aDepartment of Health Sciences, International University of La Rioja, UNIR, Logroño, Spain;
bIntelecto Psychological Centre, Jerez de la Frontera, Spain;
cFaculty of Health Sciences. Public University of Navarra, Navarra, Spain
dSan Carlos Clinic Hospital, Madrid, Spain
Introduction and objectives: The relationship between allergic diseases and behavioural disorders is still unclear. The objective of this study is to describe and compare children’s behaviour (internalising and externalising) across a sample of children between 6 and 11-years-old with and without allergic diseases.
Materials and methods: A cross-sectional, observational case-control study that comprises a survey of 366 families (194 cases and 172 controls) including a Child Behaviour Checklist (CBCL) and a sociodemographic questionnaire with questions related to family, school education, health conditions, and allergy symptoms was administered.
Results: Children with a diagnosis of allergy showed higher scores in the overall CBCL score (standardised mean differences [SMD] = 0.47; CI: 0.26–0.68) and in the internalising and externalising factors (SMD = 0.52 and SMD = 0.36, respectively) than non-allergic children. Odds ratio analyses showed a higher risk (OR = 2.76; CI 95% [1.61 to 4.72]) of developing a behavioural difficulty in children diagnosed with allergies. Age and level of asthma appears as modulatory variables.
Conclusions: Children diagnosed with allergies at age 6 to 11 years show larger behavioural problems than non-allergic children, especially in internalising behaviours. These findings suggest the importance of attending to them and treating them in the early stages of the diagnosis to avoid future psychological disorders.
Key words: allergy, behaviour, internalising and externalising, child, parent
*Corresponding author: Pilar Berzosa-Grande, International University of La Rioja, C/ Gran Vía Rey Juan Carlos I, 41, 26002 Logroño, La Rioja, Spain. E-mail address: email@example.com
Received 29 July 2020; Accepted 18 November 2020; Available online 1 July 2021
Copyright: Berzosa-Grande MP et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/
The prevalence of allergic diseases has increased for more than 50 years worldwide, especially in industrialised countries1 and in children under the age of 18.2–4 This rise in the prevalence of allergies have a great impact on societies and generates large health-care costs.5,6 Families and children with allergic diseases are particularly affected and bear the greatest burden7 which is reflected in a reduction in their quality of life,8 an increased risk of psychological disorders,9 and numerous medical and non-medical comorbidities.10
Over the past few decades, evidence about the relationship between common allergies (related to environmental factors, foods or drugs), their main symptoms (such as asthma, allergic rhinitis (AR) or atopic dermatitis (AD)) and mental health problems in children and young adults has become stronger.11–14 Asthma has been related with a higher risk of internalising disorders (such as anxiety and depression),15 externalising disorders (such as oppositional defiant or disruptive behaviour disorders)16,17 or poorer social and mental well-being.18 Different studies with children and pre-schoolers with AR have shown a relationship with internalising and sleep problem behaviours.19–22 In addition, AD has been associated in different studies with several mental comorbidities such as attention deficit disorder, anxiety and depression.23 However, a recent meta-analysis of 35 studies on AD has found opposite results.24
On the other hand, the relation between allergic diseases and these internalising/externalising difficulties is not clear. Some psychological approaches have suggested that children could have psychological adjustment difficulties because of an allergy and its symptoms,25 or that these could be influenced by intra-familiar or socio-emotional factors related with the family context.26–29 Others have explored the relationship with an underlying biological process related to the serotoninergic system.30,31
Despite this evidence, there is still a lack of studies assessing outcomes with well-validated instruments that compare a clinical allergic sample with a similar control sample of non-allergic children, or that assess the possible relationship between multiple comorbid allergies and problematic behaviours.19
The aim of this study is to assess the relationship between allergic diseases and behavioural problems (internalising and externalising). It was also studied the possible influence of intra-familiar conditions (such as level of stress inside the family, affective expressions, resilience and parental authority) into the origin of behavioural problems in allergic children. In addition, we aim to assess the relation between the severity of the allergy (mild or moderate asthma and the number of allergic comorbidities) with the degree of behavioural problems.
The principal hypothesis of this study was that children (aged 6 to 11 years) with a diagnosis of allergic disease would show higher behavioural problems (internalising and externalising problems), assessed with the Child Behaviour Checklist (CBCL)32 than children without a diagnosis of allergic disease.
The secondary hypothesis was that children (aged 6 to 11 years) with a diagnosis of allergic disease would show higher scores in the eight syndrome subscales of the CBCL scale32 (anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behaviour and aggressive behaviour) than children without a diagnosis of allergic disease.
Third hypothesis was that there is a positive relation between the severity of the allergy (assessed by the degree of asthma and the number of allergic comorbidities) and the level of behavioural problems.
This study design was carried out as a multicentre, case-control, cross-sectional study.
The study population included two groups. The first group (cases) consisted of families with a child diagnosed with an allergic disease. To be eligible to be included in this group, families had to have a child: (1) male or female (from 6 years to 11 years), (2) being treated in an external paediatric pneumology/allergology service, (3) with a clinician diagnose of mild or moderate environmental allergy (including pollen, mould, dust or pets), food allergy, medication allergy, allergic asthma, AR or AD, (4) allergy symptomatology must be stable and well-controlled by a clinician. Exclusion criteria included: (1) children with a severe clinical diagnosis of allergy, (2) comorbidity of another primary pathology, (3) direct family (parents or siblings) with a severe mental disorder (DSM-V criteria) and (4) being hospitalised. The sample of this group was recruited from the Clinical Hospital of San Carlos, located in Madrid (Spain). A clinician informed families individually about the study and its purposes and asked them about their interest in participating in the study.
The second group (controls) consisted of families with healthy children. To be included in this group, families had to have a child: male or female (from 6 years to 11 years). Exclusion criteria for this group included having a child: (1) with a clinical diagnosis of allergy, (2) comorbidity of another primary pathology, (3) direct family (parents or siblings) with a severe mental disorder (DSM-V criteria) and (4) being hospitalised. The full sample of this group was recruited from a state financed school in Madrid (Spain). In this case, the team had a previous meeting with the families to inform them about the study and its purposes. Forms (informed consent and survey) were mailed by post to their homes. Families interested in participating forwarded the documentation with the requested information.
Parents of both groups signed the written informed consent form before their inclusion in the study. Study approval was obtained in April 2019 from the Ethical and Scientific Research Committee of the San Carlos Clinic Hospital, Madrid (Spain) (Internal Code: 19/108-E).
To collect sociodemographic information, the team developed an ad hoc questionnaire with questions related to age, sex, number of brothers and sisters of the child, and family structure (nuclear, separated, adoptive, etc...).
To detect the emotional circumstances of the family context, a brief ad hoc questionnaire where parents used a 3-Likert scale (low, medium or high) was used to rate their perceived level of stress inside the family, affective expressions, resilience to copy with problems and difficulties, and their authority or effectiveness in establishing rules at home (Supplementary material).
Allergy information about the participants in the case group was collected directly from the medical file by a clinician. It includes allergen (pollen, mould, dust, pets, food and medication), level of asthma (mild or moderate), AD, AR and food intolerance. Participants in the control group were also asked about all of these questions in order to ensure that they did not suffer from allergies or show allergy symptoms.
To assess the behavioural problems, parents completed the CBCL.32 The CBCL can be applied to subjects aged from 4 to 16 years. It includes 113 statements recorded in a 0–3 Likert scale (0 = “false or rarely”; 2 = “true or very often”). The items are grouped in nine independent factors: anxious/depressed, withdrawn/depressed, somatic complaints, social problems, attention problems, rule-breaking behaviour, aggressive behaviour and other problems. The scale gives three summary scores related to internalising behaviour problems (formed by the sum of the factors of anxious/depressed, withdrawn/depressed and somatic complaints), externalising behavioural problems (sum of rule-breaking behaviour and aggressive behaviour) and a total score (obtained by the addition of all the factors). To interpret the scores, direct scores must be converted to a T scale where scores between 65 and 70 are considered a critical borderline clinical range. Higher scores mean higher levels of behavioural problems. We used the Spanish version of the CBCL for children between 6 and 18 years.33
Parents completed the parent rating scale of the CBCL and the ad hoc questionnaires.
Taking into account that the 10% of the general child population can show any disruptive behaviour34 and accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 195 subjects are necessary in both groups to find a statistically significant difference in proportions, expected to be 0.1 in allergic group and 0.2 in the control group.
Sample description is reported by means and SDs for continuous variables, whereas frequencies and percentages describe categorical variables.
To contrast the main hypothesis of the study, we used simple means of comparisons (Student’s t-test or the Mann–Whitney U test). In addition, simple mean difference and standardised mean differences (SMD) with 95% confidence intervals (CI) are reported. SMD can be easily interpreted following the rule of thumb: scores from 0 to 0.2 indicate a small effect, values close to 0.5 suggest medium effect, and 0.8 or above can be interpreted as large effect.35 Odds ratios (OR) and 95% confidence ratios (CI) were determined. To calculate the OR, we separated the obtained CBCL scores using a T score of 65 as the cut-off point, marked by the original authors of the scale as “clinical range.” An OR of >1 can be interpreted as higher odds of the described event occurring given the particular exposure. In case of any statistically significant differences in sociodemographic or familiar variables between groups, secondary analysis will be performed by logistic regression, adjusting for covariates.
The association between the allergy severity (assessed by the degree of asthma and the number of allergic comorbidities) and the level of behavioural problems was examined using a Student’s t-test (degree of asthma has only two categories) and a Pearson correlation (one participant could have from one to four allergies). For these dose-relation analyses, we used the allergic sample.
An independent and blinded statistician performed analyses using SPSS V.21 (IBM SPSS Statistics for MAC, Version 24.0. Armonk, NY: IBM Corp.) and Jamovi 1.2 (The jamovi project) Jamovi (Version 1.2).
A total of 456 families were assessed for eligibility out of which 23 (5.04%) did not meet the selection criteria and 67 refused to participate (14.69%). Finally, we recruited a total sample of 366 families (80.26%; 194 cases and 172 controls) from May 2019 to July 2019. Table 1 presents the main sample characteristics obtained with the questionnaire divided by groups.
Table 1 Sociodemographic description of the sample.
|Variables||Total (N=366)||Allergic (n=194)||Control (n=172)||P value|
|Age, mean (SD)||8.68 (1.71)||9.01 (1.62)||8.31 (1.72)||<.001|
|Female gender, n (%)||173 (47.3)||85 (43.8)||88 (51.2)||.160|
|Allergy, n (%)|
|Level of asthma, n (%)|
|Atopic dermatitis, n (%)||123 (63.4)||123 (63.4)||0||<.001|
|Rhinitis, n (%)||171 (88.14)||171 (88.14)||0||<.001|
|Alimentary intolerance, n (%)||12 (3.27)||12 (6.18)||0||<.001|
|Family structure, n (%)|
|Nuclear||251 (68.6)||130 (67)||122 (70.9)||.091|
|Separated or divorced||54 (14.7)||28 (14.4)||26 (15.1)|
|Stepfamily||26 (7.1)||16 (8.2)||10 (5.8)|
|Adoptive||5 (1.4)||1 (0.5)||4 (2.3)|
|Single parent||20 (5.5)||15 (7.7)||5 (2.9)|
|Others||10 (2.7)||4 (2.1)||5 (2.9)|
|Family perceived stress|
|Low||220 (60.2)||111 (57.2)||109 (63.4)||.668|
|Medium||123 (33.6)||71 (36.6)||52 (30.2)|
|High||23 (6.2)||12 (6.2)||11 (6.4)|
|Parents affective expression|
|Low||19 (5.2)||11 (5.7)||8 (4.7)||.804|
|Medium||25 (6.8)||12 (6.2)||13 (7.6)|
|High||322 (88)||171 (88.1)||151 (87.8)|
|Low||64 (17.5)||31 (16)||33 (19.2)||.187|
|Medium||187 (51.1)||94 (48.5)||93 (54.1)|
|High||115(31.4)||69 (35.6)||46 (26.7)|
|Low||37 (9.9)||18 (9.3)||19 (10.5)||.508|
|Medium||189 (51.8)||106 (54.6)||83 (48.5)|
|High||140 (38.5)||70 (36.1)||70 (40.9)|
The total sample had a mean age of 8.68 years, while the allergic group showed a higher mean age than the control group. Overall, allergic children reported allergies to environmental elements (pollen, mould, dust or pets). Further, 38 children indicated food allergies and only five showed allergy to pharmacological compounds. All children in the allergic sample were diagnosed with asthma, and 123 had AD. The most frequent family structure was traditional or nuclear followed by separated or divorced parents. The family context emotional circumstances assessment indicated that the level of stress was predominately low, with a high degree of affective expressions, and medium degree of resilience and authority.
No significant differences were observed between allergic and control groups in relation to intra-familiar conditions.
Table 2 shows the scores on the CBCL scale. The overall sample obtained a mean total score of 26.71, indicating non-clinical behaviour. Allergic children showed higher scores, with a significant mean difference of 10.27 points above the control group (SMD = 0.47; CI 95% [0.26 to 0.68]). Internalising and externalising subscales reported similar differences between groups with medium effect sizes (SMD = 0.52; CI 95% [0.32 to 0.73] and SMD = 0.36; CI 95% [0.15 to 0.56] respectively).
Table 2 Comparisons of CBCL scores by groups.
|Total (N = 366)||Allergic (n = 194)||Control (n = 172)||P Value||Mean difference||SMD (95% CI)||OR (95% CI)|
|CBCL Total, mean (SD)||26.71 (21.32)||31.28 (22.45)||21.55 (18.74)||<0.001||−10.27||0.47 (0.26–0.68)||2.76 (1.61–4.72)|
|Anxious/Depressed||3.39 (3.52)||4.06 (3.88)||2.63 (2.9)||<0.001||−1.55||0.41 (0.21–0.62)||2.83 (1.41–5.66)|
|Withdrawn/Depressed||1.63 (2.32)||2 (2.65)||1.21 (1.8)||<0.001||−0.88||0.34 (0.14–0.55)||1.5 (0.84–2.67)|
|Somatic complaints||2.33 (2.7)||3.03 (2.98)||1.54 (2.07)||<0.001||−1.49||0.57 (0.36–0.78)||1.51 (1.38–4.53)|
|Social problems||2.45 (2.7)||2.93 (2.89)||1.91 (2.35)||<0.001||−1.08||0.38 (0.18–0.59)||3.31 (1.52–7.19)|
|Thought problems||2.07 (2.53)||2.57 (2.71)||1.5 (2.18)||<0.001||−1.18||0.43 (0.22–0.64)||2.41 (1.19–4.89)|
|Attention problems||4.18 (3.71)||4.69 (3.78)||3.61 (3.55)||0.002||−1.18||0.29 (0.09–0.5)||1.44 (0.71–2.91)|
|Rule-breaking behaviour||1.63 (1.96)||1.74 (2.11)||1.5 (1.76)||0.221||−0.25||0.12 (−0.08–0.33)||1.89 (0.72–4.91)|
|Aggressive behaviour||5.02 (4.61)||5.92 (4.81)||4 (4.16)||<0.001||−1.93||0.42 (0.22–0.63)||2.5 (1.17–5.36)|
|Others||3.97 (2.96)||4.29 (3.02)||3.61 (2.86)||0.025||−0.69||0.26 (0.06–0.47)||—|
|Internalising||7.36 (7.29)||9.10 (8.14)||5.39 (5.59)||<0.001||−3.93||0.52 (0.32–0.73)||2.45 (1.54–3.89)|
|Externalising||6.65 (6.14)||7.67 (6.41)||5.50 (5.62)||<0.001||−2.18||0.36 (0.15–0.56)||1.77 (1.03–3.04)|
CBCL: Child Behaviour Check List; CI: Confidence Interval; SD: Standard Deviation; SMD: Standardised Mean Difference; OR: Odds Ratio.
The remaining factors, except “rule-breaking,” showed similar statistical results (p > 0.025) with medium effect sizes. The biggest differences were detected in the “somatic complaints” (SMD = 0.57) and “thought problems” (SMD = 0.43) subscales, while the smallest differences were in the “attention problems” (SMD = 0.29) and “others” (SMD = 0.26).
Logistic regressions adjusting for covariates (age and number of siblings) reported similar results (P values <0.01 for the total score, internalising and externalising subscales, and P values less than 0.05 for the remaining factors except for “rule-breaking”). A comparison between the younger participants (6–8 years) and the older participants (9–11 years) showed smaller differences (SMD) in all scores, especially in externalising subdomain (Table 3).
Table 3 Comparisons of CBCL scores by groups and by age (under and over 9 years old).
|Under 9 years||Over 9 years|
|Allergic (n = 78)||Control (n = 95)||P Value||SMD (95% CI)||Allergic (n = 116)||Control (n = 77)||P Value||SMD (95% CI)|
|CBCL Total, mean (SD)||30.69 (21.53)||19.08 (16.06)||<0.001||0.62 (5.96–17.25)||31.68 (23.14)||24.61 (21.31)||0.033||0.31 (0.56–13.57)|
|Anxious/Depressed||4.01 (3.88)||2.28 (2.63)||<0.001||0.53 (0.74–2.71)||4.10 (3.90)||3.08 (3.17)||0.056||0.28 (−0.02–2.07)|
|Withdrawn/Depressed||1.62 (1.96)||1.12 (1.81)||0.084||0.26 (−0.06–1.06)||2.27 (3.01)||1.34 (1.80)||0.016||0.35 (0.17–1.62)|
|Somatic complaints||3.05 (3.37)||1.38 (1.83)||<0.001||0.63 (0.87–2.46)||3.02 (2.71)||1.74 (2.34)||<0.001||0.49 (0.53–2.02)|
|Social problems||2.74 (2.66)||1.72 (1.95)||0.004||0.44 (0.52–2.67)||3.06 (3.05)||2.17 (2.77)||0.041||0.30 (0.03–1.74)|
|Thought problems||2.62 (82.63)||1.39 (2.13)||<0.001||0.51 (0.5–1.94)||2.55 (2.79)||1.65 (2.26)||0.019||0.34 (0.15–1.65)|
|Attention problems||4.81 (3.86)||3.21 (3.30)||0.004||0.44 (0.52–2.67)||4.62 (3.75)||4.12 (3.80)||0.364||0.13 (−0.58–1.59)|
|Rule-breaking behaviour||1.58 (1.83)||1.27 (1.61)||0.248||0.17 (−0.21–0.82)||1.86 (2.28)||1.78 (1.92)||0.793||0.03 (−0.53–0.70)|
|Aggressive behaviour||5.97 (4.37)||3.36 (3.38)||<0.001||0.67 (1.45–3.78)||5.90 (5.10)||4.81 (4.88)||0.140||0.21 (−0.36–2.54)|
|Others||4.29 (3.35)||3.36 (2.60)||0.040||0.31 (0.04–1.83)||4.30 (2.79)||3.94 83.15)||0.397||0.12 (−0.48–1.21)|
|Internalising||8.68 (8.31)||4.78 (5.05)||<0.001||0.58 (1.87–5.92)||9.39 (8.06)||6.16 (6.15)||0.003||0.43 (1.09–5.36)|
|Externalising||7.55 (5.66)||4.63 (4.62)||<0.001||0.62 (5.96–17.25)||7.76 (6.91)||6.58 (6.53)||0.239||0.17 (−0.78–3.13)|
According to the results, children with allergies are 2.76 times more likely to have behaviour problems than children without allergies (P ≤ 0.001; 95% CI [1.61 to 4.72]). The OR of the externalising and the internalising subscales showed similar, significant results (P = 0.03 and 0.001, respectively) indicating the same relationship. The OR was bigger in the internalising factors than in the externalising factors (2.45 against 1.77). The “social problems” factor obtained the highest OR of the overall scale (OR = 3.31; 95% CI [1.52 to 7.19]) followed by the factors: “anxious/depressed” (OR = 2.83; 95% CI [1.41 to 5.66]), “withdrawn/depressed,” “attention problems” and “rule breaking behaviour” factors showed smallest and non-statistically significant OR (95% CI included value of 1).
Comparisons between those children with mild or moderate level of asthma showed higher and significant scores in the subsample of moderate asthma (Table 4) in the total score and in the internalising subdomain.
Table 4 Comparisons of CBCL scores by level of asthma (mild or moderate).
|Mild asthma (n = 151)||Moderate asthma (n = 43)||P value||Mean Difference||SMD (95% CI)|
|CBCL Total, mean (SD)||29.3 (21.4)||38.3 (24.8)||0.019||−9.08||0.4 (1.51–16.64)|
|Internalising||8.49 (7.68)||11.3 (9.41)||0.049||−2.77||0.34 (0.01–5.52)|
|Externalising||7.26 (6.05)||9.12 (7.47)||0.09||−1.85||0.29 (0.32–4.03)|
CBCL: Child Behaviour Check List; CI: Confidence Interval; SD: Standard Deviation; SMD: Standardised Mean Difference.
Correlations between the number of allergies and CBCL scores did not show relevant results (P < 0.05).
The prevalence of allergies in infants has grown in the last decades.36 Allergies are very often associated with physical, mental and emotional problems that can be detected through children’s behaviours and feelings.22
The results of this study confirm the main hypothesis in children with allergic diseases showing a higher risk of suffering from behavioural problems (internalising and externalising) than healthy subjects. Both types of factors show differences, with those in internalising factors appearing to be greater. These results are similar in other studies.19,37
The secondary hypothesis also appears to be confirmed. Children with allergies showed higher scores in all the subscales with the exception of “rule-breaking behaviour.”
The fact that the subscale of “rule-breaking behaviour” did not show significant differences and the absence of differences in the emotional climate in the family (stress, affective expression, resilience or authority) could be related, in agreement with similar studies that indicated a relationship between oppositional-defiant behaviours and parental discipline styles, socio-environmental factors and personality.38,39 However, this point needs further research.
Analysing each subscale, “somatic complaints” stand out for having the largest mean differences. Obviously, this is directly related to the symptoms derived from the allergies (asthmatic, rhinitis and AD). The rest of the subscales can be connected following other similar studies.21,40 Those children with social problems, thought problems or attention problems experience difficulties in expressing their feelings and emotions which can produce anxious/depressed symptoms or aggressive behaviours. These two subscales have shown the biggest differences in each factor (internalising and externalising, respectively). Secondary analyses comparing scores by group and age have revealed very interesting results that need be explored further in detail. It seems that these differences tend to decrease as the children get older. Maybe this can be related to own maturation process of the child, the acquisition of new behavioural skills or to the less dependency of the parents.
Third hypothesis related with dose-relation analyses showed mixed results. While there was a relation between asthma degree (mild or moderate) and general and internalising behavioural problems, these relations disappear when compared with number of allergies. This situation may be due to the dispersion of the data and a larger sample size may be required.
Despite the efforts to control methodological aspects, these results must be considered within the context of some limitations. Firstly, the study’s principal limitation is related to its cross-sectional design. It would be desirable to carry out a longitudinal study to increase the internal validity of the results. Secondly, despite efforts to recruit subjects in different groups, we failed in the control group, where the number of participants was less than expected in sample size calculations. This limitation could be associated with the lack of parental involvement in a study whose results do not concern them. Thirdly, we have used a simple and ad hoc questionnaire to assess some variables (the aspects related with the allergy and the emotional climate in the family). It would be desirable to use a more precise and well-validated tool to asses these aspects and to make comparisons with other similar and possible studies. In this context, findings should be interpreted with caution and it is not possible to ensure that these differences imply a causal phenomenon.
Last, in this study, odds ratio results indicated that all factors including overall CBCL score and each individual factor showed a higher risk of clinical behavioural problems in the sample of allergic children. In some cases, the risk of showing difficulties or problems is more than three times in the case group than in the control group (social problems). These findings suggest the need to investigate new strategies and interventions to treat and prevent possible mental health diseases in childhood, which is such an important stage in a person’s development.41
These findings suggest an important association between suffering from allergies and the presence of behavioural problems in children from 6 to 11 years. This relationship is stronger in internalising behaviours. Age of the children and moderate asthma appear to be protective variables. Because of the importance of children’s proper mental and physical development and their transition to adulthood, clinicians should pay more attention to possible symptoms related to mental health or behavioural problems, especially in children with multiple allergic diseases or comorbidities. Early treatment and prevention programmes with children and their families that could avoid or reduce the probability of manifesting these difficulties in successive stages may be warranted.
We are grateful to Jennifer Benítez Navas from the Intelecto Psychological Centre, Jerez de la Frontera (Spain).
This study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).
All participants signed an informed consent. The author for correspondence is in possession of this document.
This research did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
The authors have no conflicts of interest to disclose.
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