Automated Pain Assessment in Children Using Electrodermal Activity and Video Data Fusion via Machine Learning.

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.

Youth and Parent Appraisals of Participation in a Study of Spontaneous and Induced Pediatric Clinical Pain.

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 0 (very negative) -to-10 (very positive) scale, both parents 9.4(1.3) [mean(SD)] and youth 7.9(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 they would tell another youth to participate. Ethical issues regarding instigation of pain in youth for research purposes are examined.

Human Eosinophils Express a Distinct Gene Expression Program in Response to IL-3 Compared with Common ß-Chain Cytokines IL-5 and GM-CSF.

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 ß 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 ß-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.

Automated Pain Assessment using Electrodermal Activity Data and Machine Learning.

Objective pain assessment is required for appropriate pain management in the clinical setting. However, clinical gold standard pain assessment is based on subjective methods. Automated pain detection from physiological data may provide important objective information to better standardize pain assessment. Specifically, electrodermal activity (EDA) can identify features of stress and anxiety induced by varying pain levels. However, notable variability in EDA measurement exists and research to date has demonstrated sensitivity but lack of specificity in pain assessment. In this paper, we use timescale decomposition (TSD) to extract salient features from EDA signals to identify an accurate and automated EDA pain detection algorithm to sensitively and specifically distinguish pain from no-pain conditions.

Automated Pain Detection in Facial Videos of Children using Human-Assisted Transfer Learning.

Accurately determining pain levels in children is difficult, even for trained professionals and parents. Facial activity provides sensitive and specific information about pain, and computer vision algorithms have been developed to automatically detect Facial Action Units (AUs) defined by the Facial Action Coding System (FACS). Our prior work utilized information from computer vision, i.e., automatically detected facial AUs, to develop classifiers to distinguish between pain and no-pain conditions. However, application of pain/no-pain classifiers based on automated AU codings across different environmental domains results in diminished performance. In contrast, classifiers based on manually coded AUs demonstrate reduced environmentally-based variability in performance. In this paper, we train a machine learning model to recognize pain using AUs coded by a computer vision system embedded in a software package called iMotions. We also study the relationship between iMotions (automatically) and human (manually) coded AUs. We find that AUs coded automatically are different from those coded by a human trained in the FACS system, and that the human coder is less sensitive to environmental changes. To improve classification performance in the current work, we applied transfer learning by training another machine learning model to map automated AU codings to a subspace of manual AU codings to enable more robust pain recognition performance when only automatically coded AUs are available for the test data. With this transfer learning method, we improved the Area Under the ROC Curve (AUC) on independent data from new participants in our target domain from 0.67 to 0.72.

Towards Automated Pain Detection in Children using Facial and Electrodermal Activity.

Accurately determining pain levels in children is difficult, even for trained professionals and parents. Facial activity and electro- dermal activity (EDA) provide rich information about pain, and both have been used in automated pain detection. In this paper, we discuss preliminary steps towards fusing models trained on video and EDA features respectively. We compare fusion models using original video features and those using transferred video features which are less sensitive to environmental changes. We demonstrate the benefit of the fusion and the transferred video features with a special test case involving domain adaptation and improved performance relative to using EDA and video features alone.

Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes.

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.

Potent benzoazepinone γ-secretase modulators with improved bioavailability.

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 Aß42 lowering maintained in both transgenic mouse and rat.

Discovery of novel triazolobenzazepinones as γ-secretase modulators with central Aß42 lowering in rodents and rhesus monkeys.

Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aß42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aß42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aß42 levels.

Automated Assessment of Children's Postoperative Pain Using Computer Vision.

BACKGROUND: Current pain assessment methods in youth are suboptimal and vulnerable to bias and underrecognition of clinical pain. Facial expressions are a sensitive, specific biomarker of the presence and severity of pain, and computer vision (CV) and machine-learning (ML) techniques enable reliable, valid measurement of pain-related facial expressions from video. We developed and evaluated a CVML approach to measure pain-related facial expressions for automated pain assessment in youth. METHODS: A CVML-based model for assessment of pediatric postoperative pain was developed from videos of 50 neurotypical youth 5 to 18 years old in both endogenous/ongoing and exogenous/transient pain conditions after laparoscopic appendectomy. Model accuracy was assessed for self-reported pain ratings in children and time since surgery, and compared with by-proxy parent and nurse estimates of observed pain in youth. RESULTS: Model detection of pain versus no-pain demonstrated good-to-excellent accuracy (Area under the receiver operating characteristic curve 0.84-0.94) in both ongoing and transient pain conditions. Model detection of pain severity demonstrated moderate-to-strong correlations (r = 0.65-0.86 within; r = 0.47-0.61 across subjects) for both pain conditions. The model performed equivalently to nurses but not as well as parents in detecting pain versus no-pain conditions, but performed equivalently to parents in estimating pain severity. Nurses were more likely than the model to underestimate youth self-reported pain ratings. Demographic factors did not affect model performance. CONCLUSIONS: CVML pain assessment models derived from automatic facial expression measurements demonstrated good-to-excellent accuracy in binary pain classifications, strong correlations with patient self-reported pain ratings, and parent-equivalent estimation of children's pain levels over typical pain trajectories in youth after appendectomy.

LP-925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents that improve glycemic control by inhibiting SGLT2-mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP-925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild-type (WT) mice. We first tested LP-925219 inhibition of glucose transport by HEK293 cells expressing SGLT1 or SGLT2, and then characterized LP-925219 pharmacokinetics. We found that LP-925219 was a potent inhibitor of mouse SGLT1 (IC50 = 22.6 nmol/L) and SGLT2 (IC50 = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half-life (7 h). We next delivered LP-925219 by oral gavage to WT, SGLT1 knockout (KO), SGLT2 KO, and SGLT1/SGLT2 double KO (DKO) mice and measured their 24-h UGE. We found that, in vehicle-treated mice, DKO UGE was maximal and SGLT2 KO, SGLT1 KO, and WT UGEs were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP-925219 dosed at 60 mg/kg twice daily increased UGE of SGLT1 KO, SGLT2 KO, and WT mice to DKO UGE levels. These findings show that orally available dual SGLT1/SGLT2 inhibitors can maximize 24-h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT2 inhibitors.

Variación de la neutralidad del PH salival a cinco minutos de ingesta de alimentos derivados del maíz en universitarios de 17 a 22 años / Variation of salivary pH neutrality at five minutes of ingestion of foods derived from corn in university students aged 17 to 22 years old

Objetivo: establecer la variación de la neutralidad en el pH salival a cinco minutos de la ingesta de alimentos derivados del maíz. Metodología: el diseño corresponde a un estudio observacional, transversal comparativo. El universo de estudio fue conformado por 125 universitarios, de los cuales se seleccionó la muestra por conveniencia, aplicando criterios de inclusión y exclusión, obteniendo una muestra de 60 estudiantes que fueron distribuidos al azar por medio de una tabla aleatoria en cuatro grupos correspondientes a cada uno de los tres alimentos seleccionados para el estudio y parafina. Previo a la recolección de muestras se indicó: no lavarse los dientes, comer o beber (excepto agua) no realizar ejercicio extenuante mínimo una hora antes de la recolección de saliva. Los datos se recolectaron en cuatro días, en un horario de 8:00 a 10:00 am, haciendo dos tomas de muestra de saliva, una antes de la ingesta de alimentos y masticación de parafina y otra a cinco minutos de la ingesta. Posteriormente ambas muestras de saliva fueron medidas por medio de un pH metro (METROHM 632 PH-METER) para determinar el pH salival que presentaban, se registraron los valores en cuatro tablas, una por cada grupo; conformadas por tres columnas que correspondían al número correlativo del estudiante, pH inicial y pH a cinco minutos de ingesta del alimento. Para el análisis de datos se empleó el paquete estadístico SPSS. Se realizó prueba t y análisis de varianza ANOVA, el nivel de significancia fue de 5%. Resultados: se encontró que las variaciones producidas por los alimentos derivados del maíz investigados no son significativas a los cinco minutos de ingesta (p 0,68), existiendo diferencias significativa entre los grupos de alimento (p 0,000). La única variación no significativa estadísticamente entre pH inicial y pH a cinco minutos de ingesta, fue para el grupo C (tamal de elote) (p 0,123). Las comparaciones entre grupo mostraron que no existen diferencias significativas estadísticamente entre los grupos A y D (p 0,797), B y C (p 0,359) y entre C y D (p 0,109). Conclusiones: los resultados evidencian que a 5 minutos de la ingesta, los alimentos derivados del maíz investigados no producen una variación del pH salival fuera del rango de neutralidad.

Objective: to establish the variation of neutrality in salivary pH five minutes after the ingestion of foods derived from corn. Methodology: the design corresponds to an observational, cross-sectional comparative study. The study universe was made up of 125 university students, of which the sample was selected for convenience, applying inclusion and exclusion criteria, obtaining a sample of 60 students who were randomly distributed through a random table into four groups corresponding to each one of the three foods selected for the study and paraffin. Before collecting samples, it was indicated: do not brush teeth, eat or drink (except water) do not perform strenuous exercise at least one hour before collecting saliva. The data was collected in four days, from 8:00 to 10:00 am, taking two saliva samples, one before eating food and chewing paraffin and another five minutes after ingestion. Subsequently, both saliva samples were measured by means of a pH meter (METROHM 632 PH-METER) to determine the salivary pH they presented, the values were recorded in four tables, one for each group; made up of three columns that corresponded to the correlative number of the student, initial pH and pH at five minutes of food intake. The SPSS statistical package was used for data analysis. T-test and ANOVA analysis of variance were performed; the level of significance was 5%. Results: it was found that the variations produced by the foods derived from the investigated corn are not significant after five minutes of ingestion (p 0.68), with significant differences between the food groups (p 0.000). The only statistically non-significant variation between initial pH and pH at five minutes of ingestion was for group C (corn tamale) (p 0.123). Comparisons between groups showed that there are no statistically significant differences between groups A and D (p 0.797), B and C (p 0.359) and between C and D (p 0.109). Conclusions: the results show that 5 minutes after ingestion, the foods derived from corn investigated do not produce a variation in salivary pH outside the neutrality range.

El costo y la toma de decisiones en las investigaciones de salud / The cost and decision making in health research

Se realizó un tema de actualidad con el objetivo de argumentar como la aplicación de la clasificación de los costos en las investigaciones en salud permiten lograr una mayor exactitud en los resultados obtenidos. Permite valorar lo relacionado con la utilización de recursos disponibles en el proceso de producción, consumo, distribución y financiamiento de la salud. Los costos son una importante herramienta que posibilita la toma de decisiones en la práctica asistencial diaria y en la elección de la mejor alternativa investigativa que permite valorar desde la pérdida social generada por la salud hasta el impacto económico, social y organizativo que implica sobre el individuo o sociedad la investigación. Sin dudas la aplicación del estudio de los costos garantiza la mayor eficiencia en los servicios prestados. Su correcta utilización logra el éxito del binomio calidad-eficiencia

A current topic was developed in order to explain how the application of the classification of costs in health research allows a greater accuracy in the obtained results. It allows assessing everything concerning the use of available resources in the process of production, consumption, distribution and health financing. Costs are an important tool that enables decision making in daily clinical practice and in choosing the best reseach alternative which allows to assess from either the social loss generated by health care or the economic, social and organizational impact that research implies for the individual or society. There is no doubt that the application of the study of the costs ensures greater efficiency in the services provided. Its proper use success in achieving the equality-efficiency binomial

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors.

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.

Triazoles as γ-secretase modulators.

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 Aß42 in Sprague-Dawley rats.

Role of specific cytochrome P450 isoforms in the conversion of phenoxypropoxybiguanide analogs in human liver microsomes to potent antimalarial dihydrotriazines.

Phenoxypropoxybiguanides, such as PS-15, are antimalarial prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, WR99210, the active metabolite of PS-15, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Recently, in vitro metabolism of a new series of phenoxypropoxybiguanide analogs has examined the production of the active triazine metabolites by human liver microsomes. The purpose of this investigation was to elucidate the primary cytochrome P450 isoforms involved in the production of active metabolites in the current lead candidate. By using expressed human recombinant isoform preparations, specific chemical inhibitors, and isoform-specific inhibitory antibodies, the primary cytochrome P450 isoforms involved in the in vitro metabolic activation of JPC-2056 were elucidated. Unlike proguanil, which is metabolized primarily by CYP2C19, the results indicate that CYP3A4 plays a more important role in the metabolism of both PS-15 and JPC-2056. Whereas CYP2D6 appears to play a major role in the metabolism of PS-15 to WR99210, it appears less important in the conversion of JPC-2056 to JPC-2067. These results are encouraging, considering the prominence of CYP2C19 and CYP2D6 polymorphisms in certain populations at risk for contracting malaria, because the current clinical prodrug candidate from this series may be less dependent on these enzymes for metabolic activation.

Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate--JPC2056--in cynomolgus monkeys using an in vivo in vitro model.

OBJECTIVES: To assess the antimalarial pharmacodynamics and pharmacokinetics of the novel dihydrofolate reductase (DHFR) inhibitor, JPC2056 and its principal active metabolite JPC2067 in cynomolgus monkeys using an in vivo-in vitro model. METHODS: In a two-phase crossover design, five cynomolgus monkeys were administered a single dose (20 mg/kg) and multiple doses (20 mg/kg daily for 3 days) of JPC2056. Plasma samples collected from treated monkeys were assessed for in vitro antimalarial activity against Plasmodium falciparum lines having wild-type (D6), double-mutant (K1) and quadruple-mutant (TM90-C2A) DHFR-thymidylate synthase (TS) and a P. falciparum line transformed with a Plasmodium vivax dhfr-ts quadruple-mutant allele (D6-PvDHFR). Plasma JPC2056 and JPC2067 concentrations were measured by LC-mass spectrometry. RESULTS: The mean inhibitory dilution (ID(90)) of monkey plasma at 3 h after drug administration against D6, K1 and TM90-C2A was, respectively, 1253, 585 and 869 after the single-dose regimen and 1613, 1120 and 1396 following the multiple-dose regimen. Less activity was observed with the same monkey plasma samples against the D6-PvDHFR line, with a mean ID(90) of 53 after multiple dosing. Geometric mean plasma concentrations of JPC2056 and JPC2067 at 3 h after drug administration were, respectively, 113 and 12 ng/mL after the single dose and 150 and 17 ng/mL after multiple dosing. The mean elimination half-life of JPC2056 was shorter than its metabolite after both regimens (single dose, 7.3 versus 11.8 h; multiple doses, 6.6 versus 11.1 h). CONCLUSIONS: The high potency of JPC2056 against P. falciparum DHFR-TS quadruple-mutant lines provides optimism for the future development of JPC2056 for the treatment of malaria infections.

In vitro and in vivo efficacy and in vitro metabolism of 1-phenyl-3-aryl-2-propen-1-ones against Plasmodium falciparum.

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.

Tetraoxane antimalarials and their reaction with Fe(II).

Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.

In vitro metabolism of phenoxypropoxybiguanide analogues in human liver microsomes to potent antimalarial dihydrotriazines.

Phenoxypropoxybiguanides, such as 1 (PS-15), are prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Unfortunately, manufacturing processes and gastrointestinal intolerance have prevented the clinical development of 1. In vitro antimalarial activity and in vitro metabolism studies have been performed on newly synthesized phenoxypropoxybiguanide analogues. All of the active dihydrotriazine metabolites exhibited potent antimalarial activity with in vitro IC(50) values less than 0.04 ng/mL. In vitro metabolism studies in human liver microsomes identified the production of not only the active dihydrotriazine metabolite, but also a desalkylation on the carbonyl chain, and multiple hydroxylated metabolites. The V(max) for production of the active metabolites ranged from 10.8 to 27.7 pmol/min/mg protein with the K(m) ranging from 44.8 to 221 microM. The results of these studies will be used to guide the selection of a lead candidate.