pegloticase infusion. All 10 patients had an initial, rapid decrease in sUA, but two patients discontinued treatment before infusion 12. One patient had increased sUA with a mild infusion reaction, and one patient was lost to follow-up after infusion 5. No new safety concerns emerged. A gout flare occurred in 1 patient and was treated with prednisone. LFT and blood cell parameters were stable over the study period, except in two patients. One had a mild, transient LFT elevation that resolved without treatment, one had an LFT elevation and pancytopenia that improved with methotrexate discontinuation and transfusion, respectively. This patient remained on pegloticase and continued as a responder.Conclusion:This case series suggests that methotrexate, when used as a co-therapy with pegloticase, allows more patients to complete therapy and to achieve the full therapeutic response. No new safety concerns emerged.References:[1]Lipsky PE, et al.Arthritis Res Ther2014;16:R60.[2]Sundy JS, et al.JAMA2011;306:711-20.[3]Krieckaert CL, et al.Arthritis Res Ther2010;12:217.[4]Botson J and Peterson J.Ann Rheum Dis.2019; 78: A1289.[5]Bessen SY, et al.Semin Arthritis Rheum.2019;49:56-61.[6]Berhanu AA, et al.Semin Arthritis Rheum.2017;46:754-758.Disclosure of Interests: :John Albert Consultant of: Horizon Therapeutics, Speakers bureau: Horizon Therapeutics, Tony Hosey Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics
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Masri, K., K. Winterling e B. Lamoreaux. "THU0434 LEFLUNOMIDE CO-THERAPY WITH PEGLOTICASE IN UNCONTROLLED GOUT". Annals of the Rheumatic Diseases 79, Suppl 1 (junho de 2020): 454.3–454. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3891.
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Background:Pegloticase is a PEGylated biologic for uncontrolled gout that has well-established efficacy. However, anti-drug antibody (ADA) development causes many patients to discontinue treatment before receiving the full therapeutic course.1ADAs bind to the pegloticase molecule, leading to reduced therapeutic efficacy and discontinuation of therapy.2Emerging data indicates that co-treatment with pegloticase and immunomodulating agents may prevent ADA development, allowing more patients to receive a full course of treatment. Prior case reports describe the results of pegloticase treatment with methotrexate, azathioprine or cyclosporine3-6; however, the literature does not contain information on the use of leflunomide with pegloticase.Objectives:To evaluate overall pegloticase responder rate in uncontrolled gout patients co-treated with leflunomide.Methods:This retrospective study was conducted in a rheumatology practice where an immunomodulatory agent is typically used in conjunction with pegloticase. Patients co-treated with oral leflunomide (20 mg/day) and pegloticase (8 mg/infusion) were included. Extracted data included demographics, gout characteristics, pegloticase therapy parameters (serum uric acid [sUA], number of infusions), leflunomide therapy parameters (timing with respect to the first pegloticase infusion, dose, route), adverse events (e.g., gout flare, infusion reactions), and safety information (clinical laboratory parameters). Prior to each infusion all patients were administered a standard prophylaxis regimen of fexofenadine the night before and day of infusion, solumedrol day of infusion. The primary outcome was the proportion of pegloticase responders, defined as those receiving ≥12 infusions.Results:At data collection, 10 patients (5 male, 72.7 ± 12.5 years old, baseline sUA = 6.59 ± 3.15 mg/dL) had been co-treated with pegloticase and leflunomide. 4 patients (40%) received ≥12 infusions of pegloticase; 2 patients began treatment but were lost to follow-up, though neither of these patients experienced a rise in sUA during therapy. Of the 6 patients described, 4 met the primary outcome for a responder and 2 were lost to follow-up, resulting in 4/6 or 66% response rate. The 4 remaining patients had not reached their 12thinfusion at time of data cutoff and were ongoing with a mean of 8.0 ± 1.6 infusions (range: 6-10 infusions). No new safety concerns emerged. One patient had 3 gout flares during treatment and 1 patient required emergency care because of loss of consciousness and wooziness prior to pegloticase infusion due to pre-medication with solumedrol. No clinically meaningful laboratory value changes occurred, with the exception of a mild and transient ALT rise in 1 patient.Conclusion:Preliminary evidence suggests that low-to-moderate immunomodulation can minimize or prevent ADA formation against pegloticase and increase the number of patients fully benefitting from pegloticase. No prior studies have examined the effect of leflunomide on pegloticase responder rates. The current study indicates that oral leflunomide may be a viable immunomodulator for patients with uncontrolled gout undergoing pegloticase therapy.References:[1]Sundy JS, et al.JAMA, 2011;306(7):711-720[2]Lipsky PE, et al.Arthritis Res Ther2014;16:R60.[3]Botson J and Peterson J.Ann Rheum Dis.2019; 78: A1289.[4]Berhanu AA, et al.Semin Arthritis Rheum, 2017;46(6):754-758[5]Hershfeld MS, et al.Arthritis Res Ther, 2014;16(2):R63[6]Bessen MY, et al.Int J Clin Rheum, 2019;14(6):238-245Disclosure of Interests: :Karim Masri Shareholder of: Horizon Therapeutics, Corbus Pharmaceuticals, Gilead, Lineage Cell Therapeutics, Speakers bureau: Horizon Therapeutics, Pfizer, Novartis, Lilly, Kevin Winterling Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics
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Laino, M., M. Enguita, S. Castañeda, J. Loricera, C. Moriano, C. Lasa, V. Calvo-Río et al. "POS1142 SPANISH NATIONAL REGISTRY OF BELIMUMAB IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS". Annals of the Rheumatic Diseases 82, Suppl 1 (30 de maio de 2023): 899.3–901. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2650.
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BackgroundBelimumab (BLM) is a monoclonal antibody that inhibits B-lymphocyte stimulating factor (BlyS) approved as a specific treatment for systemic lupus erythematosus (SLE) in 2011. We present the experience with BLM in a Spanish cohort with more than 460 patients.ObjectivesTo describe demographic characteristics, efficacy and safety of BLM in patients with SLE in Spanish population since its approval.MethodsDescriptive, retrospective, multicenter study in patients diagnosed with SLE according to EULAR/ACR 2019, SLICC and/or ACR 1997 diagnostic criteria. Data regarding SLE patients treated with BLM were collected from medical records (2011-2022). Demographic features, efficacy, laboratory variables, SLEDAI, renal involvement, steroid dose, administration routes and safety were assessed. To see whether a trend in BLM prescription had changed or not over time, two periods of time were analyzed: 2011-2016 (period1) and 2017-2022 (period2).ResultsBaseline characteristics of patients are summarized in Table 1.A total of 462 patients (36 hospitals) were included, 50.9% were on intravenous (IV), 34% on subcutaneous (SC) and 15.1% switched from IV to SC route. The median number of pre-BLM csDMARD use was 2.0 (2.0-3.0), being hydroxychloroquine (HCQ) the most frequently used (94.5%). Fifty-two patients were treated with IV cyclophosphamide with a median of 6 bolus received. At the time of BLM start, 443 patients were on prednisone with a median dose of 6.2 mg (5.0-10.0). Significant decreases in prednisone dose, SLEDAI and anti-DNA antibodies were observed from baseline until the last visit, whereas complement C3 and C4 values raised (Figure 1). A total of 118 patients (27.4%) had renal involvement with a median proteinuria of 1.0 g/day (0.5-2.4). Renal biopsy was done in 102 out of 118 patients, being class IV (33%), class III (21%) and class V (16%) the most frequently reported. After BLM, 73.3% of these patients improved (median proteinuria of 0.2 g/day (0.1-0.7).In period1, 100 patients started BLM compared to 362 in period2. The median time from SLE diagnosis to BLM begin was 7.1 (4.0-13.7) and 6.2 (2.1 -14.4) years in period1 and period2, respectively (p=0.454). We found a trend to use more csDMARD before BLM treatment in period1: 2.5 (2-3) vs. 2 (2-3) (p=0.088).A total of 143 (30.5%) patients discontinued treatment mostly due to inefficacy (55.9%) and infections (11.9%). In fact, 116 patients developed infections, mostly mild; 2 patients died, 16 had COVID-19 and 4 patients developed tumors requiring discontinuation of the drug.ConclusionIn our cohort of SLE patients in a real-world setting, BLM has been effective, safe and seems to be a good choice to treat renal involvement.References[1]Navarra SV, Guzmán RM, Gallacher AE, et al. Lancet. 2011;377(9767):721-31.[2]Stohl W, Hiepe; rt al. Arthritis Rheum. 2012;64(7):2328-37.[3]Furie R, Rovin BH, Houssiau F, et al. N Engl J Med. 2020;383(12):1117-1128.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Syofiyardi, Syofiyardi, Riyadiyanto Riyadiyanto e Siti Maisarah. "Biodiversity in PT Pertamina Patra Niaga Fuel Terminal Sei Siak Mor 1 Sumbagut". International Journal of Social Service and Research 2, n.º 12 (24 de dezembro de 2022): 1299–309. http://dx.doi.org/10.46799/ijssr.v2i12.178.
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The areas of Tanjung Rhu and Limbungan villages are areas that are bordered by the Siak river. The existence of the Siak River in the Pekanbaru community is one of the connecting routes with other areas, as well as the entry of goods from within and outside the Pekanbaru area. Where there is the main port of the Daku River which is still used for its function today as transportation access. This transportation access has an impact on river abrasion. This study aims to acknowledge biodiversity condition in PT Pertamina. This study uses descriptive qualitative methods with data collection techniques, documentation studies, and in-depth interviews. The results of the study show that the condition of the Siak River in recent times has not received special attention from the government. PT Pertamina Patra Niaga Fuel Terminal Sei Siak highlights environmental aspects and the sustainability of biodiversity around the company's operations in order to be maintained and sustainable by initiating an Ecotourism program by planting mangrove seedlings, planting several types of trees and plants to reduce carbon dioxide and maintaining aquatic biota ecosystems. as well as the mainland. There are also animal conservation activities, namely the Serindit Bird to maintain endemic animal ecosystems in the Semut Island Ecotourism Area.
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Antonelli, David M., e Martin Cowie. "A convenient general route to a series of diphosphine-bridged heterobinuclear complexes that contain rhodium and structures of the mixed-valent complexes [RhM(CO)4(Ph2PCH2PPh2)2] (M = Mn, Re)". Organometallics 9, n.º 6 (junho de 1990): 1818–26. http://dx.doi.org/10.1021/om00156a022.
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Hebing, R., I. Muller, M. Lin, S. Mahmoud, S. Heil, W. Lems, M. Nurmohamed, R. De Jonge e G. Jansen. "AB0251 INCREASED ACCUMULATION OF ERYTHROCYTE METHOTREXATE POLYGLUTAMATES DURING EARLY PHASE SUBCUTANEOUS VERSUS ORAL METHOTREXATE TREATMENT OF RHEUMATOID ARTHRITIS PATIENTS". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 1151.1–1151. http://dx.doi.org/10.1136/annrheumdis-2021-eular.525.
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Background:Optimal dosing of methotrexate (MTX) for individual rheumatoid arthritis (RA) patients to achieve adequate disease control is an ongoing challenge. Assessment of erythrocyte MTX-polyglutamates (PGs) levels has been employed as a tool to monitor clinical response of RA patients in the first 3-12 months of treatment and MTX-PG2-4 and total MTX-PGs were associated with a lower DAS28 over 9 months.1 However, data from earlier time points, MTX-PG6 and per route of administration are unavailable.Objectives:To investigate the pharmacokinetics and -dynamics of erythrocyte MTX-PG accumulation in RA patients receiving oral or subcutaneous MTX in the early phase (1, 2, and 3 months) of MTX treatment initiation.Methods:In a clinical prospective cohort study (MeMo study (NTR7149)), newly diagnosed RA patients were administered oral (n=24) or subcutaneous (n=22) MTX, mostly according to the COBRA-light schedule (start 10 mg MTX, increased to 25 mg MTX in 8 weeks). At 1, 2, and 3 months after start of therapy, blood was collected and individual MTX-PGs (MTX-PG1 – MTX-PG6) were analyzed in erythrocytes at a minimal detection limit of 1 nmol/L, using a validated UHPLC-MS/MS method with labeled internal standards.1 Dosing, concomitant treatments and DAS28-ESR assessments were in conformity with clinical practice. Adverse events were recorded.Results:46 consecutive patients were included in this study; 76% female, mean age: 57.8 years, BMI: 25.8, 20% smokers, mean baseline DAS28-ESR: 3.5. Notwithstanding marked interpatient variability, patients starting subcutaneous MTX had accumulated significantly higher (approximately 2-fold) long chain MTX-PGs (MTX-PG4-6) when compared to patients in the oral MTX group at 1 and 2 months (Figure 1A, Table 1). Similarly, MTX-PG1-6 and MTX-PG3 accumulation were higher in subcutaneous MTX-users at month 1 (p=0.022 and p=0.011) compared to the oral group (median 68.6 nmol/L (IQR:40.5) vs 51.9 (55.6) and 17.4 (11.1) vs 11.2 (15.6), respectively (Figure 1B, Table 1).Table 1.Linear regression of MTX-PG levels and administration route, corrected for age, baseline DAS28, smoking, BMI, eGFR and MTX dose.monthß (P-value)1ß (P-value)2ß (P-value)3MTX-PG1-61.65 (0.022)1.51 (0.073)1.30 (0.233)MTX-PG1,21.13 (0.599)1.19 (0.470)1.12 (0.623)MTX-PG31.75 (0.011)1.51 (0.071)1.19 (0.439)MTX-PG4-61.97 (0.036)2.04 (0.033)1.55 (0.136)Mean MTX dose at baseline was 10.5mg (SD 1.5) for both groups, 15.4 (4.4) and 16.8 (1.8) at 1 month and 22.8 (3.9) and 22.4 (5.2) at 2 months for oral and subcutaneous use respectively.DAS28 decreased with 1.6 in the oral group and 1.1 in the subcutaneous group (p=0.382). With and without corrections for age, baseline DAS28, eGFR, MTX dose (1 month before sampling), smoking and BMI, no significant relation between MTX-PG concentrations and DAS28 was observed during the first 3 months of treatment.43 patients reported any side effect, mostly headache and dizziness, which was similar in both groups and uncorrelated with MTX-PG levels.No association was found between MTX-PG1 levels and number of days between timing of blood withdrawal and last administration.Figure 1.Erythrocyte long chain MTX-PG(A) and total MTX-PG(B) accumulation in RA patients of the first 3 months of oral(C) or subcutaneous(D) MTX administration. At 3 months, 18 patients using oral and 18 patients using subcutaneous MTX were still continuing MTX treatment. Medians and IQR are depicted.Conclusion:This study shows the feasibility of measuring erythrocyte MTX-PGs early on in the treatment of RA patients with MTX and demonstrated significantly higher accumulation of MTX-PGs following subcutaneous versus oral MTX administration. Early phase erythrocyte MTX-PG analyses may hold potential for positioning in optimizing individual patient MTX dose scheduling.References:[1]de Rotte MC, et al. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis. Ann Rheum Dis 2015(74):408-14.Acknowledgements:We would like to thank all participating patients and Pfizer (grant 53233663 / WI230458).Disclosure of Interests:Renske Hebing Grant/research support from: Pfizer, Ittai Muller: None declared, Marry Lin: None declared, Sohaila Mahmoud: None declared, Sandra Heil: None declared, WIllem Lems: None declared, Michael Nurmohamed: None declared, Robert De Jonge: None declared, Gerrit Jansen: None declared
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Hebing, R., M. Lin, E. Struys, S. Mahmoud, I. Muller, W. Lems, B. van den Bemt, G. Jansen, R. De Jonge e M. Nurmohamed. "AB0061 PHARMACOKINETICS OF METHOTREXATE POLYGLUTAMATES IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF RA PATIENTS IS SIMILAR AFTER SUBCUTANEOUS OR ORAL ADMINISTRATION IN THE METHOTREXATE MONITORING (MeMo) TRIAL". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 1164.2–1164. http://dx.doi.org/10.1136/annrheumdis-2022-eular.781.
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BackgroundPharmacokinetics of methotrexate (MTX) after oral and subcutaneous administration to RA patients differs: MTX levels in plasma and MTX-polyglutamate (MTX-PG) accumulation in erythrocytes are higher during equidosed subcutaneous compared to oral MTX treatment. (1,2) No data are available whether administration route of MTX differentially impacts the intracellular concentrations of MTX-PGs in peripheral blood mononuclear cells (PBMCs) during MTX therapy.ObjectivesTo investigate the pharmacokinetics of MTX-PGs in PBMCs of newly diagnosed RA patients receiving oral or subcutaneous MTX in the early phase (1, 2, 3 and 6 months) of MTX treatment.MethodsIn a clinical prospective cohort study (MeMo study (NTR7149)), RA patients wereadministered oral (n=24) or subcutaneous (n=22) MTX up to 25 mg MTX/week, as described before. (1) At 1, 2, 3 and 6 months after the start of therapy, PBMCs were isolated via Ficoll density gradient centrifugation. Individual MTX-PG forms (MTX-PG1-6) in PBMCs were analyzed by a UPLC-MS/MS method including custom-made stable isotopes of MTX-PG1-6 as internal standards (3). UPLC-MS/MS measurements of the PBMCs were performed with a Waters Acquity BEH C18 column coupled to an AB Sciex 6500+ with the ESI operating on the positive mode. Dosing, concomitant treatments and DAS28-ESR assessments were in conformity with clinical practice. (4)Results46 consecutive patients were included in this study; 76% female, mean age: 57.8 years, BMI: 25.8, smokers: 20%, mean baseline DAS28-ESR: 3.5, as described before. (1) MTX dose at baseline was 10.5 mg (SD: 1.5) for both groups, 15.4 mg (4.4) and 16.8 mg (1.8) at 1 month, 22.8 mg (3.9) and 22.4 mg (5.2) at 2 months, 20.1 mg (6.3) and 20.8 mg (5.6) at 3 months, and 19.7 mg (6.1) and 18.5 mg (6.7) at 6 months for oral and subcutaneous use, respectively. MTX-PG analyses in PBMCs for individual and total MTX-PGs revealed no significant differences between oral and subcutaneous administration groups at 1, 2, 3, and 6 months (Figure 1). Linear regression of LN transformed MTX-PG levels in PBMCs and administration route, corrected for age, baseline DAS28, smoking, BMI, eGFR and MTX dose, showed a trend towards higher MTX-PG levels in PBMCs after subcutaneous MTX administration compared to oral administration (data not shown). MTX-PG distribution in PBMCs was mainly composed of MTX-PG1 (58%), and to a lesser extent MTX-PG2 (27%) and MTX-PG3 (15%). Longer chain MTX-PGs beyond MTX-PG4 were detectable in PBMCs, but at levels lower than MTX-PG1-3 (mean: 4.0 – 6.7 fmol/106 cells). Total MTX-PG accumulation in PBMCs was approximately 10-20 fold higher than in erythrocytes. PBMC accumulation was rather stable, whereas RBC MTX-PG accumulation increased between 1 to 3 months to reach a plateau (Figure 1).Figure 1.Loess regression of MTX-PG concentrations in PBMCs (MTX-PG1-3) and RBCs (MTX-PG1-6) of RA patients during the first 6 months of oral or subcutaneous MTX administration. At 6 months, 18 patients using oral and 18 patients using subcutaneous MTX were still continuing MTX treatment. Means (lines) and SE (grey areas) are depicted.ConclusionThis study demonstrated that MTX-PG accumulation in PBMCs early on in the MTX treatment of RA patients was not significantly different between oral or subcutaneous MTX administration routes.References[1]RCF Hebing et al, Arthritis Rheum (2021); 60:339-348[2]M Hoekstra et al, J Rheumatol (2004); 31:645-8[3]E Den Boer et al, Anal Bioanal Chem (2013); 405: 1673-1681[4]J Smolen et al, Ann Rheum Dis (2020); 79:685-699AcknowledgementsWe would like to thank all participating patients and Pfizer (grant 53233663 / WI230458), NVKC (Noyons grant) and AmsterdamUMC (AI&II extension grant).Disclosure of InterestsRenske Hebing Grant/research support from: Pfizer, grant number 53233663 / WI230458, Amsterdam UMC (AI&II extension grant), NVKC (Netherlands Society for Clinical Chemistry, Noyons grant), Marry Lin: None declared, Eduard Struys: None declared, Sohaila Mahmoud: None declared, Ittai Muller: None declared, WIllem Lems: None declared, Bart van den Bemt Speakers bureau: Pfizer, UCB, Sanofi-Aventis, Galapagos, Amgen and Eli Lilly, Gerrit Jansen: None declared, Robert De Jonge Grant/research support from: NVKC (Netherlands Society for Clinical Chemistry, Noyons grant), Michael Nurmohamed Grant/research support from: Pfizer grant
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Prendiville, J., N. Thatcher, M. Lind, R. McIntosh, A. Ghosh, P. Stern e D. Crowther. "Recombinant human interleukin-4 (rhu IL-4) administered by the intravenous and subcutaneous routes in patients with advanced cancer—A phase I toxicity study and pharmacokinetic analysis". European Journal of Cancer 29, n.º 12 (janeiro de 1993): 1700–1707. http://dx.doi.org/10.1016/0959-8049(93)90108-r.
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Da Silva, Daniella Matos, Eneida Janiscki Da Lozzo, Dorly de Freitas Buchi, Carolina De Oliveira e Simone Domit Guérios. "Oral, topical, and inhalation of Calcarea carbonica derivative complex (M8) to treat inflammatory mammary carcinoma in dogs". International Journal of High Dilution Research - ISSN 1982-6206 11, n.º 40 (21 de dezembro de 2021): 166–67. http://dx.doi.org/10.51910/ijhdr.v11i40.594.
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Background: Inflammatory mammary carcinoma (IMC) is locally aggressive, fast growing, highly malignant tumor that affects humans and dogs. Affected dogs usually are presented with generalized edema, pain, erythema, and skin ulceration in mammary glands. Surgery is not recommended and an effective treatment has not been established [1]. Calcarea carbonica derivative complex (M8) has demonstrated anticancer properties in a murine model, by improving innate immune response against tumor cells [2]. M8 is a complex high diluted medication comprised of Calcarea carbonica 16x, Aconitum napellus 20x, Arsenicum album 18x, Asa foetida 20x, Conium maculatum 17x, Ipecacuanha 13x, Phosphorus 20x, Rhus toxicodendron 17x, Silicea 20x, Sulphur 24x, and Thuya occidentalis 19x, dilution procedures have followed standard methodology described at the Brazilian Homeopathic Pharmacopoeia.
Aims: To describe different routes of M8 administration associated with oral pyroxican (non-steroidal anti-inflammatory drug) to treat dogs with IMC.
Methodology: Three female dogs with 10 years old median age were presented to the Veterinary Teaching Hospital at Federal University of Parana, Curitiba (HV-UFPR) with cytological and clinical diagnosis of IMC. Patients were treated with oral (0.5 mL,q12h), topical (q12h) and inhalatory (2 mL, q24h, through an ultrasonic inhalation device) M8, and oral pyroxican (0.3mg/kg, q24h).Thoracic radiographs showed pulmonary metastasis in all dogs.
Results: 7 days after initiating treatment all patients had clinical improvement. It was observed reduction on mammary glands inflammation and decreased pain sensitivity. One patient had 8 month of complete remission. The other two patients died 1 and 2 month after initial treatment. However none of the patients had pulmonary progressive disease, showed by radiographic examinations. Owners revealed treatment satisfaction in regards to quality of life improvement, easy M8 administration, good M8 palatability for dogs, and inflammation reduction.
Conclusion: The present report suggests that M8 influenced positively the anti -inflammatory treatment.
Keywords: Calcarea carbonica complex; inflammatory mammary carcinoma; routes of administration
References
[1] Sorenmo K. Canine mammary gland tumors. Veterinary Clinics of North America: Small Animal Practice. 2003 33(3):573-96.
[2] Oliveira CC, Abud APR, Oliveira SM, Guimarães FSF, Andrade LF, Di Bernardi RP, Coletto ELO, Kuczera D, Da Lozzo EJ, Gonçalves JP, Trindade ES, Buchi DF. Developments on drug discovery and on new therapeutics: highly diluted tinctures act as biological response modifiers. BMC Complementary and Alternative Medicine 2011, 11(101): 2-11.
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Rouse, P., T. Ingram, M. Standage e R. Sengupta. "POS0207-HPR FEAR OF MOVEMENT MEDIATES THE RELATIONSHIP BETWEEN PAIN CATASTROPHISING AND PHYSICAL FUNCTION IN PEOPLE LIVING WITH AXIAL SPONDYLOARTHRITIS: A CROSS-SECTIONAL MEDIATION ANALYSIS". Annals of the Rheumatic Diseases 82, Suppl 1 (30 de maio de 2023): 329.2–330. http://dx.doi.org/10.1136/annrheumdis-2023-eular.662.
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BackgroundAxial spondyloarthritis (axSpA) typically affects the axial skeleton and sacroiliac joints causing patients to experience pain, reduced movement, and impaired physical function. A range of treatment options are available to help axSpA patients reduce pain and maintain physical function and thereby enhance health-related quality of life. The European Alliance of Associations for Rheumatology (EULAR) identified activity as integral to the management of inflammatory arthritides, however, the majority of people living with axSpA are not sufficiently active to maintain physical function [1]. According to the Fear-Avoidance Model of Pain, fear of movement and pain catastrophizing contribute to poorer physical function via reduced activity and disuse [2]. Yet to date, no research has tested the theorized mediating role of fear of movement in the relationship between pain catastrophizing and physical function in people living with axSpA.ObjectivesTo examine the mediating role of fear of movement in the relationship between pain catastrophizing and physical function in people living with axSpA.MethodsParticipants (N= 98, 70% female,MAge = 45.62 SD 12.16) completed an online survey (December 2020 – May 2021) distributed in the United Kingdom via the National Axial Spondyloarthritis Society (n ≈ 3,500; NASS, 2019). The Tampa Scale for Kinesiophobia (TSK-11) was used to measure fear of movement with participants rating 11-items from 1 (strongly disagree) to 4 (strongly agree). The Pain Catastrophising Scale (PCS) contains 13-items, each rated on a scale from 0 (not at all) to 4 (all the time). Both instruments have shown strong internal consistency in people living with axSpA [3,4]. The Bath Ankylosing Spondylitis Functional Index (BASFI) was used to assess physical function with higher scores indicating poorer function. Data were analysed using IBM SPSS (Version 28). The PROCESS SPSS macro was used, and interpretation made using the percentile bootstrap 95% confidence intervals from 5000 bootstrap samples. Standardised effects with values.01,.09, and.25 represent small, medium, and large effects [5].Results:Table 1.Descriptive statistics and Bivariate correlations for the variables.MSD231Pain Catastrophizing18.3413.65.647**.419**2Fear of Movement24.997.22.414**3Physical Function3.732.59Bivariate correlations showed pain catastrophizing to have a significant medium and positive relationship with physical function and a large positive relationship with fear of movement. Mediation analysis (F= 12.67,p<.05,R2=.21) revealed that pain catastrophizing had a large positive direct effect on physical function (β=.259) and fear of movement (β=.647). Fear of movement had a large positive direct effect on physical function(β=.246).A significant medium and positive indirect effect of pain catastrophising on physical function via fear of movement was observed(β=.160, CI =.002 -.320).ConclusionPain catastrophizing is experienced by people living with axSpA and can lead to the avoidance of movement, and as a result, compromised physical function. Our test of the Fear-Avoidance Model showed that pain catastrophizing significantly predicted the physical function of people living with axSpA and that this relationship was mediated by fear of movement. Fear of movement is a modifiable construct that can be a treatment target for health professionals to improve the physical function of people living with axSpA. Identifying modifiable factors that contribute to disease outcomes is critical to improve the care and quality of life for people living with a disease currently without a cure.References[1]O’Dwyer T, O’Shea F, Wilson F. Rheum Int. 2015; 35(3):393-404.[2]Vlaeyen JW, Linton SJ. Pain. 2012; 153(6):1144-1147.[3]Swinnen TW, Vlaeyen JWS, Dankaerts W, Westhovens R, de Vlam K. J of Rheum. 2018; 45(3):357-366.[4]Kieskamp SC, Paap D, Carbo MJ, Wink F, Bos R, Bootsma H, et al. Rheum. 2021; 60(10):4476-4485.[5]Cohen J. Psych Bull; Citeseer; 1992.AcknowledgementsWe thank the Bath Institute for Rheumatic.Diseases (BIRD) for funding to support this research.Disclosure of InterestsPeter Rouse: None declared, Thomas Ingram: None declared, Martyn Standage: None declared, Raj Sengupta Speakers bureau: Abbvie, Biogen, Celgene, Lilly, Novartis, Roche, UCB, Consultant of: Advisory boards for Abbvie, Biogen, Lilly, Novartis, UCB, Grant/research support from: Yes - Abbvie, Celgene, Novartis, UCB.
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Soloviev, Vladimir Olegovich. "Two Approaches to Hamiltonian Bigravity". Universe 8, n.º 2 (12 de fevereiro de 2022): 119. http://dx.doi.org/10.3390/universe8020119.
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Bigravity is one of the most natural modifications of General Relativity (GR), as it is based on the equivalence principle. However, its canonical structure appears rather complicated because of the unusual form of the interaction between two metrics. As a consequence, there are different approaches that are difficult to compare in detail. This work is a first attempt to obtain a synthetic picture of the Hamiltonian formalism for bigravity. Here, we are trying to combine two rather different approaches to gain a binocular view of the theory. The first publications on the subject were based on metric formalism. It was proved that both massive gravity and bigravity with de Rham–Gabadadze–Tolley (dRGT) potential were free of Boulware–Deser (BD) ghosts. This proof was based on the transformation of variables involving a 3×3-matrix which could be treated as the root of a quadratic equation involving two spatial metrics and a new 3-vector introduced instead of the standard shift variable. Therefore, this matrix occurred as an implicit function of the abovementioned variables. After a substantial amount of time, it became possible to calculate the algebra of constraints in full using this method. However, in another approach also based on metric variables and implicit functions, similar calculations were completed earlier. It is not a new matrix, but the potential itself has been taken as an implicit function of two spatial metrics and four functions constructed of two pairs of lapses and shifts. Finally, a straightforward route to canonical bigravity is to apply tetrad (or vierbein) variables. The matrix square root involved in the dRGT potential can be explicitly extracted if tetrads fulfill the symmetry condition. A full treatment has been developed in first-order formalism by treating tetrads and connections as independent variables. In that case, the theory contains many more variables and constraints than in metric formalism. An essential simplification occurs in second-order vierbein formalism. The potential is given explicitly as a polynomial of bilinear combinations of the two tetrads. The 3×3-matrix introduced in the pioneer papers can be expressed explicitly through canonical coordinates, and the celebrated transformation of variables arises in the Dirac constraint analysis.
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Money, John. "Provincialism and The English “Ancien Regime”: Samuel Pipe-Wolferstan and “The Confessional State,” 1776–1820". Albion 21, n.º 3 (1989): 389–425. http://dx.doi.org/10.2307/4050087.
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Imagine, if you will, a ship at sea. At a distance, it could be Jason and the Argonauts, or the Flying Dutchman, or even Captain Ahab. By the cut of its jib as it looms out of the mist, however, it seems rather to be a sieve, such as that in which the Jumblies once put forth. On the poop, sextant in hand, his grizzled features set in Churchillian grimace but instantly recognizable by the ancient Connecticut watchcap which tops them, stands—no, not Walter Mitty—but Hexter the Navigator. As a veteran of many earlier voyages, real and imaginary, he has a longer memory than his shipmates. He thinks this is a Liberty Ship, and he is trying to chart the course laid out in the sailing instructions, originally constituted by a long line of sea-lawyers and perfected by Victorian hydrographers. Right forrard, another ancient mariner, of the kind the lower deck calls Three-badge Killick (a leading seaman of long service who has never made it to Petty Officer), swings the lead. He is Plumb. In the crow's nest, bo'suns Tawney and Hill stand watch with their mates Stone and Thompson. As boy seamen long ago, they, too, were brought up on the old sailing instructions; but having, before the present voyage, served in capital ships, they consider that they have progressed far beyond such common lore. So wise are they indeed that they are convinced that this, too, is a Capital Ship, which, as everybody knows, can only sail forwards, and can therefore have only one destination. In the rigging, the rest of the fo'csle hands, a rabble of cabin boys and greenhorns press-ganged in 1968, who have barely passed for able seaman and still need the old guard to show them the ropes, likewise scan the horizon for the inevitable landfall and keep a weather eye open for that ill-omened denizen of these waters, Namier's Albatross. The intrepid helmsman, however, just as young but experienced beyond his years, knows better. Apprenticed to a line of tars that stretches back to old admiral Clarendon, he has learnt his craft the hard way, at the rope's end, and he has very little use for the sailing instructions of Liberty Ships or the great circle routes programmed, rhumb line by reductionist rhumb line, into the automatic pilots of their capital counterparts. He is Revisionist, a most unteleologic Ulysses, content (the journey not Ithaca's the thing) to sail his narrative barque (Narrenschiff?) before the winds of change for ever. Only one thing jars this whimsical homeric simile. Proof though he is against Circe and her reifications, our Ulysses has still his achilles' heel. Perhaps because he has come up through the hawse-hole himself, he has occasional bouts of nautical nostalgie de la boue: like Bertram, the sociologist of the sea in “Dry Cargo,” the Navigator's hoary parable on Doing History (another time, another voyage), he itches to pull on a pair of footnotes, go below and sample the bilgewater which, this being after all a sieve, slops around the hold.
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Pendolino, M., T. Serban, D. Camellino, P. Diana, A. Giusti e G. Bianchi. "AB0499 STEP-DOWN APPROACH IN METHOTREXATE USE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS (STEMETRA): A PILOT STUDY DEMONSTRATING EFFICACY AND SAFETY OF SHORT-TERM HIGH DOSE METHOTREXATE". Annals of the Rheumatic Diseases 82, Suppl 1 (30 de maio de 2023): 1444–45. http://dx.doi.org/10.1136/annrheumdis-2023-eular.5648.
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BackgroundMethotrexate (MTX) is the cornerstone of Rheumatoid Arthritis (RA) treatment, showing a suitable efficacy-safety profile, relatively low-cost, and versatile routes and dosage administration. However, there are no clear indications yet on the optimal use of MTX in RA, whereas existing recommendations disagree on relevant aspects (eg. route, starting and maximal dose, titration increase/decrease, and intervals to monitor toxicity) [1].ObjectivesTo evaluate the efficacy and the safety of a step-down strategy to use subcutaneous (sc) MTX in patients with RA.MethodsSTEMETRA is a 16-week open-label, monocentric, pilot study. The protocol treatment schedule consisted of the administration of MTX 50 mg sc/week for 4 consecutive weeks, followed by 25 mg/week for 4 weeks, and then 15 mg/week for 4 weeks. All patients received oral supplementation of folinic acid (leucovorin) 12 mg, 12 hours after the injection of MTX.ResultsFifteen patients (10 females and 5 males; mean age, 60 years (±11)) diagnosed with RA according to 2010 ACR/EULAR classification criteria and naïve to any RA treatment were enrolled. One patient was lost to follow-up after week 12; 4 patients withdrew because of adverse events; therefore, 10 patients concluded the study. A total of 14 adverse events occurred in 7 patients; 7 were of mild entity and tolerated by patients, 3 solved, and 4 were persistent and lead to withdrawal of the drug (Table 1). Mean DAS28(CRP) at baseline was 5.6 (±1.4), whereas, at week 16, mean DAS28(CRP) was 1.6(±1). Most patients who concluded the study achieved ACR70 response and the state of remission (7 out of 10), whereas 3 still showed moderate disease activity.ConclusionIn this study, step-down MTX approach was effective in inducing remission in most of the patients enrolled. According to data reported in other studies (2,3), one third of them showed adverse events leading to the withdrawal of the drug. On the contrary, different studies in which MTX was used as in current clinical practice (at lower dosages) showed lower efficacy: in the ORAL START study, ACR70 response was reached only in 12% of naïve patients 6 months after MTX monotherapy (4), whereas in the PREMIER study, 26% of patients receiving MTX monotherapy obtained ACR70 response after one year [5]. Thus, short-term higher dose MTX usage could be more effective in order to reach remission earlier. Nonetheless these results should be confirmed in larger populations of patients. In conclusion, this approach could be considered as a valid regimen for a more optimal use of MTX.References[1]Valerio V, Kwok M, Loewen H, et al. Clin Rheumatol. 2021 Apr;40(4):1259-1271. PMID: 32876784[2]Due E, Blomberg M, Skov L, et al. Acta Derm Venereol. 2012 Jul;92(4):353-4. PMID: 22001863[3]Bassel K. El-Zorkany, Sherif M. Gamal, et al. The Egypt Rheumatol Vol 35, Issue 2, 2013, Pages 53-57,https://doi.org/10.1016/j.ejr.2013.01.003[4]Lee EB, Fleischmann R, Hall S, et al. N Engl J Med. 2014 Jun 19;370(25):2377-86. PMID: 24941177[5]Breedveld FC, Weisman MH, Kavanaugh AF, et al. Arthritis Rheum. 2006 Jan;54(1):26-37. PMID: 16385520Table 1.Adverse eventsADVERSE EVENTN (%)Grade/withdrawal (week of appearance)Headache1 (6.6)Mild (W4)Cutaneous local reaction1 (6.6)Mild (W4)Nausea2 (13.3)Mild (W4)Diarrhoea1(6.6)Moderate/Withdrawal (W8)Lack of appetite1 (6.6)Mild (W8)Dizziness1 (6.6)Moderate/Withdrawal (W12)Fatigue2 (13.3)Mild (W16)Urinary tract infection4 (24)Moderate/Withdrawal (2 out of 4 patients) (W12)Moderate (2 out of 4 patients) (W4)Increased transaminases1 (6.6)Moderate (W2, solved in W8) – alcohol abuseFigure 1.Percentage of patients in ACR response.*W12: total patients: 14. *W16: total patients: 10 patientsAcknowledgements:NIL.Disclosure of InterestsNone Declared.
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Mouna, G., M. Jguirim, N. Benchekaya, S. Zrour, I. Bejia, M. Touzi e N. Bergaoui. "AB0871 Factors associated with radiographic hip involvement in ankylosing spondylitis". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 1558.2–1558. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4851.
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BackgroundHip involvement is a classic feature of ankylosing spondylitis (AS). It causes functional impairement and disability in patients with AS. Although, many studies have looked at factors associated with radiographic hip involvement, these remain debated.ObjectivesTo define the factors associated with radiographic hip involvement in patients with AS.MethodsA cross-sectional comparative study of 105 patients was performed. Hip involvement was defined as hip pain considered related to AS inflammation and confirmed radiographically. The patients were classified into two categories: (1) no hip involvement, (2) hip involvement according to a Bath Ankylosing Spondylitis Radiology Index (BASRI)-hip score ≥2. Multivariate logistic regression analyses were used to identify the factors associated with radiographic hip involvement.ResultsFifty-three patients had radiological hip involvement and 52 patients were whithout hip involvement. Multivariate logistic regression analyses showed male sex (OR 6.383 IC 1.553-26.29, p=0.010), Bath Ankylosing Spondylitis Functional Index (BASFI) score (OR 1.436, IC 1.079-1.913, p=0.013), and BASRI-spine score (OR 1.456, IC 1.190-1.783, p<0.001) to be significantly associated with radiographic hip involvement, and an inverse relation-ship with age at onset (OR 0.955, IC 0.995-0.998, p=0.038) was seen.ConclusionMale sex, younger age at onset, worse BASFI score and worse BASRI-spine score are associated with radiographic hip involvement. AS patients with risk factors for radiographic hip involvement should be diagnosed at an early stage to improve their quality of life.References[1]Zhao J, Zheng W, Zhang C, Li J, Liu D, Xu W. Radiographic hip involvement in ankylosing spondylitis: factors associated with severe hip diseases. J Rheumatol. 2015 Jan;42(1):106-10.[2]Burki V, Gossec L, Payet J, Durnez A, Elhai M, Fabreguet I, Koumakis E, Meyer M, Paternotte S, Roure F, Dougados M. Prevalence and characteristics of hip involvement in spondyloarthritis: a single-centre observational study of 275 patients. Clin Exp Rheumatol. 2012 Jul-Aug;30(4):481-6. Epub 2012 Aug 29.[3]Chen HA, Chen CH, Liao HT, Lin YJ, Chen PC, Chen WS, et al. Factors associated with radiographic spinal involvement and hip involvement in ankylosing spondylitis. Semin Arthritis Rheum 2011;40:552-8.Disclosure of InterestsNone declared
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Mahroug, M., H. Azzouzi, H. Boutaibi, O. Lamkhanat e I. Linda. "AB0274 METHOTREXATE INTOLERANCE IN MOROCCAN RHEUMATOID ARTHRITIS PATIENTS". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 1162.4–1163. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3315.
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Background:Methotrexate intolerance is a principal reason for treatment discontinuation, hence the interest in a more in-depth study.Objectives:We aimed to study the prevalence of methotrexate gastrointestinal intolerance and determine its associated factors in rheumatoid arthritis (RA) patients.Methods:We designed a cross-sectional study on our RA patients recruited in January 2021 at our rheumatology department. Methotrexate Intolerance Severity Score (MISS) [1], previously validated in juvenile idiopathic arthritis patients, was used to determine methotrexate (MTX) intolerance prevalence in RA patients. The MISS consisted of four domains: abdominal pain, nausea, vomiting, and behavioral symptoms, occurring before (anticipatory), after, and when thinking of MTX (associative). MTX intolerance was defined as six or more points on the MISS. Our statistical analysis was based on a descriptive study and logistic regression with SPSS20.Results:We included 102 RA patients with a mean age of 51.60 ± 14.33 years, Women were predominant (93.1%). The mean disease duration was 14.86 ± 9.78 years, with a mean methotrexate use duration of 7.42 ± 6.44 years. The mean dose of methotrexate was 12.13 ± 9.06 mg per week. The prevalence of methotrexate intolerance was 55.9%, and seventy-six patients (74.5 %) experienced at least one gastrointestinal symptom during MTX treatment. After MTX administration, the most prevalent gastrointestinal symptom was nausea (93% of the intolerant patient), whereas abdominal pain occurred in 73.7% and vomiting in 57.9%. These symptoms were also prevalent before and when thinking of MTX. Anticipatory nausea was reported in 45.6% and associative nausea in 54.5% of the cases, abdominal pain occurred anticipatory in 22.8% and associative in 42.1 %, anticipatory vomiting was the least prevalent, affecting 8.8 %. Behavioral symptoms affected 87.7% of intolerant patients, with restlessness being the most prominent symptom in 71.9% of them. Among the intolerant patients, 45 patients (79%) took parenteral MTX, and 12 (21.1%) took methotrexate orally. In comparison, young patients (49.11 ± 14.95 years) were more intolerant to MTX than old (54.76 ± 13 years, p = 0.048) ones. However, in univariate logistic regression analysis, we did not find any significant association between methotrexate administration route, dose, duration, and digestive intolerance.Conclusion:Methotrexate intolerance was highly prevalent in our RA population. These results strengthen the idea that early detection of MTX intolerance may avoid effective treatment discontinuation, especially in younger patients.References:[1]Bulatović M, Heijstek MW, Verkaaik M, van Dijkhuizen EH, Armbrust W, Hoppenreijs EP et al. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis Rheum. 2011 Jul; 63(7):2007-13.Disclosure of Interests:None declared
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Grassi, M., V. Giorgi, M. Nebuloni, P. Zerbi, M. R. Gismondo, F. Salaffi, P. Sarzi-Puttini, S. G. Rimoldi e A. Manzotti. "AB0671 NO EVIDENCE OF SARS-COV-2 IN THE KNEE JOINT: A CADAVER STUDY". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 1367.2–1368. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2033.
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Background:Despite the considerable research efforts being made to learn more about COVID-19, little is known about the presence of SARS-CoV-2 genetic material in biological fluids other than respiratory droplets, blood, and feces 1,2. In particular, little is known about the presence of SARS-CoV-2 in the joints either post mortem3 or in vivo4. To the best of our knowledge, only Lopéz-Gonzalez et al.5 have published a description of acute arthritides occurring during hospitalisation due to COVID-19, and they did not find any SARS-CoV-2 genetic material in the patients’ synovial fluid samples.Objectives:The aim of this post mortem study was to assess the presence of SARS-CoV-2 RNA in the knee synovial fluid, synovial tissue, and bone tissue of COVID-19 patients in order to discover whether the joint is a possible route of transmission during orthopaedic surgical procedures, and clarify the possible role of SARS-CoV-2 as a directly arthritogenic virus.Methods:Post mortem synovial fluid, synovial tissue and bone tissue samples were collected from the knees of five patients who died of COVID-19 in our hospital between September and October 2020, and analysed for the presence of SARS-CoV-2 using a commercial real-time polymerase chain reaction (RT-PCR) panel. Quantitative RT-PCR was used to test post mortem nasopharyngeal swabs of all of the patients.Results:No SARS-CoV-2 RNA was detected in any of the knee samples, despite the positivity of the throat swab.Conclusion:Our findings indicate that SARS-CoV-2 was not detected in knee synovial fluid, synovial membrane or bone. Therefore, our results suggest that all healthcare professionals performing surgical procedures on the joints of COVID-19 patients are exposed to a risk of contagion due to exposure to respiratory droplets, blood and body fluids, but not to direct exposure to joint- or bone-related tissues. Furthermore, given that some case reports of arthritis in COVID-19 patients 5-8 show that it is possible that COVID-19 patients display viral-mediated arthralgias and arthritis, the absence of the virus in the knee highlighted by our study suggests that it is unlikely that SARS-CoV-2 has a direct inflammatory action on the joint, but it could induce an inflammation-related reaction, manifesting as a reactive arthritis 9.References:[1]Cheng ZJ, Shan J. 2019 Novel coronavirus: where we are and what we know. Infection. 2020;(0123456789):1-9. doi:10.1007/s15010-020-01401-y[2]Chen Y, Chen L, Deng Q, et al. The Presence of SARS-CoV-2 RNA in Feces of COVID-19 Patients. J Med Virol. April 2020. doi:10.1002/jmv.25825[3]Maiese A, Manetti AC, La Russa R, et al. Autopsy findings in COVID-19-related deaths: a literature review. Forensic Sci Med Pathol. 2020. doi:10.1007/s12024-020-00310-8[4]Baldanti F, Novazzi F, Cassaniti I, Piralla A, Di A, Bruno R. Detection of the SARS-CoV-2 in different biologic specimens from positive patients with COVID-19, in Northern Italy. Authorea. 2020. doi:10.22541/au.159724509.93056098[5]López-González M-C, Peral-Garrido ML, Calabuig I, et al. Case series of acute arthritis during COVID-19 admission. Ann Rheum Dis. 2020;0(0):annrheumdis-2020-217914. doi:10.1136/annrheumdis-2020-217914[6]Parisi S, Borrelli R, Bianchi S, Fusaro E. Viral arthritis and COVID-19. Lancet Rheumatol. 2020;2(11):e655-e657. doi:10.1016/S2665-9913(20)30348-9[7]Alivernini S, Cingolani A, Gessi M, et al. Comparative analysis of synovial inflammation after SARS-CoV-2 infection. Ann Rheum Dis. 2020;0(0):2-3. doi:10.1136/annrheumdis-2020-218315[8]Talarico R, Stagnaro C, Ferro F, Carli L, Mosca M. Symmetric peripheral polyarthritis developed during SARS-CoV-2 infection. Lancet Rheumatol. 2020;2(9):e518-e519. doi:10.1016/S2665-9913(20)30216-2[9]Di Carlo M, Tardella M, Salaffi F. Can SARS-CoV-2 induce reactive arthritis? Clin Exp Rheumatol. 2020;In press.Acknowledgements:We would like to thank the clinical staff of the Pathology Unit for their collaboration in performing the autopsies.Disclosure of Interests:None declared
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Gaujoux-Viala, C., E. Dernis, E. Senbel, H. Herman-Demars, J. Becker, A. Courbeyrette e R. M. Flipo. "POS0635 METHOTREXATE MAINTENANCE ONE YEAR AFTER INITIATION OF A FIRST TARGETED THERAPY: RESULTS OF THE PROSPECTIVE STRATEGE 2 STUDY". Annals of the Rheumatic Diseases 82, Suppl 1 (30 de maio de 2023): 593.2–593. http://dx.doi.org/10.1136/annrheumdis-2023-eular.3939.
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BackgroundMethotrexate (MTX) is the first line standard of care for the management of rheumatoid arthritis (RA). In the event of an inadequate response to MTX and the presence of a poor RA prognosis factor, recommendations include initiation of biological (bDMARD) or synthetic (tsDMARD) targeted therapy in combination with MTX.ObjectivesSTRATEGE 2 aims to establish the maintenance of MTX within two years of initiating a first targeted therapy.MethodsSTRATEGE 2 is a non-interventional study including RA patients treated with MTX for at least 3 months and requiring initiation of a first b/tsDMARD due to disease activity. The primary endpoint is maintenance of MTX unchanged within 12 months of initiation of targeted therapy. Non-maintenance is defined as: permanent discontinuation of MTX and/or dose reduction and/or transition from the subcutaneous route (SC) to oral (PO). Then, univariate and multivariate analysis was applied to identify potential predictors of MTX maintenance.ResultsBetween Feb. 2019 and Dec. 2020, 53 French sites included 186 RA patients. Among them, data from 180 patients were analysable: 73.4% female, mean age 56.4 ±13.6 years, mean diagnostic oldness of 5.6 ±7.2 years, MTX treatment since 4.3 ±5.3 years, 71.7% via SC and the average dose was 19.9 ±3.9 mg/wk. The mean DAS28 score was 4.3 ±1.2 and the mean HAQ score was 1.0 ±0.7.At the end of the inclusion consultation, rheumatologists initiated a first targeted therapy: 8.6% by bDMARDs (anti-TNF: 58.4%, anti-IL6: 12.7%, Abatacept/Rituximab: 18.5%) and 10.4% by tsDMARDs. MTX was maintained unchanged in 76.1%, changed in 21.7% and stopped in 2.2% of the cases. The changes consisted of a dose reduction to 13.8 ±3.8 mg/wk for 19.4% of patients and a pathway change for 31.4% (from SC to PO).Approximately 12 months (377.8 ± 41.5 days) after initiation of targeted therapy, 95% of patients completed a follow-up visit (N=171). Of these patients, 6.4% had discontinued targeted therapy, 85.9% were on bDMARD (anti-TNF: 50.3%, anti-IL6: 12.8%, Abatacept/Rituximab: 22.8%) and 14.1% on tsDMARD.The average MTX dose was 18.0 ±4.2 mg/wk and MTX was administered SC for 59.4% of patients. According to the composite endpoint definition, MTX was maintained for 40.9% of patients. Non-maintenance was represented by 30% discontinuation, 44% of patients with a dose decrease only, 3% of patients with only a change in route of administration (from SC to PO) and 23% of patients with the two strategies.Using univariate analysis, three factors were selected for the multivariate: age (p=0.009), physicians’ mode of practice (p=0.096) and patients who estimate having completely participated in the decision-making for the targeted therapy (p= 0.197). Only age was significative (OR=1.06, 95%CI [1.03,1.10], p<0.001), decision-making shows a strong trend (p=0.052) and both characteristics were adjusted on the mode of practice (p=0.256).ConclusionThere are many therapeutic adaptations in the year following the initiation of b/tsDMARD. Twelve months after the introduction of b/tsDMARD, more than 8 out of 10 patients retained MTX as a combination therapy. Nearly 46% of patients had an adaptation of this treatment (dose reduction and/or return to the PO route). These practices are in line with the latest EULAR guidelines [1] which recommend the association of b/tsDMARDs with MTX.Reference[1]Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023;82:3–18.AcknowledgementsThe authors wish to acknowledge RCTs for their contribution to the statistical analysis, the investigators, centres and patients.Disclosure of InterestsCécile Gaujoux-Viala Consultant of: AbbVie; Amgen; Boehringer Ingelheim, Bristol-Myers Squibb; Celgene; Eli Lilly; Galapagos; Gilead Sciences, Inc.; Janssen; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; and UCB Pharma., Grant/research support from: AbbVie; Amgen; Boehringer Ingelheim, Bristol-Myers Squibb; Celgene; Eli Lilly; Galapagos; Gilead Sciences, Inc.; Janssen; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; and UCB Pharma., Emmanuelle Dernis Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Nordic Pharma, Novartis, Pfizer, Roche, Roche-Chugaï, Sandoz, Sanofi and UCB Pharma., Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Nordic Pharma, Novartis, Pfizer, Roche, Roche-Chugaï, Sandoz, Sanofi and UCB Pharma., Eric Senbel Consultant of: Abbvie, Amgen, Biogen, Celltrion, Fresenius Kabi, Janssen, Lilly, MSD, Nordic Pharma, Pfizer, Roche-Chugai and Sandoz, Sanofi., Hélène Herman-Demars Employee of: Nordic Pharma France, Jennifer Becker Employee of: Nordic Pharma France, Agnès Courbeyrette Employee of: Nordic Pharma France, René-Marc Flipo Consultant of: Abbvie, Bristol-Myers Squibb, Eli-Lilly, Janssen, MSD, Nordic-Pharma, Novartis, Pfizer, Roche-Chugaï, Sandoz and Sanofi., Grant/research support from: Abbvie, Bristol-Myers Squibb, Eli-Lilly, Janssen, MSD, Nordic-Pharma, Novartis, Pfizer, Roche-Chugaï, Sandoz and Sanofi.
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Serrano-Combarro, A., B. Atienza-Mateo, N. Del-Val, L. Ibarrola Paino, I. Casafont-Solé, R. Melero, A. Pérez Linaza et al. "AB0416 SUBCUTANEUS VS INTRAVENOUS ABATACEPT IN RHEUMATOID ARTHRITIS-INTERSTITIAL LUNG DISEASE. NATIONAL MULTICENTER STUDY OF 392 PATIENTS". Annals of the Rheumatic Diseases 82, Suppl 1 (30 de maio de 2023): 1395–96. http://dx.doi.org/10.1136/annrheumdis-2023-eular.5219.
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BackgroundInterstitial lung disease (ILD) is a severe extra-articular manifestation of rheumatoid arthritis (RA). Abatacept (ABA) has demonstrated efficacy in RA-ILD[1-2].Clinical trials have shown equivalence in subcutaneous (SC) and intravenous (IV) administration of ABA for articular manifestations[3].However, it has not been studied in RA-ILD.Objectivesto compare the effectiveness of ABA in RA-ILD patients according to the route of administration (IV-ABA vs SC-ABA).MethodsNational multicenter study of RA-ILD patients on treatment with ABA. They were divided into 2 groups according to the route of administration: a) IV, and b) SC. We analyzed from baseline the following outcomes in both groups:a) forced vital capacity (FVC),b) diffusing capacity of the lungs for carbon monoxide (DLCO),c) chest high resolution computed tomography (HRCT),d) dyspnea (assessed with the modified Medical Research Council scale),e) arthritis activity (assessed with DAS28-ESR or described in clinical records), andf) sparing corticosteroids effect.ResultsWe studied a total of 392 [SC-ABA/IV-AB; 288/91(available data)] patients. Baseline demographic and clinical characteristics are shown inTable 1. Patients were followed-up for a median [IQR] of 24 [10-48] months. FVC and DLCO remain stable during the first 24 months in both SC-ABA and IV-ABA[Figure 1].Dyspnea stabilized or improved in 85% of patients (89% of IV-ABA; 83% of SC-ABA). ABA was withdrawn in 80 patients: 60 (39%) in SC-ABA group and 20 (22%) in IV-ABA group. ILD worsening and articular inefficacy were the most common reasons of ABA discontinuation.ConclusionIn RA-ILD, ABA seems equally effective and safe regardless of the route of administration IV or SC.References[1] Rheumatology (Oxford). 2020 Dec 1;59(12):3906-3916.[2] Rheumatology (Oxford). 2021 Dec 24;61(1):299-308.[3] Arthritis Rheum. 2011 Oct;63(10):2854-64.Table 1.Main general features at baseline of RA-ILD patients with subcutaneous vs intravenous ABA.All ABA (n=392)ABA IV (n=91)ABA SC (n=288)pAge, years mean±SD65 ± 1066 ± 1066 ± 100.85Women n (%)226 (58)54 (59)166 (58)0.77Smoker ever n (%)210 (54)49 (54)154 (53)0.95ILD duration up to ABA, months, median [IQR]11 (3-38)11 (2-48)10 (3-36)0.65RF n (%)347 (89)78 (86)256 (89)0.41ACPA n (%)344 (89)76 (85)256 (90)0.25DAS28-ESR4.35±1.584.19±1.524.38±1.530.35ILD pattern n (%) NIU172 (44)47 (52)122 (42) NINE117 (30)20 (22)94 (33)0.14 Other98 (25)23 (26)72 (25)FVC (% of the predicted) mean±SD87 ± 2182 ± 2288 ± 210.26DLCO (% of the predicted) mean±SD67 ± 2067 ± 2067 ± 190.97Prednisone at baseline, mg/day, median [IQR]5 (5-10)7.5 (5-10)5 (5-10)0.34ACPA, anti-citrullinated protein antibodies; DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; RF, rheumatoid factor; UIP, usual interstitial pneumonia.Figure 1.Evolution of pulmonary function tests (mean % of the predicted FVC and DLCO) in RA-ILD patients with SC-ABA vs IV-ABA therapy at baseline and 24 months.Members of the Spanish Collaborative Group of Abatacept in RA-ILD patients:Luis Arboleya-Rodríguez, Javier Narváez, Juan Carlos Fernández, Belén Miguel, Iván Cabezas, Andrea García Valle, Clara Aguilera Cros, S. Romero-Yuste, Ignacio Villa Blanco, Sabela Fernández Aguado, Raquel Almodóvar, C. Ojeda-García, C. Aguilera-Cros, B. García-Magallón, Antonio Juan Mas, M. J. Moreno-Ramos, A. Ruibal-Escribano, Rosa Expósito, José Antonio Bernal, Evelin C. Cervantes, S. Rodríguez-García, R. Castellanos-Moreira, Iván Castellví, Manuel Rodríguez, Eva Salgado, Enrique Raya, Pilar Morales, Lorena Expósito, Mª Noelia Álvarez, José Luis Andreu, E. F. Vicente-Rabaneda, A. M. López-Robles, M. López-Corbeto, C. Hidalgo-Calleja, J.C. Fernández-López, Alejandro Olivé, S. Rodríguez-Muguruza, Iñigo Hernández, N. Quillis-Marti, J.A. Bernal-Vidal, A. García-Aparicio, S. Castro-Oreiro, J. Fernández-Melón, P. Vela Casasempere, María C. Fito, M. Rodríguez-Gómez, D. Palma-Sánchez, L. Expósito-Pérez, José María Andreu.Acknowledgements:NIL.Disclosure of InterestsAna Serrano-Combarro: None declared, Belén Atienza-Mateo: None declared, N. Del-Val: None declared, Libe Ibarrola Paino: None declared, Ivette Casafont-Solé: None declared, Rafael Melero: None declared, Alba Pérez Linaza: None declared, Isabel Serrano-García: None declared, Santos Castañeda: None declared, Rafaela Ortega Castro: None declared, Jerusalem Calvo Gutierrez: None declared, Natalia Mena-Vázquez: None declared, Nuria Vegas-Revenga: None declared, Lucía Domínguez Casas: None declared, C. Delgado-Beltran: None declared, Carolina Díez: None declared, Trinidad Pérez Sandoval: None declared, M. Retuerto-Guerrero: None declared, Lorena Pérez Albaladejo: None declared, R. López-Sánchez: None declared, Mª Guadalupe Mazano: None declared, Anahy Brandy-Garcia: None declared, Patricia López Viejo: None declared, Gemma Bonilla: None declared, Olga Maiz: None declared, Maria del Carmen Carrasco Cubero: None declared, Marta Garijo Bufort: None declared, Mireia Moreno: None declared, ANA URRUTICOECHEA-ARANA: None declared, Sergi Ordoñez: None declared, C. González-Montagut Gómez: None declared, C. Peralta-Ginés: None declared, Juan Ramón De Dios Jiménez de Aberásturi: None declared, Maria Camila Osorio: None declared, Elena Cañadillas: None declared, Fernando Lozano Morillo: None declared, Tomas Vazquez Rodriguez: None declared, Patricia Carreira: None declared, J M Blanco: None declared, Carlos Fernández-Díaz: None declared, J. Loricera: None declared, Iván Ferraz-Amaro: None declared, Diego Ferrer: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen, Galapagos and MSD, Consultant of: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD, novartis and Roche.
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Simons, G., J. Veldwijk, R. Disantostefano, M. Englbrecht, C. Radawski, L. Valor, J. Humphreys, I. N. Bruce, K. Raza e M. Falahee. "OP0276 PREFERENCES FOR TREATMENTS TO PREVENT RHEUMATOID ARTHRITIS: DISCRETE CHOICE SURVEY OF RHEUMATOID ARTHRITIS PATIENTS’ FIRST-DEGREE RELATIVES IN THE UNITED KINGDOM AND GERMANY." Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 183–84. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1579.
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BackgroundThere is a growing research focus on the development of interventions to reduce risk of rheumatoid arthritis (RA) in at-risk individuals.(1) A recent survey of the general population asked to assume a 60% risk of RA established that hypothetical preventive treatments were acceptable to most participants.(2) However the preferences of individuals who actually have an elevated risk of RA, such as first-degree relatives (FDRs) of RA patients, are not well understood.ObjectivesTo quantify FDRs’ preferences for preventive treatments for RA.MethodsAdult FDRs in the UK and Germany were invited to take part in a web-based survey via patients with clinician-confirmed RA either during a rheumatology clinic visit or by mail. In addition, FDRs taking part in a UK-based prospective cohort (PREVeNT-RA) were invited via email. Participants received information about RA followed by questions to check comprehension, and an introduction to the survey including warm-up questions. They were asked to imagine they were experiencing arthralgia and had positive autoantibody tests indicating a 60% chance of developing RA in the next two years. Using a discrete choice experiment, participants were offered a series of 15 choices between no treatment and two unlabeled hypothetical treatments to reduce risk of RA. Treatments were defined by six attributes with varying levels, describing benefits, risks, and frequency/route of administration (Table 1). Attribute selection and presentation was informed by qualitative research, ranking surveys, systematic literature review, and expert opinion. Survey layout was informed by patient research partners and qualitative pre-testing. A two-class latent class analysis was used to estimate preferences and calculate relative importance of treatment attributes and predicted uptake. A panel mixed logit model was used to obtain maximum acceptable risk estimates.Table 1.Treatment attributes and levelsAttributeLevelsChance of developing RA reduced from 60% to10%; 20%; 30%; 40%How the treatment is takenA shallow injection under the skinA drip into the veinOne or two tabletsHow often the medication has to be takenDailyWeeklyMonthlyEvery 6 monthsChance of mild side effects2%; 5%; 10%Chance of a serious infection due to treatment0%; 1%; 5%Chance of a serious side effect that is potentially irreversible1 in 100,000 people20 in 100,000 people100 in 100,000 peopleResults356 FDRs (252 female, 289 in the UK) responded. While treatment effectiveness was the most important attribute in both classes (Figure 1), the importance of other attributes differed between classes, with method and frequency of treatment administration being more important in class 2 and risk of mild side effects only impacting treatment choice in class 1. Perceived risk of developing RA predicted class assignment; those with higher perceived risk were more likely to belong to class 1. On average, the predicted uptake of treatment profiles estimating prevention candidates: abatacept; atorvastatin; hydroxychloroquine; tolerogenic cell-based therapy; and no treatment would be 50%, 15%, 9%, 18% and 0%, respectively. Finally, the maximum acceptable risk participants were willing to accept were 81%, 25% and 3% point increases in risk of mild side effects, serious infection, and serious side effects, respectively, for medicines that would reduce their risk of developing RA in the upcoming two years from 60% to 20%.ConclusionEffective preventive treatments for RA were acceptable to FDRs asked to assume a 60% chance of developing RA. Mode and frequency of treatment administration had a greater impact on treatment choices for participants with a lower perceived risk of RA. These findings are informative for target product profile development, endpoint selection, benefit-risk assessment, regulatory approval, and development of informational resources for those at risk of RA.References[1]Mankia et al. Ann Rheum Dis. 2021;80(10):1286-98.[2]Simons et al. Ann Rheum Dis. 2021;80:96-7.AcknowledgementsOn behalf of the PREFER project. PREFER received funding from the IMI 2 Joint Undertaking (grant No. 115966), which receives support from the EU’s Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations (EFPIA). This abstract and its contents reflect the view of the presenter and not the view of PREFER, IMI, the European Union or EFPIA. K. Raza is supported by the NIHR Birmingham Biomedical Research Centre.Disclosure of InterestsGwenda Simons: None declared, Jorien Veldwijk: None declared, Rachael DiSantostefano Shareholder of: Johnson & Johnson, Employee of: Janssen Research and Development, Matthias Englbrecht Speakers bureau: Abbvie, Chugai, Eli Lilly, Novartis, Roche, Sanofi, Munidpharma, Paid instructor for: Abbvie, Chugai, Roche, Consultant of: Abbvie, Novartis, Roche, Sanofi, Grant/research support from: Roche, Chugai, Christine Radawski Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, Larissa Valor: None declared, Jenny Humphreys: None declared, Ian N. Bruce: None declared, Karim Raza Consultant of: Abbvie, Sanofi, Grant/research support from: Bristol Myers Squibb, Marie Falahee: None declared
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Vela Casasempere, P., L. Tudela, R. Caño-Alameda e S. Gomez-Sabater. "AB0760 EVOLUTION OF PATIENTS WITH GIANT CELL ARTERITIS: BEFORE AND AFTER THE BIOLOGICAL ERA". Annals of the Rheumatic Diseases 82, Suppl 1 (30 de maio de 2023): 1586. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4492.
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BackgroundGiant cell arteritis (GCA) is the most common form of systemic vasculitis. The standard treatment to induce and maintain remission of GCA is based on the use of glucocorticoids (GC), often requiring high doses and for long periods of time. It has been associated with adverse events, sometimes severe, in up to 95% of cases (fractures, diabetes mellitus, hypertension, sepsis). In 2017, the first specific drug for this entity, tocilizumab (TCZ), an anti-IL-6 antibody, was approved. To date, there are few communications in clinical practice comparing the classical treatment scheme with the use of TCZ early.ObjectivesTo compare patients treated with the standard regimen (corticosteroid monotherapy) versus those treated early with TCZ, in terms of the dose of corticosteroid received, use of immunosuppressants, and adverse events.MethodsA retrospective observational study was carried out. Patients diagnosed with GCA in the Rheumatology section of the HGU Dr. Balmis during the period January 1, 2011, to November 1, 2021, were selected. Until 2017, patients received the standard regimen (corticosteroid monotherapy); from 2017, TCZ was associated early. Demographic data, treatment data (prednisone doses at months 1,3,6,12,18 and 24; use of immunosuppressants), and adverse events were collected. A descriptive analysis of the different variables was performed. The χ2 test or Fisher’s exact test was used for the association between qualitative variables. For quantitative variables, mean comparison was performed using the t-student test.ResultsWe obtained 73 patients (37% male and 63% female) with a mean age at diagnosis of 74.47 ± 8.4 years. All received initial corticosteroid treatment; 28 were also administered early TCZ (38.4%), the preferred route being subcutaneous (96.4%). The time between diagnosis and initiation of steroid treatment was a median of 0 days (median, IC 0-0), being 60 days for TCZ (IC 30-97). The use of immunosuppressants was higher in the glucocorticoid-only group than in the group treated with TCZ (57.8% vs. 21.4%, p=0.002). Prednisone dose was higher in the standard group at all follow-up time points (p<0.001). No differences were found in the occurrence of adverse events, except infections, which were more frequent in the standard treatment group (standard 28.9% vs TCZ 3.6%, p=0.008).ConclusionTocilizumab allows a greater and faster reduction of corticosteroids, compared to standard corticosteroid monotherapy, lower use of other immunosuppressants, and is associated with a lower frequency of infections.References[1]Palmowski A, Buttgereit F. Reducing the Toxicity of Long-Term Glucocorticoid Treatment in[2]Large Vessel Vasculitis. Curr Rheumatol Rep. 12 de octubre de 2020;22(12):85.[3]Hellmich B, Agueda A, Monti S, Buttgereit F, De Boysson H, Brouwer E, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2020;79(1):19-130.[4]Stone JH, Klearman M, Collinson N. Trial of tocilizumab in giant-cell arteritis. New Engl J Med 2017;377(15):1494-1495.Acknowledgements:NIL.Disclosure of InterestsPaloma Vela Casasempere Speakers bureau: ROCHE, Grant/research support from: ROCHE, Lorena Tudela: None declared, Rocio Caño-Alameda: None declared, Silvia Gomez-Sabater: None declared.
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Park, J. W., M. J. Kim, H. A. Kim, J. Kim, E. B. Lee e K. Shin. "POS0628 FAILURE TO SUSTAIN TREATMENT TARGET AFTER TAPERING TOCILIZUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS: 4-YEAR LONGITUDINAL DATA FROM A NATIONWIDE COHORT". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 552.1–552. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2818.
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Background:Tapering biologic therapy after achieving clinical remission or low disease activity (LDA) has become a viable option in daily clinical practice of treating patients with rheumatoid arthritis (RA). There are yet few studies investigating its effectiveness and safety compared with those of standard biologic treatment, especially with non-tumor necrosis factor inhibitors.Objectives:To investigate the effectiveness and safety of tapering tocilizumab (TCZ) in patients with RA who attained LDA after TCZ therapy.Methods:Data were collected from a nationwide cohort of patients with RA receiving biologic therapy in South Korea (KOBIO-RA). This study included 350 patients who were treated with TCZ and achieved Clinical Disease Activity Index (CDAI)-LDA or remission (CDAI ≤ 10) after one year of treatment. We performed a longitudinal analysis utilizing clinical data measured in all 1-year intervals using generalized estimating equations (GEE). A total of 575 one-year intervals were divided into two groups according to the dose quotient (DQ, 0-100%) of TCZ within the interval (tapering group vs. standard treatment group). The main outcome of this study was loss of CDAI-LDA in the following 1-year interval.Results:Tapering TCZ was conducted in 282 (49.0%) intervals with a mean (SD) DQ of 66.0 (15.5). Loss of CDAI-LDA occurred in 91 (15.1%) intervals. Multivariable GEE showed significantly increased loss of CDAI-LDA (adjusted OR (95% CI): 1.76 [1.01 to 3.07]) in the tapering group after adjusting for previous biologics use, route of TCZ administration, concomitant glucocorticoid use, and CDAI measured in the previous follow-up. In addition, the likelihood to achieve DAS28-deep remission (DAS28-ESR < 1.98) was also significantly lower in the tapering group (adjusted OR 0.68 [0.46 to 0.99]). In contrast, there was no significant difference in the proportion of fulfilling other remission criteria between the two groups (Table 1). Development any adverse drug event or event of special interest was comparable in both groups except for hypercholesterolemia, which was lower in the tapering group.Table 1.Demographic characteristics and csDMARDs before first bDMARDLoss of CDAI-LDADAS28-remissionDAS28-deep remissionCDAI-remissionSDAI-remissionACR/EULAR remissionUnadjusted OR (95% CI)(vs. standard-dose group)1.02 (0.67 to 1.55)1.03 (0.71 to 1.49)0.76 (0.54 to 1.06)1.23 (0.75 to 2.00)0.92 (0.59 to 1.44)0.98 (0.65 to 1.48)Adjusted OR(95% CI)(vs. standard-dose group)1.76 (1.01 to 3.07)0.87 (0.54 to 1.38)0.68 (0.46 to 0.99)0.94 (0.57 to 1.55)0.87 (0.54 to 1.38)0.76 (0.50 to 1.18)CDAI, clinical disease activity index; CI, confidence interval; DAS, disease activity score; LDA, low disease activity; OR, odds ratio; SDAI, simplified disease activity index.Conclusion:Tapering TCZ after achieving LDA in patients with RA increases the risk of losing the benefit of LDA without a significant merit in safety.References:[1]Smolen JS et al. Maintenance, reduction or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet. 2013;381:918-29.[2]Schett G et al. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis. 2016;75:1428-37.Disclosure of Interests:None declared
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Isomura, Y., Y. Yamasaki, Y. Shirai e M. Kuwana. "AB0436 OUTCOMES OF DOSE-REDUCTION OR DISCONTINUATION OF TOCILIZUMAB IN PATIENTS WITH EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 1246.3–1247. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2471.
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Background:Potential efficacy and favorable safety profiles of tocilizumab (TCZ) have been demonstrated in patients with diffuse cutaneous systemic sclerosis (dcSSc) [1, 2]. However, clinical outcomes after dose-reduction or discontinuation of TCZ due to an improvement of skin thickness remain unclear.Objectives:To investigate the clinical outcomes after dose-reduction or discontinuation of TCZ in patients with dcSSc in a real-world setting.Methods:This is a single-center, retrospective, observational study using a database of consecutive SSc patients who visited our center between April 2014 and October 2020. For this study, we selected eligible patients from the database based on the following criteria: patients who (i) fulfilled the ACR/EULAR classification criteria, (ii) were classified as having dcSSc, (iii) had been treated with TCZ for at least 6 months, and (iv) were follow-up >6 months after TCZ introduction. Clinical information including demographic and clinical characteristics at TCZ introduction; dosing, administration route, and adherence of TCZ; and serial clinical parameters (modified Rondan total skin thickness score [mRSS], and percent predicted forced vital capacity [%FVC]), safety profiles, and outcomes after TCZ introduction regardless of TCZ continuation were extracted from the database.Results:Of 404 patients enrolled in the database, 13 dcSSc patients were eligible for this study. Baseline characteristics included a mean age of 51 ± 9 years, 85% female, disease duration of 27 ± 24 months, and mRSS of 19.5 ± 10.6. Seven patients (54%) had HRCT-confirmed ILD at baseline, and 9 (69%) were positive for anti-topoisomerase I antibody. Two (14%) and 11 (85%) were on mycophenolate mofetil and low-dose prednisolone (7.2 ± 6.0 mg/day), respectively. Seven patients (54%) each had active skin disease and elevated inflammatory markers defined in the phase III clinical trial [2], while only 4 (31%) fulfilled the inclusion criteria. TCZ was initially administered intravenously (8 mg/kg every 4 weeks) in 8 patients and subcutaneously in 5 (162 mg every 2 weeks in 4 and every week in one). At one year, mRSS was improved from 20.9 ± 11.4 to 10.7 ± 8.9 in 11 patients (p = 0.007), and %FVC was stable in 7 patients with ILD (76.8 ± 15.0 to 78.6 ± 16.1). During the observation period of 60.4 ± 26.7 months, 4 patients were treated with a stable dose of TCZ, while TCZ dose was reduced and/or discontinued in 9. Four of them discontinued TCZ due to adverse events (n = 2; acute lung injury and phlegmon) or prominent improvement of skin thickening (n = 2). Of 9 patients with dose reduction/discontinuation of TCZ, 4 patients who discontinued TCZ (n = 3) or received dose reduction of TCZ (n = 1) experienced a recurrence of progressive skin thickening together with inflammatory complications, including edematous induration of the skin, progression of ILD, polyarthritis, and/or pericarditis with increased inflammatory markers. The interval between dose-reduction/discontinuation of TCZ and clinical worsening ranged from 2 to 11 months. These manifestations were promptly improved by dose-escalation or resumption of TCZ in all patients except one who experienced progressive ILD and died of respiratory failure 27 months later.Conclusion:In dcSSc patients who experienced improvement of skin thickness during treatment with TCZ, dose-reduction or discontinuation of TCZ may result in a recurrence of the disease. Randomized comparative studies are necessary to examine optimal timing for dose-reduction or discontinuation of TCZ in dcSSc patients after improvement of skin thickness.References:[1]Khanna, D., et al., Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis, 2018. 77(2):212-220.[2]Khanna, D., et al., Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med, 2020; 8(10): 963-974.Disclosure of Interests:Yohei Isomura: None declared, Yoshioki Yamasaki Speakers bureau: Boehringer-Ingelheim, Nippon Shinyaku, Bristol Myers, Yuichiro Shirai Speakers bureau: Janssen, Grant/research support from: Janssen, Masataka Kuwana Speakers bureau: Abbie, Astellas, Asahi Kasei Parma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, MBL, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Tanabe-Mitsubishi, Consultant of: Boehringer-Ingelheim, Chugai, Corbus, MBL, Mochida, Grant/research support from: Boehringer-Ingelheim, Chugai, Eisai, MBL, Ono Pharmaceuticals, Tanabe-Mitsubishi
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Calderón-Goercke, M., D. Prieto-Peña, S. Castañeda, C. Moriano, E. Becerra-Fernández, M. Revenga, N. Alvarez-Rivas et al. "OP0033 OPTIMIZATION OF TOCILIZUMAB THERAPY IN GIANT CELL ARTERITIS. A MULTICENTER REAL-LIFE STUDY OF 134 PATIENTS". Annals of the Rheumatic Diseases 79, Suppl 1 (junho de 2020): 23.1–23. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2574.
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Background:Tocilizumab (TCZ) is the only biological agent approved in Giant Cell Arteritis (GCA). There is general agreement on the initial and the standard maintenance dose of TCZ. However, information on duration and optimization of TCZ in GCA is scarce.Objectives:Our aim was to assess efficacy and safety of TCZ therapy optimization in an unselected wide series of GCA in clinical practice.Methods:Multicenter study, 134 patients with GCA who received TCZ due to inefficacy/adverse events of previous therapy. Once complete remission was reached and based on a shared decision between patient and physician TCZ was optimized in some cases. Optimization was done by decreasing the dose and/or prolonging the TCZ dosing interval progressively.Results:134 GCA patients treated with TCZ (101w/33m); mean age 73.0±8.8 years. TCZ was administered IV to 106 (79.1%) patients and SC to 28 (20.9%). TCZ was optimized in 43 (32.1%) patients. No demographic, clinical manifestations or laboratory data differences had been found at TCZ onset (TABLE). After a follow up of 12 [6-15.5] months, and a complete remission for 6 [3-12] months; the first TCZ optimization was performed. Median prednisone dose at first TCZ optimization was 2.5 [0-5] mg/day. TCZ IV was optimized from 8 to 4 mg/kg/4weeks in 12 of 106 (11.3%) and from 162 mg/SC/week to 162 mg/SC/2weeks in 9 of 28 (32.1%) cases. Five (11.6%) of the 43 optimized cases relapsed. In 4 cases, the relapses were treated increasing TCZ up to the pre-optimization dose, in 1 case the route of administration was change (4 mg/kg/4week to 162 mg/SC/week). In 8 of 43 optimized patients (18.6%), it was possible to withdraw TCZ after complete remission for 30 [16.25-45.75] months. Regarding adverse events and severe infections were similar in both groups. The mean TCZ treatment costs were lower in the optimized group.Conclusion:Once remission is reached in GCA patients under TCZ treatment, optimization of TCZ may be performed. Based on our experience it could be performed by reducing the dose with IV TCZ or by prolonging dosing interval with SC TCZ.References:[1]Calderón-Goercke M et al. Semin Arthritis Rheum 2019 Aug;49(1): 126-135.TABLE.OPTIMIZED-TCZ GROUP (n=43)NON-OPTIMIZED TCZ GROUP (n=91)pBASAL FEATURES AT TCZ ONSETGENERAL FEATURESAge, years, mean± SD68.9±8.771.4±8.50.125Sex, female/male n(%)32/1068/240.779Time from GCA diagnosis to TCZ onset (months), median [IQR]19.5[7.75-45]10.5[4 – 25]0.047SYSTEMIC MANIFESTATIONSFever, n(%)1(2.4)8(8.7)0.176Constitutional syndrome, n(%)11(26.2)19(20.7)0.476PMR, n(%)18(42.9)56(60.9)0.052ISCHEMIC MANIFESTATIONSVisual involvement, n(%)5(11.9)23(25)0.084Headache, n(%)26(61.9)42(45.7)0.081Jaw claudication, n(%)1(2.4)11(12)0.072CORTICOSTEROIDS AT TCZ ONSETPrednisone dose, mg/d mean (SD)15.1±11.125±17.40.001FOLLOW-UP ON TCZ THERAPY (MONTHS), MEDIAN [IQR]24[18-27]6 [3-18]0.000Relapses, n(%)5(11.6)5(5.5)0.207End follow-up remission, n(%)40(93)84(92)0.99Severe side efects, n(%)14(32.6)22(24.2)0.307Seriuos infections, n(%)6(14)10(11)0.878Cost, (mean) euros per yearIVSC7 538.47 329.011 726.411 726.4--Disclosure of Interests:Monica Calderón-Goercke: None declared, D. Prieto-Peña: None declared, Santos Castañeda: None declared, Clara Moriano: None declared, Elena Becerra-Fernández: None declared, Marcelino Revenga: None declared, Noelia Alvarez-Rivas: None declared, Carles Galisteo: None declared, Águeda Prior-Español: None declared, E. Galindez: None declared, Cristina Hidalgo: None declared, Sara Manrique Arija: None declared, Eugenio de Miguel Grant/research support from: Yes (Abbvie, Novartis, Pfizer), Consultant of: Yes (Abbvie, Novartis, Pfizer), Paid instructor for: yes (AbbVie, Novartis, Pfizer, MSD, BMS, UCB, Roche, Grunental, Janssen, Sanofi), Speakers bureau: yes (AbbVie, Novartis, Pfizer, MSD, BMS, UCB, Roche, Grunental, Janssen, Sanofi), Eva Salgado-Pérez: None declared, Vicente Aldasoro Speakers bureau: Roche, Abbvie, MSD, UCB, Pfizer, Menarini, Grunenthal, Gebro, Novartis, Janssen, Ignacio Villa-Blanco Consultant of: UCB, Speakers bureau: Novartis, MSD, Lilly, Susana Romero-Yuste: None declared, J. Narváez: None declared, Catalina Gomez-Arango: None declared, Eva Perez-Pampín: None declared, Rafael Melero: None declared, Francisca Sivera: None declared, Alejandro Olive: None declared, María Álvarez del Buergo: None declared, Luisa Marena Rojas: None declared, Carlos Fernández-López: None declared, Francisco Navarro: None declared, Enrique Raya: None declared, Beatriz Arca: None declared, Roser Solans-Laqué: None declared, Arantxa Conesa: None declared, Carlos Vázquez: None declared, Jose Andrés Román-Ivorra: None declared, Pau Lluch: None declared, Paloma Vela-Casasempere: None declared, Carmen Torres-Martín: None declared, Juan Carlos Nieto Speakers bureau: Pfizer, Abbvie, MSD, Novartis, Janssen, Lilly, Nordic Pharma, BMS, Gebro, FAES Farma, Roche, Sanofi, Carmen Ordas-Calvo: None declared, Cristina Luna-Gomez: None declared, Francisco J. Toyos Sáenz de Miera: None declared, Nagore Fernández-Llanio: None declared, Antonio García: None declared, J. Luis Hernández: None declared, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD, Ricardo Blanco Grant/research support from: AbbVie, MSD, and Roche, Speakers bureau: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, and MSD
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Dupont, Louis. "Essai d’évaluation des effets économiques de grandes manifestations sportives : le cas de la Route du rhum en Guadeloupe". Études caribéennes, n.º 19 (22 de outubro de 2012). http://dx.doi.org/10.4000/etudescaribeennes.5296.
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Mehmood, Yasir, Hammad Yousaf, Umar Farooq, Rana Khalid Mahmood, Mahpara Gondal, Humayun Riaz, Hafiz Umar, Hafiza Aisha Sadiqa e Mueen Mohsin. "A Clinical Trial of Multi Herbal Preparation (EZCol) Syrup for Constipation in Pakistani Population". Journal of Pharmaceutical Research International, 31 de janeiro de 2020, 1–7. http://dx.doi.org/10.9734/jpri/2019/v31i630386.
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Background: Constipation is one of the symptoms of intestinal syndrome which would be happened along with some other disease in patients. There are several treatment available to cure the constipation but use of stimulant laxative in chronic and acute constipation is more safe and useful of any age patients. In this cross sectional study we clinically observed the efficacy of multi herbal extract (Cassia senna, Rheum palmatum and Cuscuta reflexa) in constipation. We have used local company syrup (EZCol syrup). This syrup contains multi herbs and senna leaves extract is main ingredient of this syrup. The active constituents of enna leaves are Sennosides which considered as an effective treatment for constipation. Sennosides increase the transfer rate of materials from the large intestine. We aimed to assure the effect of senna leaves extract along with other herbal extract (Rheum palmatum and Cuscuta reflexa) for the treatment of constipation.
Materials and Methods: In this study, 35 patients were observed after taking the syrup (dose 15 mL 2 time/daily for 3 days). A questionnaire (ROUTE2-003) was developed and distributed to the patients after prescription of EZCol syrup. The study was approved form ethical committee of Rashid Lateef Medical College and Arif Memorial Teaching Hospital, Lahore Pakistan.
Results: Treatment was continued for 3 days and data was compiled and result shown significant cure in constipation. Maximum patients felt relief from constipation just within 3 days. Some patients felt diarrhea at third day. Moreover no further significant complications were found in patients.
Conclusion: Senna is an FDA-approved over-the-counter (OTC) laxative. Senna leaves extract is a safe, effective and well-tolerated herbal supplement for the treatment of constipation having no significant adverse effect.
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Abid, Muna, Mohammed Ibrahim e Zakia Abid. "Evaluation of Hepatoprotective Activity of Whole Fruit Extracts of Luffa Acutangula. Var. Amara and Rhizome Extracts of Rheum Emodi in CCl4 - Induced Chronic Hepatotoxicity". Journal of Pharmaceutical Research International, 16 de março de 2022, 26–38. http://dx.doi.org/10.9734/jpri/2022/v34i24b35939.
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To investigate the hepatoprotective activity of whole fruit extracts of Luffa acutangula.var. amara and rhizome extracts of Rheum emodi in CCl4 treated rats. The dried powders of L. amara and R. emodi were extracted successively with petroleum ether, ethanol and distilled water. The hepatoprotective capacity of the extract of the whole fruits of L. amara and the rhizomes of R. emodi was analyzed in liver injured CCl4- treated male rats. The present study explored the possibilities of using low doses of both plant extracts (150mg/kg, and 300mg/kg bw, po route) to treat CCL4 intoxicated albino rats in both acute and chronic models of hepatic damage, evident by increased serum levels of glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), direct bilirubin, total bilirubin, cholesterol and triglycerides, all being implicated in considerable hepatic damage.
Histopathological examination in CCl4 treated rats revealed collapse of liver parenchyma with early fibrosis and chronic inflammatory cell infiltration in patchy areas around central vein (Pic.group-2) when compared to the control group. Histopathological and physical examinations also indicated their effectiveness with their dose tolerability and liver protection.
Ethanolic and aqueous extracts of the whole fruits of L. amara and rhizomes of R. emodi were indicative of more hepatoprotective properties when compared to the petroleum ether extracts of both plants against CCl4 induced liver damage as confirmed from hepatic serum marker enzyme activities and histopathological studies.
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Rao, A. K., e Rudra Prakash Malik. "A 3D field-theoretic example for Hodge theory". Europhysics Letters, 4 de julho de 2024. http://dx.doi.org/10.1209/0295-5075/ad5f25.
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Abstract We focus on the continuous symmetry transformations for the three (2 + 1)-dimensional (3D) system of a combination of the free Abelian 1-form and 2-form gauge theories within the framework of Becchi-Rouet-Stora-Tyutin (BRST) formalism. We establish that this combined system is a tractable field-theoretic model of Hodge theory. The symmetry operators of our present system provide the physical realizations of the de Rham cohomological operators of differential geometry at the algebraic level. Our present investigation is important in the sense that, for the first time, we are able to establish an odd dimensional (i.e. D = 3) field-theoretic system to be an example for Hodge theory (besides earlier works on a few interesting (0 + 1)-dimensional (1D) toy models as well as a set of well-known N = 2 SUSY quantum mechanical systems of physical interest). For the sake of brevity, we have purposely not taken into account the 3D Chern-Simon term for the Abelian 1-form gauge field in our theory which allows the mass as well as the gauge-invariance to co-exist together.