Does precocious puberty and its treatment cause the emotional and behavioural problems in children?

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Özge Köprülü, Gözde Yazkan Akgül This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4835395/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Central precocious puberty (CPP) occurs as a result of early activation of the hypothalamic-pituitary-gonadal axis. In recent years, especially after the COVID pandemic, presentations with signs of precocious puberty and cases requiring treatment have increased all over the world. Recent studies have showed that CPP patients are more likely to have social and psychiatric problems than their peers of the same age and gender. The aim of our study is to examine the psychiatric symptoms and quality of life of the children newly diagnosed with CPP and cases under treatment more than one year and to compare these symptoms with age and gender-matched healthy children. The research was planned as a cross-sectional study and included 47 female and 3 male patients (n = 50) who were followed up for CPP. The control group (CG) consisted of healthy children matched with the case group in terms of age and gender (n = 25). The case group was divided into two groups; patients who were newly diagnosed and did not receive treatment yet and patients who had been receiving treatment for at least one year. Sociodemographic form, Pediatric Quality of Life Inventory, Revised Child Anxiety and Depression Scale-Child Version (RCADS-CV), Strengths and Difficulties Questionnaire (SDQ), TURGAY DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) were applied to the children and their families. 50 cases diagnosed with CPP with a mean age of 8.95±1.07 years (25 at diagnosis, 25 on follow-up) and 25 healthy children with a mean age of 8.79±1.02 years were enrolled the study. 94% of CPP group (PG) (n = 47) and 84% of control group (CG) (n = 21) were girls. When the child and parent forms have evaluated; there was no significant difference between three groups in terms of quality of life (child and parent forms), anxiety and depression scores, strengths and difficulties scores. Similar results were obtained between three groups in terms of inattention and hyperactivity scores, oppositional defiance and conduct disorder scores according to the scale. Conclusion : In the present study, psychiatric symptoms and quality of life were compared between the three groups and no significant difference was detected. While it is a favorable finding that there is no difference in terms of these symptoms in children with early adolescence, it is crucial to consider children with a chronic disease in a multidisciplinary approach and to assess the cases for the potential negative impacts on their quality of life. precocious puberty quality of life affective reactivity inattention and hyperactivity What is Known? Although it is predicted that children experiencing precocious puberty may experience depressive and anxiety-related symptoms, and their quality of life may be affected due to having a chronic disease, there are no consistent results in this regard. What is new? There is no difference in terms of psychiatric symptoms and quality of life in children who were diagnosed with precocious puberty and received treatment for a certain period of time after the diagnosis of PP compared to children without PP. Furthermore, our study is the first study comparing children with precocious puberty who received treatment with those who did not. Introduction The onset of puberty symptoms at an early age has been frequently observed in recent years[ 1 ]. During the COVID-19 pandemic, the number of presentations with precocious puberty features and patients requiring treatment has increased in our country and all over the world[ 2 ], [ 3 ]. Precocious puberty (PP) is defined as the onset of physical signs of puberty before the age of 8 years in girls and 9 years in boys or the onset of menstruation before the age of 10 years[ 4 ]. Patients may present with early progression of secondary sexual characteristics, inappropriate body appearance and psychological behavioural abnormalities[ 5 ]. Rapid bone maturation due to precocious puberty may lead to short stature in adulthood[ 5 ]. Central precocious puberty (CPP) results from early activation of the hypothalamic-pituitary-gonadal axis[ 6 ]. GnRH analogs are used to treatment of central precocious puberty and are highly effective in suppressing the HPG axis[ 5 ]. While the primary medical reason for the treatment of CPP is to preserve adult height potential, a second commonly cited reason is to alleviate psychological distress associated with early pubertal development[ 7 ]. Adolescence and puberty is a period of major mental and psychological changes as well as biological changes[ 8 ]. While the structure of the body changes, region-specific, changes in brain structure, brain function and neurochemical transmission processes are also seen[ 9 ]. It is a challenge for the adolescent trying to adapt to his/her changing body and brain to complete his/her identity development and keep his/her social adaptive skills at a positive level in the process of individualization in order to adapt to these changes[ 10 ]. While even a normal course of adolescence can cause difficulties for the adolescents and their families, it has been found that children who experience precocious puberty are more likely to have social and psychiatric problems than their peers of the same age and gender[ 11 ]. Hormonal changes during puberty are known to increase the risk of developing emotional and behavioural problems[ 10 ]. In children who experience precocious puberty, the delay between physical and psychological maturity may also make them more vulnerable to psychopathologies[ 12 ]. Epidemiological studies have shown that early onset of puberty in girls is associated with earlier onset of sexuality, earlier age of pregnancy and lower educational attainment, regardless of cognitive ability and socioeconomic status[ 13 ]. Previous studies of children with CPP have reported irritability, aggression, depressive symptoms and anxiety-related symptoms[ 14 ]. In another study conducted in our country, while the depressive scores of the children were similar, significant difference was found only in terms of anxiety disorder[ 15 ]. In children, the impact of precocious puberty on quality of life has also been reported. While some studies found low quality of life, others found no difference in quality of life between the CPP group and healthy controls[ 1 ], [ 15 ], [ 16 ] The aim of our study was to investigate psychiatric symptoms such as anxiety, depression and irritability and quality of life in children diagnosed with central precocious puberty and to compare these data with age- and sex-matched children without central precocious puberty. Materials and methods The research was designed as a cross-sectional study. Written informed consent was obtained from the children and their parents before the study. The study protocol was approved by the Ethics Committee of Tekirdag Namık Kemal University, Faculty of Medical (2022.119.06.09) in light of the Helsinki Declaration. Detailed information about the study was given to the parents and children who were voluntary to participate in the study. Written informed consent was obtained from the healthy group and their parents. Participants Children diagnosed with CPP at the Pediatric Endocrinology Department of Tekirdag IFC City Hospital between December 2020 and April 2022 were included in the current study. The study group included 47 female and 3 male patients (n = 50) who were followed up for CPP at the Pediatric Endocrinology Department of Tekirdag IFC City Hospital. The diagnosis of CPP was based on signs and symptoms of CPP, elevated level of basal or stimulated gonadotropin levels and advanced bone age. All patients and their families agreed to participate in the study and constituted the CPP group. The children's clinical data (physical examination and laboratory findings) were evaluated from the medical file records and scales were applied to the subjects. Children with CPP were divided into two groups as at diagnosis (Group PP1) and at follow-up and after more than one year of treatment (Group PP2). The control group consisted of age and sex-matched children who were admitted to pediatric outpatient clinics of Tekirdag IFC City Hospital without any chronic disease and who volunteered to participate in the study. Twenty-five children and their families agreed to participate in the study. Twenty-one female and 4 male (n = 25) children constituted the Control Group (CG). Exclusion criteria for both groups were the presence of intellectual disability, any neurological disorder, psychotic disorder, and autism spectrum disorder, as these individuals may have difficulty in completing the study procedure. Individuals with any chronic and/or severe medical illness were also excluded to eliminate any possible confounding effects. Clinical Measures The sociodemographic information of the children was obtained by using the sociodemographic information form developed by the researchers. In the clinical information form; auxological data, physical examination, the laboratory and radiological findings of the participants were evaluated. The Strengths and Difficulties Questionnaire Children (SDQ-C) and Parent (SDQ-P) forms were used to assess the behavioural characteristics of the participants [ 17 ], [ 18 ]. The Turkish validity and reliability study was conducted by Guvenir et al. [ 19 ]. The questionnaire is a short behavioural screening questionnaire used to examine mental well-being. The SDQ examines 25 attributes, divided into 5 scales: Emotional problems, behavioural problems, Hyperactivity and inattention, Peer relationship problems, Prosocial behaviours. Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) was developed by Turgay and adapted and translated into Turkish by Ercan et al. [ 20 ]. The T-DSM-IV-S (parent and teacher forms) is based on the DSM-IV criteria and assesses hyperactivity-impulsivity (nine items), inattention (nine items), opposition–defiance disorder (eight items) and conduct disorder (15 items). The severity of each symptom is estimated on a fourpoint Likert-type scale (0 = not at all, 1 = just a little, 2 = quite a bit, and 3 = very much). Subscale scores on the T-DSM-IV-S are calculated by summing the item scores for each subscale. The Revised Child Anxiety and Depression Scale-Child Version (RCADS-CV) is a self-report questionnaire that assesses the clinical symptoms of anxiety and depression based on DSM-IV criteria. The RCADS-CV has been shown to be a reliable and valid instrument in different cultures and languages as well as in Turkish [ 21 ]. It consists of 47 items with six subscales corresponding to generalised anxiety disorder (GAD), major depressive disorder (MDD), separation anxiety disorder (SAD), social phobia (SP), panic disorder (PD), and obsessive-compulsive disorder (OCD). It is a four-point Likert-type scale (0 = never, 1 = sometimes, 2 = often, and 3 = always). The general anxiety score is obtained by the sum of the first five sub-scales, and the internalisation score is obtained by the sum of all sub-scales. The scale has no cut-off score. In our study, RCADS-CV-children (RCADS-CV-C) and RCADS-CV-parent (RCADS-C-P) forms were used. The Pediatric Quality of Life Inventory (PedsQL) developed by Varni et al. [ 22 ] in 1999, aims to evaluate the general quality of life in children aged 2–18 years. The scale consists of four subscales assessing physical, emotional, social, and school-related functioning. A validity and reliability study for the Turkish form of the inventory was conducted for 2–18 age group. PedsQL evaluates areas of functionality with 4 subheadings: 8 items are physical, 5 items are emotional, 5 items are social, and 5 items are school functionality, for a total of 23 items. Scoring is done in 3 areas: total physical health score, total psychosocial health score, which evaluates emotional, social and school functioning, and total score. It is accepted that the higher the total score, the higher the quality of life. The Turkish validity and reliability study was conducted by Memik et al [ 23 ]. In our study, the children (PedsQL-C) and parent forms (PedsQL-P) of PedsQL were used. Statistical analyses SPSS 25.0 (IBM Corporation, Armonk, New York, United States) was used in the analysis of the variables. First, preliminary analysis of the assumptions of parametric statistics was conducted. The Kolmogorov–Smirnov test was used to check the normal distribution of the variables. When the assumption of normality was met, parametric statistical tests were used. When the assumption of normality was not met, non-parametric statistical tests were used. The Student’s t-test or Mann–Whitney U- tests were used to asses differences between two groups according to the normal distribution of the measured parameters. Chi-square test was used to compare the categorical variables. Quantitative variables were expressed as mean (standard deviation), median (25th percentile / 75th percentile), while categorical variables were shown as number (n) and frequency (%). The variables were analyzed at 95% confidence level, and a p value less than 0.05 was considered as significant. Results The group PP1 (mean age: 8.23 ± 0.91 years), PP2 (mean age: 9.68 ± 0.66years) and CG (mean age: 8,79 ± 1,02years) were not similar in age (p = 0), due to the difference between PP1 and PP2. All cases of the PP1 group (n = 25), 88% of the PP2 group (n = 22) and 84% of the CG (n:21) were female. The clinic characteristics of group PP1, PP2 and CG are summarised in Table 1 . Pubertal stages were Tanner 2 in four of the patients, Tanner 3 in 13 of the patients, Tanner 4 in 20 of the patients and Tanner 5 in 13 of the patients. The 12% (n:3) and 13.6% (n:3) of the children had early menarche in group PP1 and PP2, respectively. The duration of GnRHa treatment in group PP2 ranged from 13 to 36 months. The mean duration of treatment was 14.42 ± 5.65 months. Table 1 Sociodemographic and clinical features of PP and CG PP1 n:25 PP2 n:25 CG n:25 Age (year) 8.23 ± 0.91 (6.21–9.7) 9.68 ± 0.66 (7.7-10.68) 8.79 ± 1.02 (6.5–9.9) Female/Male 25/0 22/3 21/4 Menarche at diagnosis 12% (n:3) 13.6% (n:3) - Data were presented as mean ± SD The SDQ-C, SDQ-P, PedsQL-C and PedsQL-P scores are shown in Table 2 . The three groups had similar scores in the SDQ-behavior, SDQ-emotional and total scores in the child and parent questionnaires (p = 0.812, p = 0.79, p = 0.959 respectively in the child questionnaires and p = 0.824, p = 0.852, p = 0.599 respectively in parent questionnaires). No significant differences were found between the groups in terms of PedsQL-total scores in the child and parent forms (p = 0.505, p = 0.992; respectively). Table 2 SDQ-A, SDQ-P and PedsQL-A, PedsQL-P Scores PP1 n = 25 PP2 n = 25 CG n = 25 p value SDQ-A emotional 2 (0,5 − 2,5) 1 (0–3) 1 (0–2) 0,790 SDQ-A behaviour 1 (0–2) 1 (0–2) 1 (0,5 − 2) 0,812 SDQ-A ADHD 4 (2–5) 4 (2–5) 4 (3–5) 0,585 SDQ-A peer 2 (0–2,5) 2 (0–3) 1 (0–2,5) 0,710 SDQ-A prosocial 9 (7,5–10) 8 (6–10) 9 (8–10) 0,917 SDQ-A total 10 (4–11) 8 (5–11) 8 (5,5–10) 0,959 SDQ-P- emotional 1 (0–3,5) 2 (1–2) 1 (0–2,5) 0,852 SDQ-P behavioural 1 (0,5 − 2) 1 (0–2) 1 (0–1,5) 0,824 SDQ-P ADHD 3 (2–5) 4 (2–5) 3 (2–5) 0,804 SDQ-P peer 2 (1–3) 1 (1–4) 1 (0–2,5) 0,406 SDQ-P total 9 (5,5–11,5) 8 (6–12) 7 (4–10,5) 0,599 PedsQL-C pyshical 84,375 (71,875 − 89,062) 78,125 (71,875 − 89,062) 81,25 (68,75–90,625) 0,928 PedsQL-C psychosocial 83,333 (75–92,5) 83,333 (77,5–93,333) 90 (83,33–95) 0,289 PedsQL-C total 83,437 (73,359 − 90,468) 82,968 (74,531 − 91,875) 87,812 (81,2591,718) 0,505 PedsQL-P pyschical 79,687 (61,718 − 91,406) 81,25 (71,875 − 90,625) 87,5 (64,843 − 100) 0,751 PedsQL-P psychosocial 84,166 (65,416 − 93,333) 85 (66,666 − 93,333) 82,5 (71,25–92,083) 0,987 PedsQL-P total 84,296 (63,710 − 91,445) 82,968 (67,812 − 91,406) 81,796 (69,804 − 90,976) 0,992 Data were presented as median (25-75th percentiles) (SDQ-A): The Strengths and Difficulties Questionnaire-Adolescent; (SDQ-P): The Strengths and Difficulties Questionnaire-Parent; PedsQL-A: Pediatric Quality of Life Inventory -Adolescent Form; PedsQL-P: Pediatric Quality of Life Inventory-Parent Form The RCADS-CV-C and RCADS-CV-P scores of PP1, PP2 and CG are shown in Table 3 . No significant difference was found between groups in terms of RCADS-CV scores. Internalizing and anxiety scores were similar between groups for children (p = 0.987, p = 0.929 respectively) and parents (p = 0.942, p = 0.824 respectively). Table 3 RCADS-CV-A and RCADS-CV-P scores PP1 n:25 PP2 n:25 CG n:25 p RCADS-CV-C anx.dep. score 38 (33–45) 39 (30–47) 37 (32,5–46) 0,987 RCADS-CV-A anxiety score 39 (32–44) 40 (31–49) 38 (31,5–46,5) 0,929 RCADS-CV-P anx.dep. score 45,5 (42,75 − 55) 49 (41–55) 46 (42,5–55) 0,942 RCADS-CV-P anxiety score 45,5 (42–54,75) 48,5 (41,25–57) 46 (41,5–55,5) 0,824 Data were presented as median (25-75th percentiles) RCADS-CV-A: Revised Child Anxiety and Depression Scale-Child Version-Adolescent Form RCADS-CV-P: Revised Child Anxiety and Depression Scale-Child Version-Parent Form The ARI-C and ARI-P scores of the groups are given in Table 4 . The ARI scores were found to be similar between the three groups in children and parent forms (p = 0.581, 0.730 respectively). Table 4 ARI-A, ARI-P and T-DSM-IV-S scores PP1 n: 25 PP2 n: 25 CG n: 25 p ARI-C-total 5 (0–7) 2 (1–4,25) 1 (1–2) 0,581 ARI-P total 2 (0–6) 2 (0,5 − 3,5) 1 (0–2) 0,730 T-DSM-IV-S-IA 4,5 (3,25 − 9,5) 6 (0–10) 4 (1–6) 0,439 T-DSM-IV-S-HA 4 (1,25 − 6,5) 5 (1–11) 4 (2–7) 0,913 T-DSM-IV-S-ODD 4,5 (1–9,25) 3 (2–8) 3 (1–5) 0,892 T-DSM-IV-S-CD 0 (0–0) 0 (0–2) 0 (0–0) 0,359 T-DSM-IV-S-Total 14,5 (6–21) 15 (3–30) 17,5 (6,75 − 28,25) 0,903 Data were presented median (25-75th percentiles) ARI-C: Affective Reactivity Index- Children Form; ARI-P: Affective Reactivity Index- Parent Form; T-DSM-IV-S-IA: Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale-Inattention Score T-DSM-IV-S-HA Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale- Hyperactivity T-DSM-IV-S-ODD Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale-Oppositional Defiant Score T-DSM-IV-S-CD Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale- Conduct Disorder Score Discussion In the current study, we analysed behavioural and emotional problems, quality of life, anxiety, and depressive status of children with CPP (at diagnosis and at follow-up), and compared the results with age- and sex-matched healthy controls. In terms of behavioural and emotional problems, quality of life, anxiety and depressive status, the CPP groups did not differ from age-matched controls. In contrast to previous reports on elevated behavioral and emotional problems in children with CPP[ 24 ], we found no significant differences in SDQ-A and SDQ-P scores between the three groups. In both groups with CPP, children and parents reported similar behavioural and emotional problems with CG. During puberty, it is known that psychological changes are known to follow physiological changes as a result of the activation of hypothalamic-pituitary axis[ 25 ]. As the children in the CPP group were younger and the possible effects of hormonal changes were treated in the early period, it is suggested that children diagnosed with CPP did not experience any emotional and behavioural differences. The fact that both parents and children consistently reported no emotional and behavioural changes, strengthens this conclusion. In TURGAY scale which evaluates the symptoms of attention deficit hyperactivity, oppositional defiant disorder and conduct disorder, similar scores were found between the three groups. During adolescence, children experience some behavioural and emotional difficulties, increased risk-taking behaviour and impulsivity as well as difficulties in controlling anger[ 26 ]. In a cross-sectional study conducted in 2023, externalising behaviours were found to be more prevalent in female adolescents with CPP compared to the control group[ 27 ]. In another study, although the score assessing externalising behaviours was not considered to be clinically significant, it was found to be higher in adolescent girls compared to the control group. It was also suggested that the effect on behaviour emerged at a later age[ 28 ]. The findings of our study indicate that, although biological markers of adolescence have been observed in children, it is believed that their behavioural manifestations are more closely associated with their psychosocial developmental stage and chronological age than with this biological process. Furthermore, the data suggest that children do not exhibit behavioural patterns that are unique to the adolescent period. The majority of studies conducted thus far on precocious puberty in children have focused on girls. In some of these studies, elevated rates of depression and anxiety have been observed in children experiencing precocious puberty[ 14 ], [ 29 ]. The onset of menarche has been shown as a reason for depressive symptoms[ 29 ]. Among anxiety disorders, social anxiety, which is associated with a lower self-image, has been reported to be more prevalent[ 15 ]. Conversely, similar to our study, some studies have reported that the groups diagnosed and treated with CPP did not exhibit any differences in terms of depressive and anxiety symptoms[ 30 ]. It is known that there should be a serious psychosocial stressor for the emergence of depression in childhood in association with the development of children's cognitive and emotional abilities[ 31 ]. Since the children in our study were relatively younger, it is thought that they did not differ from healthy children in terms of depressive and anxiety symptoms, even if they exhibited symptoms of adolescence. It is established that children with a chronic disease experience a negative impact on their quality of life[ 32 ], [ 33 ]. There are limited studies that have analysed the quality of life of children with precocious puberty. In one of these studies, the CPP group included both treated and newly diagnosed children and no significant differences were identified in the quality of life of this group in comparison to healthy children[ 15 ]. In another study a total of 193 children were examined, including 59 children with CPP, 53 children with premature telarche, and 81 healthy children and their parents. No significant differences were found between the CPP, PT and control groups[ 1 ]. In our study, the quality of life of the group of children newly diagnosed with CPP and the group of children who had been receiving treatment for at least one year was found to be similar to that of healthy children according to both self-report and parental report. The favourable response to treatment and the absence of significant adverse effects during the treatment indicate that psychological well-being in children is associated with a high level of quality of life. It should be noted that our study has some limitations. First of all, the limited sample size makes it difficult to generalise our results. Although children's psychiatric symptoms were assessed through scales, it is possible that structured psychiatric interviews for children might yield more accurate diagnoses of potential psychiatric disorders. A more detailed evaluation of children's physical characteristics such as height and weight, which change with the puberty process, could have provided a more accurate interpretation of the results. Furthermore, psychological problems that may arise in the longer term can be evaluated by longitudinal follow-up of the study groups. Conclusion In the present study, psychiatric symptoms and quality of life were compared between the three groups and no significant difference was detected. While it is a favorable finding that there is no difference in terms of these symptoms in children with early adolescence, it is crucial to consider children with a chronic disease in a multidisciplinary approach and to assess the cases for the potential negative impacts on their quality of life. Declarations Funding: The authors received no funding for the research. Author Contribution ÖK and GYA drafted the study protocol and wrote the manuscript. ÖK and GYA collected the data. ÖK and GYA revised the manuscript. All authors approved the final version. Data Availability All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author. References Yılmazer İN, Abseyi SN, Şenyazar G, Berberoğlu M, Şıklar Z, Aycan Z (2024) Evaluation of quality of life in children with precocious puberty, Clin. Endocrinol. 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Ambul Pediatr 3(6):329–341. 10.1367/1539-4409(2003)0032.0.CO;2 Nursu ÇAKINMEMİK, Belma AĞAOĞLU, Ayşen COŞKUN, Özden Ş, ÜNERİ, Işık KARAKAYA (2007) The Validity and Reliability of the Turkish Pediatric Quality of Life Inventory for Children 13–18 Years Old. Türk Psikiyatri Dergisi 18(4):353–363 Kaltiala-Heino R, Marttunen M, Rantanen P, Rimpelä M (2003) Early puberty is associated with mental health problems in middle adolescence, Soc. Sci. Med. , vol. 57, no. 6, pp. 1055–1064, Sep. 10.1016/S0277-9536(02)00480-X Spaziani M et al (Jan. 2021) Hypothalamo-Pituitary axis and puberty. Mol Cell Endocrinol 520:111094. 10.1016/j.mce.2020.111094 Tuğba KALYONCU, Burcu ÖZBARAN (2018) Fast and Furious: Adolescence and Attention Deficit Hyperactivity Disorder. Turk Klin Child Psychiatry-Spec Top 4(2):175–179 Yongkittikasem K, Sinsophonphap T (2023) Behavioral Problems of Girls with Central Precocious Puberty, Vajira Med. J. J. Urban Med. , vol. 67, p. none, 10.14456/VMJ.2023.15 Kim EY, Lee MI (2012) Psychosocial Aspects in Girls with Idiopathic Precocious Puberty. Psychiatry Investig 9(1):25. 10.4306/pi.2012.9.1.25 Huang H, Liu L, Su S, Xie D (May 2021) Self-consciousness and depression in precocious pubertal children. J Int Med Res 49(5):030006052110202. 10.1177/03000605211020227 Yang JH et al (2013) Depression and self-concept in girls with perception of pubertal onset. Ann Pediatr Endocrinol Metab 18(3):135. 10.6065/apem.2013.18.3.135 Goodyer IM, Herbert J, Tamplin A, Altham PME (2000) Recent life events, cortisol, dehydroepiandrosterone and the onset of major depression in high-risk adolescents, Br. J. Psychiatry , vol. 177, no. 6, pp. 499–504, Dec. 10.1192/bjp.177.6.499 Yazkan Akgül G, Köprülü Ö (May 2024) Examination of quality of life and psychiatric symptoms in childhood Graves’ disease. J Pediatr Endocrinol Metab 37(5):445–450. 10.1515/jpem-2023-0550 Didsbury MS et al (2016) Dec., Socio-economic status and quality of life in children with chronic disease: A systematic review, J. Paediatr. Child Health , vol. 52, no. 12, pp. 1062–1069, 10.1111/jpc.13407 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4835395","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":345810220,"identity":"1217a9ab-e28e-443e-8f55-42fdf0c69dab","order_by":0,"name":"Özge Köprülü","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIie3RPQuCQBjA8ScOzuUhV0XrM1wIjfZhhFqOliCIhoLAyc/jrAi5XEFb0aI1NzgEQUunW8vpGHT/6eG4H9wLgE73w7lgRM2A/a4EAQVAIgfanVi8IdBKTDM/lc/QR3Z5pPeK+y4FUt7OCmJvxcIbhAGy6zxgaRzIg1HP4wrC0mjq2GEiCR9baUwkQeooSYazd0MuoiabDmRv7HtVTc5Yk6yd2BESB44B2oJ77BDnSEnLXeSLldVr6Q/7uRgVq3g9MY1deVcR+SOM4NcCUW6vM4req3WTTqfT/XUfzrpFTy5Uy4EAAAAASUVORK5CYII=","orcid":"","institution":"Division of Pediatric Endocrinology,Tekirdağ IFC City Hospital","correspondingAuthor":true,"prefix":"","firstName":"Özge","middleName":"","lastName":"Köprülü","suffix":""},{"id":345810221,"identity":"e586c124-562e-418e-ab0d-09fb9cc60765","order_by":1,"name":"Gözde Yazkan Akgül","email":"","orcid":"","institution":"School of Medicine, Child and Adolescent Psychiatry Department, Marmara University","correspondingAuthor":false,"prefix":"","firstName":"Gözde","middleName":"Yazkan","lastName":"Akgül","suffix":""}],"badges":[],"createdAt":"2024-07-31 12:14:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4835395/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4835395/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":65510033,"identity":"98f2b372-fcb7-4bb0-a5c7-53c56d305b3f","added_by":"auto","created_at":"2024-09-28 18:46:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":539966,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4835395/v1/0f0814ec-3a82-477d-bec9-831851b555fc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Does precocious puberty and its treatment cause the emotional and behavioural problems in children?","fulltext":[{"header":"What is Known?","content":"\u003cp\u003eAlthough it is predicted that children experiencing precocious puberty may experience depressive and anxiety-related symptoms, and their quality of life may be affected due to having a chronic disease, there are no consistent results in this regard.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is new?\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no difference in terms of psychiatric symptoms and quality of life in children who were diagnosed with precocious puberty and received treatment for a certain period of time after the diagnosis of PP compared to children without PP. Furthermore, our study is the first study comparing children with precocious puberty who received treatment with those who did not.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe onset of puberty symptoms at an early age has been frequently observed in recent years[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. During the COVID-19 pandemic, the number of presentations with precocious puberty features and patients requiring treatment has increased in our country and all over the world[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Precocious puberty (PP) is defined as the onset of physical signs of puberty before the age of 8 years in girls and 9 years in boys or the onset of menstruation before the age of 10 years[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Patients may present with early progression of secondary sexual characteristics, inappropriate body appearance and psychological behavioural abnormalities[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Rapid bone maturation due to precocious puberty may lead to short stature in adulthood[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Central precocious puberty (CPP) results from early activation of the hypothalamic-pituitary-gonadal axis[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. GnRH analogs are used to treatment of central precocious puberty and are highly effective in suppressing the HPG axis[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. While the primary medical reason for the treatment of CPP is to preserve adult height potential, a second commonly cited reason is to alleviate psychological distress associated with early pubertal development[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdolescence and puberty is a period of major mental and psychological changes as well as biological changes[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. While the structure of the body changes, region-specific, changes in brain structure, brain function and neurochemical transmission processes are also seen[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. It is a challenge for the adolescent trying to adapt to his/her changing body and brain to complete his/her identity development and keep his/her social adaptive skills at a positive level in the process of individualization in order to adapt to these changes[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While even a normal course of adolescence can cause difficulties for the adolescents and their families, it has been found that children who experience precocious puberty are more likely to have social and psychiatric problems than their peers of the same age and gender[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHormonal changes during puberty are known to increase the risk of developing emotional and behavioural problems[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In children who experience precocious puberty, the delay between physical and psychological maturity may also make them more vulnerable to psychopathologies[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Epidemiological studies have shown that early onset of puberty in girls is associated with earlier onset of sexuality, earlier age of pregnancy and lower educational attainment, regardless of cognitive ability and socioeconomic status[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Previous studies of children with CPP have reported irritability, aggression, depressive symptoms and anxiety-related symptoms[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In another study conducted in our country, while the depressive scores of the children were similar, significant difference was found only in terms of anxiety disorder[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In children, the impact of precocious puberty on quality of life has also been reported. While some studies found low quality of life, others found no difference in quality of life between the CPP group and healthy controls[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe aim of our study was to investigate psychiatric symptoms such as anxiety, depression and irritability and quality of life in children diagnosed with central precocious puberty and to compare these data with age- and sex-matched children without central precocious puberty.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe research was designed as a cross-sectional study. Written informed consent was obtained from the children and their parents before the study. The study protocol was approved by the Ethics Committee of Tekirdag Namık Kemal University, Faculty of Medical (2022.119.06.09) in light of the Helsinki Declaration. Detailed information about the study was given to the parents and children who were voluntary to participate in the study. Written informed consent was obtained from the healthy group and their parents.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eChildren diagnosed with CPP at the Pediatric Endocrinology Department of Tekirdag IFC City Hospital between December 2020 and April 2022 were included in the current study.\u003c/p\u003e \u003cp\u003eThe study group included 47 female and 3 male patients (n\u0026thinsp;=\u0026thinsp;50) who were followed up for CPP at the Pediatric Endocrinology Department of Tekirdag IFC City Hospital. The diagnosis of CPP was based on signs and symptoms of CPP, elevated level of basal or stimulated gonadotropin levels and advanced bone age. All patients and their families agreed to participate in the study and constituted the CPP group. The children's clinical data (physical examination and laboratory findings) were evaluated from the medical file records and scales were applied to the subjects. Children with CPP were divided into two groups as at diagnosis (Group PP1) and at follow-up and after more than one year of treatment (Group PP2).\u003c/p\u003e \u003cp\u003eThe control group consisted of age and sex-matched children who were admitted to pediatric outpatient clinics of Tekirdag IFC City Hospital without any chronic disease and who volunteered to participate in the study. Twenty-five children and their families agreed to participate in the study. Twenty-one female and 4 male (n\u0026thinsp;=\u0026thinsp;25) children constituted the Control Group (CG).\u003c/p\u003e \u003cp\u003eExclusion criteria for both groups were the presence of intellectual disability, any neurological disorder, psychotic disorder, and autism spectrum disorder, as these individuals may have difficulty in completing the study procedure. Individuals with any chronic and/or severe medical illness were also excluded to eliminate any possible confounding effects.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical Measures\u003c/h2\u003e \u003cp\u003e The sociodemographic information of the children was obtained by using the sociodemographic information form developed by the researchers. In the clinical information form; auxological data, physical examination, the laboratory and radiological findings of the participants were evaluated.\u003c/p\u003e \u003cp\u003eThe Strengths and Difficulties Questionnaire Children (SDQ-C) and Parent (SDQ-P) forms were used to assess the behavioural characteristics of the participants [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The Turkish validity and reliability study was conducted by Guvenir et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The questionnaire is a short behavioural screening questionnaire used to examine mental well-being. The SDQ examines 25 attributes, divided into 5 scales: Emotional problems, behavioural problems, Hyperactivity and inattention, Peer relationship problems, Prosocial behaviours.\u003c/p\u003e \u003cp\u003eTurgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) was developed by Turgay and adapted and translated into Turkish by Ercan\u003c/p\u003e \u003cp\u003eet al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The T-DSM-IV-S (parent and teacher forms) is based on the DSM-IV criteria and assesses hyperactivity-impulsivity (nine items), inattention (nine items), opposition\u0026ndash;defiance disorder (eight items) and conduct disorder (15 items). The severity of each symptom is estimated on a fourpoint Likert-type scale (0\u0026thinsp;=\u0026thinsp;not at all, 1\u0026thinsp;=\u0026thinsp;just a little, 2\u0026thinsp;=\u0026thinsp;quite a bit, and 3\u0026thinsp;=\u0026thinsp;very much). Subscale scores on the T-DSM-IV-S are calculated by summing the item scores for each subscale.\u003c/p\u003e \u003cp\u003eThe Revised Child Anxiety and Depression Scale-Child Version (RCADS-CV) is a self-report questionnaire that assesses the clinical symptoms of anxiety and depression based on DSM-IV criteria. The RCADS-CV has been shown to be a reliable and valid instrument in different cultures and languages as well as in Turkish [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. It consists of 47 items with six subscales corresponding to generalised anxiety disorder (GAD), major depressive disorder (MDD), separation anxiety disorder (SAD), social phobia (SP), panic disorder (PD), and obsessive-compulsive disorder (OCD). It is a four-point Likert-type scale (0\u0026thinsp;=\u0026thinsp;never, 1\u0026thinsp;=\u0026thinsp;sometimes, 2\u0026thinsp;=\u0026thinsp;often, and 3\u0026thinsp;=\u0026thinsp;always). The general anxiety score is obtained by the sum of the first five sub-scales, and the internalisation score is obtained by the sum of all sub-scales. The scale has no cut-off score. In our study, RCADS-CV-children (RCADS-CV-C) and RCADS-CV-parent (RCADS-C-P) forms were used.\u003c/p\u003e \u003cp\u003eThe Pediatric Quality of Life Inventory (PedsQL) developed by Varni et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] in 1999, aims to evaluate the general quality of life in children aged 2\u0026ndash;18 years. The scale consists of four subscales assessing physical, emotional, social, and school-related functioning. A validity and reliability study for the Turkish form of the inventory was conducted for 2\u0026ndash;18 age group. PedsQL evaluates areas of functionality with 4 subheadings: 8 items are physical, 5 items are emotional, 5 items are social, and 5 items are school functionality, for a total of 23 items. Scoring is done in 3 areas: total physical health score, total psychosocial health score, which evaluates emotional, social and school functioning, and total score. It is accepted that the higher the total score, the higher the quality of life. The Turkish validity and reliability study was conducted by Memik et al [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In our study, the children (PedsQL-C) and parent forms (PedsQL-P) of PedsQL were used.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eSPSS 25.0 (IBM Corporation, Armonk, New York, United States) was used in the analysis of the variables. First, preliminary analysis of the assumptions of parametric statistics was conducted. The Kolmogorov\u0026ndash;Smirnov test was used to check the normal distribution of the variables. When the assumption of normality was met, parametric statistical tests were used. When the assumption of normality was not met, non-parametric statistical tests were used. The Student\u0026rsquo;s t-test or Mann\u0026ndash;Whitney U- tests were used to asses differences between two groups according to the normal distribution of the measured parameters. Chi-square test was used to compare the categorical variables. Quantitative variables were expressed as mean (standard deviation), median (25th percentile / 75th percentile), while categorical variables were shown as number (n) and frequency (%). The variables were analyzed at 95% confidence level, and a p value less than 0.05 was considered as significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe group PP1 (mean age: 8.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91 years), PP2 (mean age: 9.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66years) and CG (mean age: 8,79\u0026thinsp;\u0026plusmn;\u0026thinsp;1,02years) were not similar in age (p\u0026thinsp;=\u0026thinsp;0), due to the difference between PP1 and PP2. All cases of the PP1 group (n\u0026thinsp;=\u0026thinsp;25), 88% of the PP2 group (n\u0026thinsp;=\u0026thinsp;22) and 84% of the CG (n:21) were female. The clinic characteristics of group PP1, PP2 and CG are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Pubertal stages were Tanner 2 in four of the patients, Tanner 3 in 13 of the patients, Tanner 4 in 20 of the patients and Tanner 5 in 13 of the patients. The 12% (n:3) and 13.6% (n:3) of the children had early menarche in group PP1 and PP2, respectively. The duration of GnRHa treatment in group PP2 ranged from 13 to 36 months. The mean duration of treatment was 14.42\u0026thinsp;\u0026plusmn;\u0026thinsp;5.65 months.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSociodemographic and clinical features of PP and CG\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP1\u003c/p\u003e \u003cp\u003en:25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePP2\u003c/p\u003e \u003cp\u003en:25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCG\u003c/p\u003e \u003cp\u003en:25\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (year)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e \u003cp\u003e(6.21\u0026ndash;9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e \u003cp\u003e(7.7-10.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e \u003cp\u003e(6.5\u0026ndash;9.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale/Male\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMenarche at diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12% (n:3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.6% (n:3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe SDQ-C, SDQ-P, PedsQL-C and PedsQL-P scores are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The three groups had similar scores in the SDQ-behavior, SDQ-emotional and total scores in the child and parent questionnaires (p\u0026thinsp;=\u0026thinsp;0.812, p\u0026thinsp;=\u0026thinsp;0.79, p\u0026thinsp;=\u0026thinsp;0.959 respectively in the child questionnaires and p\u0026thinsp;=\u0026thinsp;0.824, p\u0026thinsp;=\u0026thinsp;0.852, p\u0026thinsp;=\u0026thinsp;0.599 respectively in parent questionnaires). No significant differences were found between the groups in terms of PedsQL-total scores in the child and parent forms (p\u0026thinsp;=\u0026thinsp;0.505, p\u0026thinsp;=\u0026thinsp;0.992; respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSDQ-A, SDQ-P and PedsQL-A, PedsQL-P Scores\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP1\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePP2\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCG\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-A emotional\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0,5\u0026thinsp;\u0026minus;\u0026thinsp;2,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,790\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-A behaviour\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0,5\u0026thinsp;\u0026minus;\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,812\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-A ADHD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (3\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,585\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-A peer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0\u0026ndash;2,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;2,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-A prosocial\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (7,5\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (6\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (8\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,917\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-A total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (4\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (5\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (5,5\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,959\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-P- emotional\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;3,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;2,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,852\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-P behavioural\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0,5\u0026thinsp;\u0026minus;\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;1,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,824\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-P ADHD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,804\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-P peer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;2,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,406\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSDQ-P total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (5,5\u0026ndash;11,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (6\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (4\u0026ndash;10,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,599\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePedsQL-C pyshical\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84,375\u003c/p\u003e \u003cp\u003e(71,875\u0026thinsp;\u0026minus;\u0026thinsp;89,062)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78,125\u003c/p\u003e \u003cp\u003e(71,875\u0026thinsp;\u0026minus;\u0026thinsp;89,062)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81,25\u003c/p\u003e \u003cp\u003e(68,75\u0026ndash;90,625)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,928\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePedsQL-C psychosocial\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83,333\u003c/p\u003e \u003cp\u003e(75\u0026ndash;92,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83,333\u003c/p\u003e \u003cp\u003e(77,5\u0026ndash;93,333)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90\u003c/p\u003e \u003cp\u003e(83,33\u0026ndash;95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,289\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePedsQL-C total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83,437\u003c/p\u003e \u003cp\u003e(73,359\u0026thinsp;\u0026minus;\u0026thinsp;90,468)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82,968\u003c/p\u003e \u003cp\u003e(74,531\u0026thinsp;\u0026minus;\u0026thinsp;91,875)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87,812\u003c/p\u003e \u003cp\u003e(81,2591,718)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePedsQL-P pyschical\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79,687\u003c/p\u003e \u003cp\u003e(61,718\u0026thinsp;\u0026minus;\u0026thinsp;91,406)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81,25\u003c/p\u003e \u003cp\u003e(71,875\u0026thinsp;\u0026minus;\u0026thinsp;90,625)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87,5\u003c/p\u003e \u003cp\u003e(64,843\u0026thinsp;\u0026minus;\u0026thinsp;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,751\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePedsQL-P psychosocial\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84,166\u003c/p\u003e \u003cp\u003e(65,416\u0026thinsp;\u0026minus;\u0026thinsp;93,333)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85\u003c/p\u003e \u003cp\u003e(66,666\u0026thinsp;\u0026minus;\u0026thinsp;93,333)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82,5\u003c/p\u003e \u003cp\u003e(71,25\u0026ndash;92,083)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,987\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePedsQL-P total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84,296\u003c/p\u003e \u003cp\u003e(63,710\u0026thinsp;\u0026minus;\u0026thinsp;91,445)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82,968\u003c/p\u003e \u003cp\u003e(67,812\u0026thinsp;\u0026minus;\u0026thinsp;91,406)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81,796\u003c/p\u003e \u003cp\u003e(69,804\u0026thinsp;\u0026minus;\u0026thinsp;90,976)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,992\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData were presented as median (25-75th percentiles)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003e(SDQ-A): The Strengths and Difficulties Questionnaire-Adolescent; (SDQ-P): The Strengths and Difficulties Questionnaire-Parent; PedsQL-A: Pediatric Quality of Life Inventory -Adolescent Form; PedsQL-P: Pediatric Quality of Life Inventory-Parent Form\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe RCADS-CV-C and RCADS-CV-P scores of PP1, PP2 and CG are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. No significant difference was found between groups in terms of RCADS-CV scores. Internalizing and anxiety scores were similar between groups for children (p\u0026thinsp;=\u0026thinsp;0.987, p\u0026thinsp;=\u0026thinsp;0.929 respectively) and parents (p\u0026thinsp;=\u0026thinsp;0.942, p\u0026thinsp;=\u0026thinsp;0.824 respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRCADS-CV-A and RCADS-CV-P scores\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP1\u003c/p\u003e \u003cp\u003en:25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePP2\u003c/p\u003e \u003cp\u003en:25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCG\u003c/p\u003e \u003cp\u003en:25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRCADS-CV-C anx.dep. score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (33\u0026ndash;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (30\u0026ndash;47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (32,5\u0026ndash;46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,987\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRCADS-CV-A anxiety score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (32\u0026ndash;44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (31\u0026ndash;49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (31,5\u0026ndash;46,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,929\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRCADS-CV-P anx.dep. score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45,5 (42,75\u0026thinsp;\u0026minus;\u0026thinsp;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (41\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (42,5\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,942\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRCADS-CV-P anxiety score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45,5 (42\u0026ndash;54,75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48,5 (41,25\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (41,5\u0026ndash;55,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,824\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData were presented as median (25-75th percentiles)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eRCADS-CV-A: Revised Child Anxiety and Depression Scale-Child Version-Adolescent Form\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eRCADS-CV-P: Revised Child Anxiety and Depression Scale-Child Version-Parent Form\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe ARI-C and ARI-P scores of the groups are given in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The ARI scores were found to be similar between the three groups in children and parent forms (p\u0026thinsp;=\u0026thinsp;0.581, 0.730 respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eARI-A, ARI-P and T-DSM-IV-S scores\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP1\u003c/p\u003e \u003cp\u003en: 25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePP2\u003c/p\u003e \u003cp\u003en: 25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCG\u003c/p\u003e \u003cp\u003en: 25\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eARI-C-total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;4,25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,581\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eARI-P total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0,5\u0026thinsp;\u0026minus;\u0026thinsp;3,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,730\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT-DSM-IV-S-IA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,5 (3,25\u0026thinsp;\u0026minus;\u0026thinsp;9,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (0\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (1\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,439\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT-DSM-IV-S-HA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (1,25\u0026thinsp;\u0026minus;\u0026thinsp;6,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (1\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,913\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT-DSM-IV-S-ODD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,5 (1\u0026ndash;9,25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,892\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT-DSM-IV-S-CD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,359\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT-DSM-IV-S-Total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14,5\u003c/p\u003e \u003cp\u003e(6\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003cp\u003e(3\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17,5\u003c/p\u003e \u003cp\u003e(6,75\u0026thinsp;\u0026minus;\u0026thinsp;28,25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,903\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData were presented median (25-75th percentiles)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eARI-C: Affective Reactivity Index- Children Form; ARI-P: Affective Reactivity Index- Parent Form;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eT-DSM-IV-S-IA: Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale-Inattention Score\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eT-DSM-IV-S-HA Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale- Hyperactivity\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eT-DSM-IV-S-ODD Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale-Oppositional Defiant Score\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eT-DSM-IV-S-CD Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale- Conduct Disorder Score\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the current study, we analysed behavioural and emotional problems, quality of life, anxiety, and depressive status of children with CPP (at diagnosis and at follow-up), and compared the results with age- and sex-matched healthy controls. In terms of behavioural and emotional problems, quality of life, anxiety and depressive status, the CPP groups did not differ from age-matched controls.\u003c/p\u003e \u003cp\u003eIn contrast to previous reports on elevated behavioral and emotional problems in children with CPP[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], we found no significant differences in SDQ-A and SDQ-P scores between the three groups. In both groups with CPP, children and parents reported similar behavioural and emotional problems with CG. During puberty, it is known that psychological changes are known to follow physiological changes as a result of the activation of hypothalamic-pituitary axis[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. As the children in the CPP group were younger and the possible effects of hormonal changes were treated in the early period, it is suggested that children diagnosed with CPP did not experience any emotional and behavioural differences. The fact that both parents and children consistently reported no emotional and behavioural changes, strengthens this conclusion.\u003c/p\u003e \u003cp\u003eIn TURGAY scale which evaluates the symptoms of attention deficit hyperactivity, oppositional defiant disorder and conduct disorder, similar scores were found between the three groups. During adolescence, children experience some behavioural and emotional difficulties, increased risk-taking behaviour and impulsivity as well as difficulties in controlling anger[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In a cross-sectional study conducted in 2023, externalising behaviours were found to be more prevalent in female adolescents with CPP compared to the control group[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In another study, although the score assessing externalising behaviours was not considered to be clinically significant, it was found to be higher in adolescent girls compared to the control group. It was also suggested that the effect on behaviour emerged at a later age[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The findings of our study indicate that, although biological markers of adolescence have been observed in children, it is believed that their behavioural manifestations are more closely associated with their psychosocial developmental stage and chronological age than with this biological process. Furthermore, the data suggest that children do not exhibit behavioural patterns that are unique to the adolescent period.\u003c/p\u003e \u003cp\u003eThe majority of studies conducted thus far on precocious puberty in children have focused on girls. In some of these studies, elevated rates of depression and anxiety have been observed in children experiencing precocious puberty[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The onset of menarche has been shown as a reason for depressive symptoms[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Among anxiety disorders, social anxiety, which is associated with a lower self-image, has been reported to be more prevalent[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Conversely, similar to our study, some studies have reported that the groups diagnosed and treated with CPP did not exhibit any differences in terms of depressive and anxiety symptoms[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It is known that there should be a serious psychosocial stressor for the emergence of depression in childhood in association with the development of children's cognitive and emotional abilities[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Since the children in our study were relatively younger, it is thought that they did not differ from healthy children in terms of depressive and anxiety symptoms, even if they exhibited symptoms of adolescence.\u003c/p\u003e \u003cp\u003eIt is established that children with a chronic disease experience a negative impact on their quality of life[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. There are limited studies that have analysed the quality of life of children with precocious puberty. In one of these studies, the CPP group included both treated and newly diagnosed children and no significant differences were identified in the quality of life of this group in comparison to healthy children[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In another study a total of 193 children were examined, including 59 children with CPP, 53 children with premature telarche, and 81 healthy children and their parents. No significant differences were found between the CPP, PT and control groups[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In our study, the quality of life of the group of children newly diagnosed with CPP and the group of children who had been receiving treatment for at least one year was found to be similar to that of healthy children according to both self-report and parental report. The favourable response to treatment and the absence of significant adverse effects during the treatment indicate that psychological well-being in children is associated with a high level of quality of life.\u003c/p\u003e \u003cp\u003eIt should be noted that our study has some limitations. First of all, the limited sample size makes it difficult to generalise our results. Although children's psychiatric symptoms were assessed through scales, it is possible that structured psychiatric interviews for children might yield more accurate diagnoses of potential psychiatric disorders. A more detailed evaluation of children's physical characteristics such as height and weight, which change with the puberty process, could have provided a more accurate interpretation of the results. Furthermore, psychological problems that may arise in the longer term can be evaluated by longitudinal follow-up of the study groups.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn the present study, psychiatric symptoms and quality of life were compared between the three groups and no significant difference was detected. While it is a favorable finding that there is no difference in terms of these symptoms in children with early adolescence, it is crucial to consider children with a chronic disease in a multidisciplinary approach and to assess the cases for the potential negative impacts on their quality of life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThe authors received no funding for the research.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e\u0026Ouml;K and GYA drafted the study protocol and wrote the manuscript. \u0026Ouml;K and GYA collected the data. \u0026Ouml;K and GYA revised the manuscript. All authors approved the final version.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed during this study are included in this article. 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Child Health\u003c/em\u003e, vol. 52, no. 12, pp. 1062\u0026ndash;1069, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jpc.13407\u003c/span\u003e\u003cspan address=\"10.1111/jpc.13407\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"precocious puberty, quality of life, affective reactivity, inattention and hyperactivity","lastPublishedDoi":"10.21203/rs.3.rs-4835395/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4835395/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCentral precocious puberty (CPP) occurs as a result of early activation of the hypothalamic-pituitary-gonadal axis. In recent years, especially after the COVID pandemic, presentations with signs of precocious puberty and cases requiring treatment have increased all over the world. Recent studies have showed that CPP patients are more likely to have social and psychiatric problems than their peers of the same age and gender. The aim of our study is to examine the psychiatric symptoms and quality of life of the children newly diagnosed with CPP and cases under treatment more than one year and to compare these symptoms with age and gender-matched healthy children. The research was planned as a cross-sectional study and included 47 female and 3 male patients (n = 50) who were followed up for CPP. The control group (CG) consisted of healthy children matched with the case group in terms of age and gender (n = 25). The case group was divided into two groups; patients who were newly diagnosed and did not receive treatment yet and patients who had been receiving treatment for at least one year. Sociodemographic form, Pediatric Quality of Life Inventory, Revised Child Anxiety and Depression Scale-Child Version (RCADS-CV), Strengths and Difficulties Questionnaire (SDQ), TURGAY DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) were applied to the children and their families. 50 cases diagnosed with CPP with a mean age of 8.95±1.07 years (25 at diagnosis, 25 on follow-up) and 25 healthy children with a mean age of 8.79±1.02 years were enrolled the study. 94% of CPP group (PG) (n = 47) and 84% of control group (CG) (n = 21) were girls. When the child and parent forms have evaluated; there was no significant difference between three groups in terms of quality of life (child and parent forms), anxiety and depression scores, strengths and difficulties scores. Similar results were obtained between three groups in terms of inattention and hyperactivity scores, oppositional defiance and conduct disorder scores according to the scale.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConclusion\u003c/em\u003e: In the present study, psychiatric symptoms and quality of life were compared between the three groups and no significant difference was detected. While it is a favorable finding that there is no difference in terms of these symptoms in children with early adolescence, it is crucial to consider children with a chronic disease in a multidisciplinary approach and to assess the cases for the potential negative impacts on their quality of life.\u003c/p\u003e","manuscriptTitle":"Does precocious puberty and its treatment cause the emotional and behavioural problems in children?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-03 07:33:31","doi":"10.21203/rs.3.rs-4835395/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"960dc4bd-6a41-4151-92f9-86a32866f58b","owner":[],"postedDate":"September 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-28T18:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-03 07:33:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4835395","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4835395","identity":"rs-4835395","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}