Function In Preschool Children Research Articles

Lung Function in Preschool Children in Low and Middle Income Countries: An Under-Represented Potential Tool to Strengthen Child Health.

BackgroundThe burden of respiratory disease is high in low-middle income countries (LMIC). Pulmonary function tests are useful as an objective measure of lung health and to track progression. Spirometry is the commonest test, but its use is limited in preschool children. Other lung function methods have been developed but their use in LMIC has not been well described.AimTo review the use of preschool lung function testing in children in LMIC, with particular reference to feasibility and clinical applications.MethodsElectronic databases “PubMed”, “Scopus”,” Web of Science”, and “EBSCO host” were searched for publications in low and middle income countries on preschool lung function testing, including spirometry, fractional exhaled nitric oxide (FeNO), oscillometry, interrupter technique, tidal breathing and multiple breath washout (MBW), from 1 January 2011 to 31 January 2022. Papers in English were included and those including only children ≥6 years were excluded.ResultA total of 61 papers from LMIC in Asia, South America, Africa, Eurasia or the Middle East were included. Of these, 40 included spirometry, 7 FeNO, 15 oscillometry, 2 interrupter technique, and 2 tidal breathing. The papers covered test feasibility (19/61), clinical application (46/61) or epidemiological studies (13/61). Lung function testing was successful in preschool children from LMIC. Spirometry was the most technically demanding and success gradually increased with age.ConclusionPreschool lung function testing is under-represented in LMIC for the burden of respiratory disease. These tests have the potential to strengthen respiratory care in LMIC, however access needs to be improved.

Early Pseudomonas aeruginosa predicts poorer pulmonary function in preschool children with cystic fibrosis

BackgroundWe previously reported relatively normal pulmonary function (2 years of age) and computed tomography (CT, 1 year of age) in cystic fibrosis (CF) newborn screened (NBS) infants. We now report follow up of these children to preschool age. Methods67 NBS children with CF and 41 healthy controls underwent pulmonary function tests in infancy (∼3 months, 1 year and 2 years) and at preschool (3–6 years). Broncho-alveolar lavage (BAL) and CT were undertaken in those with CF at 1 year. Primary outcomes at preschool were lung clearance index (LCI) and forced expired volume (FEV0.75). Risk factors for lung function impairment were identified by regression modelling, emphasising factors that could be identified or measured in the first 2 years of life. ResultsAt preschool age children with CF had poorer lung function than controls, mean(95% CI) difference in LCI z-score: 1.47(0.96;1.97) and FEV0.75 z-score -0.54(-0.98; -0.10). Isolation of Pseudomonas aeruginosa before 6 months was a highly significant predictor of raised (abnormal) preschool LCI, associated with a mean (95%CI) increase of 1.69(0.43, 2.95) z-scores, compared to those with no Pseudomonas aeruginosa during the first 2 years of life. Including 2 year LCI and 1 year CT data in the predictive model increased the r2 from 13% to 61%. ConclusionsLung function deteriorates after 2 years in NBS children with CF. Isolation of Pseudomonas aeruginosa before 6 months and minor abnormalities of infant lung function tests and CT in infancy are associated with higher preschool LCI.

Effects of facial expression and gaze interaction on brain dynamics during a working memory task in preschool children.

Executive functioning in preschool children is important for building social relationships during the early stages of development. We investigated the brain dynamics of preschool children during an attention-shifting task involving congruent and incongruent gaze directions in emotional facial expressions (neutral, angry, and happy faces). Ignoring distracting stimuli (gaze direction and expression), participants (17 preschool children and 17 young adults) were required to detect and memorize the location (left or right) of a target symbol as a simple working memory task (i.e., no general priming paradigm in which a target appears after a cue stimulus). For the preschool children, the frontal late positive response and the central and parietal P3 responses increased for angry faces. In addition, a parietal midline α (Pmα) power to change attention levels decreased mainly during the encoding of a target for angry faces, possibly causing an association of no congruency effect on reaction times (i.e., no faster response in the congruent than incongruent gaze condition). For the adults, parietal P3 response and frontal midline θ (Fmθ) power increased mainly during the encoding period for incongruent gaze shifts in happy faces. The Pmα power for happy faces decreased for incongruent gaze during the encoding period and increased for congruent gaze during the first retention period. These results suggest that adults can quickly shift attention to a target in happy faces, sufficiently allocating attentional resources to ignore incongruent gazes and detect a target, which can attenuate a congruency effect on reaction times. By contrast, possibly because of underdeveloped brain activity, preschool children did not show the happy face superiority effect and they may be more responsive to angry faces. These observations imply a crucial key point to build better relationships between developing preschoolers and their parents and educators, incorporating nonverbal communication into social and emotional learning.

The structure of executive functions in preschool children and chimpanzees

Executive functions (EF) are a core aspect of cognition. Research with adult humans has produced evidence for unity and diversity in the structure of EF. Studies with preschoolers favour a 1-factor model, in which variation in EF tasks is best explained by a single underlying trait on which all EF tasks load. How EF are structured in nonhuman primates remains unknown. This study starts to fill this gap through a comparative, multi-trait multi-method test battery with preschoolers (N = 185) and chimpanzees (N = 55). The battery aimed at measuring working memory updating, inhibition, and attention shifting with three non-verbal tasks per function. For both species the correlations between tasks were low to moderate and not confined to tasks within the same putative function. Factor analyses produced some evidence for the unity of executive functions in both groups, in that our analyses revealed shared variance. However, we could not conclusively distinguish between 1-, 2- or 3-factor models. We discuss the implications of our findings with respect to the ecological validity of current psychometric research.

The Effect of Constraint-Induced Movement Therapy Combined With Repetitive Transcranial Magnetic Stimulation on Hand Function in Preschool Children With Unilateral Cerebral Palsy: A Randomized Controlled Preliminary Study.

Constraint-induced movement therapy (CIMT) combined with repetitive transcranial magnetic stimulation (rTMS) have shown great potential in improving function in schoolchildren with unilateral cerebral palsy attributed to perinatal stroke. However, the prospect of application in preschool children with unilateral cerebral palsy (UCP) attributed to various brain disorders remains unclear. In this prospective, assessor-blinded, randomized controlled study, 40 preschool children with UCP (aged 2.5–6 years) were randomized to receive 10 days of CIMT combined with active or sham rTMS. Assessments were performed at baseline, 2 weeks, and 6 months post-intervention to investigate upper limb extremity, social life ability, and perceived changes by parents and motor-evoked potentials. Overall, 35 participants completed the trial. The CIMT plus active stimulation group had greater gains in the affected hand function (range of motion, accuracy, and fluency) than the CIMT plus sham stimulation group (P < 0.05), but there was no significant difference in muscular tone, social life ability, and perceived changes by parents between the two groups (P > 0.05). In addition, there was no significant difference in hand function between children with and without motor-evoked potential (P > 0.05). No participants reported severe adverse events during the study session. In short, the treatment of CIMT combined with rTMS is safe and feasible for preschool children with UCP attributed to various brain disorders. Randomized controlled studies with large samples and long-term effects are warranted.

Breakdancing Movement Based on Image Recognition Promotes Preschool Children's Executive Function and Intervention Plan.

With the continuous development of science and technology, people can apply more and more technology to the cultivation of children's abilities. In the process of cultivating children's ability, the most fancy is the study of executive function, and this is the research topic of this article. In the past, training methods such as music, mindfulness, and exercise have been used in the study of children's executive abilities to promote the development of preschool children's executive functions. While various approaches have had some effect, researchers have been exploring more comprehensive approaches to effective training. This article is aimed at studying how to use image recognition technology to conduct an intervention analysis of breakdancing in promoting the executive function of preschool children. For this reason, this paper proposes image recognition technology based on deep learning neural network and conducts research, analysis, and improvement on related technologies obtained from deep learning. This makes it more suitable for the research topic of this article and design-related experiments and analysis to explore its related performance. The experimental results in this paper show that the improved image recognition technology has improved accuracy by 31.2%. And the performance of its algorithm is also improved by 21%, which can be very effective in monitoring preschool children during breakdancing.

ADHD Behaviors and Social Functioning in Preschool Children: The Moderating Role of Emotion Recognition

ADHD Behaviors and Social Functioning in Preschool Children: The Moderating Role of Emotion Recognition

The relationship between emotion understanding, theory of mind and executive function in preschool children

The relationship between emotion understanding, theory of mind and executive function in preschool children

Opportunities for the Development of Cognitive Functions in Preschool Children Through Emotions

Educational practice currently deals with the emotions of preschool children to a small extent, so we are of the opinion that their preparation is not sufficient for the school and for life, too. We came to this knowledge when we were working with preschool children hospitalized in hospital. The aim of the presented study is to analyse the opportunities of developing cognitive functions of preschool children through working with their emotions. The goal was set because of that in the practice is not the sufficient account of an association of the child’s cognitive and emotional development. We approached this goal through qualitative and quantitative research, in which the level of partial cognitive functions of children before and after working with their emotions were diagnosed. To diagnose children from the research group, we used the B. Sindelar method and the B. Bays method “PATH”. In the practical part we present the goal of the research - the importance of the relationship between cognitive functions and emotions. The sub-targets are formulated in research questions and hypotheses about differences in children's performance, which were statistically verified. Based on the survey, a discussion and conclusions for practice are formulated.

Neurocognitive functioning in preschool children with sickle cell disease.

Children with sickle cell disease (SCD) experience neurodevelopmental delays; however, there is limited research with preschool-age children. This study examined neurocognitive risk and protective factors in preschoolers with SCD. Sixty-two patients with SCD (60% HbSS/HbSβ0 -thalassemia; 40% HbSC/HbSβ+ -thalassemia) between the ages of 3 and 6years (mean = 4.77years) received a neuropsychological evaluation as routine systematic surveillance. Patients were not selected for disease severity, prior central nervous system findings, or existing cognitive concerns. Thirty-four patients (82% HbSS/HbSβ0 -thalassemia) were prescribed hydroxyurea (HU) at the time of their neuropsychological evaluation. On average, these patients had been prescribed HU at 2.15 (standard deviation = 1.45)years of age. The average dose was 28.8mg/kg/day. Besides genotype, there were no group differences in medical or demographic factors based on HU treatment status. Patients with HbSS/HbSβ0 -thalassemia scored below normative expectations on measures of intelligence, verbal comprehension, and school readiness (false discovery rate-adjusted p-value [pFDR ]<.05). Age, sickle genotype, and HU treatment exposure were not associated with measured neurocognitive outcomes (pFDR >.05). Greater social vulnerability at the community level was associated with poorer performance on measures of intellectual functioning, verbal comprehension, visuomotor control, and school readiness, as well as parent report of executive dysfunction (pFDR <.05). Greater household socioeconomic status was positively associated with academic readiness. Preschoolers with severe SCD (HbSS/HbSβ0 -thalassemia) perform below age expectations on measures of intelligence and academic readiness. Sociodemographic factors were stronger drivers of neurocognitive performance than disease severity or disease-modifying treatment. Neurodevelopmental interventions targeting the home and broader community environment are needed.

Feasibility of an intervention to facilitate time and everyday functioning in preschoolers

Background Children in need of special support (INS) often display delays in time-processing ability (TPA) affecting everyday functioning. Typically developing (TD) children are not yet mature to use the information of a clock. Aim To investigate the feasibility of an intervention program, MyTime, to facilitate TPA and everyday functioning in pre-school children, including the subjective experiences of pre-school staff and the children. Materials and Methods The intervention sample consisted of 20 children: 4 INS and 16 TD. Intervention was given daily in 8 weeks with MyTime in the pre-school environment. Data collection procedures were evaluated and children were assessed for TPA pre- and post intervention. Everyday functioning were assessed by teachers, parents and children. Experiences of the intervention were assessed by a group interview with teachers and a Talking Mats© evaluation with children. Results MyTime worked well in pre-school and indicated an increase in the children’s TPA and everyday functioning. The program was perceived simple to use by teachers and children highlighted the importance to understand the duration of time. Conclusion The program MyTime was found to be feasible in the pre-school environment. Significance: The assessment and program design can be used to investigate intervention effectiveness in a randomised study.

Multidisciplinary Evaluation of Pacifier Removal on Oro-Dentofacial Structures: A Controlled Clinical Trial.

It is well recognized that pacifier habit leads to occlusal and orofacial functional changes in children. However, the effects of the interruption of prolonged pacifier habit on the development of the dento-facial complex has not yet been fully characterized. Thus, the aim of this study was to investigate the influence of pacifier removal on aspects of oro-dentofacial morphology and function in preschool children. For that, a pacifier group (n = 28) and a control group (n = 32) of 4-year-old children with and without pacifier habit, respectively, were followed up by a group of dentists and speech therapists at baseline, 6 and 12 months after habit removal. Bite force and lip pressure were assessed using digital systems, and the evaluation of breathing and speech functions was performed using validated protocols, together with the measurements of dental casts and facial anthropometry. The Two-way mixed model ANOVA was used in data analysis. After 12 months, a decrease in malocclusion frequency was observed in pacifier group. Additionally, a change over time was observed in facial, intermolar and palate depth measurements, as well in bite and lip forces and speech function scores, increasing in both groups (p < 0.01). The upper and lower intercanine widths and breathing scores differed between groups at baseline and changed over time reducing the differences. The presence of speech distortions was more frequent in the pacifier group at baseline and decreased over time (p < 0.05). The interruption of pacifier habit improved the maxillary and mandibular intercanine widths, as well as the breathing and speech functions, overcoming the oro-dentofacial changes found.Trial Registration: This clinical trial was registered in the Brazilian Clinical Trials Registry (ReBEC; http://www.ensaiosclinicos.gov.br/), protocol no. RBR-728MJ2.

The relationship between the use of digital devices and cognitive development in preschool children: Evidence from scholarly literature

Introduction. Preschool children are active users of digital devices, which affects their cognitive development. The nature of these impacts has not been sufficiently studied, and there are different opinions of experts on this issue. Thus, the purpose of this article is to analyze the findings of research investigations devoted to the impact of digital devices on preschool children’s cognitive development. Materials and Methods. The authors conducted a systematic literature review of 46 full-text research articles describing the relationship between the use of digital devices (screen time and media content features) and the development of speech and mathematical skills, as well as the development of executive functions in 3-7 year-old children. The review is based on the cultural-historical approach. Results. The analysis of studies has shown that the impact of using digital devices on preschool children’s cognitive development depends on screen time, the exposure type (background TV or targeted use of digital devices), the content (educational or entertaining content), age appropriateness (age-appropriate or inappropriate content), the extent of how realistic the content is (fantasy or realistic content), the stimulus material complexity (visual or audial, black and white or color). There are also conclusions about the most relevant prospects for further research on the impact of the use of digital devices on the cognitive development of children. Conclusions. The review has indicated that long screen time negatively affects the development of speech and mathematical skills and executive functions in preschool children. The study has revealed that the content impact on cognitive development depends on the characteristics of this content. In particular, children-oriented educational content can contribute to cognitive development. Adult-oriented content can negatively affect cognitive development.

Impairment of Cardiac Autonomic Nerve Function in Pre-school Children With Intractable Epilepsy.

Objective: Intractable epilepsy and uncontrolled seizures could affect cardiac function and the autonomic nerve system with a negative impact on children's growth. The aim of this study was to investigate the variability and complexity of cardiac autonomic function in pre-school children with pediatric intractable epilepsy (PIE).Methods: Twenty four-hour Holter electrocardiograms (ECGs) from 93 patients and 46 healthy control subjects aged 3–6 years were analyzed by the methods of traditional heart rate variability (HRV), multiscale entropy (MSE), and Kurths–Wessel symbolization entropy (KWSE). Receiver operating characteristic (ROC) curve analysis was used to estimate the overall discrimination ability. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) models were also analyzed.Results: Pre-school children with PIE had significantly lower HRV measurements than healthy controls in time (Mean_RR, SDRR, RMSSD, pNN50) and frequency (VLF, LF, HF, LF/HF, TP) domains. For the MSE analysis, area 1_5 in awake state was lower, and areas 6_15 and 6_20 in sleep state were higher in PIE with a significant statistical difference. KWSE in the PIE group was also inferior to that in healthy controls. In ROC curve analysis, pNN50 had the greatest discriminatory power for PIE. Based on both NRI and IDI models, the combination of MSE indices (wake: area1_5 and sleep: area6_20) and KWSE (m = 2, τ = 1, α = 0.16) with traditional HRV measures had greater discriminatory power than any of the single HRV measures.Significance: Impaired HRV and complexity were found in pre-school children with PIE. HRV, MSE, and KWSE could discriminate patients with PIE from subjects with normal cardiac complexity. These findings suggested that the MSE and KWSE methods may be helpful for assessing and understanding heart rate dynamics in younger children with epilepsy.

Hair cortisol concentration and neurocognitive functions in preschool children at risk of developing attention deficit hyperactivity disorder

ObjectiveSex differences have been shown in the relation between hair cortisol concentration (HCC) and ADHD symptoms. As an extension of these findings, we analyze whether a child’s sex modulates the associations between HCC and ADHD-related neurocognitive functions. MethodsA community-based sample of 122 children was tested at age 4–5 (T1) and 8 (T2) years. At T1 and T2, ADHD symptoms were assessed with clinical parent interviews and parent and teacher questionnaires. Neurocognitive functions (i.e. T1: inhibitory control, working memory (WM), T2: verbal and performance intelligence (IQ-p)) were assessed using (neuro-)psychological tests. At T1, HCC was analyzed in the most proximal 3 cm scalp hair segment using luminescence immunoassay. ResultsExclusively in boys, low HCC correlated with low WM and IQ-p. The sex-by-HCC interaction effect on WM was significant. In boys, HCC completely explained the links of ADHD inattention symptoms with WM and IQ-p, respectively. ConclusionResults suggest a specific neurocognitive/endocrine profile in preschool boys at risk of developing ADHD, comprising hypocortisolism combined with memory and attention deficits.

Associations of perioperative characteristics with motor function in preschool children born with esophageal atresia.

BackgroundChildren born with esophageal atresia experience long‐term neurodevelopmental deficits, with unknown origin.AimsTo find associations between perioperative variables during primary esophageal atresia repair and motor function at age 5 years.MethodsThis ambidirectional cohort study included children born with esophageal atresia who consecutively had been operated on in the Erasmus MC‐Sophia Children's Hospital, University Medical Center, Rotterdam, from January 2007 through June 2013. The perioperative data of this cohort were collected retrospectively; the motor function data prospectively.ResultsAfter exclusion of patients with syndromal congenital diseases (n = 8) and lost to follow‐up (n = 10), the data of 53 children were included. The mean (SD) total motor function impairment z‐score at 5 years of age was −0.66 (0.99), significantly below normal (p < .001). In multivariable linear regression analysis, number of postoperative days endotracheal intubation (B = −0.211, 95% CI: −0.389 to −0.033, p = .021) was negatively associated with motor outcome, whereas high blood pressure (B = 0.022, 95% CI 0.001 to 0.042, p = .038) was positively associated. Preoperative nasal oxygen supplementation versus room air (B = 0.706, 95% CI: 0.132 to 1.280, p = .016) was positively associated with motor outcome, which we cannot explain.ConclusionsMotor function in 5‐year‐old esophageal atresia patients was impaired and negatively associated with the number of postoperative days of endotracheal intubation and positively associated with high blood pressure. Prospective studies with critical perioperative monitoring and monitoring during stay at the intensive care unit are recommended.

Relationship Between Iodine Status and Thyroid Function in Preschool Children: From the Environmental and Development of Children (EDC) Study

Background: We investigated iodine status and its association with thyroid function among preschool children residing in iodine-sufficient area. Methods: From the Environment and Development of Children study, 477 children were evaluated for thyroid function and urine iodine concentration (UIC) at age 6 during 2015-2017. After excluding children born with multiple birth and with congenital hypothyroidism or Hashimoto thyroiditis, 439 (231 boys) were included. Subclinical hypothyroidism (SCH) was defined as thyroid stimulating hormone (TSH) levels between 4.9-10 μIU/mL with normal free T4 levels. Iodine status was evaluated by UIC and children were categorized into 4 groups: iodine deficient (UIC < 100 μg/L), adequate (UIC, 100-299 μg/L), mild excessive (UIC, 300-999 μg/L), severe excessive (UIC ≥ 1000 μg/L). Results: Goiter was palpated in 64 (14.6%) with female predominance (26.0% vs. 4.3%, P < 0.001). Serum level of free T4 and T3 was 1.2 ± 0.1 ng/dL and 148.1 ± 18.5 ng/dL, respectively. The median TSH level was 2.3 (0.53-8.59) μIU/mL and the prevalence of SCH was 4.3% without sex-difference. The median UIC level was 606.2 (19.9-16409.7) μg/L, higher in boys (684 vs. 545 μg/L, P = 0.021) than in girls. Iodine was deficient in 19 (4.3%), adequate in 96 (21.9%), mild excessive in 170 (38.7%), and severe excessive in 145 (35.1%). After excluding 19 iodine deficient children, the relationship between iodine status and thyroid function was evaluated by multiple regression analysis after adjusting for age, sex, birth weight, gestational age, body mass index Z-score, and family history. As iodine status increased from adequate, mild excessive to severe excessive group, T3 levels decreased, and TSH levels increased with marginal significance (P for trend < 0.1 for T3 and TSH). When stratified by sex, similar association was found in only girls (P for trend = 0.043 for T3, and 0.062 for TSH) but not in boys, and mild excessive group showed lower free T4 levels (β = -0.05, P = 0.013) and severe excessive group had lower T3 levels (β = -7.04, P = 0.035) than iodine adequate group in only girls, but not in boys. Conclusion: Iodine was deficient in 4.3%, adequate in 21.9%, and excessive in 73.8% among preschool children residing in South Korea. As iodine status increased from adequate to excessive group, TSH levels increased with decreasing free T4 and T3 levels in girls.

Prenatal Bisphenol A Exposure and Early Childhood Behavior and Cognitive Function: A Chinese Birth Cohort Study

Introduction: Biomonitoring of bisphenol A (BPA) in human blood is still scarce, although already noticeable. We aimed to examine the associations between prenatal serum BPA concentrations and behavior and cognitive function in preschool children. Methods: A total of 1,782 mother-child pairs with complete demographic information, blood samples, and psychological measurements were included from the China-Anhui Birth Cohort (C-ABCS). We detected serum BPA concentrations and assessed children’s neurodevelopment using a set of psychometric scales. Results: The median prenatal maternal serum BPA concentration was 0.23 (P25, P75: 0.07, 0.52) ng/mL, with a detection frequency of 85.19%. Compared with the girls with the lowest concentrations, those with highest BPA concentrations had increased risks of inhibitory self-control impairment [relative risk (RR) = 3.66, 95% confidence interval (CI): 1.53, 7.58], emergent metacognition impairment (RR = 1.70, 95% CI: 1.07, 2.78), conduct problem (RR = 1.68, 95% CI: 1.12, 2.39), peer relationship problem (RR = 2.57, 95% CI: 1.33, 4.47), higher total difficulties score (RR = 1.76, 95% CI: 1.12, 2.67), and higher impact factor score (RR = 1.52, 95% CI: 1.11, 2.05), while the boys with the highest prenatal BPA concentrations had an increased risk of conduct problem compared with those with the lowest concentrations (RR = 1.59, 95% CI: 1.09, 2.24) (P-interaction = 0.011). After stratification by age, high prenatal BPA concentrations were associated with increased ADHD (RR = 4.44, 95% CI: 1.54, 10.85) among children aged 3 years, not among children aged 4 years. Conclusion: Our study revealed the sex-specific and age-specific impacts of prenatal BPA exposure on preschool children’s cognitive and behavioral development.

Research progress in executive function in preschool children with development language disorder

Research progress in executive function in preschool children with development language disorder

Evolutionary lung function evaluated by impulse oscillometry in preschoolers with asthma.

Impulse oscillometry (IOS) is useful for measuring lung function in preschool children. Our objec tive was to describe the alterations and evolutionary profile of IOS in asthmatic children under 6 years of age after one year of follow-up. 62 preschoolers performed IOS at the begin ning of the study and after one year. The proportion of altered IOS and bronchodilator response (BR +) at both times was compared, in addition to sub-analysis according to asthma control and presence of atopy. For the statistical analysis, we used McNemar's %2 and the Student's t-test with a 5% a error. The initial IOS was altered in 80.6% and in 64.5%% after one year (p = 0.04). 77.4% of the children presented BR+ at the beginning of the study and 83.9% after one year. The uncontrolled asthma group presented a significant improvement in the X5 and D5-20 means, but the controlled asthma group did not. In atopic patients, only uncontrolled asthmatics improved X5, AX, and D5-20. IOS shows alterations in a high percentage of preschoolers with uncontrolled asthma, which decreases significantly at one year, but remains altered and with BR + in most children. Ad ditional studies are required to identify different preschool asthma phenotypes and their evolution with treatment.