Research priorities in pediatric rheumatology: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus

<p>Abstract</p> <p>Background</p> <p>North American pediatric rheumatologists have created an investigator-initiated research network (the Childhood Arthritis and Rheumatology Research Alliance – CARRA) to facilitate multi-centre studies. One of the first projects undertaken by this network was to define, by consensus, research priorities for the group, and if possible a first group-sponsored clinical trial in which all members could participate.</p> <p>Methods</p> <p>We determined consensus using the Delphi approach. This approach has been used extensively in health research to reach consensus in large groups. It uses several successive iterations of surveys eliciting ideas and opinions from specialists in the field. Three surveys were designed based on this method and were distributed to members of CARRA to elicit and rank-order research priorities.</p> <p>Results</p> <p>A response rate of 87.6% was achieved in the final survey. The most highly ranked research suggestion was to study infliximab treatment of uveitis unresponsive to methotrexate. Other highly ranked suggestions were to study i) the treatment of systemic arthritis with anakinra and ii) the treatment of pediatric systemic lupus erythematosus with mycophenolate mofetil.</p> <p>Conclusion</p> <p>The Delphi approach was an effective and practical method to define research priorities in this group. Ongoing discussion and cooperation among pediatric rheumatologists in CARRA and others world-wide will help in developing further research priorities and to facilitate the execution of clinical trials in the future.</p

Research-based versus clinical serum creatinine measurements and the association of acute kidney injury with subsequent kidney function: findings from the Chronic Renal Insufficiency Cohort study.

Background:Observational studies relying on clinically obtained data have shown that acute kidney injury (AKI) is linked to accelerated chronic kidney disease (CKD) progression. However, prior reports lacked uniform collection of important confounders such as proteinuria and pre-AKI kidney function trajectory, and may be susceptible to ascertainment bias, as patients may be more likely to undergo kidney function testing after AKI. Methods:We studied 444 adults with CKD who participated in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study and were concurrent members of a large integrated healthcare delivery system. We estimated glomerular filtration rate (eGFR) trajectories using serum creatinine measurements from (i) the CRIC research protocol (yearly) and (ii) routine clinical care. We used linear mixed effects models to evaluate the associations of AKI with acute absolute change in eGFR and post-AKI eGFR slope, and explored whether these varied by source of creatinine results. Models were adjusted for demographic characteristics, diabetes status and albuminuria. Results:During median follow-up of 8.5 years, mean rate of eGFR loss was -0.31 mL/min/1.73&nbsp;m2/year overall, and 73 individuals experienced AKI (55% Stage 1). A significant interaction existed between AKI and source of serum creatinine for acute absolute change in eGFR level after discharge; in contrast, AKI was independently associated with a faster rate of eGFR decline (mean additional loss of -0.67 mL/min/1.73&nbsp;m2/year), which was not impacted by source of serum creatinine. Conclusions:AKI is independently associated with subsequent steeper eGFR decline regardless of the serum creatinine source used, but the strength of association is smaller than observed in prior studies after taking into account key confounders such as pre-AKI eGFR slope and albuminuria

Aerobic Exercise during Pregnancy and Presence of Fetal-Maternal Heart Rate Synchronization

It has been shown that short-term direct interaction between maternal and fetal heart rates may take place and that this interaction is affected by the rate of maternal respiration. The aim of this study was to determine the effect of maternal aerobic exercise during pregnancy on the occurrence of fetal-maternal heart rate synchronization.In 40 pregnant women at the 36th week of gestation, 21 of whom exercised regularly, we acquired 18 min. RR interval time series obtained simultaneously in the mothers and their fetuses from magnetocardiographic recordings. The time series of the two groups were examined with respect to their heart rate variability, the maternal respiratory rate and the presence of synchronization epochs as determined on the basis of synchrograms. Surrogate data were used to assess whether the occurrence of synchronization was due to chance.In the original data, we found synchronization occurred less often in pregnancies in which the mothers had exercised regularly. These subjects also displayed higher combined fetal-maternal heart rate variability and lower maternal respiratory rates. Analysis of the surrogate data showed shorter epochs of synchronization and a lack of the phase coordination found between maternal and fetal beat timing in the original data.The results suggest that fetal-maternal heart rate coupling is present but generally weak. Maternal exercise has a damping effect on its occurrence, most likely due to an increase in beat-to-beat differences, higher vagal tone and slower breathing rates

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

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

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

The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods

<p>Abstract</p> <p>Background</p> <p>The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors.</p> <p>Methods</p> <p>The Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study was established to examine how a hospitalized episode of AKI independently affects the risk of chronic kidney disease development and progression, cardiovascular events, death, and other important patient-centered outcomes. This prospective study will enroll a cohort of 1100 adult participants with a broad range of AKI and matched hospitalized participants without AKI at three Clinical Research Centers, as well as 100 children undergoing cardiac surgery at three Clinical Research Centers. Participants will be followed for up to four years, and will undergo serial evaluation during the index hospitalization, at three months post-hospitalization, and at annual clinic visits, with telephone interviews occurring during the intervening six-month intervals. Biospecimens will be collected at each visit, along with information on lifestyle behaviors, quality of life and functional status, cognitive function, receipt of therapies, interim renal and cardiovascular events, electrocardiography and urinalysis.</p> <p>Conclusions</p> <p>ASSESS-AKI will characterize the short-term and long-term natural history of AKI, evaluate the incremental utility of novel blood and urine biomarkers to refine the diagnosis and prognosis of AKI, and identify a subset of high-risk patients who could be targeted for future clinical trials to improve outcomes after AKI.</p