ADHD Atten Def Hyp Disord (2011) 3:2128 DOI 10.

1007/s12402-010-0041-z

ORIGINAL ARTICLE

Childhood obesity and parental smoking as risk factors for childhood ADHD in Liverpool children
Gibby Koshy Ali Delpisheh Bernard J. Brabin

Received: 30 April 2010 / Accepted: 17 October 2010 / Published online: 15 December 2010 Springer-Verlag 2010

Abstract ADHD prevalence has risen in parallel with rising prevalence of pregnancy smoking and childhood obesity. The objective was to determine the epidemiological association of pregnancy smoking and childhood obesity with ADHD. A cross-sectional community study was conducted in 2006 using a parental questionnaire. A total of 1,074 schoolchildren aged 511 years were enrolled from 15 primary schools in a lower socio-economic area of Merseyside. ADHD was dened by the question does your child have Attention Decit Hyperactivity Disorder, (ADHD), which has been diagnosed by a doctor? The prevalence estimates for childhood obesity, maternal smoking during pregnancy and childhood ADHD were 14.9% (116/777), 28.0% (269/955), and 3.4% (32/945), respectively. ADHD prevalence increased vefold in children with obesity (RR, 4.80, 95% CI 2.210.4, P \ 0.001) and more than twofold in children of mothers who smoked during pregnancy (RR, 2.44, 95% CI 1.24.9, P = 0.02). Regression analysis adjusting for obesity, overweight, maternal smoking during pregnancy, heavy maternal smoking, household member smoking during pregnancy, doctor-diagnosed asthma, preterm birth, and low birthweight showed signicant independent
G. Koshy A. Delpisheh B. J. Brabin (&) Child and Reproductive Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK e-mail: B.J.Brabin@liv.ac.uk B. J. Brabin Department of Community Child Health, Royal Liverpool Childrens Hospital, Alder Hey, NHS Trust, Liverpool, UK B. J. Brabin Emma Kinderziekenhuis, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

associations of ADHD prevalence with obesity (AOR, 4.66, 95% CI 1.5713.89, P = 0.006) and pregnancy smoking (AOR, 3.19, 95% CI 1.089.49, P = 0.04). There was a positive doseresponse association of ADHD with the number of maternal cigarettes smoked during pregnancy. Measures to reduce both smoking among pregnant women and childhood obesity might reduce prevalence of childhood ADHD. Keywords Smoking ADHD Childhood Obesity Pregnancy

Background Attention decit hyperactivity disorder (ADHD) is the most common neuro-psychiatric disorder in childhood (Buitelaar and Medori 2009). World-wide prevalence ranges between 4 and 12% (Lynch et al. 2006; Bloom et al. 2006) and affects up to 5% of children and between 2 and 4% of adults in the United Kingdom (NICE 2000). The effects of childhood ADHD continue into adulthood inuencing social relationships and increasing anti-social behaviour (Biederman et al. 1997; Murphy and Barkley 1996). It has been estimated that about 30% of men and women smoke in the United Kingdom with heavy smokers mostly belonging to the age group of 2040 years (Tourmaa 1995), which for women covers the child-bearing years. Smoking prevalence is high in the north-west of England with as many as 1 in 3 women smoking during pregnancy (32%), (National UK smoking statistics 2007). There are about 700,000 births annually in the United Kingdom, which equates to 245,000 infants annually exposed in utero to cigarette smoke (National UK smoking statistics 2007).

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Obesity prevalence is also high and rising in children (Chinn and Rone 2001), and childhood obesity risk has been linked to pregnancy smoking in studies from Germany, USA (Von Kries et al. 2002; Chen et al. 2006) and in recent studies from Merseyside, UK (Koshy et al. 2010). In the USA, increased ADHD among children has occurred in parallel with an increase in pregnancy smoking prevalence (Robison et al. 1999, 2002; Ilana et al. 2010). An association of maternal smoking with offspring ADHD has been shown in Japanese and UK children of which a signicant part might be explained by genetic factors (Thapar et al. 2003; Yoshimasu et al. 2009). However, these studies did not control for childhood obesity, and although an association between obesity and ADHD has also been reported (Agranat-Meged et al. 2005), the combined risk for ADHD of both maternal pregnancy smoking and childhood obesity has not been estimated. The present study aimed to determine the association of both childhood obesity and pregnancy smoking with ADHD in the same UK population where the prevalence of obesity is rising and which has high maternal smoking prevalence. A further aim was to assess the level of this association in relation to the number of cigarettes smoked by the mother.

Methods The questionnaire was distributed to parents by class teachers and information on child age and sex, birth outcomes (pre-term birth and low birthweight), socio-economic status was requested. Questions were also asked about presence of smokers in the household, dose and duration of parental smoking including number of cigarettes smoked and duration of smoking. Pregnancy smoking was dened as mothers who smoked at least one cigarette a day during pregnancy in response to the question Did the mother of this child smoke during pregnancy? Dose of smoking was based on the question How many cigarettes did you smoke a day? Heavy pregnancy smoking was dened as women who smoked more than 10 cigarettes per day, light smoking as mothers who smoked less than this amount, and non-smokers as mothers who reported no smoking at any time during their pregnancy. The cut-off value of 10 cigarettes per day was adopted in the present study, as this value has been used in previous reports (Berkey et al. 1984; Cornelius et al. 2001a; Soares et al. 2007). Information on maternal age, breast feeding habits, and pet ownership was also obtained. The birthweight of the child was requested. Denitions used for analysis

Subjects and methods Subjects A retrospective cross-sectional survey was conducted in 2006 using a standardised respiratory health survey instrument to determine the association of ADHD risk with childhood obesity prevalence and maternal smoking during pregnancy. A total of 1074 schoolchildren aged 511 years from 10 primary schools from South Sefton in Liverpool, and 5 schools in Seacombe, Wallasey were enrolled using a parent-completed questionnaire that was distributed to all parents in the 15 schools. Questionnaires were delivered to schools and surveys completed concurrently in South Sefton, Waterloo, Netherton, and Bootle (north and east of the Mersey estuary), and Wallasey (south of the Mersey estuary). These schools were selected, as they were located in areas of lower socio-economic status and situated within a three mile radius of each other (Rizwan et al. 2004). All school registered children were invited to participate following written informed parental consent. A reminder letter and questionnaires were forwarded to parents, if no response was received in the initial distribution. A school revisit was made to measure absentees and to distribute a second questionnaire to parental non-responders. Children returned questionnaires during the following 2-week period. Children were dened as low birthweight, if \2.5 kg at delivery and preterm according to the parental response to the prematurity question Was your baby born prematurely? Ascertainment of prematurity by the question Was your baby born prematurely? is dependent on the mothers knowledge and understanding of gestational age at delivery, which may have been explained in a number of ways by the attending doctor or nurse. The validity of the answers is supported by the observation that distribution of birthweights in this population was comparable to reference percentiles and supports the validity of parental recall of birthweight values (Kelly et al. 1995). ADHD was dened by the question does your child have attention decit hyperactivity disorder, (ADHD), which has been diagnosed by a doctor? Doctor-diagnosed asthma was dened by the question Has your child ever been diagnosed as having asthma or bronchial asthma by the doctor? Socio-economic status was assessed by quartiles of the Townsend Deprivation Index that is derived from household postcodes and is based on overcrowding, car ownership, home ownership, and unemployment. The score ranges from -6 to ?12 with values below zero indicating better and above zero worse socio economic status (Dolan et al. 1995; Gilthrope 1995). Pregnancy drinking habit was requested by the question Did the mother take any alcoholic drinks during the pregnancy of this child?.

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Childhood obesity and parental smoking as risk factors for childhood ADHD in Liverpool children

23

The weight and height of children whose parents had completed the questionnaire were measured. Children were asked to remove shoes and heavy garments. Height was measured to the nearest millimetre using a Minimeter scale (Raven Equipment Ltd), and weight was measured to the nearest 100 g using electronic scales (Seca). Children who were absent from class during the anthropometric survey were seen subsequently at a repeat visit. Body mass index (BMI) (wt/ht2) and anthropometric z-scores were calculated for the childs age and sex using Epi Info (Nutri) version 6 that uses the 2000 NCHS reference growth data. The standard used was the 2000 CDC growth reference (CDC 2001), which has been widely recommended for international anthropometric data analysis. Childhood obesity was dened as: BMI z score C 1.64 SD and overweight as: BMI z score C 1.04 SD (Bundred et al. 2001). Statistical methods SPSS (Statistical package for social sciences) statistical package version 17 was used for all the analysis. A univariate procedure was used to check central tendency and variation of continuous variables (age, birthweight, weight, and height). Means and SDs and 95% CI were calculated for all continuous variables. Cross-tabulation tables were created between dichotomous outcomes (presence or absence of pregnancy cigarette smoke exposure) and the potential predictors that were categorical variables. Chisquare test or Fishers exact test statistics were computed and the Students t-test used for comparison of means. The association between exposure to tobacco smoke in utero and the risk of ADHD was expressed as a relative risk (RR) with 95% condence intervals (CIs). Multiple logistic regression models with a backward stepwise method were used to estimate adjusted odds ratios for predicting risk of ADHD with pregnancy smoking and childhood obesity. Covariates included in the model were those with P \ 0.2 in the univariate analysis. These were obesity, overweight, maternal smoking during pregnancy, maternal heavy smoking, doctor-diagnosed asthma, preterm birth, and household member smoking during pregnancy. Low birthweight was also included in the model because of its interaction with preterm birth and its potential biologically plausible effect. Population attributable risk (PAR) was calculated by Prevexp (RR - 1)/Prevexp (RR - 1) ?1, where Prevexp is the prevalence of the outcome and RR the risk estimate. Condentiality of the data and results was maintained. Ethical approval for the study was provided by the Royal Liverpool Childrens Hospital NHS Trust, Alder Hey and the Liverpool School of Tropical Medicine Ethical Committees.

Results Table 1 summarises the sample description. Parental compliance for school questionnaire completion was 30.3% (1,074/3,540) and ranged between 15.3 and 55.3% across the 15 schools. Approximately 3% were not distributed to parents due to their childs school absenteeism. The mean age of children enrolled was 7.3 years. There
Table 1 Sample characteristics of children Characteristic Mean age SD (years) Sex (M:F) ADHDa (%) ADHD male (%) ADHD female (%) Socio-economic status (%) Low birthweight (%) Preterm birth (%) Mean birthweight (gms)c Mean Body Mass indexd Mean weight z-score Male Female Mean height z-score Male Female Mean BMI z-score Male Female MSDPe (%) PSDPf (%) HSDP (%) Doctor-diagnosed asthma (%) Obesityh (%) Obesity male (%) Obesity female (%) Overweight (%) Overweight male (%) Overweight female (%) Compliancej (%)
a b c d e f g h i j i g b

Values 7.28 1.91 (983) 48.7:51.3 (1,074) 3.4 (945) 3.0 (945) 3.8 (945) 90.9 (833) 7.3 (1,009) 12.9 (1,033) 3.21 0.67 (1,009) 17.69 3.85 (777) 0.69 1.17 (777) 0.72 1.16 0.67 1.19 0.53 1.63 (777) 0.52 1.59 0.54 1.60 0.45 1.37 (777) 0.46 1.41 0.44 1.40 28.0 (955) 37.9 (762) 44.0 (944) 19.4 (949) 14.9 (777) 13.4 (367) 16.4 (410) 30.7 (777) 28.1 (367) 33.1 (410) 30.3 (1,074/3,540)

Attention Decit Hyperactivity disorder Townsend score [ ? 4 grams (SD) kg/m2(SD) Maternal smoking during pregnancy Paternal smoking during pregnancy Household member smoking during pregnancy BMI z score [ 1.64 (95th percentile) BMI z score [ 1.04 (85th percentile) For parental questionnaire completion; Brackets : Sample size

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G. Koshy et al. Table 2 continued Characteristic LBWh Yes No Preterm Yes No Yes No Child \7 years Yes No 3.9 (15/386) 3.0 (16/531) 1.25 0.305.18 1.00 1.29 0.652.58 0.47 0.8 (1/133) 3.6 (27/749) 2.2 (4/181) 3.3 (24/717) 0.66 0.231.88 0.63 0.21 0.031.52 0.12 2.2 (2/92) 3.4 (23/685) 0.65 0.162.70 0.76 ADHDa present RR 95% CI P value

were fewer children with BMI measurements (n = 777) than with completed questionnaires due primarily to parental refusal for children to be measured, and due to absenteeism. Low birth weight was reported in 7.3% (78/1009) and preterm birth in 12.9% (139/1,033). Overweight and obesity prevalence were 30.7% (239/777) and 14.9% (116/ 777), respectively. Children were reported to have ADHD by 3.4% (32/945) of parents, and prevalence was higher in girls (3.8 vs. 3.0%) (P = 0.59). Doctor-diagnosed asthma was reported for 19.4% (184/949) of children. Overall, 28.0% (267/955) of mothers reported cigarette smoking during pregnancy, and 36% (43/121) were heavy smokers. Paternal smoking prevalence was 37.9%. Based on the Townsend score, 90.9% of children were classied in the upper quartile that corresponds to a lower socio-economic class category (?4 to ?12). Table 2 shows the univariate analysis of study characteristics in relation to risk estimates for childhood ADHD. Prevalence of ADHD was 10.1% (11/109) in children with

Alcohol consumptioni

Townsend upper quartilej Yes 3.5 (25/708) No Single parent Yes No Mother \19 years 2.9 (9/310) 3.1 (18/575) 2.8 (2/72) 2.8 (23/816) 4.2 (2/48) 2.0 (6/307) 3.5 (12/342) 3.1 (17/551) 2.8 (2/71)

0.93

0.432.04

1.00

Table 2 Characteristics in relation to reported ADHD Characteristic Sex (%) Male Female MSDPb Yes No Heavy smokersc Yes No Light smokersd Yes No PSDP Yes No HSDPf Yes No DDA No Obesity Yes No Overweight Yes No 4.5 (10/222) 2.6 (13/502) 1.74 0.773.91 0.18 10.1 (11/109) 2.1 (13/618) 4.80 2.2110.43 \0.001
g e

Yes P value No Yes No Breast feeding Yes No

a b c d

0.99

0.244.10

1.00

ADHDa present

RR

95% CI

Pet ownership(dog/cat) 3.0 (14/465) 3.8 (18/480) 5.6 (14/251) 2.3 (15/655) 12.8 (5/43) 4.5 (15/336) 6.4 (5/78) 4.5 (15/336) 2.1 (3/144) 3.5 (22/623) 4.4 (17/397) 2.2 (11/491) 6.5 (11/170) 2.6 (19/701) 2.45 1.195.06 0.02 1.91 0.914.03 0.12 1.48 0.553.95 0.44 2.87 1.107.47 0.04 2.44 1.194.97 0.02 0.80 0.401.59 0.59 2.13 0.4410.26 0.30

1.14

0.552.35

0.85

Attention decit hyperactivity disorder Maternal smoking during pregnancy heavy maternal smokers [10 cigarettes/day light maternal smokers 110 cigarettes/day PSDP Paternal smoking alone during pregnancy Household member smoking during pregnancy Doctor-diagnosed asthma Low birthweight (\2.5 kg) Alcohol consumption during pregnancy Townsend score [ ?4

e f g

0.59

0.181.94

0.60

h i j

Yes

obesity (RR; 4.80, 95% CI 2.210.4, P \ 0.001), 5.6% (14/ 251) in children born to mothers who smoked during pregnancy (RR; 2.44, 95% CI 1.14.9, P = 0.02), and 6.5% (11/170) in children with doctor-diagnosed asthma (RR; 2.45, 95% CI 1.25.1, P = 0.01). Signicant associations were not identied for paternal smoking during the mothers pregnancy, low birthweight, maternal alcohol consumption in pregnancy, maternal or child age, offspring gender or socio-economic status. A backward stepwise logistic regression model was employed that included the following variables: maternal

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Childhood obesity and parental smoking as risk factors for childhood ADHD in Liverpool children Table 3 Adjusted odds ratio for childhood ADHD Variable Obesity Heavy maternal smokera MSDPb DDAc Preterm birth Upper quartiled HSDPe LBWf Overweight
a b c d e f

25

AOR 4.66 10.03 3.19 2.14 0.34 1.99 1.43 1.54 0.74

95% CI 1.5713.89 1.6261.99 1.089.49 0.676.04 0.091.68 0.2516.06 0.464.47 0.337.24 0.153.60

P value 0.006 0.013 0.037 0.198 0.348 0.520 0.542 0.585 0.709

smokers and 52.0% for heavy maternal smokers. The PAR estimate for childhood obesity was 26.7%.

Discussion Maternal smoking during pregnancy and childhood obesity was independently associated with ADHD. Mothers who smoked during pregnancy were at approximately threefold increased risk for an offspring with ADHD, and heavy maternal smokers were at ten times greater risk after adjusting for several confounding factors including socioeconomic status. There was no association with light maternal cigarette smoking or with paternal smoking during the mothers pregnancy. Linnet et al. (2005) in a case control study of Danish children, which assessed prenatal cigarette smoke exposure and risk for developing childhood ADHD, estimated a threefold increased risk of a hyperkinetic disorder compared with non-smokers, which is comparable to the estimates in the present study. The prevalence of 3.4% of reported ADHD is lower than expected for a population sample. This may have arisen due to sampling bias in view of the low questionnaire response rate (30.3%). Comparison of the Townsend score distribution for socio-economic status for this survey was similar to that for a 1998 community survey of these same primary schools but that achieved 78.1% compliance (Rizwan et al. 2004). The comparability of the socio-economic scores of this study with previous studies of the same population, but which had higher compliance rates, increases condence that the present sample is representative. In the present study, the prevalence of ADHD was higher among female children, although this difference was not signicant. Higher female prevalence has been reported among US children between 5 and 18 years of age (Robison et al. 2002). Conversely, most ADHD studies have reported higher prevalence among male children (Al Hamed et al. 2008; Van den ban et al. 2010).

Heavy smokers [10 cigarettes/day Maternal smoking during pregnancy Doctor-diagnosed asthma Townsend score [ ?4 Household member smoking during pregnancy Low birthweight

smoking during pregnancy, doctor-diagnosed asthma, childhood obesity, overweight, heavy maternal smoking, preterm birth, low birthweight, and household member smoking during pregnancy (Table 3). Signicant independent risk of ADHD was associated with obesity (AOR; 4.66, 95% CI 1.5713.89, P = 0.006), pregnancy smoking (AOR; 3.19, 95% CI 1.089.49, P = 0.04), and heavy maternal smoking during pregnancy (AOR; 10.03, 95% CI 1.6261.99, P = 0.013). There was a signicant trend towards a higher prevalence of ADHD with increasing number of maternal cigarettes smoked during pregnancy. Prevalence increased from 4.5% (15/336) for non-smokers to 6.4% (5/78) for light smokers, and 12.8% (5/43) for heavy smokers (v2 trend, P \ 0.001). Table 4 shows the prevalence estimates and population attributable risks of ADHD in children whose mothers where the only household smoker during the mothers pregnancy. The PAR estimates for ADHD attributable to maternal smoking during pregnancy were 10.2% for light

Table 4 ADHD population attributable risk, maternal smoking and childhood obesity

Category Maternal pregnancy smoking Prevalence in light maternal smokers (%) Adjusted OR Prevalence in heavy maternal smokers (%) Adjusted OR Prevalence in parental non-smokers (%)a

ADHD prevalence (n/N)

PAR (95%CI)

6.4 (5/78) 2.89 (0.3822.09) 12.8 (5/43) 10.03 (1.6261.99)* 4.5 (15/336) 10.1 (11/109) 4.65 (1.5713.89)** 2.1 (13/618)

10.2 (-3.955.9) 52.0 (6.987.9)

* a

P \ 0.05;

**

P \ 0.005

Childhood obesity Prevalence in childhood obesity (%) Adjusted OR Prevalence in non-obese childrenb 26.7 (5.492.7)

Mother and father both nonsmokers

b Non-obese BMI zscore \ 1.64 SD

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Heavy maternal smoking at C 10 cigarettes per day has been associated with early childhood physical aggression, when the mother had a history of anti-social behaviour and the effects were greater in families living under lowincome conditions (Huijbregts et al. 2008). In the present study, an independent association with lower socio-economic status was not identied, but the majority of households were situated in low socio-economic areas. A doseresponse association with ADHD risk has been reported previously (Kotimaa et al. 2003), although the confounding effect of childhood obesity was not included in the risk estimates. It is important to control for the effect of obesity, because a doseresponse association of cigarette smoke exposure in pregnancy with increased childhood obesity risk has been reported (Von Kries et al. 2002). A doseresponse effect of pregnancy smoking with childhood obesity has also been observed in an analysis of cross-sectional community surveys for the 1998 and 2006 studies undertaken in the same primary schools as surveyed in the present analysis (Koshy et al. 2010). Previous work in this same school population has also shown that among boys, those whose mothers smoked during pregnancy had lower right-hand 2D: 4D ratios than those whose mothers did not smoke (Rizwan et al. 2007). The link between maternal smoking during pregnancy and 2D:4D nger length ratio supports a causal association between foetal testosterone and behaviours, such as hyperactivity and conduct disorder. This could indicate a potential causative mechanism for the association of pregnancy smoking with ADHD risk in the present study. The role of foetal testosterone in aetiology of ADHD has been challenged in one study that showed no difference in the 2D : 4D ratio between cases and controls or with cognitive or behavioural aspects of ADHD (Lemiere et al. 2010). Finger length ratio was not measured in the present study. Other mechanisms that may explain the risk include compromised utero-placental and foetal blood ow leading to altered brain cell structure and number through apoptosis (Button et al. 2007; Albuquerque et al. 2004; Plessen et al. 2006; Roy and Sabherwal.1998; Arnsten 2009); toxinmediated effects inuencing brain dopamine and serotonin turnover (Walker et al. 1999; Cornelius et al. 2001b; Brook et al. 2000; Wakschlag and Hans 2000; Muneoka et al. 1997) and metabolic gene polymorphisms of the dopamine receptor gene DRD4 on chromosome 11 and DAT gene on chromosome 5, which are part of the brains dopamine system and are located at synapses between brain cells and have nicotinic receptors that are activated by smoking leading to increased risk of the severe combined type of ADHD (Todd and Neuman 2007; Faddagh et al. 2004). In the present study, childhood ADHD was independently associated with a 4.7 fold increased risk of childhood obesity. Proposed mechanisms to explain this

association include excess eating as a mood enhancer in ADHD (Davis et al. 2006); food additives and articial avouring in junk food (Kemp 2008; Cruz and Bahna 2006); or as a consequence of an environmental oversampling syndrome that is explained as an excess of both nutritional intake and sensory stimulation and the overlapping effects of medications used in both these conditions (Bazar et al. 2006). The high population attributable risk of ADHD related to heavy maternal smoking suggests that more than one mechanism is likely to be operating as high cigarette use would be more likely to induce multiple effects. The independent link of heavy maternal cigarette smoking with childhood obesity (Koshy et al. 2010) and the high population attributable risk of ADHD associated with obesity reect possible metabolic inuences and health consequences of maternal cigarette smoking in pregnancy. Prevalence of ADHD was also higher among children with doctor-diagnosed asthma, which may reect that asthmatic children are more likely to have behavioural problems (Blackman and Gurka 2007). Due to the potential effects of confounding factors, it cannot be concluded that ADHD could be prevented by preventing pregnant women from smoking, or by preventing children from gaining excessive weight. Data on maternal psychopathology and maternal ADHD, which are known factors associated with heavy maternal smoking and childhood ADHD, were not available in the present study. These associations are also governed by geneenvironment interactions. It has been established that both ADHD and smoking are highly heritable, with genetic factors accounting for between 60 and 80% and 56% of the two phenotypes, respectively (Faraone et al. 2005, Li et al. 2003). A number of similar genetic markers for smoking and ADHD phenotypes have been identied from candidate gene studies (Maher 2002, Munafo et al. 2004, Todd et al. 2005). Conclusion Maternal smoking during pregnancy and childhood obesity were independently associated with childhood ADHD. Women with heavy cigarette smoking were at greatest risk of ADHD in their offspring. Identifying children in school surveys with obesity and ADHD, while important, does not allow the past exposure to pregnancy smoking to be addressed. While these associations may not be causal, they nevertheless indicate important risk groups. Further research is required on the underlying mechanisms and their role in causality.
Acknowledgments The co-operation of Mr Greg Harper from the Liverpool School of Tropical Medicine and Dr. Jane Richardson, who helped with optical reading of the questionnaires, are gratefully

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Childhood obesity and parental smoking as risk factors for childhood ADHD in Liverpool children acknowledged. We thank the head teachers and school children for participating in the study. The 2006 survey was funded by the Liverpool Childrens Research Fund and Leverhulme Research Fund. Conict of interest of interest. The authors declare that they have no conict

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