Plasma exosomes from children with juvenile dermatomyositis are taken up by human aortic endothelial cells and are associated with altered gene expression in those cells

BACKGROUND: The pathology of juvenile dermatomyositis (JDM) is characterized by prominent vessel wall and perivascular inflammation. This feature of the disease has remained unexplained and under-investigated. We have hypothesized that plasma exosomes, which play an important role in inter-cellular communication, may play a role in the vascular injury associated with JDM. OBJECTIVE: To characterize the circulating exosomes of children with JDM and determine whether the small RNA cargoes within those exosomes are capable of altering transcriptional programs within endothelial cells. DESIGN/METHODS: We purified exosomes from plasma samples of children with active, untreated JDM (n = 6) and healthy controls (n = 9). We characterized the small RNA cargoes in JDM and control exosomes by RNA sequencing using the Illumina HiSeq 2500 platform. We then incubated isolated exosomes from healthy controls and children with JDM with cultured human aortic endothelial cells (HAEC) for 24 h. Fluorescence microscopy was used to confirm that both control and JDM exosomes were taken up by HAEC. RNA was then purified from HAEC that had been incubated with either control or JDM exosomes and sequenced on the Illumina platform. Differential expression of mRNAs from HAEC incubated with control or JDM exosomes was ascertained using standard computational methods. Finally, we assessed the degree to which differential gene expression in HAEC could be attributed to the different small RNA cargoes in JDM vs control exosomes using conventional and novel analytic methods. RESULTS: We identified 10 small RNA molecules that showed differential abundance when we compared JDM and healthy control exosomes. Fluorescence microscopy of labeled exosomes confirmed that both JDM and control exosomes were taken up by HAEC. Differential gene expression analysis revealed 59 genes that showed differential expression between HAEC incubated with JDM exosomes vs HAEC incubated with exosomes from controls. Statistical analysis of gene expression data demonstrated that multiple miRNAs exerted transcriptional control on multiple genes with HAEC. CONCLUSIONS: Plasma exosomes from children with active, untreated JDM are taken up by HAEC and are associated with alterations in gene expression in those cells. These findings provide new insight into potential mechanisms leading to the targeting of vascular tissue by the immune system in JDM

Adipose Tissue Distribution and Survival Among Women with Nonmetastatic Breast Cancer.

ObjectivePrevious studies of breast cancer survival have not considered specific depots of adipose tissue such as subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT).MethodsThis study assessed these relationships among 3,235 women with stage II and III breast cancer diagnosed between 2005 and 2013 at Kaiser Permanente Northern California and between 2000 and 2012 at Dana Farber Cancer Institute. SAT and VAT areas (in centimeters squared) were calculated from routine computed tomography scans within 6 (median: 1.2) months of diagnosis, covariates were collected from electronic health records, and vital status was assessed by death records. Hazard ratios (HRs) and 95% CIs were estimated using Cox regression.ResultsSAT and VAT ranged from 19.0 to 891 cm2 and from 0.484 to 454 cm2 , respectively. SAT was related to increased risk of death (127-cm2 increase; HR [95% CI]: 1.13 [1.02-1.26]), but no relationship was found with VAT (78.18-cm2 increase; HR [95% CI]: 1.02 [0.91-1.14]). An association with VAT was noted among women with stage II cancer (stage II: HR: 1.17 [95% CI: 0.99-1.39]; stage III: HR: 0.90 [95% CI: 0.76-1.07]; P interaction < 0.01). Joint increases in SAT and VAT were associated with mortality above either alone (simultaneous 1-SD increase: HR 1.19 [95% CI: 1.05-1.34]).ConclusionsSAT may be an underappreciated risk factor for breast cancer-related death

Purpose in the Machine: Do Traffic Simulators Produce Distributionally Equivalent Outcomes for Reinforcement Learning Applications?

Traffic simulators are used to generate data for learning in intelligent transportation systems (ITSs). A key question is to what extent their modelling assumptions affect the capabilities of ITSs to adapt to various scenarios when deployed in the real world. This work focuses on two simulators commonly used to train reinforcement learning (RL) agents for traffic applications, CityFlow and SUMO. A controlled virtual experiment varying driver behavior and simulation scale finds evidence against distributional equivalence in RL-relevant measures from these simulators, with the root mean squared error and KL divergence being significantly greater than 0 for all assessed measures. While granular real-world validation generally remains infeasible, these findings suggest that traffic simulators are not a deus ex machina for RL training: understanding the impacts of inter-simulator differences is necessary to train and deploy RL-based ITSs.Comment: 12 pages; accepted version, published at the 2023 Winter Simulation Conference (WSC '23

Effect of ovariectomy on the progression of chronic kidney disease-mineral bone disorder (CKD-MBD) in female Cy/+ rats

Male Cy/+ rats have shown a relatively consistent pattern of progressive kidney disease development that displays multiple key features of late stage chronic kidney disease-mineral bone disorder (CKD-MBD), specifically the development of cortical bone porosity. However, progression of disease in female Cy/+ rats, assessed in limited studies, is more heterogeneous and to date has failed to show development of the CKD-MBD phenotype, thus limiting their use as a practical model of progressive CKD-MBD. Animal and human studies suggest that estrogen may be protective against kidney disease in addition to its established protective effect on bone. Therefore, in this study, we aimed to determine the effect of ovariectomy (OVX) on the biochemical and skeletal manifestations of CKD-MBD in Cy/+ female rats. We hypothesized that OVX would accelerate development of the biochemical and skeletal features of CKD-MBD in female Cy/+ rats, similar to those seen in male Cy/+ rats. Female Cy/+ rats underwent OVX (n = 8) or Sham (n = 8) surgery at 15 weeks of age. Blood was collected every 5 weeks post-surgery until 35 weeks of age, when the rats underwent a 4-day metabolic balance, and the tibia and final blood were collected at the time of sacrifice. OVX produced the expected changes in trabecular and cortical parameters consistent with post-menopausal disease, and negative phosphorus balance compared with Sham. However, indicators of CKD-MBD were similar between OVX and Sham (similar kidney weight, plasma blood urea nitrogen, creatinine, creatinine clearance, phosphorus, calcium, parathyroid hormone, and no cortical porosity). Contrary to our hypothesis, OVX did not produce evidence of development of the CKD-MBD phenotype in female Cy/+ rats

The value of kinetic glomerular filtration rate estimation on medication dosing in acute kidney injury.

BackgroundIn acute kidney injury (AKI), medication dosing based on Cockcroft-Gault creatinine clearance (CrCl) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rates (eGFR) are not valid when serum creatinine (SCr) is not in steady state. The aim of this study was to determine the impact of a kinetic estimating equation that incorporates fluctuations in SCrs on drug dosing in critically ill patients.MethodsWe used data from participants enrolled in the NIH Acute Respiratory Distress Syndrome Network Fluid and Catheters Treatment Trial to simulate drug dosing category changes with the application of the kinetic estimating equation developed by Chen. We evaluated whether kinetic estimation of renal function would change medication dosing categories (≥60, 30-59, 15-29, and <15mL/min) compared with the use of CrCl or CKD-EPI eGFR.ResultsThe use of kinetic CrCl and CKD-EPI eGFR resulted in a large enough change in estimated renal function to require medication dosing recategorization in 19.3% [95 CI 16.8%-21.9%] and 23.4% [95% CI 20.7%-26.1%] of participants, respectively. As expected, recategorization occurred more frequently in those with AKI. When we examined individual days for those with AKI, dosing discordance was observed in 8.5% of total days using the CG CrCl and 10.2% of total days using the CKD-EPI equation compared with the kinetic counterparts.ConclusionIn a critically ill population, use of kinetic estimates of renal function impacted medication dosing in a substantial proportion of AKI participants. Use of kinetic estimates in clinical practice should lower the incidence of medication toxicity as well as avoid subtherapeutic dosing during renal recovery

Crack opening behavior in ceramic matrix composites

The evolution of matrix cracks in a melt‐infiltrated SiC/SiC ceramic matrix composite (CMC) under uniaxial tension was examined using scanning electron microscopy (SEM) combined with digital image correlation (DIC) and manual crack opening displacement (COD) measurements. CMC modeling and life prediction strongly depend a thorough understanding of when matrix cracks occur, the extent of cracking for given conditions (time‐temperature‐environment‐stress), and the interactions of matrix cracks with fibers and interfaces. In this work, strain relaxation due to matrix cracking, the relationship between CODs and applied stress, and damage evolution at stresses below the proportional limit were assessed. Direct experimental observation of strain relaxation adjacent to regions of matrix cracking is presented and discussed. Additionally, crack openings were found to increase linearly with increasing applied stress, and no crack was found to pass fully through the gage cross‐section. This calls into question the modeling assumption of through‐cracks for all loading conditions and fiber architectures, which can obscure oxidation mechanisms that are active in realistic cracking conditions. Finally, the combination of SEM with DIC is demonstrated throughout to be a powerful means for damage identification and quantification in CMCs at stresses well below the proportional limit.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138389/1/jace14976_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138389/2/jace14976.pd

Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content.

A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling. Here, we show that OCT1, widely characterized as a drug transporter, plays a key role in modulating hepatic glucose and lipid metabolism, potentially by mediating thiamine (vitamin B1) uptake and hence its levels in the liver. Deletion of Oct1 in mice resulted in reduced activity of thiamine-dependent enzymes, including pyruvate dehydrogenase (PDH), which disrupted the hepatic glucose-fatty acid cycle and shifted the source of energy production from glucose to fatty acids, leading to a reduction in glucose utilization, increased gluconeogenesis, and altered lipid metabolism. In turn, these effects resulted in increased total body adiposity and systemic levels of glucose and lipids. Importantly, wild-type mice on thiamine deficient diets (TDs) exhibited impaired glucose metabolism that phenocopied Oct1 deficient mice. Collectively, our study reveals a critical role of hepatic thiamine deficiency through OCT1 deficiency in promoting the metabolic inflexibility that leads to the pathogenesis of cardiometabolic disease

ComprehENotes, an Instrument to Assess Patient Reading Comprehension of Electronic Health Record Notes: Development and Validation

BACKGROUND: Patient portals are widely adopted in the United States and allow millions of patients access to their electronic health records (EHRs), including their EHR clinical notes. A patient\u27s ability to understand the information in the EHR is dependent on their overall health literacy. Although many tests of health literacy exist, none specifically focuses on EHR note comprehension. OBJECTIVE: The aim of this paper was to develop an instrument to assess patients\u27 EHR note comprehension. METHODS: We identified 6 common diseases or conditions (heart failure, diabetes, cancer, hypertension, chronic obstructive pulmonary disease, and liver failure) and selected 5 representative EHR notes for each disease or condition. One note that did not contain natural language text was removed. Questions were generated from these notes using Sentence Verification Technique and were analyzed using item response theory (IRT) to identify a set of questions that represent a good test of ability for EHR note comprehension. RESULTS: Using Sentence Verification Technique, 154 questions were generated from the 29 EHR notes initially obtained. Of these, 83 were manually selected for inclusion in the Amazon Mechanical Turk crowdsourcing tasks and 55 were ultimately retained following IRT analysis. A follow-up validation with a second Amazon Mechanical Turk task and IRT analysis confirmed that the 55 questions test a latent ability dimension for EHR note comprehension. A short test of 14 items was created along with the 55-item test. CONCLUSIONS: We developed ComprehENotes, an instrument for assessing EHR note comprehension from existing EHR notes, gathered responses using crowdsourcing, and used IRT to analyze those responses, thus resulting in a set of questions to measure EHR note comprehension. Crowdsourced responses from Amazon Mechanical Turk can be used to estimate item parameters and select a subset of items for inclusion in the test set using IRT. The final set of questions is the first test of EHR note comprehension