Search

Objective: Pain assessment in children continues to challenge clinicians and researchers, as subjective experiences of pain require inference through observable behaviors, both involuntary and deliberate. The presented approach supplements the subjective self-report-based method by fusing electrodermal activity (EDA) recordings with video facial expressions to develop an objective pain assessment metric. Such an approach is specifically important for assessing pain in children who are not capable of providing accurate self-pain reports, requiring nonverbal pain assessment. We demonstrate the performance of our approach using data recorded from children in post-operative recovery following laparoscopic appendectomy. We examined separately and combined the usefulness of EDA and video facial expression data as predictors of children's self-reports of pain following surgery through recovery. Findings indicate that EDA and facial expression data independently provide above chance sensitivities and specificities, but their fusion for classifying clinically significant pain vs. clinically nonsignificant pain achieved substantial improvement, yielding 90.91% accuracy, with 100% sensitivity and 81.82% specificity. The multimodal measures capitalize upon different features of the complex pain response. Thus, this paper presents both evidence for the utility of a weighted maximum likelihood algorithm as a novel feature selection method for EDA and video facial expression data and an accurate and objective automated classification algorithm capable ofdiscriminating clinically significant pain from clinically nonsignificant pain in children. [ABSTRACT FROM AUTHOR]

Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common β subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the β-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies. [ABSTRACT FROM AUTHOR]

The current study examined youths' and their parents' perceptions concerning participation in an investigation of spontaneous and induced pain during recovery from laparoscopic appendectomy. Youth (age range = 5–17 years) and their parents independently completed surveys about their study participation. On a scale from 0 (very negative) to 10 (very positive), both parents (M = 9.4, SD = 1.3) and youth (M = 7.9, SD = 2.4) rated their experience as positive. Among youth, experience ratings did not differ by pain severity and survey responses did not differ by age. Most youth (83%) reported that they would tell another youth to participate. Ethical issues regarding instigation of pain in youth for research purposes are examined. [ABSTRACT FROM AUTHOR]

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control. [ABSTRACT FROM AUTHOR]

The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer’s disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aβ42 lowering maintained in both transgenic mouse and rat. [ABSTRACT FROM AUTHOR]

Abstract: Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aβ42 in Sprague–Dawley rats. [Copyright &y& Elsevier]

Abstract: Investigation of a series of 1-phenyl-3-aryl-2-propen-1-ones resulted in the identification of nine inhibitors with submicromolar efficacy against at least one Plasmodium falciparum strain in vitro. These inhibitors were inactive when given orally in a Plasmodium berghei infected mouse model. Significant compound degradation occurred upon their exposure to a liver microsome preparation, suggesting metabolic instability may be responsible for the lack of activity in vivo. [Copyright &y& Elsevier]