Добірка наукової літератури з теми "378:37.091.3:796.011.3 (043.5)"

Background:DISCOVER 1 & 2, two double-blind, phase-3, psoriatic arthritis (PsA) trials of guselkumab (GUS, an IL-23 inhibitor), demonstrated significant improvement with GUS vs placebo (PBO) in signs and symptoms of PsA, with good tolerability, at week (w) 24 during the PBO-controlled period.1,2 Beyond w24, all patients (pts) switched to GUS. Continued treatment maintained efficacy through w52.3,4Objectives:To describe pooled safety results from the DISCOVER 1 & 2 trials through 1-year of GUS treatment.Methods:Adults with active PsA (DISCOVER 1: ≥3 tender/swollen joints and C-Reactive protein [CRP] ≥0.3 mg/dL; DISCOVER 2: ≥5 tender/swollen joints and CRP ≥0.6 mg/dL) were randomized to subcutaneous GUS 100 mg at w0, w4, then every 8 w (q8w); GUS 100 mg q4w; or PBO. At w24, PBO pts switched to GUS 100 mg q4w. Pts were biologic naive except ~30% pts in DISCOVER 1. Safety was reported through w60 in DISCOVER 1 and through w52 in DISCOVER 2.Results:Baseline characteristics were similar between treatment groups in the pooled studies. Through w24 and 1 year, numbers of pts per 100 patient years with ≥1 event were similar among treatment groups for adverse events (AEs), serious AEs, infections, serious infections, and discontinuations due to AE (Table 1). At 1 year, there were no cases of active tuberculosis, opportunistic infections (including candida), or inflammatory bowel disease in GUS-treated pts; 2 deaths in PBO pts; and low incidences that were similar across treatment groups for malignancy, major adverse cardiac events, and injection-site reactions. Incidence of anti-GUS antibodies was 4.5%, and most were not neutralizing. Mild elevations in serum hepatic transaminases and decreases in neutrophil counts were consistent at 1 year with the results at w24 (Table 1).Conclusion:GUS regimens of q8w and q4w were well tolerated in PsA pts through 1 year of treatment in the phase-3 DISCOVER trials, consistent with the w24 results. No meaningful differences between incidences of AEs were reported in the q8w and q4w groups. The safety profile of GUS in PsA pts is generally comparable with the previously established safety profile of GUS.References:[1]Deodhar A et al. Lancet. 2020;395:1115[2]Mease P et al. Lancet. 2020;395:1126[3]Ritchlin C et al. EULAR 2020 # SAT0397[4]McInnes I et al. EULAR 2020 # SAT0402Table 1.Number of Patients with AEs per 100 PY and Incidence of AEs of InterestTime Period24 Weeks1 Year*Treatment GroupPBOGUS SC 100 mgPBO to GUS‡GUS SC 100 mgDosing ScheduleMatchingq8wq4wGUSCombined†q4wq8wq4wGUSCombined‡ N3723753737483523753731100Total PY Follow-Up173173172346204384385589Patients with AEs per 100 PY, n (95% CI)≥1 AE143 (123, 166)148 (127, 171)154 (132, 178)151 (136, 167)92 (77, 108)114 (100, 130)115 (101, 131)109 (100, 117)≥1 Serious AE7.1 (3.7, 12)4.1 (1.6, 8.4)4.7 (2.0, 9.3)4.4 (2.5, 7.3)7.0 (3.8, 11.8)4.8 (2.9, 7.6)4.0 (2.2, 6.6)4.9 (3.6, 6.6)≥1 Infection50 (39, 62)47 (37, 59)52 (42, 65)49 (42, 58)39 (31, 49)41 (34, 48)38 (31, 45)39 (35, 44)≥1 Serious Infection1.7 (0.4, 5.1)0.6 (0.0, 3.2)1.8 (0.4, 5.1)1.2 (0.3, 3.0)2.5 (0.8, 5.8)1.3 (0.4, 3.1)0.8 (0.2, 2.3)1.3 (0.7, 2.3)Discontinued due to AE4.1 (1.6, 8.4)2.9 (1.0, 6.8)4.7 (2.0, 9.3)3.8 (2.0, 6.5)3.5 (1.4, 7.1)2.1 (0.9, 4.1)2.6 (1.3, 4.8)2.6 (1.7, 3.8)AEs of Interest§, n (%)Death2 (0.5)0000000Malignancy1 (0.3)2 (0.5)02 (0.3)1 (0.3)2 (0.5)03 (0.3)Major Adverse Cardiac Events1 (0.3)01 (0.3)1 (0.1)001 (0.3)1 (0.1)Opportunistic Infections00000000Tuberculosis00000000Inflammatory Bowel Disease1 (0.3)0000000Injection-Site Reaction1 (0.3)5 (1.3)4 (1.1)9 (1.2)4 (1.1)6 (1.6)9 (2.4)19 (1.7)Anti-GUS Antibody+-6/373 (1.6)9/371 (2.4)15/744 (2.0)14/350 (4.0)18/373 (4.8)17/371 (4.6)49/1094 (4.5)*Through w60 for DISCOVER 1 and w52 for DISCOVER 2; †Combined GUS q8w and q4w; ‡For patients who switched from PBO to GUS, only data on and after first GUS administration were included in this group; §PBO N=370.AE, adverse event; CI, confidence interval; GUS, guselkumab; PBO, placebo; PY, patient year; q4w, every 4 weeks; q8w, every 8 weeks; SC, subcutaneous; w, weekDisclosure of Interests:Christopher T. Ritchlin Grant/research support from: Received grant/research support from UCB Pharma, AbbVie, Amgen, consultation fees from UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Proton Rahman Speakers bureau: Received speakers fees from Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, Pfizer, Grant/research support from: Received grant/research support from Janssen and Novartis, consultation fees from Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, and Pfizer., Philip Helliwell Consultant of: Consultation fees paid to charity (AbbVie, Amgen, Pfizer, UCB) or himself (Celgene, Galapagos), Grant/research support from: Received grants/research support paid to charity (AbbVie, Janssen, Novartis), Wolf-Henning Boehncke Consultant of: Received consultation fees from Janssen, Grant/research support from: Received grant/research support from Janssen Research & Development, LLC, Iain McInnes Consultant of: Received consultation fees from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: Received grant/research support from Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Alice B Gottlieb Speakers bureau: Received speakers fees from Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB, Consultant of: Received consultation fees from Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB, Grant/research support from: Received grant/research support from Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB, Shelly Kafka Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Alexa Kollmeier Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Xie L Xu Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, May Shawi Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Shihong Sheng Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Prasheen Agarwal Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Bei Zhou Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Paraneedharan Ramachandran Shareholder of: Shareholder of Johnson & Johnson, Employee of: Employee of Janssen Research & Development, LLC, Philip J Mease Speakers bureau: Received speakers fees from Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Consultant of: Received consultation fees from Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB, Grant/research support from: Received grant/research support from Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB.

AbstractObjectiveTo investigate whether low vitamin D status was related to insulin resistance (IR) or impaired fasting glucose (IFG) in Korean adolescents, after adjusting for total body fat mass (FM).DesignA cross-sectional study.SettingKorea National Health and Nutrition Examination Survey (KNAHNES) 2009–2010.SubjectsIn total, 1466 participants (769 males) aged 10–19 years were assessed for serum 25-hydroxyvitamin D (25(OH)D) levels, for FM by whole-body dual-energy X-ray absorptiometry and for IR by homeostasis model assessment (HOMA-IR) after an 8 h fast.ResultsAge-, sex-, season- and physical-activity-adjusted regression models showed that serum 25(OH)D levels were significantly related to markers of adiposity (P = 0·016 for FM (g), P = 0·023 for FM (%) and P = 0·035 for fat mass index). When the participants were stratified into three 25(OH)D categories (<37·5 nmol/l (n 553), 37·5 to < 50 nmol/l (n 543) and ≥ 50 nmol/l (n 370)), significantly decreasing trends were observed for fasting insulin (all P < 0·001), HOMA-IR (all P < 0·001) and the odds ratios for IFG (all P for trend < 0·05) from the lowest to the highest 25(OH)D category, after adjustments for age, sex, physical activity and all markers of adiposity. In the multivariate logistic regression analysis, the likelihood of participants in the lowest serum 25(OH)D category having IFG was 2·96–3·15 compared with those in the highest 25(OH)D category (all P < 0·05).ConclusionsThere was a significant inverse relationship between vitamin D status and IR and the risk of IFG, independent of adiposity, in Korean adolescents.

Abstract Objective : We describe the Mayo Clinic experience in 797 newly-diagnosed patients with acute myeloid leukemia (AML) serially treated with 7+3 induction chemotherapy that included 3 days of daunorubicin at a daily dose of 60 mg/m2 (dauno-60; n=239) or 90 mg/m2 (dauno-90; n=52), or idarubicin 12 mg/m2 (IDA-12; n=506). Our objective was to compare overall (OS) and relapse-free (RFS) survival outcome. Methods : Newly-diagnosed AML patients seen at our institution and received intensive induction chemotherapy were identified from the Mayo Clinic AML database. Treatment period spanned from January 2004 through May 2021. Follow-up information was updated as of June 2021. Conventional criteria were used to diagnose AML, assign cytogenetic risk category, and classify treatment response. Results : The study group included 797 patients (median age 60 years, range 18-88; 58% males): 506 (63%) patients received IDA-12, 239 (30%) dauno-60, and 52 (7%) dauno-90. The respective median (range) ages were 60 (18-88), 61 (19-82), and 53 (22-72) years (p=0.01) (Table). Primary, secondary, and therapy-related AML accounted for 65%, 25% and 10% of patients treated with IDA-12, 69%, 22%, and 9% of those treated with dauno-60, and 75%, 23% and 2% of patients treated with dauno-90, respectively (p=0.1). The corresponding frequencies of adverse karyotype were 34%, 25% and 25% (p=0.05). CR/CRi was documented in 78% (620/793) of all evaluable patients: IDA-12 80% (400/503), dauno-60 75% (175/238), and dauno-90 87% (45/52) (p=0.1). 210 (34%) patients underwent allogenic hematopoietic stem cell transplant (AHSCT), including 125 (25%), 59 (25%) and 26 (50%) patients, in the three treatment groups, respectively (p=0.0004). After a median (range) follow up 19 (0.2-203) months, 348 (54%) relapses and 518 (65%) deaths were documented. Median (range) survivals for IDA-12, dauno-60 and dauno-90 groups were 21 (0.3-243), 14.5 (0.45-198), and 27.7 (0.2-180) months (p=0.07; figure 1). The respective 1-, 3-, and 5-year OS rates were 67%, 42%, and 34% (IDA-12); 66%, 37%, and 30% (dauno-60); and 78%, 51%, and 49% (dauno-90), respectively; the trend favoring dauno-90 was no longer apparent during age-adjusted analysis (p=0.33). Multivariable analysis that accounted for age, cytogenetic risk category, FLT3-ITD/NPM1 status and AML subtype confirmed the lack of additional contribution from IDA-12 vs dauno-60 vs dauno-90 (p=0.2) while affirming the independent prognostic value of the other four variables; AHSCT carried an additional predictive value for superior survival without altering these results. A total of 348 (54%) relapses were documented: 228 (57%) in the IDA-12; 99 (57%) in the dauno-60; and 21 (47%) in the dauno-90 cohorts (p=0.7); RFS was similar in the three treatment groups (p=0.1; figure 2). Conclusion :In the current large single-institution study of consecutive adult patients with AML, neither the choice of anthracycline (idarubicin vs daunorubicin) or the dose of daunorubicin (60 vs 90 mg/m2) appeared to effect outcome in terms of remission rates or overall or relapse-free survival. The study otherwise confirms the independent favorable effect of younger age, non-adverse karyotype, FLT3-ITD-/NPM1+ status, and AHSCT. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee; Omeros: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding.

Background:Tofacitinib (TOFA) is the first JAKi approved for psoriatic arthritis (PsA) in Europe (July 2018). TOFA has shown efficacy in refractory patients to anti-TNF in Randomized Clinical Trials (RCT) (Gladman D. NEJM 2017; 377: 1525-36).Objectives:To assess efficacy and safety of TOFA in clinical practice (CP). To compare the profile of CP with RCTMethods:Study of 87 patients of CP with PsA treated with TOFA; Results are expressed as percentage, mean±SD or median [IRQ].Results:87 patients (28♀/59♂), mean age of 52.8±11.4 years (Table 1). Pattern of joint involvement was: peripheral (n=60), axial (1) and mixed (26). Presented also enthesitis (49.4%), nail involvement (30.2%) and dactylitis (31%).Prior TOFA, most patients (80%) received oral prednisone, synthetic immunosuppressants (mean 2.3±0.9) and biological therapy (BT) (3.6±1.9): etanercept (n=58), adalimumab (54), infliximab (31), golimumab (37), certolizumab (30), secukinumab (54), ustekinumab (39) and ixekizumab (2). Apremilast was used in 17.After a mean follow-up of 12.3±9.3 years from PsA diagnosis, TOFA was started (5 mg/12 h). In 48 (55.2%) TOFA was used in combined therapy: methotrexate (30) and leflunomide (15). In the remaining 39, monotherapy was prescribed.Patients of CP compared with RCT have a longer duration of PsA, worst functional disability (HAQ) and received a higher proportion of corticosteroids and BT (anti-TNF and non-anti-TNF) (Table 1).Patients improved in activity indexes (PASI, DAS28, DAPSA) and laboratory test (table 2). Minor side effects were reported in 21 patients (gastrointestinal symptoms), and TOFA was discontinued in 29 due to inefficiency mainly.Conclusion:Patients of CP had a longer evolution and received a greater number of biologics than those of RCT. TOFA as in RCT seems effective, rapid and relatively safe for refractory PsA.Table 1.Baseline featuresCLINICAL TRIALGladmanN=131CLINICAL PRACTICEN=87Age, years (mean±SD)49.5±12.352.8±11.4Sex, n (%)67M/64F (51/49)59M/28F (68/32.2)Duration PsA, years (mean±SD)9.6±7.612,3±9.3HAQ-DI1.3±0.71.4±0.7 (n=26)Swollen joint count, mean±SD12.1±10.65.7±5.8Painful joint count, mean±SD20.5±13.08.0±6.6Elevated CRP, n (%)85 (65)55 (63.2)PASI score, median [IQR]7.6 [0.6-32.2]9.0 [4.2-15]Oral glucocorticoid, n (%)37(28)44(50.5)Concomitant synthetic DMARDs, n (%)- Methotrexate98 (75)30 (34.4)- Leflunomide12 (9)15 (17.2)- Sulfasalazine21 (16)6 (6.9)- Others2 (2)N. of previous TNF inhibitors, mean±SD1.7±1.02.4±1.4Previous use of other biological no anti-TNF, n (%)11 (8)68 (78.2)Table 2.Table 2. Improvement at 1st, 6thand 12thmonthBaselinen=871st monthn=776th monthn=5212th monthn=20Nail involvement, n (%)17 (19.5)Improvement, n (%)5 (35.7)6 (60)5 (83.3)Enthesitis, n (%)28 (32.2)Improvement, n (%)8 (47.1)10 (58.8)3 (50)Dactylitis, n (%)16 (18.4)Improvement, n (%)9 (69.2)6 (85.7)0 (0)CRP mg/dl, median [IQR]1.9 [0.3-5]0.5 [0.1-2.2]0.5 [0.3-1.2]0.4 [0.4-3.7]p (vs baseline)0.0040.0050.66DAS28, median [IQR]4.8 [4.1-5.403.7 [2.8-4.6]2.8 [2.2-3.8]2.9 [2.2-3.7]p (vs baseline)<0.001<0.001<0.001DAPSA, median [IQR]28 [18.41-34.05]15.5 [10.1-25.7]9 [6.07-15]4.3 [2.4-8]p (vs baseline)<0.001<0.001<0.001PASI, median [IQR]5 [1-14]1.4 [0-7]0 [0-4]0.05 [0-2.7]p (vs baseline)0.1920.1050.300Disclosure of Interests:E. Galindez: None declared, D. Prieto-Peña: None declared, José Luis Martín-Varillas Grant/research support from: AbbVie, Pfizer, Janssen and Celgene, Speakers bureau: Pfizer and Lilly, Beatriz Joven-Ibáñez Speakers bureau: Abbvie, Celgene, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Olga Rusinovich: None declared, RAQUEL ALMODOVAR Speakers bureau: Abbvie, Celgene, Janssen, Lilly, Novartis, Pfizer., Juanjo J Alegre-Sancho Consultant of: UCB, Roche, Sanofi, Boehringer, Celltrion, Paid instructor for: GSK, Speakers bureau: MSD, GSK, Lilly, Sanofi, Roche, UCB, Actelion, Pfizer, Abbvie, Novartis, LARA MENDEZ DIAZ: None declared, Agusti Sellas-Fernández Speakers bureau: Abbott, Lilly, Celgene, Pfizer, Schering-Plough, Janssen, Novartis, and Nordic Pharma, À Martínez-Ferrer: None declared, Rosario Garcia de Vicuna Grant/research support from: BMS, Lilly, MSD, Novartis, Roche, Consultant of: Abbvie, Biogen, BMS, Celltrion, Gebro, Lilly, Mylan, Pfizer, Sandoz, Sanofi, Paid instructor for: Lilly, Speakers bureau: BMS, Lilly, Pfizer, Sandoz, Sanofi, Clara Ventín-Rodríguez: None declared, Julio Ramirez: None declared, Manuel Moreno: None declared, Maria jose Moreno: None declared, María del Carmen Castro Villegas: None declared, Antia Crespo Golmar: None declared, Natalia Palmou-Fontana: None declared, FRANCISCO ORTIZ SANJUAN: None declared, Ximena Elizabeth Larco Rojas: None declared, Antonio Juan Mas: None declared, Christian Y Soleto: None declared, Iñigo Gorostiza: 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

Climate change induced sea-level rise (SLR) is on its increase globally. Regionally the lowlands of China, Vietnam, Bangladesh, and islands of the Malaysian, Indonesian and Philippine archipelagos are among the world’s most threatened regions. Sea-level rise has major impacts on the ecosystems and society. It threatens coastal populations, economic activities, and fragile ecosystems as mangroves, coastal salt-marches and wetlands. This paper provides a summary of the current state of knowledge of sea level-rise and its effects on both human and natural ecosystems. The focus is on coastal urban areas and low lying deltas in South-East Asia and Vietnam, as one of the most threatened areas in the world. About 3 mm per year reflects the growing consensus on the average SLR worldwide. The trend speeds up during recent decades. The figures are subject to local, temporal and methodological variation. In Vietnam the average values of 3.3 mm per year during the 1993-2014 period are above the worldwide average. Although a basic conceptual understanding exists that the increasing global frequency of the strongest tropical cyclones is related with the increasing temperature and SLR, this relationship is insufficiently understood. Moreover the precise, complex environmental, economic, social, and health impacts are currently unclear. SLR, storms and changing precipitation patterns increase flood risks, in particular in urban areas. Part of the current scientific debate is on how urban agglomeration can be made more resilient to flood risks. Where originally mainly technical interventions dominated this discussion, it becomes increasingly clear that proactive special planning, flood defense, flood risk mitigation, flood preparation, and flood recovery are important, but costly instruments. Next to the main focus on SLR and its effects on resilience, the paper reviews main SLR associated impacts: Floods and inundation, salinization, shoreline change, and effects on mangroves and wetlands. The hazards of SLR related floods increase fastest in urban areas. This is related with both the increasing surface major cities are expected to occupy during the decades to come and the increasing coastal population. In particular Asia and its megacities in the southern part of the continent are increasingly at risk. The discussion points to complexity, inter-disciplinarity, and the related uncertainty, as core characteristics. An integrated combination of mitigation, adaptation and resilience measures is currently considered as the most indicated way to resist SLR today and in the near future.References Aerts J.C.J.H., Hassan A., Savenije H.H.G., Khan M.F., 2000. Using GIS tools and rapid assessment techniques for determining salt intrusion: Stream a river basin management instrument. 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Context.— Multifocal prostate cancer at radical prostatectomy (RP) may be graded with assessment of each individual tumor nodule (TN) or global grading of all TNs in aggregate. Objective.— To assess case-level grade variability between these 2 grading approaches. Design.— We reviewed 776 RPs with multifocal prostate cancer with 2 or more separate TNs of different Grade Groups (GGs). Two separate grades were assigned to each RP: one based on the TN with the highest grade and a global grade based on the Gleason pattern volumes for all TNs. We then compared the results of these 2 methods. Results.— The case-level grade changed by 1 or more GGs between the 2 grading methods in 35% (132 of 374) of GG3 through GG5 cases. Twelve percent (37 of 309) of GG2 cases with Gleason pattern 4 more than 5% based on individual TN grading decreased their Gleason pattern 4 to less than 5% based on the global approach. Minor tertiary pattern 5 (Gleason pattern 5 &lt;5%) was observed in 6.8% (11 of 161) of GG4 (Gleason score 3 + 5 = 8 and 5 + 3 = 8) and GG5 cases with global grading. The risk of grade discrepancy between the 2 methods was associated with the highest-grade TN volume (inverse relationship), patient age, and number of TNs (P &lt; .001, P = .003, and P &lt; .001, respectively). Conclusions.— The global grading approach resulted in a lower grade in 35% of GG3 through GG5 cases compared with grading based on the highest-grade TN. Two significant risk factors for this discrepancy with a global grading approach occur when the highest-grade TN has a relatively small tumor volume and with the higher number of TNs per RP. The observed grade variability between the 2 grading schemes most likely limits the interchangeability of post-RP multi-institutional databases if those institutions use different grading approaches.