Search

Purpose Guselkumab, an interleukin (IL)-23 inhibitor, effectively treats moderate-to-severe plaque psoriasis. Materials and methods ECLIPSE, was a Phase 3, multicenter, 56-week, double-blinded, active-comparator study of guselkumab vs. secukinumab (IL-17A inhibitor) in patients with moderate-to-severe psoriasis. Patients were treated with guselkumab 100 mg (n = 534) or secukinumab 300 mg (n = 514) through week 44. Efficacy (at least a 90% and 100% improvement from baseline in Psoriasis Area and Severity Index [PASI 90 and PASI 100], Investigator's Global Assessment [IGA] 0/1, and IGA 0) was analyzed across subpopulations defined by baseline: age ( Results Overall, 1048 patients were randomized. At week 48, numerically greater proportions of patients achieved PASI 90, PASI 100, IGA 0/1, and IGA 0 with guselkumab vs. secukinumab regardless of baseline age, body weight, BMI, disease severity, body region, and prior medication. The largest differences were in patients ≥65 years old and patients weighing >100 kg. Conclusions Guselkumab treatment provided greater efficacy vs. secukinumab at week 48 in most subpopulations of patients with psoriasis.

Background Guselkumab (GUS, an antibody against IL-23) and secukinumab (SEC, an antibody against IL-17A) are both approved for the treatment of psoriasis (PsO). Up to 30% of patients with PsO may have psoriatic arthritis (PsA). The ECLIPSE study compared efficacy and safety of GUS vs SEC in patients with plaque PsO. Post hoc analyses examined outcomes in the subgroup of patients with self-reported PsA. Methods ECLIPSE was a randomised, double-blind trial of adults with moderate-to-severe plaque PsO who received GUS 100 mg at Week (W)0, W4, then every 8 weeks, or SEC 300 mg at W0, W1, W2, W3, and W4, then every 4 weeks, both through W44. The primary endpoint was the proportion of patients achieving ≥90% improvement compared to baseline in the Psoriasis Area and Severity Index (PASI) score at W48. Cochran-Mantel Haenszel chi-square testing stratified by investigator was used to compare treatment-group responses. Results Overall, treatment groups [GUS (n = 534), SEC (n = 514)] were comparable at baseline: weight 89 kg, 24% body surface area PsO, and Investigator Global Assessment (IGA) moderate (76%) or severe (24%). These characteristics were similar to those of subgroups with self-reported PsA [GUS (n = 97), SEC (n = 79)]. In the overall population, the primary endpoint of PASI 90 response at W48 was achieved by 84.5% of GUS vs 70.0% of SEC patients (treatment difference 14.2 [95% CI = 9.6%, 18.8%], P < 0.001). Among patients with PsA, the primary endpoint of PASI 90 response at W48 was achieved by 82.5% of GUS vs 63.3% of SEC patients (treatment difference 19.2% [95% CI = 5.0%, 33.4%]). Beyond Week 20, in both the overall study population and the PsA subpopulation, GUS-treated patients maintained the PASI 90 response while SEC-treated patients had a reduction in response through W48. In the overall population, results of the first major secondary endpoint (proportion of patients with a PASI 75 response at both W12 and W48) showed non-inferiority of GUS vs SEC (GUS-84.6% vs SEC-80.2% of patients, p < 0.001), but superiority was not demonstrated (p = 0.062). Adverse events (AEs) observed in the overall population and PsA subgroup were generally consistent with the established safety profiles for GUS and SEC. Conclusion In the subset of patients with self-reported PsA in the ECLIPSE study, GUS demonstrated better maintenance of response and higher efficacy at approximately one year compared with SEC in the treatment of moderate to severe plaque PsO. These findings were consistent with those for the overall study population of patients with plaque PsO. AEs observed were generally consistent with the established safety profiles for GUS and SEC. Disclosures J.F. Merola: Other; J.M. has been a study investigator for Janssen. S. Li: Other; S.L. is a Janssen employee. M. Hsu: Other; M.H. is a Janssen employee. C. Karyekar: Other; C.K. is a Janssen employee. P.C. Gorecki: Other; P.G. is a Janssen employee. S. Flavin: Other; S.F. is a Janssen employee. B. Randazzo: Other; B.R. is a Janssen employee. L.C. Coates: Other; L.C. has been a study investigator for Janssen.

BACKGROUND Limited options are available for treatment of paediatric psoriasis. OBJECTIVES To evaluate the efficacy and safety of ustekinumab in paediatric patients with psoriasis (≥ 6 to 100 kg: 90 mg) administered by subcutaneous injection at weeks 0 and 4, then every 12 weeks through week 40. Study endpoints (all at week 12) included the proportions of patients achieving a Physician's Global Assessment score of cleared/minimal (PGA 0/1) and ≥ 75%/90% improvement in Psoriasis Area and Severity Index (PASI 75/90), and change in Children's Dermatology Life Quality Index (CDLQI). Serum ustekinumab concentrations, antidrug antibodies and cytokine levels were measured through week 52. Safety was evaluated through week 56. RESULTS In total, 44 patients (median age 9·5 years) received at least one dose of ustekinumab. Three patients discontinued the study agent through week 40. At week 12, 77% of patients achieved PGA 0/1, 84% achieved PASI 75 and 64% achieved PASI 90 response. The mean change in CDLQI was -6·3. Trough serum ustekinumab concentrations reached steady state at weeks 28-52. The incidence of antidrug antibodies was 10% (n = 4). Mean serum concentrations of interleukin-17A/F and interleukin-22 were significantly reduced at weeks 12 and 52. Overall, 34 patients (77%) had at least one adverse event and three (7%) had a serious adverse event. CONCLUSIONS Ustekinumab effectively treated moderate-to-severe psoriasis in paediatric patients, and no new safety concerns were identified. What is already known about this topic? Ustekinumab is approved for use in adolescents (≥ 12 to < 18 years of age) and adults (≥ 18 years) with moderate-to-severe psoriasis. What does this study add? Ustekinumab effectively treats moderate-to-severe psoriasis in paediatric patients (≥ 6 to < 12 years of age), with no new safety concerns. Linked Comment: Reich. Br J Dermatol 2020; 183:606-607.

Drug problem has contributed a rapid impact on today's society. It is not only a threat of human health but also causes a great impact on the social security issue. As drug abuse tends to organized crimes, we must consider the social network relationships among criminals to formulate better strategies against drugs. This research applied exponential random graph models (ERGMs) to analyze dynamic relations of drug crime. The strength of ERGMs is the ability to handle complicated dependency patterns which violate the basic assumption of traditional statistical methodologies. The homophily test and Monte Carlo Markov Chain (MCMC) estimation are used to explore the drug offenders' attributes and structural interactions, respectively. The experimental result shows that the homophily effect is significant on drug co-offenders relations regarding to occupation, education, nationality, drug type and recidivism. In addition, the positive 2-path coefficient indicates that drug offenders tend to share friends and form a cluster. The results of this paper reveal the advantages of structural implications in analyzing drug-related crime, as well as its ability to facilitate the cognition of crime prevention and intervention strategies.

This is a study on the development of carbon nanotube-based composite actuators using a new ionic liquid-doped electroactive ionic polymer. For scalable production purposes, a simple hot-pressing method was used. Carbon nanotube/ionic liquid-Nafion/carbon nanotube composite films were fabricated that exhibited a large output blocking force and a stable cycling life with low alternating voltage stimuli in air. Of particular interest and importance, a blocking force of 1.5 N was achieved at an applied voltage of 6 V. Operational durability was confirmed by testing in air for over 30 000 cycles (or 43 h). The superior actuation performance of the carbon nanotube/ionic liquid-Nafion/carbon nanotube composite, coupled with easy manufacturability, low driving voltage, and reliable operation, promises great potential for artificial muscle and biomimetic applications.

Introduction ECLIPSE est une etude de phase 3, randomisee, en double aveugle, multicentrique, controlee vs comparateur actif, visant a comparer l’efficacite et la tolerance du guselkumab (GUS) et du secukinumab (SEC) chez des patients atteints de psoriasis en plaques modere a severe. Le GUS a demontre une superiorite par rapport au SEC sur le critere principal d’evaluation: le PASI 90 a la semaine 48. L’objectif de cette analyse a ete d’evaluer la reponse au travers des scores de PASI absolu obtenus a la semaine 48 sous GUS et SEC dans cette etude. Materiel et methodes Les patients ont ete randomises pour recevoir 100 mg de GUS par injection sous-cutanee (SC) aux semaines 0, 4, 12, puis toutes les 8 semaines (n = 534) ou 300 mg de SEC par SC aux semaines 0, 1, 2, 3, 4, puis toutes les 4 semaines (n = 514), avec une derniere injection de GUS comme de SEC a la semaine 44. Les resultats d’efficacite obtenus a la semaine 48, fondes sur des seuils de PASI absolus de 0, ≤ 1 et ≤ 3, sont issus d’une analyse post hoc. Les donnees manquantes ont ete imputees comme « non-repondeur ». Resultats Les donnees demographiques et les caracteristiques de la maladie a l’inclusion etaient semblables d’un groupe de traitement a l’autre. Tel que rapporte precedemment, une proportion significativement plus elevee de patients du groupe GUS a atteint le critere d’evaluation principal de la reponse PASI 90 a la semaine 48 par rapport au groupe SEC (84,5 % vs 70,0 %, respectivement; p Conclusion Le traitement par GUS a permis d’obtenir des taux de reponse numeriquement plus eleves a la semaine 48 en terme de seuils de PASI absolus par rapport au SEC.

Introduction Le psoriasis est une maladie chronique necessitant un traitement a long terme. ECLIPSE est une etude de phase 3, randomisee, controlee, comparant l’efficacite du guselkumab (GUS) au secukinumab (SEC) sur 48 semaines pour le traitement du psoriasis en plaques modere a severe. Le GUS a demontre une superiorite par rapport au SEC pour le critere d’evaluation principal (proportion de patients repondeurs PASI 90 a la semaine 48 [S48]). Cette analyse a evalue l’efficacite en fonction des quartiles de masse corporelle (MC) et des categories d’indice de masse corporelle (IMC) a l’inclusion. Materiel et methodes Les patients ont ete randomises pour recevoir GUS 100 mg aux semaines 0, 4 et 12, puis toutes les 8 semaines (n = 534), ou SEC 300 mg aux semaines 0, 1, 2, 3 et 4, puis toutes les 4 semaines (n = 514), jusqu’a la semaine 44. Il n’y avait aucune restriction de poids pour participer a l’etude. Les criteres d’evaluation comprenaient les proportions de patients repondeurs PASI 90 et PASI 100 et de patients atteignant un score IGA 0 et IGA 0/1 a S48. Les donnees ont ete analysees par quartile de MC (Q1, ≤ 74 kg ; Q2, > 74 a ≤ 87 kg ; Q3, > 87 a ≤ 100 kg ; Q4, > 100 kg) et par categorie d’IMC (normal, Resultats Des proportions numeriquement plus elevees de patients ont obtenu des reponses PASI 90, PASI 100, IGA 0 et IGA 0/1 a S48 avec le GUS comparativement au SEC, dans tous les quartiles de MC ( Tableau 1 ). Les proportions de patients ayant atteint les principaux criteres d’efficacite a S48 dans les groupes GUS et SEC, respectivement (difference entre traitement[IC95 %]) par categorie d’IMC a l’inclusion etaient comme suit : PASI 90 : normal, 88,1 % vs 75,2 % (12,8 %[2,2 %, 23,5 %]) ; surpoids, 84,1 % vs 73,4 % (10,6 %[1,6 %, 19,7 %]) ; obeses, 82,5 % vs 65,3 % (17,2 %[8,8 %, 25,6 %]) ; PASI 100 : normal, 64,2 % vs 57,8 % (6,4 %[−6,8 %, 19,5 %]) ; surpoids, 61,4 % vs 53,7 % (7,7 %[−3,2 %, 18,5 %]) ; obeses, 52,5 % vs 40,4 % (12 %[2,4 %, 21,6 %]) ; IGA 0 : normal, 68,7 % vs 60,6 % (8,1 %[−4,8 %, 21,0 %]) ; surpoids, 64,2 % vs 54,2 % (10 %[−0,8 %, 20,7 %]) ; obeses, 57 % vs 43,1 % (13,8 %[4,2 %, 23,5 %]) ; IGA 0/1 : normal, 85,8 % vs 77,1 % (8,8 %[−1,9 %, 19,4 %]) ; surpoids, 86,9 % vs 81,9 % (5,0 %[−3,1 %, 13,1 %]) ; obeses, 83,0 % vs 63,9 % (13,6 %[5,4 %, 21,9 %]). Conclusion Dans les quartiles de MC et les categories d’IMC a l’inclusion, les taux de reponse a S48 etaient systematiquement plus eleves pour le GUS que pour le SEC, quels que soient les criteres, dans le traitement du psoriasis modere a severe.

Antibodies targeting interleukin (IL)-23 and IL-17A effectively treat moderate-to-severe psoriasis. ECLIPSE is the first comparator study of an IL-23p19 inhibitor, guselkumab, versus an IL-17A inhibitor, secukinumab. The primary objective of this study was to show superiority of clinical response at week 48 for guselkumab versus secukinumab.In this phase 3, multicentre, double-blind, randomised, comparator-controlled trial at 142 outpatient clinical sites in nine countries (Australia, Canada, Czech Republic, France, Germany, Hungary, Poland, Spain, and the USA), eligible patients were aged 18 years or older, had moderate-to-severe plaque-type psoriasis, and were candidates for phototherapy or systemic therapy. Eligible patients were randomly assigned with permuted block randomisation using an interactive web response system to receive either guselkumab (100 mg at weeks 0 and 4 then every 8 weeks) or secukinumab (300 mg at weeks 0, 1, 2, 3, and 4, and then every 4 weeks). The primary endpoint, the proportion of patients in the intention-to-treat population who achieved 90% reduction or more from baseline of Psoriasis Area and Severity Index (PASI 90 response) at week 48, and major secondary endpoints (the proportions of patients in the guselkumab group and in the secukinumab group who achieved a PASI 75 response at both weeks 12 and 48, a PASI 90 response at week 12, a PASI 75 response at week 12, a PASI 100 response at week 48, an Investigator's Global Assessment [IGA] score of 0 [cleared] at week 48, and an IGA score of 0 or 1 [minimal] at week 48) were to be tested in a fixed sequence to control type I error rate. Safety was evaluated in patients who received one or more doses of study drug from week 0 to 56. The study is registered with ClinicalTrials.gov, NCT03090100.This study was done between April 27, 2017, and Sept 20, 2018. 1048 eligible patients were enrolled and, of these, 534 were assigned to receive guselkumab and 514 to receive secukinumab. The proportion of patients with a PASI 90 response at week 48 was greater in the guselkumab group (451 [84%]) than in the secukinumab group (360 [70%]; p0·0001). Although non-inferiority (margin of 10 percentage points) was established for the first major secondary endpoint (452 [85%] of patients in the guselkumab group vs 412 [80%] of patients in the secukinumab group achieving a PASI 75 response at both weeks 12 and 48), superiority was not established (p=0·0616). Consequently, formal statistical testing was not done for subsequent major secondary endpoints. Proportions of patients with adverse events, infections, and serious adverse events were similar between the two treatments and, in general, safety findings were consistent with registrational trial observations.Guselkumab showed superior long-term efficacy based on PASI 90 at week 48 when compared with secukinumab for treating moderate-to-severe psoriasis. This finding could assist health-care providers in their decision making process when selecting a biologic for treating moderate-to-severe psoriasis.This study was funded by Janssen ResearchDevelopment.

Background Guselkumab (GUS, an antibody against IL-23) and secukinumab (SEC, an antibody against IL-17A) are both approved for the treatment of psoriasis (PsO). Up to 30% of patients with PsO may have psoriatic arthritis (PsA). Objectives The ECLIPSE study compared efficacy and safety of GUS vs SEC in patients with plaque PsO. Post hoc analyses examined outcomes in the subgroup of patients with self-reported psoriatic arthritis (PsA). Methods ECLIPSE was a randomized, double-blind trial of adults with moderate-to-severe plaque PsO who received GUS 100 mg at Weeks 0, 4, then every 8 weeks, or SEC 300 mg at Weeks 0, 1, 2, 3, and 4, then every 4 weeks, both through Week 44. The primary endpoint was the proportion of patients achieving ≥90% improvement compared to baseline in the Psoriasis Area and Severity Index (PASI) score at Week 48. Cochran-Mantel Haenszel chi-square testing stratified by investigator was used to compare treatment-group responses. Results Overall, treatment groups [GUS (n=534), SEC (n=514)] were comparable at baseline: weight 89kg, 24% body surface area PsO, and Investigator Global Assessment (IGA) moderate (76%) or severe (24%). These characteristics were similar to those of subgroups with self-reported PsA [GUS (n=97), SEC (n=79)]. In the overall population, the primary endpoint of PASI 90 response at Week 48 was achieved by 84.5% of GUS vs 70.0% of SEC patients (treatment difference 14.2 [95% CI=9.6%,18.8%], P Conclusion In the subset of patients with self-reported PsA in the ECLIPSE study, GUS demonstrated better maintenance of response and higher efficacy at approximately one year compared with SEC in the treatment of moderate to severe plaque PsO. These findings were consistent with those for the overall study population of patients with plaque PsO. AEs observed were generally consistent with the established safety profiles for GUS and SEC. Disclosure of Interests Joseph F Merola Grant/research support from: Janssen, Shu Li Employee of: Janssen Research & Development, LLC, Ming-Chun Hsu Employee of: Janssen Research & Development, LLC, Chetan Karyekar Shareholder of: J&J, Employee of: Janssen Scientific Affairs, LLC, Abbott, BMS, Novartis, Susan Flavin Employee of: Janssen Research & Development, LLC, Bruce Randazzo Employee of: Janssen Research & Development, LLC, Laura C Coates Grant/research support from: AbbVie, Celgene, Lilly, Novartis and Pfizer, Consultant for: AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead Sciences Inc., Janssen, Lilly, Novartis, Pfizer, Prothena Corp and UCB

Background: Previous studies showed conflicting results regarding the mortality risk in psoriasis patients with respect to disease severity and presence of psoriatic arthritis. This study aimed to determine the mortality risk in patients with mild and severe psoriasis and patients with psoriatic arthritis (PsA). Methods: A nationwide population-based cohort study was conducted based on data from the Taiwan National Health Insurance Research Database between 2002 and 2012. Incident psoriasis subjects were classified into two groups: psoriasis without arthritis and psoriasis with arthritis. Patients who had received systemic therapy and/or phototherapy were classified as having severe psoriasis, otherwise, patients were classified as having mild psoriasis. Control subjects without psoriasis were selected to match each psoriasis patient from the database within the same observational period. Cox proportional hazards analysis was used to compare the hazard ratio (HR) of time to death. Results: A total of 106,701 patients with psoriasis were included in this study. After controlling for demographics and comorbidities, psoriasis patients had a higher mortality risk compared with the control group (HR 1.41, 95% confidence interval (CI) 1.36 to 1.46). Compared with psoriasis alone, the mortality risk was not increased for PsA (HR = 1.01, 95% CI 0.93 to 1.10). Besides, severe psoriasis did not increase mortality risk compared with mild psoriasis (HR = 1.0, 95% CI 0.95 to 1.06). Conclusions: Patients with psoriasis had a higher mortality risk compared with control subjects, whereas psoriasis severity and presence of PsA had no impact on mortality risk in psoriasis patients.

Introduction ECLIPSE est une etude de phase 3, multicentrique, en double aveugle, controlee vs comparateur actif, comparant le guselkumab, un anticorps monoclonal anti-IL23, et le secukinumab, un anticorps monoclonal anti-IL17A, dans le traitement a long terme de patients adultes atteints de psoriasis en plaques modere a severe. Cette analyse a evalue la constance de la reponse sous guselkumab par rapport au secukinumab dans des sous-groupes de patients predefinis en fonction de l’âge a l’inclusion. Materiel et methodes Les patients adultes (≥ 18 ans) ont ete randomises pour recevoir 100 mg de guselkumab aux semaines 0, 4 et 12, puis toutes les 8 semaines (n = 534), ou 300 mg de secukinumab aux semaines 0, 1, 2, 3, 4, puis toutes les 4 semaines (n = 514) ; jusqu’a la semaine 44. Les patients randomises pour le guselkumab ont egalement recu des injections de placebo afin de faire correspondre le nombre et la frequence des injections a celles du secukinumab afin de maintenir l’aveugle. Les proportions de patients obtenant a la semaine 48 une reponse PASI 90, une reponse PASI 100 et un score IGA 0 ont ete analysees par categorie d’âge a l’inclusion : Resultats Les proportions de patients dans chaque categorie d’âge au debut de l’etude etaient globalement comparables entre les groupes guselkumab (n = 534) et secukinumab (n = 514) : Tableau 1 ). Les taux de reponse PASI 100 et le score IGA de 0 etaient aussi numeriquement plus eleves pour le guselkumab que pour le secukinumab, pour toutes les categories d’âge ( Tableau 1 ). Conclusion A la semaine 48, le groupe guselkumab a obtenu des taux de reponse numeriquement plus eleves que le secukinumab dans le traitement du psoriasis modere a severe quelles que soient les categories de patients definies par l’âge.

Introduction ECLIPSE est une etude de phase 3, multicentrique, en double aveugle, controlee vs comparateur actif, comparant le guselkumab, un anticorps monoclonal anti-IL23, et le secukinumab, un anticorps monoclonal anti-IL17, dans le traitement a long terme de patients adultes atteints de psoriasis en plaques modere a severe. Cette analyse a evalue la constance de la reponse sous guselkumab par rapport au secukinumab dans des sous-groupes de patients predefinis en fonction de la severite du psoriasis a l’inclusion. Materiel et methodes Les patients ont ete randomises pour recevoir 100 mg de guselkumab aux semaines 0, 4 et 12, puis toutes les 8 semaines (n = 534), ou 300 mg de secukinumab aux semaines 0, 1, 2, 3, 4, puis toutes les 4 semaines (n = 514), jusqu’a la semaine 44. Les patients randomises pour le guselkumab ont egalement recu des injections de placebo afin de faire correspondre le nombre et la frequence des injections a celles du secukinumab afin de maintenir l’aveugle. Les proportions de patients obtenant a la semaine 48 une reponse PASI 90, une reponse PASI 100 et un score IGA de 0 ont ete analysees par categories de criteres de severite de la maladie a l’inclusion : surface corporelle atteinte (SCA) Resultats Les caracteristiques de severite de la maladie a l’inclusion etaient comparables entre les groupes guselkumab (n = 534) et secukinumab (n = 514), respectivement : SCA 20 % (53,4 % vs 53,3 %), duree de la maladie 15 ans (58,4 % vs 53,5 %), score PASI 20 (35,6 % vs 36,6 %), et score IGA de 4 (23,8 % vs 23,7 %). Comme precedemment rapporte, dans l’ensemble de la population, une proportion significativement plus elevee de patients du groupe guselkumab ont obtenu une reponse PASI 90 a la semaine 48 par rapport au groupe secukinumab (84,5 % vs 70,0 %, p Conclusion A la semaine 48, le guselkumab presentait des taux de reponse numeriquement plus eleves que le secukinumab, quelles que soient les caracteristiques de severite du psoriasis a l’inclusion.

Background Phase 3 studies showed some patients maintained response for ≥6 months post-ustekinumab discontinuation. Objectives To assess clinical responses with extended ustekinumab maintenance dosing intervals. Methods Adults with moderate-to-severe plaque psoriasis received ustekinumab (45mg/90mg for weight ≤100 kg/>100 kg) at Week0, Week4, Week16 during open-label treatment. Patients achieving a Week 28 Physician's Global Assessment score of cleared/minimal (PGA=0/1) were randomized 1:4 to Group1 (approved every-12-weeks [q12wk] maintenance) or Group2 (q12-24wk response-based dosing determined by time–to-loss-of-PGA=0/1). Key endpoints included number of visits with PGA=0/1 (primary endpoint) and ≥75% improvement in Psoriasis Area and Severity Index (PASI75) between Weeks88-112, and PGA/PASI responses between Weeks28-112. Results 378 patients achieved PGA=0/1 at Week28 and were randomized to Group1 (n=76) or Group2 (n=302). Group1 patients had numerically greater mean numbers of visits with PGA=0/1 than Group2 (4.5 and 4.1, respectively; mean-difference [95%CI]: -0.46 [-1.20; 0.29]) and PASI75 (5.8 and 5.4, respectively; -0.32 [-0.96;0.33]) from Week88-112. A higher proportion of patients in Group1 (55.3%) than Group2 (38.7%) had PGA=0/1 at all seven Week88-112 visits. Maintenance of response was observed with dose-interval extension beyond q12wk (q16wk, q20wk, q24wk) in a subset of patients (28% of patients randomized to Group 2 extended maintenance dosing to q24wks and maintained high levels of response). Extending dosing interval did not affect antibody development or safety. Conclusions Efficacy was better maintained among Week28 PGA-responders randomized to continue q12wk ustekinumab versus extending maintenance dosing based on clinical response, although some patients maintained high levels of efficacy with up to q24wk dosing. This article is protected by copyright. All rights reserved.

Background Patients with psoriasis are known to have an increased number of cardiovascular (CV) risk factors and be at increased risk for CV events. Objectives We sought to describe and characterize the underdiagnosis and undertreatment of CV risk factors in patients with moderate to severe psoriasis. Methods Medical histories including diabetes, hypertension, and hyperlipidemia were obtained from 2899 patients in 3 phase III ustekinumab trials, a therapeutic anti-interleukin (IL)-12/IL-23p40 monoclonal antibody. Reported history was compared with measured fasting glucose, fasting lipids, and blood pressure. Ten-year Framingham risk scores and the proportion of patients achieving glycemic, lipid, and blood pressure targets were evaluated. Results Significant risk factors existed in patients with moderate to severe psoriasis (58.6% and 28.8% of patients had ≥2 and ≥3 established CV risk factors, respectively). Based on Framingham risk score, 18.6% of patients were at high risk and 12.3% were at intermediate risk for CV events. At baseline, a small proportion of patients with diabetes (2.3%), hypertension (9.1%), or hyperlipidemia (4.9%) were previously without a diagnosis. However, 19.1%, 21.8%, and 38.6% of patients with diabetes, hypertension, or hyperlipidemia, respectively, were untreated at baseline, and the proportion at treatment goal was not ideal (hypertension 59.6% and hyperlipidemia 69.7%), especially for diabetes (36.7%). Limitations Results are based on a clinical trial population and findings may not be generalizable to the general psoriasis population. Conclusions In this moderate to severe psoriasis population, a high prevalence of undiagnosed and undertreated CV risk factors existed, emphasizing the importance of screening patients with psoriasis for CV risk factors.

Flupirtine (Flu), a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu onK+currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifierK+current (IK(DR)) with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase ofIK(DR)inactivation rate was about 9.8 μM. Neither linopirdine (10 μM), NMDA (30 μM), nor gabazine (10 μM) reversed Flu-induced changes inIK(DR)inactivation. Addition of Flu shifted the inactivation curve ofIK(DR)to a hyperpolarized potential. Cumulative inactivation forIK(DR)was elevated in the presence of this compound. Flu increased the amplitude of M-typeK+current (IK(M)) and produced a leftward shift in the activation curve ofIK(M). In another neuronal cells (NG108-15), Flu reducedIK(DR)amplitude and enhanced the inactivation rate ofIK(DR). The results suggest that Flu acts as an open-channel blocker of delayed-rectifierK+channels in motor neurons. Flu-induced block ofIK(DR)is unlinked to binding to NMDA or GABA receptors and the effects of this agent onK+channels are not limited to its action on M-typeK+channels.

Rationale The brain circulation of the dentato-rubro-thalamo-cortical tract (DRTT) has been reported for decade, but is rarely observed using nuclear medicine imaging tools, to analyze a patient with midbrain hemiatrophy syndrome. We present a case that revealed notable interruption in the middle of the DRTT. Finding out whether the superior cerebellar peduncle of the midbrain was injured was a decisive element for developing bidirectional effect of DRTT. Patient concerns A 34-year-old right-handed female presented with progressive weakness and bradykinesia in the left-sided limbs for about 6 months. She had difficulty with hand dexterity for activities of daily life and general tasks. She reported poor balance during walking and sitting. Muscle strength was 3 in the left hand and 4 in the foot due to atrophy of left limbs. The circumference of 10 cm proximally/distally from the lateral epicondyle of the humerus was 25.7/23.8 cm at right and 24.2/20.8 cm at left in the upper limbs, and 15 cm proximally/distally from the lateral joint space was 42.1/35.0 cm at right and 43/30.8 cm at left in the lower limbs. The brain magnetic resonance imaging study revealed a small-sized right midbrain. Diagnosis Based on the distinct features of limbs atrophy and the locations of the lesions on the magnetic resonance (MR) imaging, the patient was diagnosed with midbrain hemiatrophy syndrome. Interventions The patient was only willing to accept physical and occupational training programs at our outpatient clinic. Outcomes We utilized serial anatomic and functional neuroimaging of the brain to survey the neurologic deficit. Brain perfusion single-photon emission computed tomography (SPECT) showed hypoperfusion over the left fronto-parietal regions, left anterior temporal region, and left occipital region, and also the left striatum and right cerebellum. Symptoms were gradually recovered with rehabilitation, and he was transferred to a rehabilitation facility on hospital day 40. Lessons This is the first report to demonstrate concurrent hypoperfusion of ipsilateral cerebellum and contralateral cerebral hemisphere observed on SPECT images in a case of midbrain hemiatrophy syndrome. In our case, with midbrain hemiatrophy syndrome could be explained as mutual direction effect of DRTT.

Background Ustekinumab has demonstrated significant efficacy and favorable safety in patients with moderate to severe psoriasis. Objective Characterization of patients achieving marked clinical responses (Psoriasis Area and Severity Index [PASI] 90 or Physician's Global Assessment [PGA] of cleared) in two double-blind, placebo-controlled, phase III studies. Methods PHOENIX 1 (n=766) and PHOENIX 2 (n=1,230) patients were randomized to receive placebo or ustekinumab 45 or 90 mg at weeks 0 and 4, then every 12 weeks. At week 12, placebo patients crossed over to ustekinumab. Marked responses, defined as PASI 90 or PGA of cleared, are reported. Results A significantly higher proportion of ustekinumab-treated patients in PHOENIX 1 (39.9%) and PHOENIX 2 (47.0%) achieved marked responses at week 12, compared with placebo-treated patients (pConclusion Significant proportions of ustekinumab-treated patients with moderate to severe psoriasis achieved marked clinical responses through week 28. Ustekinumab had a favorable risk-benefit profile through up to 18 months of follow-up.

Although nail psoriasis occurs frequently in patients with psoriatic skin lesions, effective treatments are limited.Occurrence of nail psoriasis by type and incidence of nail clearance using the Nail Psoriasis Severity Index were evaluated.This was a 50-week, phase III study in which 378 patients with moderate to severe psoriasis were randomized 4:1 to infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and every 8 weeks through week 46, with placebo crossover to infliximab at week 24.Of the 373 evaluated patients, 305 (81.8%) had baseline nail psoriasis. The right thumbnail was most often the worst involved nail, and pitting and onycholysis were the most common lesions. Among patients with baseline nail psoriasis, 6.9%, 26.2%, and 44.7% in the infliximab group had nail disease clearance at weeks 10, 24, and 50, respectively, versus 5.1% in the placebo group at week 24 (P.001). Mean percent improvements in Nail Psoriasis Severity Index score at weeks 10 and 24 were 26.8% and 57.2%, respectively, in the infliximab group versus -7.7% and -4.1%, respectively, in the placebo group (both P.001). At week 24, mean percent improvements in nail matrix and nail bed features were 52.9% and 69.2%, respectively (vs -1.9% and 18.4% for placebo; P.001).The study did not evaluate nail response beyond 1 year.Patients with psoriasis receiving infliximab experienced marked and sustained nail improvement.

QSFP connector is used for high bandwidth telecommunication and data communication applications. It has strict limitations on the thermal dissipation, the impedance mismatch and the electromagnetic interference. This paper proposes to modify the plastic fixture wafers and to insert additional internal heat sinker, thereby creating an new air flow channel in QSFP connector to enhance the thermal dissipation. Both the software simulation and the hardware measurement are applied to verify the performance of the proposed design. This paper also proposes an improved size design flow for the top-layer heat sinker by using Taguchi method. The designed signal factors, the control levels setup, the mathematical analysis on the simulation results are described to demonstrate the design flow.

Piceatannol is an anti-inflammatory and anti-proliferative plant-derived stilbene. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme to activate by various phytochemicals. In this study, we examined the ability of piceatannol to upregulate HO-1 expression in endothelial cells. We found piceatannol at micromolar (10-50 microM) concentrations dramatically increased HO-1 protein levels in a time-dependent manner. Piceatannol was similarly potent in the induction of HO-1 as hemin, arsenate, and 15d-PGJ2, and was more potent than some other phytochemicals including curcumin, EGCG, baicalein, and quercetin. In contrast, the similar chemical structure compounds, trans-stilbene, stilbene oxide, and resveratrol had no HO-1-inducing effects, suggesting a critical role for the hydroxyl groups in HO-1 induction. No cytotoxicity and superoxide production was observed after 10-50 microM piceatannol treatments. Piceatannol-mediated HO-1 induction was abrogated in the presence of N-acetylcysteine and glutathione, but not by other antioxidants. Induction of HO-1 by piceatannol was further enhanced by using buthionine sulfoximine. In addition, we determined that tyrosine kinase was involved in the induction of HO-1 by using tyrosine kinase inhibitors, herbimycin A, erbstatin, and genistein; in contrast, no significant changes in the pretreatment of PI3 kinase or MAP kinase inhibitors was determined. HO-1 induction was blocked by the protein kinase C inhibitors calphostin C, rottlerin, and long PMA pretreatment, whereas conventional PKC inhibitors, Go6976, and Ca2+ chelator BAPTA/AM, had no effect. Elevated HO-1 protein levels were associated with the inhibition of tumor necrosis factor-alpha (TNFalpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression. Treating ECs with zinc protoporphyrin, an HO-1 inhibito blocked the anti-inflammatory effect of piceatannol. In summary, this study identified piceatannol as a novel phytochemical inducer of HO-1 expression and identified the mechanisms involved in this process.

The convective heat transferred from the isothermal plate impinged by the jet flow with different reciprocating frequencies are studied computationally. A reciprocating jet impinges on the plate surface is available velocity to remove the heat from the plate surface, it implies that the reciprocating impinging jet is one of the good methods to enhance heat transferred from the plate surface

Summary Background Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited. Objectives To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study. Methods Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. Results In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. Conclusions Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.

Little is known about the impact of long-term use of immunosuppressive agents on immune response.Assess the impact of continuous maintenance ustekinumab treatment on patients' ability to mount immune responses to pneumococcal (T-cell-independent) and tetanus toxoid (T-cell-dependent) vaccines.Ustekinumab-treated patients with moderate-to-severe psoriasis treated in the long-term extension of the Phase 3 PHOENIX 2 trial (n=60) were compared with control psoriasis patients not receiving systemic therapy (n=56). Patients were vaccinated with both 23-valent pneumococcal and tetanus toxoid vaccines. Serum samples collected pre-vaccination and 4 weeks post-vaccination were assessed for antibody responses.No differences in the ability of ustekinumab-treated patients to respond to pneumococcal or tetanus toxoid vaccinations were observed compared with controls. A ≥2-fold increase in antibody levels in ≥7 of 14 serotypes of the pneumococcal vaccine was observed in ustekinumab-treated (96.6%) and untreated control (92.6%) patients following vaccination. Ustekinumab-treated patients achieved a ≥4-fold increase (84.7%) in anti-tetanus antibody vs. 77.8% in the control group. No differences were detected in ex-vivo responses to anti-CD3/CD28 or tetanus toxoid between ustekinumab-treated and control groups.Long-term treatment (≥3 years) with ustekinumab does not compromise the immune response to T-cell-dependent/-independent vaccines in patients with moderate-to-severe psoriasis.

The efficacy and safety profile of ustekinumab with up to three years of exposure suggested a favorable benefit-risk profile in patients with moderate to severe psoriasis.To evaluate the safety of ustekinumab in patients with moderate to severe psoriasis treated for up to four years.Safety data were pooled across four Phase II/III randomized controlled trials. Rates over time and cumulative rates of adverse events (AEs), AEs leading to treatment discontinuation, serious adverse events (SAEs), serious infections, malignancies, and major adverse cardiovascular events (MACE) (i.e., cardiovascular death, myocardial infarction [MI], or stroke as adjudicated by an independent panel of academic cardiologists) were evaluated. Observed rates of AEs of interest were compared with those expected in the general (malignancies, MI, and stroke) and psoriasis (serious infections, MI, and stroke) populations.Overall, 3,117 patients were followed for up to four years (6,791 patient-years). Rates of AEs, AEs leading to treatment discontinuation, and SAEs remained stable over time, whereas cumulative rates were generally comparable between patients who received 45 mg and 90 mg of ustekinumab. The rates of AEs of interest also remained stable over time, and cumulative rates per 100 patient-years were 0.80 and 1.32 (serious infections), 0.70 and 0.53 (nonmelanoma skin cancer), 0.63 and 0.61 (other malignancies), and 0.56 and 0.46 (MACE) in patients treated with 45 mg and 90 mg, respectively. Rates of AEs of interest were consistent with those in the general and psoriasis populations.The safety profile of long-term ustekinumab treatment with up to four years of continuous use remains consistent with previous reports, with no evidence of cumulative toxicity.

An ultra-wideband (UWB), high gain and low-noise amplifier (LNA) for wireless applications is presented in this paper. Operating at the frequency band of 0.8-6.0 GHz and fabricated in TSMC 0.18-um technology, the measured results show the gain of 17-19 dB, the noise figure (NF) less than 4.8 dB, the input third-order intercept point (IIP3) of -17 dBm, the reverse isolation less than -25 dB and the power dissipation of 43.2 mW at 1.8 V voltage supply. The chip area including pads is only 1.027mm2.

Background Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate-to-severe psoriasis. Objective To evaluate overall pooled study data to assess the safety profile of ustekinumab through 3 years of treatment. Methods Cumulative safety data were pooled from studies in 3117 ustekinumab-treated patients. Results During the placebo-controlled periods (Phase 2, PHOENIX 1, PHOENIX 2), rates of adverse events (AEs) were comparable among patients treated with placebo (50.4%), with ustekinumab 45 mg (57.6%), or with ustekinumab 90 mg (51.6%); similar findings were observed during the controlled period of the ACCEPT trial (etanercept: 70.0%; ustekinumab 45 mg: 66.0%; and ustekinumab 90 mg: 69.2%). Rates of serious AEs (SAEs) through the controlled periods were low and comparable among all groups (1.2% to 1.9%). Through 3 years, rates of AEs per 100 patient-years of follow-up (/100 patient-yrs) (45 mg: 305.2/100 patient-yrs; 90 mg: 305.9/100 patient-yrs) and SAEs (45 mg: 6.8/100 patient-yrs; 90 mg: 8.2/100 patient-yrs) were comparable between ustekinumab doses. No cases of demyelination or tuberculosis were reported in these trials. No dose response in rates of AEs, overall infections, or SAEs was apparent through 3 years. Rates of AEs, infections, SAEs, and AEs leading to study agent discontinuation remained generally stable or decreased over time. Limitations Controlled periods did not extend beyond 12 to 20 weeks. Only 1247 of the 3117 ustekinumab-treated patients were treated for 2 or more years. Conclusions The safety profile of continued ustekinumab exposure through up to 3 years is favorable and consistent with previous short-term reports.

In this work, we consider the problem of constructing linear-optimal designs for regression models, when some of the factors are not under the control of the experimenters. Such designs are referred to as marginally restricted (MR for brevity) linear-optimal designs. At first we make use of Frechet derivative to the general function o to characterize MR o-optimal designs. Then we apply this result to prove an equivalence theorem for MR linear-optimal designs. Particularly, we discuss applications to design problems in extrapolation at a point and A-optimality, which are special cases for linear criteria. An iterative algorithm for generating MR linear-optimal designs is also presented.

Background Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. Objective We sought to evaluate the impact of ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. Methods Rates of infections and malignancies were evaluated in cumulative safety data from 3117 ustekinumab-treated patients across 4 studies. Results During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45-mg (145.7), and ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. Limitations Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. Conclusions The emerging safety profile of ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years.

In Taiwan, speech technology development has been focused on Mandarin system; there is lack of related researches of domestic Taiwanese speech. This study is aimed to develop a HMM-based Taiwanese speech synthesis system, and the established sub-syllables units' database is used to be the synthesis units for all of the possible Taiwanese semantic syllables. The multiple accent corpus-based databases were developed by all combination of basic phonemes of vowels, consonants and 8-tones in Modern Literal Taiwanese (MLT) in this study. Based on the phoneme tables, this research provide fundamental database for speech analysis and synthesis in Taiwanese spelling systems. The principles and procedures in constructing phonetically balanced sentences are constituted by Taiwanese grammatical in syntax and semantics, and employ all the possible Taiwanese. Pattern recognition was applied to extract features' parameter codes including formants, pitch, amplitudes, and duration. The collected text corpus consists of MLT sentences and syllables from MLT books. A Taiwanese balanced sentences speech database including MLT sentences is established through training and analyzing system developed by windows programming, and another rare phoneme units are generated to be included in the database. The phonetic set of Taiwanese tonal phonemes is generated from the HTK recognition results. Through this research, the established TTS system may contribute to the education and training of native Taiwanese for the children, elder, and speech disabled.