Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases

Background: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity. Methods: Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores. Results: 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve. Conclusions: Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results.Fil: Riva, Natalia. Universidad de Navarra; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Brstilo, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sancho Araiz, Aymara. Universidad de Navarra; España. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Molina, Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Savransky, Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Roffé, Georgina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sanz, Marianela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Tenembaum, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Katsicas, Maria M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Trocóniz, Iñaki F.. Universidad de Navarra; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

Defining criteria for disease activity states in systemic juvenile idiopathic arthritis based on the systemic Juvenile Arthritis Disease Activity Score

Objective To develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis (sJIA), based on subjective disease state assessment by the treating pediatric rheumatologist. Methods The cutoffs definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, 6 methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, Youden index, 90% specificity, maximum agreement, and ROC curve analysis. Sixty percent of the patients were assigned to the definition cohort and 40% to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. Results The sJADAS10 cutoffs that separated ID from MiDA, MiDA from MoDA, and MoDA from HDA were ≤ 2.9, ≤ 10, and > 20.6. The cutoffs discriminated strongly among different levels of pain, between patients with or without morning stiffness, and between patients whose parents judged their disease status as remission or persistent activity/flare or were satisfied or not satisfied with current illness outcome. Conclusion The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts, and are therefore suitable for use in clinical trials and routine practice

Cleantech insinöörikoulutuksessa

Cleantech-insinoorit -projekti on Lahden ammattikorkeakoulun tekniikan alan hallinnoima ja Hameen ELY-keskuksen osarahoittama Euroopan Sosiaalirahaston hanke, jonka tavoitteena on parantaa Paijat-Hameen cleantech-osaamista seka insinoorikoulutuksen tyoelamavastaavuutta. Projektin tavoitteena on tuottaa uudenlainen koulutuksen toimintamalli, joka luo aitoja edellytyksia cleantech-innovaatioiden syntymiselle seka uusille tuotteille ja palveluille ymparistoliiketoiminnan alueella. Uuden yhteistyo- ja toimintamallin kehittaminen tekniikan alan koulutukseen perustuu yhteistyohon yrityselaman ja muiden toimijoiden kanssa. Yhteistyota on toteutettu erilaisissa opiskelija- ja T&K-projekteissa, opinnaytetoissa, koulutuksissa, tyopajoissa, seminaareissa, opintomatkoilla ja benchmarkkaamalla erilaisia kaytantoja koti- ja ulkomailla. Uusi yhteistyo- ja toimintamalli kasittaa lisaksi CDIO-/PBL-pedagogiikkaan (CDIO = Conceive – Design – Implement – Operate- / PBL = Problem Based Learning) perustuvan oppimismallin tuomisen tekniikan alan koulutukseen perinteisten insinooritietojen ja -taitojen ohella seka cleantech-osaamisen sisallyttamisen opintosuunnitelmiin. Myos tyoelamalta saadut tiedot tyoelamaosaamisen osaamis- ja muista tarpeista sisallytetaan opintosuunnitelmiin. Lahden ammattikorkeakoulu haluaa osaltaan seka kehittaa insinoorikoulutusta vastaamaan alueen cleantech-yritysten osaamistarpeita etta osallistua alueen yritysten tuotteiden, palvelujen ja prosessien kehittamiseen. Cleantech-insinoorit -projektin tarkoituksena on tunnistaa puhtaan teknologian suunnittelemisessa ja hyodyntamisessa tarvittavia tietoja ja taitoja ja integroida ne insinoorien koulutukseen. Lahden ammattikorkeakoulun tekniikan alalla on viisi koulutusohjelmaa, joista jokaisen cleantech-tarpeita on projektissa tarkasteltu. Lisaksi projektissa selvitettiin olemassa olevan tiedon avulla cleantech-sektorin tarpeita. Cleantech-osaamisen koulutustarvekartoitus tehtiin syksylla 2011, josta tarkempi koulutussuunnitelma cleantech-osaamisen parantamiseksi Paijat-Hameessa valmistui joulukuussa 2011. Kartoituksen ja yritysten haastattelujen pohjalta projektissa toteutettiin cleantech-osaamisen parantamiseksi koulutuksia vuosina 2012 – 2013. Koulutukset pureutuivat ajankohtaisiin teemoihin, kuten vihreaan ICT:hen, energia- ja materiaalitehokkuuteen, kestaviin hankintoihin seka ajankohtaisiin lainsaadannon vaatimuksiin. Tassa artikkelikokoelmassa kerrotaan Lahden ammattikorkeakoulun tekniikan alan koulutusohjelmien toimenpiteista, joilla alueen ja insinoorikoulutuksen cleantech-osaamista ja tyoelamavastaavuutta on parannettu. Raportin suomenkielisessa osassa on tarkasteltu cleantech-liiketoiminnan globaaleja markkinoita ja tulevaisuuden nakymia seka Suomen ja Lahden seudun cleantech-osaamista ja osaamistarpeita. Materiaalitekniikan koulutusohjelman artikkeleissa on kasitelty opintosuunnitelman muutostyota, joka kasittaa myos cleantech-nakokulman ja CDIO- / PBL-pedagogiikan sisallyttamisen opintosuunnitelmaan. Mekatroniikan koulutusohjelman artikkelissa on kasitelty CDIO- / PBL-pedagogiikan lahestymistapaa ja toteutumista kone- ja tuotantotekniikan koulutusohjelmassa. Raportin englanninkielinen osuus kasittelee ymparistoteknologian koulutusohjelman opintosuunnitelman muutosta, joka sisaltaa myos englanninkielisen ylemman ammattikorkeakoulututkinnon. Lisaksi englanninkieliset artikkelit kasittelevat tietotekniikan koulutusohjelman cleantech-nakokulmaa Green ICT -moduuleissa

Juvenile arthritis management in less resourced countries (JAMLess): consensus recommendations from the Cradle of Humankind

Juvenile idiopathic arthritis (JIA) is the most prevalent chronic rheumatic disease in children and young people (CYP) and a major cause of pain and disability. The vast majority of the world's children and their families live in less resourced countries (LRCs) and face significant socioeconomic and healthcare challenges. Current recommendations for standards of care and treatment for children with JIA do not consider children living in less resourced countries. In order to develop appropriate recommendations for the care of CYP with JIA in less resourced countries a meeting of experienced pediatric rheumatologists from less resourced countries was convened with additional input from a steering group of international pediatric rheumatologists with experience in developing recommendations and standards of care for JIA. Following a needs assessment survey of healthcare workers caring for CYP with JIA in LRC, a literature review was carried out and management recommendations formulated using Delphi technique and a final consensus conference. Responses from the needs assessment were received from 121/483 (25%) practitioners from 25/49 (51%) less resourced countries. From these responses, the initial 84 recommendations were refined and expanded through a series of 3 online Delphi rounds. A final list of 90 recommendations was proposed for evaluation. Evidence for each statement was reviewed, graded, and presented to the consensus group. The degree of consensus, level of agreement, and level of evidence for these recommendations are reported. Recommendations arrived at by consensus for CYP with JIA in less resourced countries cover 5 themes: (1) diagnosis, (2) referral and monitoring, (3) education and training, (4) advocacy and networks, and (5) research. Thirty-five statements were drafted. All but one statement achieved 100% consensus. The body of published evidence was small and the quality of evidence available for critical appraisal was low. Our recommendations offer novel insights and present consensus-based strategies for the management of JIA in less resourced countries. The emphasis on communicable and endemic diseases influencing the diagnosis and treatment of JIA serves as a valuable addition to existing JIA guidelines. With increasing globalization, these recommendations as a whole provide educational and clinical utility for clinicians worldwide. The low evidence base for our recommendations reflects a shortage of research specific to less resourced countries and serves as an impetus for further inquiry towards optimizing care for children with JIA around the world.status: publishe