High Dose Infliximab in the Treatment of Refractory Uveitis: Does Dose Matter?

Background. Infliximab (INF) has been shown to be beneficial in treating refractory uveitis, however, no data exist on optimal dosing and the efficacy of higher dosing. Objectives. To compare the efficacy of low-dose (LD) (<10 mg/kg), moderate-dose (MD) (≥10–15 mg/kg), and high-dose (HD) INF (≥15–20 mg/kg) in the treatment of uveitis. Methods. Retrospective chart review children with uveitis diagnosed at Childrens Hospital Los Angeles and Millers Children's Hospital, CA, USA. Results. Of the 34 INF-treated children, 6 patients received LD, 19 received MD, and 9 received HD. Average disease duration prior to therapy was 10.6, 24.6, and 37.1 months each group, respectively. Topical steroids were discontinued after an average of 3 months, 9.5 months, and 10.2 months in the LD, MD, and HD groups, respectively. We found that 66% of patients receiving LD, 42% of MD, and 66% receiving HD INF failed therapy and required either dose escalation or alternate medication for disease control. Conclusions. INF is beneficial in the treatment of uveitis, and dose escalation up to 4 times above the approved dose is often necessary to achieve disease control in patients with uveitis. Doses < 10 mg/kg every 4 weeks may not be sufficient to control disease

Coherence in macroscopic high harmonic generation for spatial focal phase distributions of monochromatic and broadband Gaussian laser pulses

Efficient application of ultrafast laser sources from high harmonic generation requires an understanding of how the spectrum can be controlled &ndash; the extent of the highest harmonics and the strength and cleanness of the harmonic lines. We study one important aspect in the coherent build-up of macroscopic high-order harmonic generation, namely the impact of different phase distributions in the focal area on the features of the generated radiation. Specifically, we compare the high harmonic signals for the commonly-used Gouy distribution of a monochromatic beam with those for the phase distribution of a short broadband Gaussian pulse. To this end, we apply a theoretical model in which the microscopic yields are obtained via interpolation of results of the time-dependent Schr&ouml;dinger equation, which are then used in an individual-emitter approach to determine the macroscopic signals. Regions of poor and good coherent build-up as a function of the position of the gas jet are identified using measures for the strength of the harmonic lines and for the impact of off-harmonic radiation. While the largest extent of the spectra as well as the strongest contribution of off-harmonic radiation is found for positioning the gas jet after the focus for both distributions, the relative strength of the harmonics is overall weaker for the short Gaussian pulse distribution and the spectra differ for a gas jet positioned at the focus. These differences are mainly caused by the additional dependence of the focal phase in the transverse direction for the short Gaussian pulse distribution. &nbsp;</p

Indentation Plastometry of Particulate Metal Matrix Composites, Highlighting Effects of Microstructural Scale

Herein, it is concerned with the use of profilometry-based indentation plastometry (PIP) to obtain mechanical property information for particulate metal matrix composites (MMCs). This type of test, together with conventional uniaxial testing, has been applied to four different MMCs (produced with various particulate contents and processing conditions). It is shown that reliable stress–strain curves can be obtained using PIP, although the possibility of premature (prenecking) fracture should be noted. Close attention is paid to scale effects. As a consequence of variations in local spatial distributions of particulate, the “representative volume” of these materials can be relatively large. This can lead to a certain amount of scatter in PIP profiles and it is advisable to carry out a number of repeat PIP tests in order to obtain macroscopic properties. Nevertheless, it is shown that PIP testing can reliably detect the relatively minor (macroscopic) anisotropy exhibited by forged materials of this type

Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate

Objectives Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment. Methods Children aged 4-17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, = 6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis). Conclusions Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate

Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing

Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center