A Toolbox for Personalized Medicine of Methotrexate Therapy in Arthritis

__Abstract__ Rheumatoid arthritis (RA) is a chronic autoimmune disease. It is characterized by swelling and pain of the joints, uncontrolled proliferation of synovial tissue and multisystem co-morbidities like cardiovascular disease and thyroid disease. RA mainly affects the joints of the extremities like hands, feet, knees, wrist and elbows. Joint damage can occur early in the disease course when the disease is not treated effectively. More than 21% of United states adults (46.4 million persons) were found to have self-reported physician diagnosed arthritis. The specific diagnose of RA has a prevalence of 1%. The prevalence of RA among women is approximately double that in men. There is still no cure for RA, despite the fact that treatment strategy has changed considerably over the years. Early initiation of therapy is effective in prevention of joint damage and results in milder medication regimens while maintaining disease remission. Early in the disease, inflammation is less self-perpetuating and easier to suppress, therefore it is important to start treatment as early as possible in order to optimize outcome, minimize medical costs, improve quality o

Neural Circuits Subserving the Retrieval of Stems and Grammatical Features in Regular and Irregular Verbs

Many languages, including English and Spanish, feature regular (dance 3 danced) and irregular (catch 3 caught) inflectional systems. According to psycholinguistic theories, regular and irregular inflections are instantiated either by a single or by two specialized mechanisms. Those theories differ in their assumptions concerning the underlying information necessary for the processing of regular verbs. Whereas single mechanism accounts have stated an increased involvement of phonological processing for regular verbs, dual accounts emphasize the prominence of grammatical information. Using event-related functional magnetic resonance imaging, we sought to delineate the brain areas involved in the generation of complex verb forms in Spanish. This language has the advantage of isolating specific differences in the regular-irregular contrasts in terms of the number of stems associated with a verb while controlling for compositionality (regular and irregular verbs apply suffixes to be inflected). The present study showed that areas related to grammatical processing are active for both types of verbs (left opercular inferior frontal gyrus). In addition, major differences between regular and irregular verbs were also observed. Several areas of the prefrontal cortex were selectively active for irregular production, presumably reflecting their role in lexical retrieval (bilateral inferior frontal area and dorsolateral prefrontal cortex). Regular verbs, however, showed increased activation in areas related to grammatical processing (anterior superior temporal gyrus/insular cortex) and in the left hippocampus, the latter possibly related to a greater implication of the phonological loop necessary for the reutilization of the same stem shared across all forms in regular verbs

Higher baseline global leukocyte DNA methylation is associated with MTX non-response in early RA patients

BACKGROUND: Low-dose methotrexate (MTX) is the first-line therapy in early rheumatoid arthritis (eRA). Up to 40% of eRA patients do not benefit from MTX therapy. MTX has been shown to inhibit one-carbon metabolism, which is involved in the donation of methyl groups. In this study, we investigate baseline global DNA methylation and changes in DNA methylation during treatment in relation to clinical non-response after 3 months of MTX treatment. METHODS: Two hundred ninety-four blood samples were collected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, ISRCTN26791028), a multicenter, stratified single-blind clinical trial of eRA patients. Global DNA (hydroxy)methylation was quantified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and validated with a global DNA LINE-1 methylation technique. MTX response was determined as ΔDAS28. Additionally, patients were stratified into two response groups according to the European League Against Rheumatism (EULAR) response criteria. Associations between global DNA methylation and response were examined using univariate regression models adjusted for baseline DAS28, baseline erythrocyte folate levels, and body mass index (BMI). RESULTS: Higher baseline global DNA methylation was associated with less decrease of DAS28 (β = 0.15, p = 0.013) and with MTX non-response (OR = 0.010, 95% CI = 0.001-0.188). This result was validated in LINE-1 elements (β = 0.22, p = 0.026). Changes in global DNA (hydroxy)methylation were not associated with MTX response over 3 months. CONCLUSIONS: These results show that higher baseline global DNA methylation in treatment naïve eRA patients is associated with decreased clinical response after 3 months of treatment of eRA patients and can be further evaluated as a predictor for MTX therapy non-response. TRIAL REGISTRATION: ISRCTN, ISRCTN26791028 , registered 23 August 2007-retrospectively registered

Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis

Objective The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients. Methods A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis. Results The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m2, ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folate<750 nmol/L. In the derivation cohort, AUC of ROC curve was 0.80 (95%CI: 0.73–0.86), and 0.80 (95%CI: 0.69–0.91) in the validation cohort. Betas of the prediction model were transformed into total risk score (range 0–8). At cutoff of 4, probability for insufficient response was 44%. Sensitivity was 71%, specificity 72%, with positive and negative predictive value of 72% and 71%. Conclusions A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX

Complex machine-learning algorithms and multivariable logistic regression on par in the prediction of insufficient clinical response to methotrexate in rheumatoid arthritis

The goals of this study were to examine whether machine-learning algorithms outper-form multivariable logistic regression in the prediction of insufficient response to methotrexate (MTX); secondly, to examine which features are essential for correct prediction; and finally, to in-vestigate whether the best performing model specifically identifies insufficient responders to MTX (combination) therapy. The prediction of insufficient response (3-month Disease Activity Score 28-Erythrocyte-sedimentation rate (DAS28-ESR) > 3.2) was assessed using logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, and extreme gradient boosting (XGBoost). The baseline features of 355 rheumatoid arthritis (RA) patients from the “treatment in the Rotterdam Early Arthritis CoHort” (tREACH) and the U-Act-Early trial were combined for analyses. The model performances were compared using area under the curve (AUC) of receiver operating characteristic (ROC) curves, 95% confidence intervals (95% CI), and sensitivity and specificity. Fi-nally, the best performing model following feature selection was tested on 101 RA patients starting tocilizumab (TCZ)-monotherapy. Logistic regression (AUC = 0.77 95% CI: 0.68–0.86) performed as well as LASSO (AUC = 0.76, 95% CI: 0.67–0.85), random forest (AUC = 0.71, 95% CI: 0.61 = 0.81), and XGBoost (AUC = 0.70, 95% CI: 0.61–0.81), yet logistic regression reached the highest sensitivity (81%). The most important features were baseline DAS28 (components). For all algorithms, models with six features performed similarly to those with 16. When applied to the TCZ-monotherapy group, logistic regression’s sensitivity significantly dropped from 83% to 69% (p = 0.03). In the current dataset, logistic regression performed equally well compared to machine-learning algorithms in the prediction of insufficient response to MTX. Models could be reduced to six features, which are more conducive for clinical implementation. Interestingly, the prediction model was specific to MTX (combination) therapy response

Опыт использования акустического доплеровского измерителя течений (АDCP) в условиях Черного моря

В статье излагается методика проведения измерений Lowered ADCP и обработки первичной информации. При последующей обработке данных широко использовался опыт МГИ НАНУ с аналогичными акустическими измерителями течений в 80-е гг. В результате обобщен опыт применения Lowered ADCP в условиях Черного моря, даны алгоритмы обработки данных, приведены профили абсолютной скорости течений на ряде станций и показано, что предлагаемый подход дает более адекватную качественную и количественную оценку профиля скорости течения, чем известные методы.The methods of measurements with Lowered ADCP and processing of the initial information are presented. During the following data processing the experience of Marine Hydrophysical Institute of NAS of Ukraine with the similar acoustic currents meters in the 80-ies was widely applied. As a result the experience of Lowered ADCP application under the Black Sea conditions is generalized, the algorithms of data processing are given, the profiles of absolute speed of currents are given on the series of stations. It is shown that the proposed approach provides more adequate qualitative and quantitative estimation of the current velocity profile than the known methods do

Un pasaje autobiográfico en prosa rimada en la obra La forma del mundo de Isaac ibn LaṬif

This article analyzes the autobiographic passage in rhymed prose that constitutes the fifth chapter of the work The Form of the World, by 13th-century Jewish thinker Isaac ibn Laṭif (ca. 1210-ca. 1280). In this passage, expressed in the first person, the author describes his personal quest for enlightenment among traditional rabbinic scholars, those whom we would call today “kabbalists” (i.e., “those who have entered the garden of the pomegranates”), and philosophers. Finally, the author presents his own enlightenment as a quasiprophetic experience prompted by a personal exegetical engagement with the biblical text.Este artículo analiza el pasaje autobiográfico en prosa rimada que constituye el capítulo quinto de la obra La forma del mundo, por el pensador judío del siglo XIII Isaac ibn Laṭif (ca. 1210-ca. 1280). En este pasaje, formulado en primera persona, el autor describe su búsqueda personal de iluminación entre expertos rabínicos tradicionales, aquellos que hoy día llamaríamos «cabalistas» (i.e., «los que han entrado en el jardín de las granadas»), y filósofos. Por último, el autor presenta su propia iluminación espiritual como una experiencia casi profética, resultado de su esfuerzo personal de exégesis sobre el texto bíblico