Recent developments in anti-rheumatic drugs in pediatrics: treatment of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common autoimmune-autoinflammatory disease in childhood and affects approximately 1 in 1,000 children. Despite advances in diagnosis and treatment options, JIA remains a chronic condition for most affected children. Recent evidence suggests that disease control at onset may determine the tempo of subsequent disease course and long-term outcomes, and raises the concept of a therapeutic window of opportunity in patients with JIA. This underscores the importance of early aggressive treatment in patients with JIA. With the advent of novel biologic therapeutics, the repertoire of agents available for treatment of children with JIA has greatly increased. The present article will summarize recent developments in the medical treatment of children with JIA and will offer insights into emerging therapies

A 2200-year record of Andean Condor diet and nest site usage reflects natural and anthropogenic stressors

Understanding how animals respond to large-scale environmental changes is difficult to achieve because monitoring data are rarely available for more than the past few decades, if at all. Here, we demonstrate how a variety of palaeoecological proxies (e.g. isotopes, geochemistry and DNA) from an Andean Condor (Vultur gryphus) guano deposit from Argentina can be used to explore breeding site fidelity and the impacts of environmental changes on avian behaviour. We found that condors used the nesting site since at least approximately 2200 years ago, with an approximately 1000-year nesting frequency slowdown from ca 1650 to 650 years before the present (yr BP). We provide evidence that the nesting slowdown coincided with a period of increased volcanic activity in the nearby Southern Volcanic Zone, which resulted in decreased availability of carrion and deterred scavenging birds. After returning to the nest site ca 650 yr BP, condor diet shifted from the carrion of native species and beached marine animals to the carrion of livestock (e.g. sheep and cattle) and exotic herbivores (e.g. red deer and European hare) introduced by European settlers. Currently, Andean Condors have elevated lead concentrations in their guano compared to the past, which is associated with human persecution linked to the shift in diet.Fil: Duda, Matthew P.. Queen's University; CanadáFil: Grooms, Christopher. Queen's University; CanadáFil: Sympson, Lorenzo. Sociedad Naturalista Andino Patagonica; ArgentinaFil: Blais, Jules M.. University of Ottawa; CanadáFil: Dagodzo, Daniel. University of Ottawa; CanadáFil: Feng, Wenxi. Queen's University; CanadáFil: Hayward, Kristen M.. Queen's University; CanadáFil: Julius, Matthew L.. St. Cloud State University; Estados UnidosFil: Kimpe, Linda E.. University of Ottawa; CanadáFil: Lambertucci, Sergio Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; ArgentinaFil: Layton Matthews, Daniel. Queen's University; CanadáFil: Lougheed, Stephen. Queen's University; CanadáFil: Massaferro, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; ArgentinaFil: Michelutti, Neal. Queen's University; CanadáFil: Pufahl, Peir K.. Queen's University; CanadáFil: Vuletich, April. Queen's University; CanadáFil: Smol, John P.. Queen's University; Canad

Observational constraints on the physical nature of submillimetre source multiplicity : chance projections are common

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. © 2018 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.Interferometric observations have demonstrated that a significant fraction of single-dish submillimetre (submm) sources are blends of multiple submm galaxies (SMGs), but the nature of this multiplicity, i.e. whether the galaxies are physically associated or chance projections, has not been determined.We performed spectroscopy of 11 SMGs in six multicomponent submm sources, obtaining spectroscopic redshifts for nine of them. For an additional two component SMGs, we detected continuum emission but no obvious features.We supplement our observed sources with four single-dish submm sources from the literature. This sample allows us to statistically constrain the physical nature of single-dish submm source multiplicity for the first time. In three (3/7, or 43 -33 +39 per cent at 95 per cent confidence) of the single-dish sources for which the nature of the blending is unambiguous, the components for which spectroscopic redshifts are available are physically associated, whereas 4/7 (57 -39 +33 per cent) have at least one unassociated component. When components whose spectra exhibit continuum but no features and for which the photometric redshift is significantly different from the spectroscopic redshift of the other component are also considered, 6/9 (67 -37 +26 per cent) of the single-dish sources are comprised of at least one unassociated component SMG. The nature of the multiplicity of one single-dish source is ambiguous. We conclude that physically associated systems and chance projections both contribute to the multicomponent single-dish submm source population. This result contradicts the conventional wisdom that bright submm sources are solely a result of merger-induced starbursts, as blending of unassociated galaxies is also important.Peer reviewe

Sociocultural Determinants of Teenage Childbearing Among Latinas in California

Objectives U.S. Latinas have a persistently high rate of teenage childbearing, which is associated with adverse outcomes for both mother and child. This study was designed to investigate the roles of socioeconomic factors and acculturation in teenage childbearing in this population. Methods Logistic regression was used to analyze the association of measures of acculturation (language spoken at home, nativity, and age at immigration) and respondents’ parents’ education with age at first birth in a stratified sample of post-partum women in California. Results The unadjusted odds ratio for teenage birth for Latinas versus non-Latina Whites was 5.2 (95% CI 4.1–6.6). Nativity was not significantly associated with teen birth, but speaking Spanish at home was positively associated and immigrating at a later age was negatively associated with teen birth. Overall, these measures of acculturation accounted for 17% (95% CI 8–28%) of the difference in odds of teen birth between Latinas and non-Latina Whites. Higher levels of education among respondents’ parents had differentially protective effects across the racial/ethnic groups. Controlling for disparities in respondents’ parents’ education without changing its differential effects across racial/ethnic groups reduced the odds ratio for Latinas compared to non-Latina Whites by 30% (95% CI 14–60%). Conclusion These findings call into question common assumptions about the protective effect of acculturation on teen fertility and suggest that improving childhood socioeconomic factors among Latinas may decrease teen childbearing

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection

Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses