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Background: Surveillance of childhood obesity is essential to guide preventive policies and interventions. Aim: To analyse trends in overweight and obesity by socioeconomic status (SES) in Argentinian schoolchildren during the last decade. Subjects and methods: Two cross-sectional studies in schoolchildren aged 6–12 years were compared. The first study was conducted in 2005/07 (n = 1418) and the second one in 2015/16 (n = 1366). Overweight and obesity were estimated by the International Obesity Task Force (IOTF) cut-offs. The type of school (public/private) and parental education level were used as measures of SES. Data were analysed by linear and logistic regression with survey year, type of school, parental education level, and sex as independent variables. Results: From 2005 to 2016 overweight and obesity increased by 7.3% and 5.0%, respectively. The change was significantly higher in boys (9.6% and 8.3%) and girls (9.6% and 5.4%) from public schools, and in children whose fathers had low (10% and 8.3%) and middle (9.0% and 5.5%) education levels. No significant changes were found in children attending private school or those whose fathers had a higher education level. Conclusions: Obesity is still increasing in this population. SES disparities are strongly associated with this trend, with stabilisation in children from high SES.

Background and Objectives: Some medications require specific medical procedures in the weeks before their start. Such procedures may meet the definition of instrumental variables (IVs). We examined how they may influence treatment effect estimation in propensity score (PS)-adjusted comparative studies, and how to remedy., Study Design and Setting: Different covariate assessment periods (CAPs) did and did not include the month preceding treatment start were used to compute PS in the French claims database (Sytème National des Données de Santé-SNDS), and 1:1 match patients with metastatic castration resistant prostate cancer initiating abiraterone acetate or docetaxel. The 36-month survival was assessed., Results: Among 1, 213 docetaxel and 2, 442 abiraterone initiators, the PS distribution resulting from the CAP [-12; 0 months] distinctly separated populations (c = 0.93; 273 matched pairs). The CAPs [-12;-1 months] identified 765 pairs (c = 0.81). Strong docetaxel treatment predictors during the month before treatment start were implantable delivery systems (1% vs. 59%), which fulfilled IV conditions. The 36-month survival was not meaningfully different under the [-12; 0 months] CAP but differed by 10% points (38% vs. 28%) after excluding month -1., Conclusion: In the setting of highly predictive pretreatment procedures, excluding the immediate pre-exposure time from the CAP will reduce the risk of including potential IVs in PS models and may reduce bias., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To conduct the direct comparison of abiraterone acetate and docetaxel for first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) in real-life settings., Methods: Data were extracted from the French nationwide claims database (SNDS) on all men aged ≥40 years starting first-line treatment with abiraterone acetate or docetaxel for mCRPC in 2014. A high-dimensional propensity score including 100 baseline characteristics was used to match patients of both groups and form two comparative cohorts. Three-year overall survival and treatment discontinuation-free survival were determined using Kaplan-Meier analysis., Results: In 2014, 2,444 patients started abiraterone for treatment of mCRPC and 1,214 started docetaxel. After trimming and matching, 716 patients were available in each group. Median overall survival tended to be longer in the abiraterone acetate cohort (23.8 months, 95% confidence interval = [21.5; 26.0]) than in the docetaxel cohort (20.3 [18.4; 21.6] months). Survival at 36 months was 34.6% for abiraterone acetate and 27.9% for docetaxel ( p = 0.0027). Treatment discontinuation-free median was longer in the abiraterone acetate cohort compared to the docetaxel cohort (10.8 [10.1; 11.7] versus 7.4 [7.0; 8.0] months)., Conclusion: The findings underline the interest of oral abiraterone acetate over intravenous docetaxel as the first-line treatment option in mCRPC.

Background: Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative., Objectives: To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs)., Methods: Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm., Results: Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV., Conclusion: The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.

Background: There is a lack of information about the burden of metastatic castration-resistant prostate cancer (mCRPC). The present work aims to estimate the incidence and prevalence of mCRPC in 2014 using the French nationwide healthcare database (SNDS)., Methods: Prevalence and incidence were estimated based on an SNDS extraction of men covered by the general healthcare insurance (86 % of the French population), and aged ≥40. Patients with mCRPC were identified amongst prostate cancer cases using an algorithm estimating a date of first metastasis management and a date of castration resistance. This algorithm was validated by clinical experts through a blind review of 200 anonymized medical charts from SNDS data. Prevalence and incidence were standardized on the European Standard Population (2013 edition)., Results: Prevalence and incidence of mCRPC were estimated as, respectively, 62 and 21 cases per 100 000 men in 2014. Less than one mCRPC case per 100 000 was observed in men aged 40-49. Maximum mCRPC incidence was in men aged 80-89 (175 per 100 000). The algorithm used for mCRPC identification had 97 % positive and 99 % negative predictive values., Conclusion: The good performances of the algorithm for mCRPC identification and the consistency of the generated results with the existing data highlight the robustness of these first estimates of mCRPC prevalence and incidence. Future updates will call for algorithm adjustment as practices evolve over time. These first real-life data will serve for future follow-up of the impact of changes in the management of prostate cancer., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: This prospective study collected quality of life (QoL) and pain data during cabazitaxel treatment in patients with advanced metastatic or castration-resistant prostate cancer (mCRPC)., Patients and Methods: Functional Assessment of Cancer Therapy-Prostate (QoL) and Brief Pain Inventory-Short Form (pain) questionnaires were collected over 6 months., Results: In 61 patients with mCRPC (median age, 72 years) from 22 centers, metastatic sites were bones (97%), lymph nodes (36%), and visceral (20%); 25% received cabazitaxel in the second line, 29% in the third line, and 46% in the fourth line or beyond. All had been previously treated with docetaxel, except one with paclitaxel, and 75% also with abiraterone, enzalutamide, or both. The median cabazitaxel duration was 3.4 months. Forty-nine patients were evaluable for QoL and 44 for pain. QoL was improved in 37%, maintained in 35%, and deteriorated in 37%. In 27%, pain decreased ≥ 1 level and remained stable in 52%. A total of 34% lowered analgesic drug level. Prostate-specific antigen response ≥ 50% was observed in 11 (32.6%) patients, of whom 7 improved QoL and 1 was stable. At 6 months, 83.6% survived (95% confidence interval, 71.7%-90.8%). A total of 46% had ≥ 1 grade ≥ 3 adverse events, mainly anemia and neutropenia., Conclusion: Although cabazitaxel was given as the third line and beyond for three-quarters of patients, over one-third had improved QoL and/or decreased pain during treatment., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cabazitaxel is a treatment of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure. The FUJI cohort aimed to confirm the real-life overall and progression-free survival (OS, PFS) and safety of cabazitaxel., Methods: Multicentre, non-interventional cohort of French mCRPC patients initiating cabazitaxel between 2013 and 2015, followed 18 months., Results: Four hundred one patients were recruited in 42 centres. At inclusion, median age was 70, main metastatic sites were bones (87%), lymph nodes (42%) and visceral (20%). 18% had cabazitaxel in 2nd-line treatment, 39% in 3rd-line and 43% in 4th-line or beyond. All had prior docetaxel, and 82% prior abiraterone, enzalutamide or both. Median duration of cabazitaxel treatment was 3.4 months. Median OS from cabazitaxel initiation was 11.9 months [95% CI: 10.1-12.9]. In multivariate analyses, grade ≥ 3 adverse events, visceral metastases, polymedication, and >5 bone metastases were associated with a shorter OS. Main grade ≥ 3 adverse events were haematological with 8% febrile neutropenia., Conclusion: Real-life survival with cabazitaxel in FUJI was shorter than in TROPIC (pivotal trial, median OS 15.1 months) or PROSELICA (clinical trial 20 vs 25 mg/m 2 , median OS, respectively, 13.4 and 14.5 months). There was no effect of treatment-line on survival. No unexpected adverse concerns were identified., Study Registration: It was registered with the European Medicines Agency EUPASS registry, available at www.encepp.eu, as EUPAS10391. It has been approved as an ENCEPP SEAL study.

Background: Venous thromboembolism (VTE) after total knee or hip replacement (TKR, THR) is usually prevented with low-molecular weight heparin (LMWH), and increasingly by direct oral anticoagulants (DOAC). The aim of the present study was to compare the benefit-risk and medical costs of DOAC vs. LMWH in a real-life setting., Methods: All patients with THR or TKR in France between Jan-1st 2013 and Sep-30th 2014, discharged to home, were identified and followed-up for 3 months in the French nationwide claims database, SNDS. DOAC users were 1:1 matched with LWMH users on gender, age and propensity score. Relative risks (RR) of hospitalized VTE, hospitalized bleeding and death were estimated using quasi-Poisson models. Medical costs were calculated according to the societal perspective, including total cost for outpatient claims and national DRG costs for hospitalisations., Results: Most DOAC users (≥ 98.8%) were matched to a LMWH patient. For the 63,238 matched THR patients, the 3-month absolute risk of VTE was 0.9‰ with DOAC and 2.5‰ with LMWH (RR = 0.35 [0.23 to 0.54]), of bleeding 1.8‰ and 2.1‰ (0.88 [0.62-1.25]), death 0.7‰ and 1.1‰ (0.68 [0.40-1.15]). For the 31,440 matched TKR patients, risks were 1.6‰ and 2.3‰ (0.69 [0.42-1.16]) for VTE, 2.4‰ and 3.8‰ (0.64 [0.43 to 0.97]) for bleeding, and 0.6‰ and 0.8‰ (0.69 [0.30-1.62]) for all-cause death. Mean medical costs were 28% and 21% lower with DOAC than LMWH for THR and TKR, respectively. This nationwide study found a very low risk of VTE, hospitalized bleeding and death after THR or TKR discharge in patients with VTE prevention in real-life setting, with better benefit-risk profiles of DOAC compared to LMWH, and associated cost savings., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To investigate sunitinib in the real-life first-line treatment of metastatic renal cell carcinoma (mRCC)., Methods: SANTORIN is a French observational multicentre cohort. Patients initiating sunitinib in first-line mRCC therapy were included (January 2008 to April 2010) and followed for 24 months. Data were collected from medical files. The outcomes were 24-month overall survival (OS) and progression-free survival (PFS), response and safety., Results: Three hundred two patients were included: median age, 64.8 years; male, 73.2%; clear cell mRCC, 83.1%; prior nephrectomy, 85.4%; >1 metastatic sites, 64.2%; brain metastases, 6.3%; ECOG-PS ≥ 2, 9.9%. Median duration of first-line therapy with sunitinib was 10.7 months. Initial sunitinib dose was 50 mg/day for 83.4% of patients; dose reduction occurred in 65.2%. Sunitinib was discontinued in 73.2% of the patients: for progression (61.1%), death (31.2%) or adverse events (6.8%). More than half (58.3%) had grade ≥3 adverse events, mainly hypertension (12.6%) and hand-foot syndrome (12.3%). The 24-month OS and PFS rates [95%CI] were 49.5% [43.7;55.0] and 16.4% [12.5;20.9], respectively. Median OS was 23.6 months [20.2;-] and median PFS 8.4 months [7.6;9.9]. Overall best response rate was 31.1%., Conclusions: Results from this large observational study suggest that effectiveness of sunitinib in first-line mRCC as predicted by clinical trials is maintained in real-life clinical practice. The expected benefit in poor-prognosis patients that were not evaluated in the pivotal clinical trial remains; however, questionable and long-term safety monitoring is still warranted. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) can be prevented by inhaled treatment. Errors in inhaler handling, not taken into account in clinical trials, could impact drug delivery and minimise treatment benefit. We aimed to assess real-life inhaler device handling in COPD patients and its association with COPD exacerbations.To this end, 212 general practitioners and 50 pulmonologists assessed the handling of 3393 devices used for continuous treatment of COPD in 2935 patients. Handling errors were observed in over 50% of handlings, regardless of the device used. Critical errors compromising drug delivery were respectively made in 15.4%, 21.2%, 29.3%, 43.8%, 46.9% and 32.1% of inhalation assessment tests with Breezhaler® (n=876), Diskus® (n=452), Handihaler® (n=598), pressurised metered-dose inhaler (pMDI) (n=422), Respimat® (n=625) and Turbuhaler® (n=420).The proportion of patients requiring hospitalisation or emergency room visits in the past 3 months for severe COPD exacerbation was 3.3% (95% CI 2.0-4.5) in the absence of error and 6.9% (95% CI 5.3-8.5) in the presence of critical error (OR 1.86, 95% CI 1.14-3.04, p<0.05).Handling errors of inhaler devices are underestimated in real life and are associated with an increased rate of severe COPD exacerbation. Training in inhaler use is an integral part of COPD management., (Copyright ©ERS 2017.)

In tetrapods, limb and axial movements are coordinated during locomotion. It is well established that inter- and intralimb coordination show considerable variations during ongoing locomotion. Much less is known about the flexibility of the axial musculoskeletal system during locomotion and the neural mechanisms involved. Here we examined this issue in the salamander Pleurodeles waltlii, which is capable of locomotion in both aquatic and terrestrial environments. Kinematics of the trunk and electromyograms from the mid-trunk epaxial myotomes were recorded during four locomotor behaviors in freely moving animals. A similar approach was used during rhythmic struggling movements since this would give some insight into the flexibility of the axial motor system. Our results show that each of the forms of locomotion and the struggling behavior is characterized by a distinct combination of mid-trunk motor patterns and cycle durations. Using in vitro electrophysiological recordings in isolated spinal cords, we observed that the spinal networks activated with bath-applied N-methyl-d-aspartate could generate these axial motor patterns. In these isolated spinal cord preparations, the limb motor nerve activities were coordinated with each mid-trunk motor pattern. Furthermore, isolated mid-trunk spinal cords and hemicords could generate the mid-trunk motor patterns. This indicates that each side of the cord comprises a network able to generate coordinated axial motor activity. The roles of descending and sensory inputs in the behavior-related changes in axial motor coordination are discussed., (Copyright © 2015 the American Physiological Society.)

Aims: To assess hospital admission rates for gastrointestinal (GI) or cardiovascular (CV) events in real-life use of nonsteroidal anti-inflammatory drugs (NSAIDs)., Methods: CADEUS is a real-life population-based cohort study of 23 535 coxib (celecoxib or rofecoxib) and 22 919 traditional NSAID (tNSAID) users. Each hospitalization reported between index day (NSAID delivery) and questionnaire submission (median = 75 days) was explored using hospital discharge summaries. An expert committee validated blindly serious GI and CV events according to predefined criteria., Results: Coxib users were older and had more GI history than tNSAID users. There were 21 hospitalizations for GI events, 12 in the coxib cohort and nine in the tNSAID cohort (respectively one and three upper GI haemorrhages and no ulcer perforations). Rates of GI events were 0.39 per 1000 patients [95% confidence interval (CI) 0.18, 0.75] for tNSAID users and 0.51 per 1000 patients (95% CI 0.26, 0.89) for coxib users. There were 21 hospitalizations for CV events, 13 in the coxib cohort and eight in the tNSAID cohort. None was fatal. Rates of CV events were, respectively, 0.59 (95% CI 0.24, 1.22), 0.51 (95% CI 0.19, 1.11) and 0.35 (95% CI 0.15, 0.69) per 1000 patients for celecoxib, rofecoxib and tNSAIDs. GI or CV event rates were not different between products even for patients >60 years old., Conclusions: Hospitalization rates for GI bleeding were 10-20 times lower than expected from published randomized clinical trials, probably because of differences in drug usage and concomitant gastroprotection. CV event rates conformed to those expected from general population data. These results emphasize the necessity of developing population healthcare databases to explore such low event rates.

Much of what we know about the flexibility of the locomotor networks in vertebrates is derived from studies examining the adaptation of limb movements during stepping in various conditions. However, the body movements play important roles during locomotion: they produce the thrust during undulatory locomotion and they help to increase the stride length during legged locomotion. In this chapter, we review our current knowledge about the flexibility in the neuronal circuits controlling the body musculature during locomotion. We focus especially on salamander because, as an amphibian, this animal is able to display a rich repertoire of aquatic and terrestrial locomotor modes., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: In mammals, new neurons are added to the olfactory bulb (OB) throughout life. Most of these new neurons, granule and periglomerular cells originate from the subventricular zone (SVZ) lining the lateral ventricles and migrate via the rostral migratory stream toward the OB. Thousands of new neurons appear each day, but the function of this ongoing neurogenesis remains unclear., Methodology/principal Findings: In this study, we irradiated adult mice to impair constitutive OB neurogenesis, and explored the functional impacts of this irradiation on the sense of smell. We found that focal irradiation of the SVZ greatly decreased the rate of production of new OB neurons, leaving other brain areas intact. This effect persisted for up to seven months after exposure to 15 Gray. Despite this robust impairment, the thresholds for detecting pure odorant molecules and short-term olfactory memory were not affected by irradiation. Similarly, the ability to distinguish between odorant molecules and the odorant-guided social behavior of irradiated mice were not affected by the decrease in the number of new neurons. Only long-term olfactory memory was found to be sensitive to SVZ irradiation., Conclusion/significance: These findings suggest that the continuous production of adult-generated neurons is involved in consolidating or restituting long-lasting olfactory traces.

The role of adult hippocampal neurogenesis in spatial learning remains a matter of debate. Here, we show that spatial learning modifies neurogenesis by inducing a cascade of events that resembles the selective stabilization process characterizing development. Learning promotes survival of relatively mature neurons, apoptosis of more immature cells, and finally, proliferation of neural precursors. These are three interrelated events mediating learning. Thus, blocking apoptosis impairs memory and inhibits learning-induced cell survival and cell proliferation. In conclusion, during learning, similar to the selective stabilization process, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons.

According to human observations of a syndrome of physical activity dependence and its consequences, we tried to examine if running activity in a free activity paradigm, where rats had a free access to activity wheel, may present a valuable animal model for physical activity dependence and most generally to behavioral dependence. The pertinence of reactivity to novelty, a well-known pharmacological dependence predictor was also tested. Given the close linkage observed in human between physical activity and drugs use and abuse, the influence of free activity in activity wheels on reactivity to amphetamine injection and reactivity to novelty were also assessed. It appeared that (1) free access to wheel may be used as a valuable model for physical activity addiction, (2) two populations differing in activity amount also differed in dependence to wheel-running. (3) Reactivity to novelty did not appeared as a predictive factor for physical activity dependence (4) activity modified novelty reactivity and (5) subjects who exhibited a high appetence to wheel-running, presented a strong reactivity to amphetamine. These results propose a model of dependency on physical activity without any pharmacological intervention, and demonstrate the existence of individual differences in the development of this addiction. In addition, these data highlight the development of a likely vulnerability to pharmacological addiction after intense and sustained physical activity, as also described in man. This model could therefore prove pertinent for studying behavioral dependencies and the underlying neurobiological mechanisms. These results may influence the way psychiatrists view behavioral dependencies and phenomena such as doping in sport or addiction to sport itself.

Recent works reported planar and conical azimuthally degenerated nematic anchorings. Here we predict an additional "anticonical" degenerated anchoring. Its energy presents two minima, parallel and perpendicular to the substrate plane, separated by a conical energy barrier. We realize this bistable anchoring on a grafted polymer brush and we observe temperature-driven transitions between the conical, planar, and anticonical degenerated anchorings. Under electric field we break the anticonical anchoring and switch between its bistable states.

Background: Prenatal stress constitutes a developmental risk factor for later psychopathology. The behavioral disorders are sustained by neurobiological alterations including long-term reduction of hippocampal neurogenesis; its deregulation has been involved in cognitive impairments, mood disorders and addiction. A major goal is to define periods in development and strategies for intervening to prevent the effects of early stressful events. We investigated the ability of a postnatal infantile stimulation to prevent prenatal stress-induced alteration in hippocampal neurogenesis., Methods: The influence of postnatal handling on prenatal stress-induced changes in hippocampal neurogenesis was examined in 4 and 26 month-old male rats. Three distinct phases of the neurogenesis were studied: proliferation, survival and neuronal differentiation., Results: Prenatal stress reduced hippocampal cell proliferation all throughout life. Furthermore, the survival rate of newborn cells, the number of immature neurons and the number of differentiated new neurons were reduced in young and old prenatally-stressed rats. All those deleterious effects were counteracted by neonatal handling., Conclusions: These data show that finer aspects of brain shaping can be rewired by environmental influences occurring at sensitive phase of development. They also suggest that infantile stimulation may reverse the appearance of behavioral disorders induced by early life stress.

Langerhans cells (LCs) are dendritic cells localized in epidermis and mucosal tissues, where they are responsible for triggering the immune response. To study LCs in the oral epithelium, organotypic cultures were prepared using gingival explants. Immunochemical techniques using anti-CD1a, anti-HLA-DR, and anti-Langerin antibodies were used to detect and quantify LCs at various times. Observations were made by light and confocal microscopy. Quantification studies showed that there is a statistically significant drop in LC numbers in the epithelial tissue after 96 h of incubation. Gingival organotypic cultures thus are a good model for studying the migration of LCs and their involvement in contact hypersensitivity and periodontal diseases. The model offers potential utility as a tool for the study of periodontal tissue in the presence of different stimuli and for conducting immunotoxicologic experiments., (Copyright 2003 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 257-263, 2004)

Background: In common with other animal models of psychopathology, the forced-swimming test (FST) suffers from the fact that it involves normal animals. Moreover, powerful antidepressant drugs such as the selective serotonin reuptake inhibitors have been found to give false negatives in this behavioral test., Methods: To circumvent these theoretical and practical difficulties, we studied the interindividual variability of the behavioral reactivity of rats in the FST. The effects of fluoxetine treatment or of a stressful experience (repeated testing in the FST) were analyzed on various behavioral responses., Results: The following observations were made in replicated experiments: 1) a dimensional behavioral response from passivity to high reactivity in the FST; 2) an antidepressant-like effect of fluoxetine only in a subgroup of animals categorized as low responders on the dimension of passivity-reactivity; and 3) a switch toward passive responses following a past experience of stress, which was corrected by fluoxetine treatment., Conclusions: It is concluded that a dimensional approach could improve the screening of antidepressant drugs and could aid the development of new ones by identifying the biobehavioral characteristics of responder and nonresponder subjects.

The treatment of a Class II, Division 1 malocclusion without the extraction of premolars is, in many situations, the best solution for the patient. Nonpremolar extraction diagnosis followed by mechanotherapy with a nontorqued, nonangulated .022 edgewise appliance and the "Twelve-Two" System of Sequential Directional Force application is described.

Control of the occlusal plane during orthodontic mechanotherapy should be an integral part of every clinician's treatment plan. The many ramifications of occlusal plane control during the treatment of normodivergent, hyperdivergent, and hypodivergent skeletal patterns are discussed. The force systems and treatment mechanics used during treatment of the three different skeletal types and the impact these systems have on occlusal plane control are explained.