Concerns have been raised over the safety of methylphenidate (MPH), with regard to adverse effects on growth and blood pressure. Our study investigates whether, and to what extent, methylphenidate use in boys with ADHD is associated with having low body mass index (BMI), having low height, and increased systolic and diastolic blood pressure.Data used for this study stem from the German KiGGS dataset. Three different groups of boys aged 6–15 years were included in the analysis: ADHD patients who used MPH for less than 12 months; ADHD patients who used MPH for 12 months or more; and ADHD patients without current MPH treatment. Each of these three groups was compared to a non-ADHD control group regarding low weight (BMI ≤ 3rd percentile), low height (≤3rd percentile) and raised systolic and diastolic blood pressure. For growth outcomes, boys were categorized according to age . Multivariable logistic regression was conducted to test for associations.n = 65 (n = 36 < 11 years), MPH ≥ 12 months: n = 53 (n = 22 < 11 years), ADHD controls: n = 320 (n = 132 < 11 years), non-ADHD controls: n = 3806 (n = 2003 < 11 years). Pre-pubertal boys with MPH use less than 12 months and pubertal/postpubertal boys with MPH use of 12 months or greater were significantly more likely to have a BMI ≤ 3rd percentile compared to non-ADHD controls. Boys from the ADHD control group were significantly less likely to have a raised systolic blood pressure compared to non-ADHD controls. Beyond that, no significant between group differences were observed for any other growth and BP parameter.4244 boys were included in the study; MPH < 12 months: The analyses of the KiGGS dataset showed that MPH use in boys with ADHD is associated with low BMI. However, this effect was only observed in certain groups. Furthermore, our analysis was unable to confirm that MPH use is also associated with low height (≤3rd percentile) and changes in blood pressure. Attention deficit hyperactivity disorder (ADHD) is characterized by pervasive and impairing hyperactivity, inattention and impulsiveness . The worEffects on growth are usually reported as minor at the group level, but there is wide variability with some children unaffected –9 and otA number of studies have investigated cardiovascular events  and cardiovascular effects (e.g. changes in BP and heart rate) associated with MPH.n = 714,258) to determine the risk of cardiovascular events among stimulant users. They reported a stimulant-related increase in risk for cardiovascular events (adjusted Hazard Ratio = 1.83 (1.10–3.04)) that persisted after restricting the analysis to only children with ADHD (n = 8300) (adjusted Hazard Ratio = 2.20 (2.15–2.24)).Dalsgaard et al.  conducteA pooled analysis of three large data sets 19–21) including more than 1.8 million patients  and height and BP in boys. Data from the German Health and Examination Survey for Children and Adolescents (KiGGS), a population-based German representative sample, were analyzed to evaluate the hypothesis that boys with ADHD and current MPH use show higher percentages of having low BMI, having low height, and of increased systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared to controls.Data for the present study stem from the KiGGS database. KiGGS was conducted by the Robert Koch Institute, Berlin, Germany, between May 2003 and May 2006. A two-stage sampling strategy was utilised: in the first stage, a representative sample of 167 German municipalities was identified. In the second stage, random samples of children and adolescents aged between 0 and 17, and stratified by sex and age, were then selected from these municipalities through local population registries. The resulting sample included 17,461 children and adolescents . Detailed information on the KiGGS dataset and the sampling strategy have been reported elsewhere , 28.Individuals were classified as having ADHD if a parent reported that a diagnosis of ADHD had been made by a physician or psychologist . CurrentFour groups of individuals were identified for inclusion in the study: two groups who were taking MPH (< 12 months and ≥ 12 months), an ADHD group not currently taking MPH and a non-ADHD control group. Matching of controls to the medicated cohort was not undertaken. Preliminary analyses revealed that there were low numbers of females and older adolescents amongst the ADHD groups generally and the MPH groups specifically and so the study was restricted to males aged between 6 and 15 years inclusive.BMI, height: Body weight was measured in underwear to the nearest 0.1 kg with a calibrated scale . Body height was measured by trained staff according to a standardized protocol to the nearest 0.1 cm using portable devices . Measurement procedures were subject to internal and external quality control measures . BMI wascardiac disease (code ca07); this variable, based on parents’ reports, was recorded in the dataset as ‘yes’, ‘no’ or ‘don’t know’.BP: Two readings of SBP and DBP were obtained using an automated oscillometric device (Datascope Accutorr Plus) at 2-min intervals after a non-strenuous part of the examination and an additional 5-min rest. The measurements were taken using the right arm, in the sitting position with the elbow at the level of the right atrium, using 1 of 4 cuff sizes which had to cover at least two-thirds of the upper arm length . The mean of the two measurements was used for analysis . The KiGGerman reference data for BMI and height were obtained , 33. TheFor the analysis of SBP and DBP, guidelines from the European Society of Hypertension  were useDefinition and classification of hypertension was as follows :ClassSBPBoth high-normal BP (≥90th to <95th percentile) and hypertension (Stage 1 (95th percentile to the 99th percentile plus 5 mmHg) or Stage 2 hypertension (>99th percentile plus 5 mmHg)) were collapsed to form “Raised SBP” and “Raised DBP” categories for the purposes of the regression analyses.For each outcome variable, mean and standard deviations (sd) was calculated. Odds Ratios (OR) and 95% Confidence Intervals (95% CI) were derived from logistic regression analyses. Each of the three ADHD groups was compared to a non-ADHD control group regarding weight (BMI ≤ 3rd percentile), height (≤3rd percentile) and raised SBP and DBP.For the outcomes BMI and height, boys were categorized according to age . The relationship between blood pressure and MPH use was examined using logistic regression adjusting for age, BMI and cardiac disease. Sensitivity analysis was conducted removing patients who had a cardiac disease code of yes or don’t know.p-value of < 0.05 was considered significant for all analyses.A i)Sample characteristics:n = 53 in MPH ≥ 12 months, n = 320 ADHD controls, and n = 3806 non-ADHD controls; 2193 (51.7%) boys of the total sample were 6–10 years old, 2051 boys (48.3%) were aged 11–15 years. For details see Table A total of 4244 boys were included in the study: n = 65 in MPH < 12 months, n = 2185) and those aged 11–15 years (n = 2044) were analyzed separately. The focus of the analyses was the percentage of boys who had low BMI, defined as BMI ≤ 3rd percentile. In the group of boys aged 6–10 years, those with MPH use of less than 12 months were significantly more likely to have a BMI ≤ 3rd percentile compared to the non-ADHD control group , p = 0.006). Whereas in the subsample of boys aged 11–15 years, those with MPH use ≥12 months were significantly more likely to have a BMI ≤ 3rd percentile compared to the non-ADHD control group (OR 3.59 (1.06–12.22), p = 0.040). Moreover, when compared to the non-ADHD control group no significant differences with regard to low weight were observed for the other groups (see Table BMI data were available for 4229 boys (99.65%). Data of the group of boys aged 6–10 years (Height data were available for 4242 boys (99.95%). In accordance with the analysis of the BMI data we distinguished between boys aged 6–10 years and 11–15 years. In both age-groups, no significant differences between the MPH and ADHD control groups and the non-ADHD control group were observed with regard to the percentage of boys with a height ≤ 3rd percentile (see Table p = 0.016). Moreover, no statistically significant differences between the MPH groups and ADHD control groups and the non-ADHD control group with regard to raised SBP nor to raised DBP could be found (See Table yes or don’t know.Blood pressure data were available for 4238 boys (99.86%). Mean SBP and mean DBP were similar across the different groups. Stage 2 hypertension based on SBP and/or DBP was generally very rare and was not observed in boys currently taking MPH. However, stage 1 hypertension based on SBP and/or DBP could be observed most frequently in those taking MPH ≥ 12 months .Several studies in children with ADHD have investigated associations between ADHD medication and height. Hanć and colleagues reported that the height of drug-naïve boys with ADHD was not significantly different from the norm . Zhang ap = 0.006). There was a trend towards an effect in the boys aged 11–15 years with MPH use ≥12 months . Boys aged 6–10 years with MPH use ≥12 months and boys 11–15 years with MPH use less than 12 months did not significantly differ from the non-ADHD control group in that respect. Several considerations might help to interpret these findings:Our analyses of the KiGGS dataset overall showed that MPH use in boys with ADHD was associated with low BMI. This effect was observed in the younger boys aged 6–10 years with MPH use of less than 12 months  can raise concerns and lead to discontinuation of medication (in particular in younger children). This could explain why low BMI was more often in boys 6–10 years of age with MPH use of less than 12 months compared to controls, but not in the group with an MPH use ≥12 months (as this sample was reduced by the number of those who had to discontinue due to earlier weight loss).A slow weight loss resulting in low BMI after more than one year of treatment. One reason for this might be a less severe post-pubertal effect of MPH on weight either due to metabolic reasons or due to a better way of coping with reduced appetite in this age group . These findings should be interpreted with caution due to the small numbers and wide confidence intervals and further research is required to verify these considerations.However, we found the opposite effect in pubertal/post-pubertal boys. This might be due to a higher proportion of The relationships between ADHD, methylphenidate use and growth appear to be complex. Some evidence suggests that there is a significant association between ADHD per se and obesity/overweight among patients, however this relationship is not consistent across studies . SchwartOur analyses of the KiGGS dataset were unable to confirm the hypotheses that MPH use in boys with ADHD is associated with increased systolic and/or diastolic BP (≥90th percentile).n = 970) ranged from − 4.3 to + 21.2 mmHg for mean SBP, and − 4.7 to + 4.0 mmHg for mean DBP. When duration of treatment was examined, the authors concluded that short-term use (≤6 months) of MPH was associated with small increases in BP that were not statistically significant whereas the data for MPH ≥ 6 months’ duration provided “a more mixed picture ...with some decreases in SBP and DBP… reported. However, it should be noted that these longer-term results were not corrected for age” [A review of the cardiovascular effects associated with MPH published in 2014 reported that changes in BP across the eight included studies  may influence the likelihood of being treated via symptom severity and also influence body weight. Follow-up data were not available which would be particularly important for assessment of growth trajectories in children. However, analyses of growth outcomes were conducted stratified by age (< 11 years and ≥ 11 years) to account for the correlation between height velocity, growth spurts and pubertal maturation. The ADHD control group consists of children with an ADHD diagnosis but no current use of MPH. However, data were not available as to whether these children were stimulant-naïve or had prior exposure to MPH. The data were not gathered for the primary purpose of investigating the current research question and such secondary analyses cannot gather additional data on prior exposure to MPH; it is acknowledged that this potential contamination effect may attenuate differences among the groups. Information on dosing of MPH was not complete for all patients and, therefore, could not be included in the analyses. Identifying the ADHD cohort within the KiGGS sample was done by parent report of an ADHD diagnosis that had been made by a physician or psychologist. Due to the large number of children included and the wide range of competing physical, psychological and social health indicators which comprised the dataset, a full psychiatric diagnostic interview was not possible. However, other studies which have examined prevalence of ADHD in the KiGGS cohort have obtained a rate of 4.8% which is well in line with other population-based estimates . The numWhen looking at the balance between risks and benefits of MPH treatment for ADHD, it needs to be considered that ADHD itself is associated with a broad range of psychosocial impairments such as; school failure, parental and family conflict, social rejection by peers, low self-esteem, higher risk for delinquent behaviour, smoking and substance use disorders. Adverse outcomes continue into adolescence and adulthood to include academic and vocational underachievement, reduced occupational functioning, emotional dysregulation, anxiety, depression, unemployment and suicide attempts, higher rates of traffic accidents, unwanted pregnancies, preterm mortality .Secondly, findings from national registry studies indicate that the use of medication, particularly stimulants, reduces the risk of accidents and trauma-related emergency department admissions and might have protective effects on substance abuse, suicidality and delinquent behaviour –46.We have used cross-sectional data from a German national representative sample to identify adverse growth and cardiovascular outcomes associated with MPH. Effects on BMI were observed among the MPH cohorts; clinicians should discuss with all patients and their parents the potential effects on growth and balance these effects with the outcomes of not treating ADHD symptoms. Particular attention should be paid to those patients in the lower growth percentiles. Serious concerns about growth warrant referral to a paediatric endocrinologist or growth expert . This st


Low birth weight (LBW), an important risk factor for early childhood mortality and morbidity, is a major public health concern in developing countries including Cambodia. This study examined the prevalence of LBW across provinces in Cambodia and changes over time, and identified the factors associated with such condition.We used children datasets from Cambodia Demographic and Health Survey (CDHS) 2010 and 2014. There were 3,522 children and 4,991 children in both surveys. Maps illustrating provincial variation in LBW prevalence were constructed. Then, multivariate analyses were conducted to assess factors independently associated with LBW in CDHS 2014.LBW prevalence remained stable between 2010 and 2014, at around 7.0% 95% CI: 5.8–8.1). all institutional births, but within significant variation across provinces. Factors independently associated with LBW included mother’s no education compared with those whose mothers had secondary or higher education , babies born to mothers with < 4 antenatal care (ANC) visits during the pregnancy compared with those whose mothers had at least 4 ANC visits . Also, first-born babies were at greater risk of LBW compared with second-born babies .The study points to key sub-populations at greater risk and regions where LBW is particularly prevalent. Programs should target provinces where LBW prevalence remains high. Illiterate women, especially those pregnant for the first time should be the program priority. The current national program policy, which recommends that pregnant women have ≥ 4 ANC visits during pregnancy should be further reinforced and implemented. Program design should consider ways to communicate the importance of making the recommended number of ANC visits among women with no formal education. Low birth weight (LBW) has been defined as a birth weight of less than 2,500 grams (or 5.5 pounds), irrespective of gestational age . LBW is LBW prevalence in Cambodia is higher than the average in East Asia and the Pacific as a whole. According to the World Bank, the prevalence of LBW in Cambodia in 2000 was 11%. Prevalence declined to around 8% of all live births in 2005 , and hasLBW is associated with a number of risk factors. These include age, education, mother’s marital status, and employment, level of household wealth, ethnic origin and body mass index (BMI) of the mothers –14. A reReducing the prevalence of LBW in Cambodia requires a better understanding of its geographic distribution and associated risk factors, to help identify sub-populations at greater risk and priority geographic regions. To the authors’ knowledge, no in-depth study of the factors associated with LBW in Cambodia has been conducted to date. Therefore, the study addresses this knowledge gap based on CDHS 2010 and 2014 data. The objectives of this study are twofold: first, to describe the prevalence of LBW across CDHS 2010 and 2014 by province using GIS mapping; and second, to explore key individual and household-level factors associated with LBW. Better understanding of such factors may help develop policies and programs with more effective strategies and interventions to reduce prevalence of LBW, thereby contributing further to the reduction of neonatal mortality in Cambodia.We used children data from CDHS 2010 and CDHS 2014 to map the distribution of LBW by province, and used CDHS 2014 to conduct logistic multivariate analyses to explore the factors associated with LBW among babies born in the 5 years preceding the survey.The CDHS is a population-based nationally representative survey in which participants were selected using a two-stage stratified cluster sampling design. In the first stage, a defined number of enumeration areas (EAs or clusters) stratified by urban-rural were selected with probability proportional to EA size. In the second stage, a defined number of households  were randomly selected from the listed households in each EA with simple random selection. Eligible women age 15–49 in the selected households were invited for interviews, and data about the women and their children born in the past 5 years preceding the survey were collected [The outcome variable of interest is the prevalence of low birth weight among the youngest singleton children born at a health facility. Based on the definition of LBW , children were classified into 2 groups: non-LBW  or LBW .2), and further categorized as: underweight (<18.5 kg/m2); normal or healthy weight (18.5–24.9 kg/m2); and overweight (≥24.9 kg/m2).The study included the following explanatory variables: household and mother’s characteristics and behaviors, access to health care during pregnancy, maternal health status, and baby’s characteristics. Maternal age at the time of giving birth was divided into 3 categories: <18 years; 18–34 years; and 35–49 years. Marital status was classified as currently married/in union or formerly married. Level of education was defined as: no schooling; primary school; and secondary and higher. Current employment status was classified into: no job or not working; agricultural jobs or self-employed; professional or technical or sales jobs; and other types of jobs, which included manual labor and unskilled jobs. Whether the mother smoked cigarettes was recoded as yes (coded 1) or no (coded 0). Mothers’ perceived problems in accessing health care is a dichotomous variable, coded 0 if the mother reported no perceived barrier and coded 1 if the mother reported 1 or more barriers . Number of ANC visits was recoded as a binary variable: mothers who made fewer than 4 visits were coded 0, and those who made 4 or more visits were coded 1. Whether the mother received ANC with nutritional counseling and health insurance coverage were both recoded as either yes or no. Mother’s anemia was defined by her hemoglobin level: severe (0–69 g/dl); moderate (70–99 g/dl); mild (100–119 g/dl); and not anemic (>120 g/dl). Because of few observations, the severe anemia category was grouped together with moderate anemia. Mother’s BMI was calculated as weight-to-height ratio  is too many for meaningful analysis (19), we regrouped them for regression analysis into 4 geographical regions, as administratively defined in Cambodia: Northwest; Northeast; Central; and South.Key socioeconomic and demographic characteristics of the sample in CDHS 2014—youngest children born in health facilities in the past 5 years preceding the survey and their mothers—were described and expressed in frequency and percentage. Outliers were rechecked for outcome variable and explanatory variables though they were cleaned in the original CDHS children dataset. The analyses were performed in STATA V14  considering sampling weights, cluster effect and urban rural stratification to adjust for the complex sampling design of the CDHS.The prevalence of LBW and its distribution across the 19 domains (provinces) was estimated, using CDHS 2010 and CDHS 2014. The results were then used to construct maps illustrating provincial variation in the prevalence of LBW and trends over time, using QGIS software V 2.18.7 (GIS Development Team). Significant difference was assessed between 2010 and 2014, using Chi-square test; and between provincial LBW in CDHS 2010 and CDHS 2014, using logistic regression.We used bivariate analyses to assess the association between prevalence of LBW and household characteristics, mother’s characteristics and behaviors, access to health care during pregnancy, maternal health status, and baby’s characteristics. Multivariate logistic regression was used to predict the independent factors associated with LBW. Odds ratios with 95% confidence intervals were reported. Finally, we restricted our multivariate logistic regression to singleton babies; therefore, the sample for multivariate logistic regression included 4,932 youngest and singleton children born at health facilities in the CDHS 2014. All covariates significantly associated with LBW at the p value ≤ 0.20 in bivariate analyses were included in the multivariate logistic regression. Also, interested covariates were included in the multivariate regression regardless their significant levels.Multicollinearity among the following variables was assessed: geographical regions, residence, household wealth index, mother’s age at the time of giving birth, anemia, BMI, and child’s birth order. No serious collinearity between variables was detected (the highest correlation coefficient was <0.6). In the final model, 9 covariates were kept. These covariates were: mother’s age at the time of giving birth; education level; reported number of ANC visits; anemia level; BMI level; child’s sex; residence ; geographical regions; and wealth index.The CDHS 2014 was approved by the National Ethics Committee for Health Research (Ref: 056 NECHR), Cambodia and the Institutional Review Board (IRB) of ICF in Rockville, Maryland, USA. The CDHS data are publicly accessible and were made available to us upon request to the DHS Program, ICF. Written consents were obtained from all participants before the interview with participants in the CDHS.Appendix 1. In CDHS 2010, Phnom Penh (14%), Kampong Cham (11%), and Kandal (11%) accounted for the 3 largest samples, while Odar Meanchey, Kratie, Preah Vihear/Stung Treng, and Modulkiri/Rattanakiri were least represented, at only about 1% each, among the 19 domains. This distribution changed slightly in CDHS 2014. Phnom Penh (10%) and Kampong Cham (14%) were the 2 largest samples, while Kandal fell to 7% of the total sample in CDHS 2014. Odar Meanchey, Kratie, Preah Vihear/Stung Treng, and Modulkiri/Rattanakiri remained the 4 smallest samples.The distribution of the sample by geographic domain (province or group of province) in CDHS 2010 and CDHS 2014 is presented in Overall, the prevalence of low birth weight among the samples  remained stable between 2010 and 2014, at about 7.0% (95% CI: 5.8–8.1) and 6.9% (95% CI: 6.1–7.9) respectively. However, the variation by province varied across the 2 surveys. Appendix 2 presents the data on LBW prevalence for the 19 domains. In 2010, the highest LBW prevalence was in Takeo province (12%) and Svay Rieng (10%), and the lowest was in Sihanouk Ville/Koh Kong (3.5%) and Odar Meanchey (2.5%). This distribution changed between 2010 and 2014. In 2014, the highest prevalence of LBW was in Siem Reap (11%) and Kampong Chhnang (10%), an increase compared with 2010 (7% for Siem Reap and 8% for Kampong Chhnang). However, the increase in both provinces was not statistically significant. LBW prevalence in Svay Rieng and Takeo declined slightly in 2014, to 9% and 10%, respectively, but not statistically significant.Prevalence of LBW among children born to mothers with no schooling, at 9%, was higher than among those born to mothers with a primary education or a secondary or higher education, at 6% each, although the difference was not statistically significant. The prevalence of LBW did not vary by mother’s age, marital status, current employment status, smoking status, perceptions of problems in accessing health service, and health insurance coverage. Yet, LBW prevalence among children born to mothers attending less than 4 ANC visits during pregnancy (10%) was significantly higher than for those born to mothers attending 4 or more ANC visits (6%). The prevalence of LBW was lower among babies born to mothers who received nutritional counseling during the ANC visits (6%) compared with those who did not (9%). There was no significant difference in the prevalence of LBW by mother’s anemia levels or body mass index (BMI). First-born babies had a higher LBW prevalence (9%) than second- and third-born babies (5%) and fourth-born or higher (7%). There were no differences in the prevalence of LBW between boy and girl babies.Prevalence of LBW was substantially higher in rural areas (7%) than urban areas (4%) but did not differ much by region: Northwest (6%), Northeast (8%), Central (6%), and South (7%). The prevalence of LBW among children born to mothers in the lowest and second household wealth quintiles (each about 8%) was higher than for those in the middle quintile (6%), the fourth quintile (6%), and highest quintile (5%). This difference was not statistically significant  In the multivariate logistic model  were 1.6 times more likely to have a LBW baby compared with those with a secondary or higher education is similar to findings of 3 studies in other countries that illiteracy of mothers is a risk factor for LBW , 14, 28.The study’s finding that mothers who attended fewer than 4 ANC visits during their last pregnancy were twice as likely to have babies with LBW, compared with mothers who attended 4 or more ANC visits, is also in line with other studies elsewhere –31. MothWhile a study in several developing countries found that rural residence and poverty are risk factors for LBW , the preThis study has 3 major limitations. First, it was limited to explanatory variables for which data were collected and reported in CDHS 2010 and CDHS 2014. Data on many potential correlates of low birth weight or risk factors were not available, such as past history of premature births or LBW, early child marriage, adolescent pregnancy, maternal HIV infection and maternal morbidity and illnesses during pregnancy, including non-communicable diseases such as hypertension, diabetes and mental disorders.Second, the available data were measured at the time of survey, not during pregnancy or at the time of delivery. While many of these variables, such as household wealth status and residence, are unlikely to have changed, others such as mother’s employment status, marital status, BMI, and anemia may differ between the time of pregnancy or delivery and the time of survey. We estimated maternal age at the time of giving birth by deducting the child’s age from the mother’s age. For BMI, the analysis did not include women who were pregnant at the time of survey but who had a live birth in the 5 years preceding the survey. Another concern was the challenge in dealing with missing data of outcome variable of LBW. However, the concern is not significant since less than 1% of the data was missing (CDHS 2014).Third, the analysis was restricted to children born at a health facility. It excluded home births because babies born at home may not have been weighed or appropriately weighed. This might bias the results, particularly since children not weighed or not appropriately weighed at birth are more likely to be born to less educated or poorer mothers who may be less aware of the importance of maternal health care or lack the financial resources to afford the minimum recommended 4 ANC visits, and therefore more likely to have LBW children.The findings suggest provincial variations in the two surveys and three risk factors. Reducing the prevalence of LBW in Cambodia is possible, but challenging. Interventions to reduce LBW should target provinces where prevalence remains relatively high, or has increased in recent years, such as Siem Reap and Kampong Chhnang. Such targeting should be guided by further in-depth studies on the factors related to LBW and maternal health care.Furthermore, the study shows that mother’s educational level; number of ANC visits during the last pregnancy, and child’s birth order are significantly associated with LBW or risk factors of LBW. These results generally confirm the findings of research in other countries. The findings that illiterate mothers have higher risk of having LBW babies and that first-born children are at greater risk than subsequent births suggest that women with no formal education, especially those who are pregnant for the first time, should be a priority for programs to reduce the incidence of LBW. The findings strongly support and reconfirm the current national program policy in Cambodia that recommends pregnant women to have at least 4 ANC visits during pregnancy. This policy should be further reinforced and implemented, with consideration for finding effective ways to reach illiterate women with information and support for antenatal care.S1 Appendix(DOC)Click here for additional data file.S2 Appendix(DOC)Click here for additional data file.S1 File(DTA)Click here for additional data file.


The location of the fluorine in structures 2-4 is discussed using bond valence sums. First principles calculations were used to explore why a pure oxide structure is obtained for the Cs containing phase (1) and in contrast an oxyfluoride phase for the Rb containing phase (2). Ion exchange experiments were performed on 1 and 2 and demonstrate the ability of these structures to exchange approximately half of the parent alkali cation with a target alkali cation in an aqueous concentrated salt solution. Optical measurements were performed on 1 and 2 and the UV-vis and fluorescence spectra show features characteristic of the Single crystals of four new layered uranyl phosphates, including three oxyfluoride-phosphates, were synthesized by molten flux methods using alkali chloride melts, and their structures were determined by single-crystal X-ray diffraction. Cs All of4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (3) and Rb4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (4), and a new sheet anion topology that is observed for both a pure oxide, Cs11[(UO2)12(PO4)3O13] (1), and an oxyfluoride, Rb11[UO2)12(PO4)3O12F2] (2).Herein we present the synthesis and structural characterization of two examples of uranium oxyfluorides that adopt the phosphuranylite topology, Cs1-4 were synthesized via molten flux methods using alkali chloride fluxes  was used as the uranium starting material, AlPO4  was used as the phosphate source, and an alkali halide, CsCl , KCl , or RbCl , or a mix thereof was used as a flux. Caution!Although the uranium precursor used contained depleted uranium, standard safety measures for handling radioactive substances must be followed. Generally, all solid reactants were loaded into either an alumina or platinum crucible and heated to 875°C in 1.5 h, held at this temperature for 12 h, then cooled at 6°C/h to 550 or 450°C depending on the melting point of the flux. After slow cooling, the furnace was shut off and allowed to rapidly cool to room temperature before sonicating the reaction mixtures in water to remove the flux and isolate the crystalline products by vacuum filtration.Compounds 11[(UO2)12(PO4)3O13] (1) was synthesized by loading 1 mmol UF4, 0.25 mmol AlPO4, and 20 mmol of CsCl in a platinum crucible with a loose-fitting platinum lid and was slow cooled to 550°C. The reaction produced red tablets (11[UO2)12(PO4)3O12F2] (2) was obtained by loading 0.5 mmol UF4, 0.125 mmol AlPO4, and 20 mmol of RbCl into a small alumina crucible in a concrete holder with a larger inverted crucible covering it. This mixture was heated as mentioned above and slow cooled to 550°C and produced similar looking orange-red tablets as in 1 in a nearly quantitative yield with no identifiable byproducts. Cs4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (3) and Rb4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (4) were obtained from reactions of 0.5 mmol UF4, 0.2 mmol AlPO4, and 5 mmol CsCl or RbCl and 5 mmol KCl loaded into an alumina crucible covered with an alumina plate held in place by rubber cement. These were heated and slow cooled to 450°C and produced a yellow crystalline product identified as a mixture of the newly reported F containing phases and either CsxK4−x[(UO2)3(PO4)2O2] orRb1.4K2.6[(UO2)3(PO4)2O2] that are visibly indistinguishable. The purity and identity of the products were determined by powder X-ray diffraction (PXRD) using a Bruker D2 Phaser equipped with a LYNXEYE silicon strip detector using a Cu Kα (λ = 1.54056 Å) source.Cs tablets  in a nea3 and 4 were both refined as two component inversion twins with a significant volume fraction of 0.414(6) for 3 and a minor twin component of 0.084(8) in 4  data collected on a Bruker D8 QUEST diffractometer equipped with an Incoatec IμS 3.0 microfocus radiation source  and a PHOTON II area detector. The reduction absorption correction was applied to the raw data using SAINT+ and SADABS within the APEX3 software Bruker, . The SHE 4 Spek, . Full cr1 and 2 there is disorder in one of the phosphate tetrahedra. Generally, the disorder in the alkali sites was treated by freely refining the sites as Cs or Rb as appropriate, and if less than one, then it was assumed that either the sites is shared by a smaller alkali cation, K+ in 3 and 4, or a disordered site across multiple positions. The presence of significant nearby electron density peaks suggests a disordered site, while the absence of these suggests sharing of the site between Cs/K or Rb/K. Mixed sites, and multiple disordered sites were constrained to occupancies of one using free variables or SUMP commands in cases of more complicated disorder, and the use of ISOR and EADP commands were implemented to constrain thermal parameters. The full details of the structure refinements are located in In all structures the refinement of the U sites is straightforward, while in all structures there is disorder among the alkali cation sites, and in structures 1 and 2 the P3 site is half occupied because it is disordered across a mirror plane and the two disordered sites are too close to both be fully occupied sites. This is also true for O23, O27, O28 which are coordinated to P3 and O29 coordinated to P1 in 1, and O28A and F28B in 2. Labeling all sites within the coordination sphere of the U sites as O in structures 2-4, does not result in charge balance, as there is an excess of negative charge. This could not be resolved by reasonable models of the alkali cation disorder and this observation, along with the identification of F in all three structures by EDS in both powdered and singly crystalline forms, confirms the presence of F. While the fluorine site could be easily located in structure 2 by using bond valence sums (BVS) and knowledge of U coordination chemistry (discussed in structure description), it was not easily identified in 3 and 4. In 3 and 4 the O3 site was fixed as a half occupied O/F shared site to maintain charge balance in the crystallographic solution, and this arbitrary assignment will be discussed in later sections.In structures 2-4 and all other elements present in each single crystal used for structure determination as well as in bulk powder samples of 1 and 2. Data were collected on a TESCAN Vega-3 SBU equipped with an EDS detector.EDS was used to verify the presence of F in 1 and 2 using a PerkinElmer Lambda 35 UV-vis scanning spectrophotometer equipped with an integrating sphere and a PerkinElmer LS55 Luminescence spectrometer. The UV-vis diffuse reflectance data were internally converted using the Kulbelka-Munk equation and then normalized 12(PO4)3O13] (1) and Rb11[UO2)12(PO4)3O12F2] (2) where 20 mg of sample was soaked in ~4 mL of concentrated salt solution in a drying oven set to 90°C for 3 days. The Rb analog, 2, was soaked in 11 m CsCl solutions while the Cs analog, 1, was soaked in 7 m RbCl or 4 m KCl solutions. Products were examined by EDS and PXRD as described above.Ion exchange experiments were performed on powder and single crystalline samples of Cs−6 eV energy convergence criteria. A 2 × 2 × 2 k-point mesh was used for sampling the Brillouin zone. The ground state geometries at 0 K were obtained by relaxing the cell volume, atomic positions, and cell symmetry until the maximum forces on each atom were < 0.01 eV/Å. To better represent the correlated nature of the U f-electrons, we employed the DFT+U method . The Ueff value was chosen to be close to that obtained from related experimental results for UO2  code VASP (Vienna Ab-initio Simulation Package) 12(PO4)3O13 and Cs11(UO2)12(PO4)3O13F2. Because the oxide and oxyfluoride compounds have different composition, we cannot directly compare their calculated total energies, i.e., thermodynamic stability. Therefore, we need to investigate their relative stability by analyzing the reaction enthalpies, ΔrH, considering the two reactions:In an effort to understand why Rb forms an oxyfluoride while Cs only an oxide, we also considered the two opposite cases, RbrH, values were calculated using:The ΔfH are the formation energies per formula unit of the products, i, and reactants, j, and the sum is over all products and reactants. ci and cj are the stoichiometric coefficients of the products and reactants, respectively. For each of the reactants and products we calculated their ΔfH using the same VASP calculations input parameters listed above.where ΔDFT gives only the reaction enthalpy at 0 K, and to include the temperature effect on the reactions, we calculate the finite temperature quasi-Gibbs formation energies, Sconf is the configurational entropy, defined as:kb is the Boltzmann constant, xi is the mole fraction of the constituent i, and the sum is over each constituent i in the compound. Note that in our calculations we do not consider the vibrational contribution to the entropy because due to their very large size, calculating this term for the title compounds is outside the current capabilities of DFT, and hence the term quasi-Gibbs energy. In the case of the gases O2, F2, and Cl2, we use tabulated values for the standard entropies 12(PO4)3O13] (1) and Rb11[UO2)12(PO4)3O12F2] (2) were first discovered as the minor product, previously unidentified red tablets, in the synthesis of Cs6[(UO2)7O4(PO4)4] and Rb6[(UO2)7O4(PO4)4], respectively 12(PO4)3O12F2] (2) proved necessary, although the reason is not well-understood. Structures 3 and 4, related to the phosphuranylite topology, were discovered when trying to optimize synthetic conditions for Cs1.4K2.6[(UO2)3O2(PO4)2], Cs1.7K4.3[(UO2)5O5(PO4)2], Rb1.4K2.6[(UO2)3O2(PO4)2] and Rb1.6K4.4[(UO2)5O5(PO4)2]. The synthesis of these phases is described and discussed in a recent publication which concluded that higher flux to reactant ratios (40 mmol flux to 0.5 mmol UF4) favored the formation of the phases Cs1.4K2.6[(UO2)3O2(PO4)2] and Rb1.4K2.6[(UO2)3O2(PO4)2], while 20 mmol of flux and 0.5 mmol UF4 lead to synthesis of Cs1.4K2.6[(UO2)3O2(PO4)2] and Cs1.7K4.3[(UO2)5O5(PO4)2] or Rb1.4K2.6[(UO2)3O2(PO4)2] and Rb1.6K4.4[(UO2)5O5(PO4)2], which could not be successfully separated 6O4F(PO4)4(UO2)] (3) and Rb4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (4), were obtained simultaneously with Cs1.4K2.6[(UO2)3O2(PO4)2] and Rb1.4K2.6[(UO2)3O2(PO4)2] by further reducing the flux to reactants ratio to 10 mmol and 5 mmol of flux with 0.5 mmol UF4; unfortunately, the title compounds could not be separated manually from Cs1.4K2.6[(UO2)3O2(PO4)2] and Rb1.4K2.6[(UO2)3O2(PO4)2], as all crystallize as yellow plates.There have been numerous reported uranium phosphate containing structures prepared by similar synthetic methods using UF4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (3) and Rb4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (4) contain relatively small amounts of potassium, and attempts were made to synthesize potassium-free Cs and Rb analogs of this uranyl oxyfluoride based on the phosphuranylite sheet topology; however, none were successful as pure CsCl or RbCl fluxes lead to the synthesis of 1, 2, Cs6[(UO2)7O4(PO4)4], Rb6[(UO2)7O4(PO4)4], Cs3[Al2O(PO4)3][(UO2)3O2], Rb3[Al2O(PO4)3][(UO2)3O2], or a mixture of these products.Cs11[(UO2)12(PO4)3O13] (1) and Rb11[UO2)12(PO4)3O12F2] (2) are two dimensional sheet structures (Pnma with lattice parameters a = 14.9561(3), b = 17.9663(4), c = 20.8520(4), and a = 14.1258(3), b = 18.0121(4), c = 20.6241(4), respectively. To our knowledge, the sheet topology present in both structures is unreported in the literature and can be deconstructed into units of the β-U3O8 topology as shown in 3O8 topology can be deconstructed into U3O16 and U2O14 units, where the U3O16 unit is a square bipyramid, edge-sharing with two pentagonal bipyramids on either side, and the U2O14 unit is two corner-sharing pentagonal bipyramids. These two units alternate to form the β-U3O8 topology as shown in 1 is also built-up of alternating U3O16 and U2O14 units and 2 contains the U3O16, U2O14, and U2O13F units where the pentagonal bipyramids corner share through the F; however, every third U3O16 unit is missing in both structures (Csructures  and crysructures .2O14 or U2O13F units) is a disordered phosphate tetrahedra with two possible orientations as shown in 2O14/U2O13F units that are located between two U3O16 units and corner share to the adjacent group of four pentagonal bipyramids. The disorder in the phosphate tetrahedron, P3 in both structures 1 and 2, is slightly different between the two structures as shown in 11[UO2)12(PO4)3O12F2] (2), the phosphate tetrahedron is half occupied and accompanied by a split oxygen/fluorine site whose occupancies sum to 1. Therefore, either the phosphate tetrahedron points up or down (with respect to the plane of the sheet), where the oxygen site corresponds to the orientation of the phosphate tetrahedron, and the fluorine site corresponds to the absence of the phosphate tetrahedron. This is supported by the P3-O28A and P3-F28B bond distances which are 1.555(8) and 2.170(8) Å, respectively where the P-F bond is much too long for the tetrahedral coordination environment of P5+. Tables of bond valences and bond distances for U and P for all structures are collected in Between the group of four pentagonal bipyramids , and therefore in the absence of the phosphate tetrahedron there are two square bipyramids   and multiple bonds are not possible for F. All of the uranyl U-O bond lengths in 2 are between 1.802(4) and 1.830(6) Å and show no significant deviation from the expected ~1.8 Å bond length. Bond valence sums of the remaining O atoms are between 1.82 and 2.30 using ro = 2.051 and B = 0.519 for U-O  of fluorine in structures 4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (3) and Rb4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (4) also contain small amounts of fluorine as identified by EDS and by the need for charge balance in the structures. Similar methods as described above were used to identify the fluorine sites(s), again excluding uranyl oxygen sites as possibilities; however, the results are less definitive than the bond valence sums of 2. In 3 all O bond valence sums are between 1.92 and 2.22, none of which signal good candidates for fluorine doping, and similarly in 4, the O BVS are between 1.78 and 2.25. This suggests that there is no preferred site for F and for this reason we have arbitrarily set the occupancy of O3 to be half occupied by both F and O, as this site has the lowest BVS in both structures 3 and 4, and the rarity of PO3F tetrahedra leaves O3 and O6 as the most plausible options. [(UO2)5(HPO4)3(PO4)F4](H9C10N2)3 synthesized hydrothermally using − source also contains phosphuranylite related layers and fluorine is present on sites similar to the ones found in 3 and 4 6O4F(PO4)4(UO2)] (3) and Rb4.4K0.6[(UO2)6O4F(PO4)4(UO2)] (4) structures are similar to the phosphuranylite mineral, KCa(H3O)3[(UO2)6O4(PO4)4(UO2)(H2O)8]  and (2) are thermodynamically unfavorable, i.e., their ΔrH values are positive. Also, the  compounds have more negative ΔrH compared to the respective  compound, indicating that forming the  is preferred over the . Experimental results confirm that this is the case for the Rb containing compound, it disagrees for that containing Cs. This discrepancy between experiment and calculations may come from the fact that the calculations are performed at 0 K, and thus, finite temperature enthalpy values could provide a different conclusion.As was mentioned previously, Cs prefers to form the oxide structure, while Rb prefers the oxyfluoride structure, and to understand the cause of this different behavior, we studied their reaction enthalpies using DFT. Shown in T > 2,200 K, implying that above that temperature the reactions are thermodynamically favorable. It is also important to note that the 13] compound becomes more negative than the 12F2] compound for T > 1,900 K, the temperature at which a phase change occurs. Moreover, above the temperature at which the 13] 12F2] 13] is thermodynamically preferred over the formation of . The results suggest that the formation of the oxide is driven by the entropy, and that at high enough temperatures, above 2,925 K from our calculations, the  can also be formed over the . Also, note that the difference between the phase change temperatures of the Cs and Rb compounds is 1,025 K, which is big enough so that a phase change is observed in one case but not the other. However, the calculated reaction temperature, ~2,200 K is much higher than the experimental one, 1,148 K. The difference arises from the absence of the other entropic contributions in our calculations, except for the gases. Because of the large size of the systems we are not able to calculate the phonon spectra, whereas introducing the vibrational contribution might lower the calculated reaction temperature to better match the experimental results.To consider the temperature effect, we calculated the 1 soaked in RbCl and KCl and 2 soaked in CsCl show small changes in the PXRD patterns shown in 1 for Rb and K, the approximate contents of the post ion-exchange products are 5.3 Cs, 5.7 Rb, and 5.4 Cs, 5.6 K, respectively. While in the exchange of Rb for Cs in 2, results in 6.3 Rb, 4.7 Cs.The ion exchange products of 11[(UO2)12(PO4)3O13] (1) and Rb11[UO2)12(PO4)3O12F2] (2) are typical of U6+ species in uranium oxide extended structures. 1 and 2 absorb broadly from 200 to 575 nm and can be classified as semiconductors. A careful look at the DFT calculated density of states  in contrast to the pure Cs, oxide structure of (1), indicating that the formation of pure oxide structure may be driven by entropy, and it might be obtained for both Rb and Cs, given high enough temperatures. The temperature difference in the temperatures at which the pure oxide structures can be obtained is 1,025 K between the Rb and Cs, which hints at the reason why we see an oxyfluoride in the Rb containing (2) and the pure oxide in the Cs (1) containing phases. Structures 1 and 2 are capable of alkali ion exchange, where approximately half of the alkali cations in the parent structure can be replaced by a target alkali species in concentrated salt solutions, although the Cs containing structure, 1, undergoes more extensive ion exchange than the Rb analog, 2, perhaps due to the larger interlayer spacing in 1. Alkali chloride fluxes continue to be a viable synthetic technique for crystallizing new uranium phosphate structures containing new structure types and further exploration should continue, in addition to expanding to alkaline fluxes in order to incorporate divalent cations and hopefully obtain new novel structure types.Three new uranyl phosphate oxyfluorides, and one uranyl phosphate, have been synthesized by molten flux methods using alumina crucible reaction vessels and alkali chloride fluxes. Their structures were determined by SXRD and the presence of fluorine was confirmed by qualitative EDS. The location of the fluorine sites was deduced using bond valence sums, although they were inconclusive for determining the location of F in www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB21EZ, UK; fax: +44 1223 336033.CCDC deposition numbers 1898442–1898445 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via CJ and H-CzL were responsible for the synthesis and structural characterization of the four new compounds and most of the written manuscript. VK and TB contributed the DFT calculations, methods, and discussion.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Conclusions: Low birthweight is associated with higher HBP risk in adolescent girls, regardless of their childhood BMI status.Objective: To investigate the relationship between low birthweight (LBW) and blood pressure and to assess whether LBW leads to a higher risk of high blood pressure (HBP) by gender in Chinese students aged 6–18 years. Also, to investigate whether the association was affected by childhood obesity. Methods: Data was obtained from a baseline dataset of a national school-based program. Anthropometric parameters, including height, weight, and blood pressure, were measured, while birthweight and other characteristics were obtained from questionnaires. Stratified chi-squared tests were used to compare the prevalence of HBP between LBW and normal birthweight (NBW) groups in each age and sex category. Multivariable logistic regressions were conducted to estimate the HBP risks in each birthweight group. Results: Both systolic and diastolic blood pressure showed a U-shaped relationship with increased birthweight. Compared to NBW groups, LBW girls showed a higher HBP risk, with an odds ratio of 1.29 : 1.02, 1.64,  Hypertension, or high blood pressure (HBP), is one of the largest contributors to cardiovascular disease disability-adjusted life-years (DALYs) . In ChinPrevious studies indicate that low birthweight (LBW), defined as a birthweight less than 2500 g, is an important indicator of intrauterine growth status and a predictor of adverse health outcomes, such as hypertension and cardio-metabolic diseases throughout life ,5,6,7. FUsing baseline data from a national school program in China, the present study aimed to evaluate the relationship of LBW with blood pressure and assess whether LBW leads to a higher HBP risk by gender in Chinese students aged 6–18 years.n = 1414), birthweight , systolic blood pressure , diastolic blood pressure , and children with a birthweight over 4000 g (n = 5893). The study was approved by the Peking University Ethics Committee (No. IRB0000105213034). All students participated and their parents signed informed consent forms.Data was obtained from the baseline data of a national school program in 2013. The sampling procedure of this study has been published previously in detail . BrieflyBirthweight data was collected using a standard parent questionnaire. Parents were required to record their children’s birthweight based on the record given by their birth certificate or by their health clinic. If they did not have one, they were asked to recall the birthweight based on measurements recorded themselves. About 70.9% of the parents of participants recorded the information of birthweight based on a health clinic card or birth certificate.All participants underwent a complete anthropometric evaluation according to a standardized study protocol . Height Blood pressure was measured according to the recommendations set out by the National High Blood Pressure Education Program (NHBPEP) Working Group in Children and Adolescents , using aLBW was defined as a birthweight less than 2500 g, according to World Health Organization . High blThe questionnaire of this survey was developed with reference to the Chinese National Survey on Students Constitution and Health (CNSSCH), which was conducted every 5 years in 31 provinces of China. Data collected via questionnaire included long term residence , daily physical activity time, family history of hypertension (yes/no), only child of the family (yes/no), and breastfed for over a month (yes/no).Physical activity included vigorous-intensity and moderate-intensity. Vigorous-intensity physical activities were described as aerobic activities that significantly increase heart rate and breathing, for example, running, basketball, football, and swimming, while moderate-intensity physical activities were described as aerobic activities that increase heart rate and breathing to some extent, for example, cycling, table tennis, badminton, and calisthenics. Children reported their activity frequency (days over the past 7 days) and duration (hours and minutes in each of those days) on an activity card. Daily physical activity time was calculated as average daily time = (days × (time in each of those days))/7.Before the survey, all eligible investigators were involved in a training session to get familiar with the whole process. 3% of all participants were asked to refill the questionnaires within a week for recheck. All questionnaires were checked for logical and integral accuracy by the time of data input.t-tests or chi-squared tests. Age-stratified chi-squared tests were conducted to compare the prevalence of HBP between the two birthweight groups. Sex-specific multivariable logistic regression models were used to compare HBP risk in different birthweight groups, as well as in BMI-stratified birthweight groups. Three models were conducted: model 1 was adjusted for age and province; model 2 was further adjusted for height, urban/rural living condition, daily physical activity (hours), family history of hypertension (yes/no), only child status (yes/no), and breastfeeding status (yes/no); model 3 was further adjusted for current BMI. All analyses were performed using Stata 14.0  and were two-sided with p < 0.05 considered as significant.Continuous variables were reported as means with standard deviation and categorical variables reported as numbers with percentages. The quadratic regression model was used to describe the association between birthweight and blood pressure values . The dif2 and 17.9 kg/m2 (p < 0.001), respectively. Other participant characteristics, including anthropometric and demographic features by birthweight groups, are shown in Among the 45,319 children, 43,220 (95.4%) were NBW, while 2099 (4.6%) were LBW. The current BMI of NBW and LBW was 18.4 kg/mIn total, 9.27% of LBW boys and 9.49% of LBW girls, versus 9.07% of NBW boys and 8.38% NBW girls had HBP, as is displayed in p = 0.033). Meanwhile, no statistically significant differences were observed in boys.p = 0.030) in normal/underweight girls, and 1.33  in overweight/obese girls, with NBW and normal/underweight girls set as a reference. However, LBW did not increase the risk of HBP in normal/underweight boys. Results for the stratified logistic regression are displayed in When children were further stratified according to their current BMI, LBW girls also showed higher risks of HBP than NBW girls, regardless of their current BMI status. For example, in the fully-adjusted model, odds ratios for HBP in LBW groups were 1.35 (95% CI: 1.02, 1.76, HBP in childhood not only predisposes people to hypertension in adulthood , it is aIt has always been of interest to explore the association between LBW and later HBP, and the results of previous studies are varied. One study conducted in Jerusalem found that LBW had little influence on blood pressure in adolescents aged 17 , while aHBP development depends a lot on one’s personal hormone milieu, endothermic system, age, and age-related adiposity accumulation, which are all sex-specific ,29 and mThe first limitation of our study is the cross-sectional design, from which we cannot conclude into a causal relationship. However, as the identification of LBW exists before childhood HBP, a causal relationship between LBW and childhood HBP is quite reasonable. Secondly, there were 17.5% of children from the present analysis who were excluded from the present research for missing birthweight data, and this may cause analysis bias. Thus, the results of our study are still in need of further verification in more representative populations. Furthermore, to assist comparisons with previous studies, the present study conducted measurements based on the 2004 version of the NHBPEP working group . AlthougLow birthweight is associated with a higher prevalence of HBP in girls. Normal/underweight girls are of the same risk of HBP as overweight/obese girls, and thus it is always of great importance to maintain the best nutrition status during pregnancy.


ADHD-like (attention deficit hyperactivity disorder) behavior in dogs may be expressed as impulsivity, inattentiveness, or aggression, compromising both dog and owner quality of life. Its treatment in a clinical setting requires behavioral modification and sometimes a medical treatment is added. There is a lack of objective tools for assessment and diagnosis of the problem, and behavioral experts mostly rely on owner reports. To address this gap, in this paper we use a self-developed computational tool which automatically analyzes movement of a dog from video footage collected during behavioral consultation. Based on a computational analysis of behavioral consultations of 12 dogs medically treated due to ADHD-like behavior and of a control group of 12 dogs with no reported behavioral problems, we identify three dimensions of characteristic movement patterns of dogs with ADHD-like behaviors, which are detectable during consultation. These include (i) high speed of movement, (ii) large coverage of room space, and (iii) frequent re-orientation in room space. These patterns can form the basis for computational methods for objective assessment of dogs with ADHD-like behavior that could help for diagnosis and clinical treatment of the disorder.Computational approaches were called for to address the challenges of more objective behavior assessment which would be less reliant on owner reports. This study aims to use computational analysis for investigating a hypothesis that dogs with ADHD-like (attention deficit hyperactivity disorder) behavior exhibit characteristic movement patterns directly observable during veterinary consultation. Behavioral consultations of 12 dogs medically treated due to ADHD-like behavior were recorded, as well as of a control group of 12 dogs with no reported behavioral problems. Computational analysis with a self-developed tool based on computer vision and machine learning was performed, analyzing 12 movement parameters that can be extracted from automatic dog tracking data. Significant differences in seven movement parameters were found, which led to the identification of three dimensions of movement patterns which may be instrumental for more objective assessment of ADHD-like behavior by clinicians, while being directly observable during consultation. These include (i) high speed, (ii) large coverage of space, and (iii) constant re-orientation in space. Computational tools used on video data collected during consultation have the potential to support quantifiable assessment of ADHD-like behavior informed by the identified dimensions. There is an increasing interest in “objectivization” of behavior assessment methods. As Karen Overall noted: “A review of behavioral data over the past decade supports a serious shift to crisper definitions of terms and quantifiable assessment of behaviors. Veterinary behavior and veterinary behavioral medicine are coming later to this approach, but the change is welcome” .One particularly relevant challenge in this context is the problem of assessment of dog ADHD-like (attention deficit hyperactivity disorder) behaviors. They are often expressed in the form of inattention, impulsivity, and aggressivity, greatly compromising life quality of the dog and its owner ,3,4. In Several assessment instruments relevant to ADHD-like behavior and its expressions such as impulsivity were considered in the literature. These include C-BARQ , the dogComputational behavior analysis may offer new tools for more objective assessment of behavior in clinical settings. It is an emerging field encapsulating the use of modern methods from computer science and engineering to quantitatively measure animal behavior . In thisOur hypothesis in this paper is that dogs with ADHD-like behavior may exhibit distinguishable movement patterns during consultation. To investigate the hypothesis, we compare a set of movement parameters  automatically extracted from video footage of behavioral consultations of 12 dogs treated due to ADHD-like behavior (we henceforth refer to this group as H-group) and of a control group (C-group) of 12 dogs with no known behavioral problems.Twenty-four dogs were selected for the study. The C-group  had a median age of 2.75 years , median weight of 22.00 kg , while the H-group  had a median age of 1.50 years , median weight of 20.58 kg  (see p = 0.58 (two-tailed)), nor did weight ). Categorical factors of sex , φ = 0.31) and neutered state , φ = −0.40) also did not differ significantly between the groups.To rule out confounding effects of demographic factors on the experimental variables we ensured that the C-group was matched to H-group in terms of demographic factors. To verify this, we checked that there was no statistically significant difference between the two groups for any demographic factor: age did not differ significantly between the two groups .)  and Petah Tikva (N = 6) clinic. A two-tailed Mann–Whitney U test found no significant difference for any of the variables (5).) see . The dogWe used a self-developed software tool, K9-Blyzer .In addition to basic movement related parameters: distance and average speed (that were previously used in the context of a vet consultation room ), we usep < 0.01, resp. Cohen’s d = 1.28, 1.45), as did most of the turn variables , number of points , straightness , and fractal dimension .Analysis of the difference in measured variables between H-group and C-group using Mann–Whitney U test  revealed several statistically significant differences, as summarized in The parameters found significant by our analysis can be related to three dimensions for further exploration in the context of quantification and objectivization of assessment of ADHD-like behavior: (i) speed (as induced by average_speed parameter), (ii) coverage of room space (as induced by distance and FD), and (iii) reorientation in space .It seems that the parameter of intensity of use is also strongly relevant to the second dimension. Indeed, while they were not found significant using the widely accepted minimal threshold of 0.8 for statistical power, they were close to it, and further experimentation with additional samples may highlight a different picture.The identified dimensions of distance and coverage of space support the suggested links of ADHD-like behavior to increased motor activity  and lackThese dimensions can form the basis for further developing computer-based instruments for quantified assessment of ADHD-like behavior. Eventually their envisioned use is for decision support system for behavioral clinicians in diagnosis and treatment of behavioral problems and disorders. It should be noted, however, that the current study considered only the differences between dogs with pure ADHD-like behavior to normal dogs, so no conclusions about the specificity of the system can be made at this stage, hence dogs with other behavioral problems, such as anxiety, may also exhibit similar patterns. This remains to be tested and is one immediate direction for future research.Moreover, the above-mentioned dimensions are not expected to replace owner-reported information but complement it in new objective ways. Another future research direction we are already involved in is integrating a web-based decision support system into the behavioral vet’s workflow, which analyzes video footage in real-time, providing the different parameters values and visualizing them. An additional research direction will be further validation of the video-tracking system using the various owner-reported questionnaires mentioned above, which continue to provide the common practice for an assessment of canine ADHD-like behavior. Finally, further data collection for a more in-depth comparison with respect to groups of dogs diagnosed with other behavioral disorders (such as anxiety or depression) is another direction we plan to explore.


Children with Autism Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD) have shown an increased risk for violence and victimization. However, research on exposure to multiple forms of victimization in different contexts are scarce. Hence, the current aim is to review the evidence about polyvictimization among children with ASD or ADHD. PsycInfo, ERIC, ERC, Scopus, and PubMed databases were systematically searched until 12 March 2019 to identify empirical studies with reported prevalence rates of at least four forms of victimization among children with ASD or ADHD. A total of 6/1300 articles were included in the review, ranging in sample sizes from 92 to 4114. The reported prevalence rates for polyvictimization were 1.8% and 23.1% for children with ASD and 7.3% for children with ADHD. The results emphasize the high prevalence of violence and victimization, including polyvictimization, among children with ASD or ADHD. Polyvictimization among children with ASD or ADHD is a highly under researched area. Significant knowledge gaps and important methodological considerations that provide important implications for future research include lack of information on cyber bullying, frequency or intensity of victimization, and the failure to include children as informants and to report health outcomes associated with polyvictimization. In many aspects related to victimization and health, children with Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) is a vulnerable group. This includes aspects in the contexts of school, home, and community and takes place face-to-face as well as on the internet. ASD and ADHD are the two most common forms of neurodevelopmental disorders in the world, affecting around 5–7% (ADHD) and 1–4% (ASD) of children . AccordiCompared to typically developing (TD) children, children with ASD and ADHD are more likely to be victims of peer victimization, child maltreatment, and other forms of victimization. Polyvictimization is used as a concept to examine vulnerability to multiple forms of victimization experienced in different contexts. However, little is known about polyvictimization among children with specific forms of disability, such as ASD or ADHD . PolyvicPeer victimization is defined as repetitive and intentional aggressive behavior that is systematic and involves inequality in power between the perpetrator(s) and the victim . Peer viAdolescents with ADHD is a group with an increased risk of peer victimization compared to TD youth. Research on ADHD has mostly been based on male samples, with focus on girls emerging relatively recently. Compared to TD youth, girls with ADHD demonstrate higher levels of peer rejection, which in turn predict poorer social adjustment and a host of problem behaviors . For youChild maltreatment, which is also referred to as child abuse or neglect, is defined as “all forms of physical and/or emotional ill-treatment, sexual abuse, neglect, negligence, and commercial or other exploitation, which results in actual or potential harm to child’s health, survival, development or dignity in the context of a relationship of responsibility trust or power. Exposure to intimate partner violence is also sometimes included as a form of child maltreatment” . ChildreFurther, ADHD symptoms of the inattentive types have shown associations with supervision neglect, physical neglect, and physical and contact sexual abuse, while the hyperactive types of symptoms have shown an increased risk for supervision neglect and physical abuse . Parentsp < 0.001) and domestic violence . Similar results were found by Fuller-Thomson and Lewis [p < 0.001; women OR = 2.55, p < 0.001), while domestic violence was only associated with elevated odds of ADHD among women .Other forms of victimization commonly reported among children and adolescents include violence in the community and in the neighborhood, both own exposure to violence and witnessing different forms of violence. Exposure to violence in combination with witnessing violence have shown to increase the risk of internalizing and externalizing problems, as well as child and adult health risk indicators . There ind Lewis  who usedIn 2005, Finkelhor, Ormrod, Turner, and Hamby  introducAs polyvictimization has been associated with mental ill-health and psychiatric symptoms ,40,41,42Research results on prevalence rates of victimization among children and youth with ASD and/or ADHD are ambiguous. One explanation of the great variation in prevalence rates could be the various forms of gathering this data where different instruments and informants are used. The main research tool used to measure polyvictimization to date has been the Juvenile Victimization Questionnaire (JVQ). The JVQ includes 34 forms of offenses against youth that cover five general areas of concern (1) Conventional crime , (2) Child Maltreatment , (3) Peer and Sibling Victimization , (4) Sexual victimization (seven questions including peer or adult perpetration), and (5) Witnessing and Indirect Victimization  . When prTo be able to enhance the knowledge and improve the life situation for children with ASD and ADHD, the aim with the current article is to review the evidence about polyvictimization among children with Attention Deficit Hyperactivity Disorder (ADHD) or Autism Spectrum Disorder (ASD). Research questions are: (i) to what degree are children with ASD or ADHD exposed to polyvictimization, (ii) what form of victimization is most commonly reported, and (iii) do the prevalence rates of victimization vary between different study characteristics such as type of informant and study design.This review was registered (registration number: CRD42019128779) with the PROSPERO international prospective register of systematic reviews, the Centre for Reviews and Dissemination, University of York, and the review protocol published on this database on 15 April 2019.In this review, polyvictimization is defined as exposure to multiple forms of abuse, victimization, or violence, including, but not limited to, conventional crime, child maltreatment, peer and sibling victimization, sexual assault, and witnessing and indirect victimization . This reStudies that have investigated prevalence rates of at least four different forms of victimization including children or adolescents with ASD or ADHD. A cutoff point of four forms of victimization to define polyvictimization was chosen for consistency with previous studies ,53,54. CThis review aimed to establish prevalence rates of polyvictimization among children and adolescents with ASD or ADHD. Studies reporting in languages other than English or Swedish, investigating children with disabilities other than ASD or ADHD, investigating fewer than four forms of victimization, or studies with a target sample older than 19 years of age are excluded in the review.Relevant studies were identified using two search strategies. First, an online search was performed in five databases: PsycInfo, ERIC, ERC, Scopus, and PubMed, until 12 March 2019. Search terms consisted of three main concepts related to the research questions: polyvictimization, children or adolescents, and ASD/ADHD diagnosis see . Second,https://handbook-5-1.cochrane.org/.All identified articles were initially assessed against the inclusion and exclusion criteria. The eligibility of the studies was based on the title and abstract. If the assessments concluded that a study was potentially eligible, the full article was retrieved for further assessment. In the second screening phase, full text papers were assessed independently by the reviewer using a standardized data extraction form designed to describe the characteristics of studies to be included as set out in the recommendations in the Cochrane Handbook Section 5.1.0 Extracted data items included the following characteristics for each study: information about the study sample , country were study was conducted, study design, sample size, survey method, survey informant, types of victimization assessed, prevalence of victimization, frequency (how often victimization occurred), and intensity (severity of the act), if reported.The quality of each study and risk of bias was assessed using the Standard Quality Assessment Criteria For Evaluating Primary Research Papers “QualSyst” . As onlyn = 3), the target group had no specified ASD or ADHD diagnosis (n = 5), no prevalence rates were reported in the results (n = 1), only one type of victimization was assessed (n = 12), victimization was not reported as the outcome (n = 1) and the article used selective subgroups including adolescents with suicidal behavior (n = 1) and depression (n = 1). Of the 12 articles excluded based on number of victimization types assessed, four examined only peer victimization, six assessed maltreatment and two assessed abuse. A total of six articles met the criteria for inclusion in this review .Among the studies included in this review, the most commonly used assessment tool to examine polyvictimization was the Juvenile Victimization Questionnaire (JVQ). Five studies used JVQ while one study used a modified scale based on the Adverse Childhood Experience (ACE) questionnaire to examine polyvictimization. The ACE questionnaire consist of seven categories of childhood exposures to abuse and household dysfunction , whereasVarious forms of victimization were examined in the included studies covering many different contexts, i.e., home, school, and community. The forms included differed between studies and were given somewhat different labels depending on what measure was used for assessing polyvictimization. The studies using JVQ included the following forms of victimization: conventional crime (sometimes expressed as property crime), child maltreatment, peer and sibling victimization, sexual assault, witnessing and indirect victimization. The study using the ACE questionnaire included the following forms of victimization: exposure to family violence, exposure to community violence, victim of family violence, victim of community violence and victim of sexual abuse or rape .In line with previous studies , items 5All of the six included studies assessed some form of conventional crime. The study by Aguado-Garcia et al.  showed aAll of the six included studies assessed child maltreatment. Five studies used the JVQ. Two of these studies included only children with ADHD as target group and found an overall prevalence rate of 16.9% for victimization in the last year  and 29.2Five of the six studies assessed some form of peer/sibling victimization using JVQ ,58,59,60All of the studies included assessments of sexual abuse. Among children with ADHD, the prevalence rates ranged from 6.6% from a lifetime perspective  and 6.7%All of the studies, except for Turner et al. , includep = 0.077) for having Asperger’s syndrome, and an OR of 1.79  for having ADHD. Paul et al. [p < 0.000), witnessed or indirect crimes , and property crimes . Further, of the children who did not experience an incident of assault or bullying within the last year, less than 5% experienced an incident of maltreatment during that period, while 46.5 % of the children who were exposed to assault/bullying also experienced an incident of maltreatment during the last year. Chan et al. [p < 0.05) and children with ADHD were 2.62 times more likely to experience four or more types of victimization (p < 0.001).All six included studies examined at least four different forms of victimization, of which polyvictimization was reported in four ,57,59,60This is the first systematic review of the evidence about polyvictimization among children and adolescents with ASD or ADHD. The included studies represent data from North America (USA), Asia (Hong Kong), and Europe . Even though five of the six included studies used the same questionnaire (the Juvenile Victimization Questionnaire), comparison of results was somewhat difficult depending on timeframes, type of respondents (self-reports or parent-reports), and definitions and presentation of the results. The time frame of experiences of victimization varied from the last three months to lifetime. Information about the frequency or intensity of the victimization was either not investigated or not reported. The results regarding polyvictimization among children and adolescents with ASD or ADHD was very scant, indicating that this is a highly under-researched area. Due to the small sample sizes and study design in most studies, it was difficult to draw any confirmatory conclusions regarding differences related to age, gender, and school placement.The overall prevalence of polyvictimization among children with ASD or ADHD could not be estimated in this review due to the small number of studies presenting these types of data. Only two studies reported prevalence rates for polyvictimization. Among children exposed to four types of victimization or more, the reported prevalence rates were 1.8% and 23.1% for children with ASD and 7.3% for children with ADHD ,60. TherAmong the reported forms of victimization, peer/sibling victimization received the highest prevalence rates, ranging from 21.5–83.3% among children with ASD and 33.5–67.9% among children with ADHD. This is similar to previous research on peer victimization among students with ASD  and ADHDOf the six included studies in this review, only one relied solely on self-reports  to measuThere are some limitations to be acknowledged. First, the review only included six studies on polyvictimization among children with ASD and ADHD, of which four reported statistics regarding polyvictimization. The sample sizes were in general small, and not all studies used control groups. This indicates that it is difficult to draw any strong conclusions regarding children with ASD or ADHD and their vulnerability to polyvictimization. Second, the inclusion criteria stated that at least four different forms of victimization needed to be investigated in order to be included in the review, meaning that studies examining multiple forms of victimization  may have been left out of the study. However, to be able to make valid comparisons between studies, this review was based on the established definition of polyvictimization and in line with previous studies, demanding four different forms of victimization. Third, only two studies included adolescents with ASD or ADHD in the same study, making it hard to draw any conclusions regarding differences between these diagnoses. However, this was not explicitly stated as an aim in the current review. Fourth, three of the included studies used clinical samples meaning that it is difficult to generalize the results to the general population.This review presents important information regarding victimization among children with autism spectrum disorder and attention deficit hyperactivity disorder. Accordingly, it highlights the high prevalence of violence and victimization, including polyvictimization, among children and youth with these disabilities. Due to the nature of the diagnoses, these children may be particularly vulnerable to victimization. The review further highlights significant knowledge gaps and important methodological considerations regarding polyvictimization among children with ASD or ADHD, which provide important implications for future research. To be able to enhance the knowledge and improve the life situation for children with ASD and ADHD, comprehensive investigations examining polyvictimization in the contexts of home, school, and community are warranted. Future studies studying victimization in this population should incorporate exposure across different contexts to be able to grasp the full magnitude of victimization. This includes questions on cyber bullying to minimize risk of under reporting, as well as information about the frequency or intensity of victimization to determine the severity and possible negative impacts. This includes information about how often each type of victimization has occurred. It is evident that there are ethical restrictions around the direct questioning of children with disabilities that prohibit researchers to perform the assessments with children and youth ,60. Howe


Attention-deficit/hyperactivity disorder (ADHD) is associated with substance use disorders  and nicotine dependence. This study aims to advance our knowledge about the association between SUD, nicotine dependence, and the course of ADHD (persistent versus remittent ADHD and late-onset ADHD).n = 62), remittent ADHD (n = 12), late-onset ADHD , unaffected siblings (n = 50), and healthy controls (n = 47) were assessed. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated by Cox regression and adjusted for clustered family data, gender, follow-up length, and current age.ADHD, SUD, and nicotine dependence were longitudinally assessed  using structured psychiatric interviews and multi-informant questionnaires in a subsample of the Dutch part of the International Multicenter ADHD Genetics study. Individuals with persistent ADHD . In contrast, levels of SUD in those with remittent ADHD were not different from healthy controls . ADHD persisters had also higher prevalence rates of nicotine dependence (24.2%) than ADHD remitters (16.7%) and healthy controls (4.3%). A similar pattern was found in initially unaffected siblings who met ADHD criteria at follow-up (“late-onset” ADHD); they had also a higher prevalence of SUD (33%) compared to stable unaffected siblings (20%) and were at significantly increased risk of development of nicotine dependence compared to healthy controls .SUD and nicotine dependence are associated with a negative ADHD outcome. Results further emphasize the need for clinicians to comprehensively assess substance use when diagnosing ADHD in adolescents and adults.The online version of this article (10.1186/s11689-018-9260-y) contains supplementary material, which is available to authorized users. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset in childhood; the disorder is characterized by a heterogeneous etiology and developmental course. Although severity of symptoms, especially of hyperactivity-impulsivity, often diminishes over time, prospective longitudinal studies have shown that the impairing symptoms of the disorder persist into adulthood in approximately two thirds of children with ADHD, with associated impairment across multiple domains . Recent Various risk factors have been associated with a more persistent course, such as higher ADHD symptom severity, presence of comorbidity (in particular conduct and mood disorders), family history of ADHD, and psychosocial and environmental adversities . LongituIt is unclear whether there is also a link between late-onset ADHD, referring to the onset of ADHD after 12 years of age, and SUD/ND. Several birth cohort studies have reported a 2.5–10.7% prevalence of a form of ADHD that first emerged in mid/late adolescence or (young) adulthood, so-called late-onset ADHD –5. ADHD n = 62), remittent ADHD (n = 12), late-onset ADHD (n = 18), unaffected siblings (n = 50), and healthy controls (n = 47). Given the extant literature that ADHD is a risk factor for SUD, we hypothesized that the persistent ADHD group would show higher rates of SUD and ND compared to the remittent ADHD group, while we expected higher prevalence rates of SUD and ND in the late-onset ADHD group compared to the stable unaffected groups . By including a high-risk group of full biological siblings of ADHD probands, this study allowed us to investigate the ADHD course and development of SUD and ND over time in this group, characterized by increased genetic and/or environmental risk for ADHD.The present study examined whether the course of ADHD is associated with increased risks for developing SUD  and ND from childhood through young adulthood. We report findings from a 10-year prospective, longitudinal study of a subsample of the Dutch International Multicenter ADHD Genetics (IMAGE) study cohort, including individuals with persistent ADHD (n = 189) were a subsample of the Dutch node of the IMAGE study, with initial assessment taking place between 2003 and 2006 (wave 1) in VU University Amsterdam and Radboud University Medical Center Nijmegen. The IMAGE study recruited families with at least one child with clinically diagnosed ADHD combined type and their siblings regardless of ADHD diagnosis. Family members were of European Caucasian descent. Inclusion criteria applying to both probands and siblings included IQ≥ 70, no diagnosis of autism, epilepsy, general learning difficulties, brain disorders, and known genetic disorders. Additional healthy control participants were recruited from primary and high schools from the same geographical regions as the participating ADHD probands and siblings. To assess SUD, all families were re-invited for an intermediate follow-up study (wave 2) and follow-up assessment 2 (wave 3) and 5 years later . The present study included all children and adolescents who participated in wave 1, 2, and 4 . For the current analysis, wave 3 was left out considering no information about SUD/ND was collected. Note that affected siblings were grouped in the ADHD affected group. Results for ADHD vs. unaffected siblings vs. healthy controls based on the diagnosis at baseline are presented in Additional file All participants n = 89 were aT-scores ≥ 63 on the Conners’ ADHD subscales inattention (L), hyperactivity/impulsivity (M), and total symptoms (N) and scores ≥ 90th percentile on the Strengths and Difficulties Questionnaire . Hyperare  at wavere  at wavere  and DSMre . ADHD tFor SUD assessment, a number of questionnaires were completed by participants at wave 2 and wave 4. The Drug Abuse Screening Test-20  was usedT-scores on the CPRS-R:L subscales anxious/shy (D) and emotional lability (J) were used to assess levels of anxiety and emotional lability.At baseline, families were recruited from clinics and via advertisements. Testing took place at the Donders Institute and Radboudumc in Nijmegen. All ratings of behavioral functioning pertained the participant’s functioning off medication. Families were financially compensated for participating in the study.T-scores of the CPRS-R:L and T-scores on the ADHD scales of the CPRS-R:L. A chi-square test assessed whether groups differed in the proportion of males. Any variables showing significant differences between groups were included as covariates. Group differences in risk of developing SUDs and ND were assessed using Cox proportional hazard models. Correction for clustered (family) data was performed using robust standard errors [All analyses were conducted using SPSS version 24.0 . Participants were divided into five groups based on prospective reports of ADHD symptoms  unaffected siblings, and healthy controls). Analyses of variance were performed to assess whether groups (persistent vs. remittent and late-onset ADHD vs. unaffected siblings) differed on IQ at baseline, age at follow-up, follow-up interval, emotional lability, and anxiety d errors . The modn = 189) with participants lost to follow up on variables reported in this study available at baseline. No significant group differences were found (.14 < p < .99).Selective attrition was investigated by comparing participants successfully followed up (n = 47). There were small but statistically significant group differences in current age, follow-up interval, gender, and IQ. All subsequent analyses were statistically corrected for current age, follow-up interval, and gender.Additional file No significant differences in anxiety and emotional lability scores were found between siblings with late-onset ADHD and (stable) unaffected siblings at baseline . Individuals with persistent ADHD were 4.6 times (95% CI 1.17–17.81) more likely to develop a SUD compared to healthy controls, whereas remitters did not differ in risk compared to healthy controls . There was no significant difference in risk of developing a SUD between persisters and remitters, although the small sample size and wide confidence interval likely contributed to this . No main effect of group was found when persisters, remitters, and healthy controls were compared on their risk of developing nicotine dependence , although, again, the overall pattern of findings suggests that persisters and remitters had higher nicotine dependence than healthy controls; see Table A main group effect was found when comparing persisters with remitters and healthy controls . Again, the pattern of findings suggests that late-onset ADHD had higher SUD levels . Those with late-onset ADHD were at increased risk of developing nicotine dependence compared to healthy controls , but not compared to unaffected siblings . Unaffected siblings and healthy controls did not significantly differ in their risk of developing nicotine dependence, although the small sample size and wide confidence interval likely contributed to this, with the pattern of findings suggesting increased prevalence of nicotine dependence in unaffected siblings compared to healthy controls  or nicotine dependence .No significant effect of stimulant medication use was found on the development of SUDs  and further emphasize the need for clinicians to make a comprehensive assessment of substance use when diagnosing ADHD.To our knowledge, this study provides the first data on the association between SUD/ND and the course of ADHD among probands with ADHD and their biological siblings in a 10-year prospective longitudinal study. Results showed that ADHD persisters were at significantly higher risk for the subsequent development of SUD relative to healthy controls, in contrast to a similar level of SUD in ADHD remitters vs healthy controls. ADHD persisters had also higher  prevalence rates of ND than ADHD remitters and healthy controls. A similar pattern of results was found for those with late-onset ADHD who had a higher prevalence of SUD compared to healthy controls, while no higher prevalence rates of SUD were found in stable unaffected siblings compared to healthy controls. Further, those with late-onset ADHD were at significantly higher risk for the subsequent development of ND compared to healthy controls, in contrast to a similar level of SUD in stable unaffected siblings versus healthy controlsPrevious research has suggested that the persistence of ADHD is a risk factor for the development of SUD . Our stuDisentangling the nature of the association between ADHD and SUD/ND remains challenging. Although the literature is consistent in showing that the onset of ADHD precedes the development of SUD, high levels of substance use in adolescence may adversely affect still-maturing prefrontal brain regions leading to behavior regulation deficits associated with ADHD . In thisOur findings offer some support for the possibility of late-onset ADHD, a proportion of biological siblings unaffected at baseline met DSM-5 criteria of ADHD in young adulthood, with age of onset after 12 but prior to 18 years of age. Since all participants were comprehensively assessed on ADHD and comorbid disorders by multi-informant questionnaires and interviews in childhood, as well as in (young) adulthood, it is unlikely that these cases represented individuals with undetected childhood symptoms  –35 or faPrevious family studies of ADHD have shown that ADHD and SUD co-aggregate in families , 36. In Some methodological limitations should be taken into account in the interpretation of the results. Given that several of the subgroup samples were relatively small, detecting significant group differences was more difficult. However, our results were in the expected direction, indicating that significant results are expected with a larger sample. Furthermore, SUD and ND were assessed by self-reports. We used adult cutoff scores for the self-report questionnaires, while not all subjects reached adulthood at the time of assessment. Although this approach would not have biased results to finding spurious case-control differences, it may have influenced our estimates of prevalence.This study contributes to the understanding of the association between substance use and the course of ADHD over time. In particular, children with persistent ADHD have higher risks of developing alcohol and/or drug dependence over time compared to healthy controls, while this was not found for individuals with remittent ADHD. The same pattern of findings was found for siblings developing late-onset ADHD versus those who remained unaffected. This suggests that SUD and ND seem to be associated with a negative ADHD outcome. Although the mechanisms governing these associations are not yet fully understood, the findings from this study underscore the clinical and public health significance of SUD in the course of ADHD. This study emphasizes the importance of preventive interventions in biological siblings, considering their increased risks of developing both SUD and ADHD.Additional file 1:Table S1. Demographic and clinical characteristics of children with attention-deficit/hyperactivity disorder (ADHD), their unaffected siblings (US) and healthy controls (HC). Table S2. Prevalence rates of substance use disorder and nicotine dependence in children with attention deficit hyperactivity disorder (ADHD), their unaffected siblings (US) and healthy controls (HC). Figure S1. Cumulative life-time risk for any substance use disorder (SUD) and nicotine dependence in Attention-deficit hyperactivity disorder (ADHD) probands (n = 74), their unaffected siblings (n = 68) and healthy controls (n = 47) at baseline. All comparisons were corrected for gender and follow-up interval. Table S3. Demographic and clinical characteristics of the Attention-deficit/hyperactivity disorder (ADHD) persistent, remittent, late-onset (LO), unaffected siblings (US) and healthy controls (HC) group. (DOCX 137 kb)