Nebraska births between 1995 and 2005 were followed until 2018 to look for intergenerational associations of low birth weight (LBW) and preterm birth (PTB). Results from generalized estimating equations revealed that mothers born LBW preterm were more likely to deliver LBW  or preterm  than mothers born with normal weight or at term. In addition, mothers who had an LBW sibling were 44% more likely to have an LBW infant . A consistent finding was also observed for mothers who had a PTB sibling . Mothers who were LBW at birth or had any LBW siblings, especially two or more siblings, were more likely to repeat this adverse birth outcome. The same association was also observed in mothers who were born preterm. In 2018, 8.3% of newborns in the United States were LBW, and 11.7% were PTB , costing22.1Data were from the Nebraska Mother Index (NMI), a population-based birth registry providing birth certificate data linkages to matrilineal multiple births and intergeneration-matrilineal births. In the United States, state-level intergenerational data linkage studies were all based on specific projects, such as linking: 1). mothers born in Tennessee in 1959–1966 and their children in 1979–1984 , 2). motWe selected the first , the second , and the third  generation from NMI, which contains information of every newborn's birth weight, gestational age (week), delivery pattern, mother's information, etc. This database indexed mothers through probabilistic linking mother's identifiable information, such as the mother's first name, last name, date of birth, social security number, and residential address . If a moAll singleton births between 2010 and 2018 from the NMI as G3  and their mothers in G2 from 1995 to 2005  were eligible for selection. According to 2.2In our study, LBW was defined as birth weights<2,500 g, and PTB was defined as having gestational ages at live delivery<37 weeks. Accordingly, four binary variables were created, indicating if a G3 infant was LBW or PTB and if the mother was LBW and PTB. The outcomes of interest were LBW and PTB of G3 infants. Six indicators of heritable effects included G2 LBW and PTB status, G2′s sibling LBW and PTB status, and the total number of LBW or PTB siblings  from each G2 mother. Mothers' demographic and medical history variables were included as covariates, including age at birth , marital status (married or unmarried), educational level , rurality , race/ethnicity , binary indicators of diabetes, hypertension, using tobacco during pregnancy, and C-section in the delivery. Rural or urban status, as well as race and ethnicity, were based on G2 at birth .2.3Following 3Among 5,118 linked mothers, the LBW and PTB rates were 7.5% and 8.9%, respectively, formerly LBW and PTB mothers accounted for 5.3% and 5.6%, and 7.2% and 10.3% had at least one LBW or PTB siblings, respectively. They were dominated by non-Hispanic White (70.5%) and Hispanic (14.8%), with<9.9% non-Hispanic Black. Over 41% of G2 had teen pregnancies (<19 years old), only 5% of them were married, and over 70% only had a high school or less education. In addition, 4.1% had diabetes during pregnancies, 7.4% had hypertension, 16.2% used tobacco, and 19.5% received C-section.In contrast, only 19% of maternal mothers (G1) were<19 years old when they delivered G2, and a majority of them (53%) were married. Over 30% used tobacco, and 16% received C-section.In In addition, mothers who had any LBW siblings were 44% more likely  to have LBW infants than the comparison group. The adjusted OR was strongest when maternal LBW siblings were equal or greater than two . A consistent finding was, likewise, observed for mothers who had any PTB sibling . Mothers who had one PTB sibling were significantly associated with delivering PTB infants , and this association was stronger when they had two or more PTB siblings .4In this study, we examined intergenerational correlations of LBW and PTB focusing on the subsequent pregnancy and their siblings. The study is a direct extension of the longitudinal study of adverse birth outcomes of the mother of multiple births  to theirThe flexibility of NMI in indexing birth outcomes from G1 mothers, allowed us to examine a mother's odds of having adverse birth outcomes according to her siblings' LBW or PTB status. If a mother had two or more LBW or PTB siblings, she was at least 71% to 140% more likely to have an LBW or PTB baby, respectively. This suggests that a G2 mother did not necessarily have to be born with an adverse outcome; if two or more of her siblings were born with an adverse outcome, she would have a greater likelihood of delivering LBW or PTB offspring. These findings to our knowledge have not been reported in previous studies in the United States.Heritable effects, such as strong matrilineal relationships of LBW and PTB, seen in this study, can be due to genetic predisposition but may also represent socioeconomic or behavioral traits that are passed down through the generations. The adjusted odds ratios in the current study were consistent with a previous study using the Illinois transgenerational dataset : controlThis study has several limitations. First, since the starting time for G2 follow-up was January 1995, the G2 mothers in our sample well<24 years old. For this reason, our findings are biased toward young age mothers. This bias might contribute to non-significant results of the education and marital status variables in all the multivariate analyses. Second, the 1995 to 2004 Nebraska birth certificate data did not record mothers' height and weight, and we were unable to include this information for gestational weight gain as confounders . Third, 5Our results showed a strong intergenerational correlation of LBW or PTB. Mothers who were LBW at their own birth or had any LBW  siblings were much more likely to repeat this adverse birth outcome than their corresponding comparison groups. The same pattern was observed for PTB.Dong Liu: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing - original draft, Supervision, Project administration. Ge Lin: Conceptualization, Methodology, Data curation, Investigation, Writing - review & editing. Dejun Su: Writing - review & editing. James M. Alexender: Writing - review & editing. Xiaoting Sun: Writing - review & editing. Ming Qu: Investigation, Resources, Writing - review & editing.


For the ADHD group, a relationship was found between environmental support and involvement in all three settings. Conclusions: The findings demonstrated differences in the participation of children and youth with ADHD across different settings, compared to those without ADHD, and confirmed the effect of environmental factors on participation, especially involvement. It is essential to consider participation measures and environmental factors when designing interventions for children and youth with ADHD.Background: Children and youth with attention deficit hyperactivity disorder (ADHD) may experience difficulties in participation, but few studies examine their participation and the environmental factors affecting participation. This study explored the participation and the environmental factors of children and youth, with and without attention deficit hyperactivity disorder (ADHD), in the following three settings: home, school, and community. Materials and Methods: Parents of 65 participants aged 6–14  with and without ADHD completed the Participation and Environment Measure for Children and Youth (PEM-CY) questionnaire, which evaluates participation and environmental factors, along with demographic and screening questionnaires. Results: The ADHD group ( The International Classification of Functioning, Disability and Health (ICF) of the World Health Organization (WHO) defines participation as “involvement in a life situation” , which iThe participation of children and youth with different health conditions (such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) and/or disabilities was found to be limited, compared to that of children with typical development ,12,13. FOne of the health conditions that may affect the participation of children and youth in different settings is attention deficit hyperactivity disorder (ADHD). This is a neurodevelopmental disorder characterized by attention deficit and/or impulsivity and hyperactivity, whose prevalence among children and youth is estimated at about 5%. Symptoms of ADHD persist in adulthood, with prevalence among adults estimated at about 2.5% ,18. A diADHD has far-reaching and long-term consequences in all functioning areas, as it affects various aspects of a person’s life, including daily functioning, employment, social participation, and family stability ,18. StudSocial difficulties of children and youth with ADHD may include peer rejection, inappropriate behavior, and/or difficulties with social skills such as collaboration, taking turns, reciprocity, and focus on conversation and play ,22. In aIn summary, most studies examining the functioning of children and youth with ADHD are often focused on their specific difficulties and disabilities rather than their overall participation. In addition, there are few studies describing the participation profile of children and youth with ADHD compared to their peers without ADHD, particularly with respect to different settings . Thus, a need exists to expand professional knowledge of the effects of ADHD on the participation of children and youth with this diagnosis, as it impacts their daily life in various settings .In addition to health conditions, various environmental factors, such as physical and sociocultural factors, may also affect a person’s development and participation ,3,29,30.However, despite increasing research on the contribution of environmental factors in explaining the participation of children and youth with disabilities, the majority of these studies have focused on children with physical disabilities , autism All this points to the need for an in-depth examination of how environmental factors impact the participation of children and youth with disabilities . SpecifiThe present study focuses on examining the participation of children and youth (aged 6–14) with and without ADHD, in home, school, and community settings, identifying the environmental supports for and barriers against participation, and examining the availability of supporting resources. Our specific objectives were to examine the following: (a) the differences between children and youth with and without ADHD with respect to participation patterns , desire for change, and the overall environmental support in each of the settings ; (b) the relationship between the overall environmental support and the participation patterns (frequency and involvement) in the different settings in each group (with and without ADHD); and (c) the differences in the participation patterns between the different settings , and to describe the environmental factors (support and barriers) that influence participation of children and youth with ADHD.A descriptive quantitative and comparison cross-sectional design was used.The study population included 65 parents of children and youth, aged 6–14, most of them (about 60%) from urban areas in the central district of Israel, who were recruited by voluntary response sampling. Most parents were married (89.5%), were aged 45 and under , and had an academic education . The participants were divided into the following two groups: (a) an ADHD group (31 participants) and (b) a non-ADHD group (34 participants) matched in age range and adjusted for gender and socioeconomic status (according to the level of family income). The inclusion criteria for each group were children and youth whose parents reported that they did (ADHD group) or did not (non-ADHD group) receive a diagnosis of ADHD from a qualified professional, with all reports confirmed by the ADHD Questionnaire   is a parThis study was approved by the Ethics Committee of the Hebrew University, Jerusalem, Israel (No. 27032018). Ads for recruiting subjects were posted on social networks and relevant forums; for the ADHD group, therapists working with children and youth with ADHD were also contacted. Parents who showed interest and agreed to participate in the study received an explanatory letter and filled out the questionnaires electronically, via email, or manually, according to their preference. The data were collected without identifying personal and/or computer information. Screening of the returned questionnaires was performed according to the exclusion and inclusion criteria , the participation patterns (frequency and involvement) were measured using mean variables. The desire for change in their child’s participation was measured as the percent of activities in which the parents indicated that desire. In addition, according to the PEM-CY manual’s guidelines, a variable was calculated for the overall environmental factors supporting participation . In order to compare the participation patterns, the desire for change, and the overall environmental support between the two groups (with and without ADHD), one-way MANOVA analysis was used. Effect-size calculation was conducted using partial eta squared, with η2 > 0.14 defined as high effect, 0.06 < η2 < 0.13 as medium, and 0.01 < η2 < 0.05 as low [Statistical analysis was performed using the SPSS version 25.0  , with a 5 as low . In ordeF = 3.91, p = 0.013; partial η2 = 0.16) and for involvement  = 14.16, p < 0.001; partial η2 = 0.41). As seen in Differences in participation patterns between the two groups were examined using a one-way MANOVA analysis. The differences between the groups on the combined dependent variables were statistically significant for frequency  = 4.83, p = 0.004, partial η2 = 0.19). In follow-up univariate ANOVAs, significant differences were found between the groups with medium-to-high effect sizes in the home and community settings, meaning that parents in the ADHD group were more interested in change than parents in the non-ADHD group at home and in the community, but not at school.The combined dependent variable of the desire for change significantly differs between the two groups  = 13.39, p < 0.001, partial η2 = 0.40), along with significant differences with high effect sizes that were found between the two groups in each setting. Thus, the ADHD group reported the overall environmental support to be lower than the non-ADHD group, indicating that, among the ADHD group, the environmental factors are less supportive of children’s participation or are less available to lend support.Examining the differences between the groups with respect to the overall environmental support, a significant difference between groups was found for the three combined settings  = 79.738, p < 0.001, partial η2 = 0.73. Pairwise comparisons with Bonferroni correction showed all three settings significantly differed from one another (p < 0.001). The frequency of participation at home was found to be higher than in the school and the community environments, and the frequency of participation in the school was found to be higher than in the community  = 3.943, p = 0.025, partial η2 = 0.12. In pairwise comparisons with Bonferroni correction, the mean of involvement at home was significantly lower than in school (p < 0.05), but no significant differences were found when comparing the involvement at home and school to the involvement in the community . In the school environment, the most supportive factor reported was “relationships with peers” (32.30%), followed by “the attitudes and actions of teachers, coaches, or staff” (25.80%). The result was similar for the community environment, where the most supportive factor for the ADHD group was “attitudes and actions of other members of the community” (29%).Examining the barriers of the ADHD group, it was found that, in the home environment, “the cognitive demands” were reported as the most common inhibitors (38.70%). In the school environment, “the cognitive demands” and “the sensory stimulation” were the most frequently reported inhibitory factors (45.20% for each of them). Similar inhibitory factors were reported in the community environment, leading with sensory stimulation (19.40%) and cognitive demands (16.10%).This study was designed to examine the participation profile as affected by environmental factors (supports and barriers) among children and youth with ADHD, compared to their peers without ADHD. Additionally, the study set out to examine the relationship between overall environmental support and participation patterns (frequency and involvement) in each group, in the following three settings: home, school, and community.Regarding the comparison of the participation patterns and the desire for change, it was found that, in the home environment, children and youth with ADHD participated less frequently and were less involved than their peers without ADHD. These findings are consistent with previous research suggesting that children with disabilities participate less frequently and are less involved at home, compared with typically developing children . They alRegarding the school setting, our findings indicated that children and youth with ADHD were less involved than children and youth without this diagnosis. This may be due to the difficulties in the social functioning of children and youth with ADHD, which comprise four of the five school-related activities in the PEM-CY questionnaire. Indeed, other studies of children with ADHD indicate high rates of peer rejection, low teacher ratings of their social skills in the classroom, difficulty in social involvement, along with difficulty in cooperation and in reciprocal conversation while playing with others ,22. AddiHowever, in our study, no significant difference was found between the groups in frequency of participation in the school environment. A possible explanation for this is that participation frequency is influenced by school policy and routine , which mRegarding the community environment, our findings indicated that the ADHD group was less involved than the non-ADHD group. This is similar to the study by Engel-Yeger and Ziv-On , which fOverall, our findings indicated lower involvement in the ADHD group compared to the non-ADHD group in all three settings. Since the construct of involvement refers to the level of concentration, emotional involvement, satisfaction, and attention when performing an activity , it is nThe results of the study found no significant association between environmental supports and participation frequency, for either of the groups (with and without ADHD). A similar finding was reported in the study of Rosenberg et al. , which eOur findings demonstrated a positive connection between environmental support and involvement among children and youth with ADHD in all the settings, confirming the need for environmental support to promote participation. In light of the importance of participation and its contribution to development, health, and well-being of children and youth, further examination is advisable to better understand the effects of increased participation on the well-being of this population.It should be noted that, in the ADHD group, a significant correlation was found in all three settings, whereas in the non-ADHD group the correlation was found to be significant only in the home environment. These differences between groups indicate that, for children and youth with ADHD, the environmental supports are more significant influences on their involvement in activities in different settings.In comparing the different settings for frequency and involvement patterns, the home was found to be the environment in which children and youth with ADHD participated most frequently, yet they were less involved. A possible explanation for this is that the home environment is the main place where most daily tasks are performed . As suchIn contrast, school was found to be an environment where children and youth with ADHD are mostly involved in school activities, which may be related to the school activities themselves that are more structured. Our results, however, were limited to activities included in the PEM-CY questionnaire, which do not necessarily highlight the difficulties of this population in executive functions ,45 and aAccording to our results, the community showed the lowest frequency of participation among children and youth with ADHD. This may result from the nature of community activities, such as group events or traveling, which may occur less frequently than home and school activities. Significantly, this low frequency was also reported by the non-ADHD group, an outcome supported by various studies that used the PEM-CY and similarly indicated highest participation frequency at home and lowest in the community ,13,34. HExamining the environmental supports and barriers influencing children and youth with ADHD indicated that the factors which stood out most frequently as inhibitors, in all three settings, were the activity demands, and in particular the cognitive demands . This finding is consistent with the cognitive difficulties of the ADHD population related to attention, concentration , and exeAnother major barrier for children and youth with ADHD in school and the community is the sensory stimulation . This refers to distractions due to unrelated stimuli, and it may therefore reflect the high prevalence of comorbidity associated with sensory modulation dysfunction . ReportsRegarding the supports, other people’s attitudes and actions were found to promote the participation of children and youth with ADHD in the three settings . Indeed, according to the literature, positive attitudes in the community and culture can promote participation , with thGiven that the environment is a potentially modifiable factor, there is considerable value in identifying which features of the home, school, and community environments are barriers to participation, so that interventions can be directed appropriately . TherefoThe present study has a number of limitations, for which further research is recommended. First, the study focused on a convenience sample of 65 children and youth with and without ADHD aged 6–14 years, which is a wide age range. Moreover, most of them have average or above-average socioeconomic status, live in the central district of Israel, and have parents with an academic education. Further studies need to include a larger and more representative sample of the two groups, including smaller age ranges, various socioeconomic strata and areas of residence, with varying levels of parents’ education, in order to enable better generalization of the findings. In addition, further studies should include children and youth with various health conditions, following the literature related to the range of health-related characteristics among representative study samples. Second, the information was based on parents’ reports regarding their children’s diagnosis of ADHD and the study criteria. Further research could include additional information from a professional regarding the ADHD type and comorbidity, such as sensory modulation dysfunction, learning disabilities, and/or DCD, which is common in this population ,46,48. AThis study described the participation profile, environmental factors (supports and barriers), and the relationship between overall environmental support and the participation patterns of frequency and involvement, among children and youth with and without ADHD, aged 6–14, based on parental reports. The findings indicated that, compared to their peers without ADHD, children and youth with ADHD participate less frequently in the home setting, they are less involved in all three settings, and their parents are more interested in changing their participation at home and in the community. Information about the specific activities to which parents want to see change is clinically important, as it can guide goal setting and targeted intervention. At the same time, children and youth with ADHD reported lower overall environmental support. Our findings showed a relationship between environmental support and involvement of children and youth with ADHD in all three settings, in contrast to children and youth without ADHD. These differences between groups reflect the interactional nature of participation, while confirming the need for environmental support to promote participation mainly among children and youth with ADHD.In addition, differences in their participation patterns were found in various settings. These findings highlight the need for a broad examination of participation in different settings. As mentioned above, since participation is a multidimensional concept, its assessment requires addressing multiple aspects, including subjective measures such as involvement.Different environmental factors were found to support or inhibit the participation of children and youth with ADHD, such as other people’s attitudes and actions, relationships with peers, activity requirements (particularly cognitive), and sensory stimuli. This knowledge can lead to a greater effort to evaluate environmental support for children and youth with ADHD and improve their participation patterns (particularly their involvement) in various activities in different settings. The resulting development of intervention programs will benefit this population and contribute to their well-being.


ObjectivesWe conducted a cross-sectional study to understand the differences in demographics and psychiatric comorbidities in adolescents with major depressive disorder (MDD) and assess the risk of suicidality due to comorbid attention-deficit/hyperactivity disorder (ADHD).MethodsWe included 141,530 adolescents  with a primary diagnosis of MDD from the nationwide inpatient sample , and grouped by a comorbid diagnosis of ADHD . Logistic regression analysis was used to measure the demographic predictors for ADHD in adolescents with MDD, and to measure the suicidal risk in ADHD versus non-ADHD.ResultsComorbid ADHD was prevalent in whites (71.9%), and males had two times higher odds (95% CI 2.25-2.41) compared to females. The most prevalent comorbidities seen in ADHD-cohort were anxiety disorders (46.3%) and substance abuse (20.1%) with 1.3 times higher odds of substance abuse (95% CI 1.41-1.65) compared to non-ADHD. Suicidal behaviors were seen in a higher proportion of the ADHD cohort compared to the non-ADHD cohort (54.3% vs. 52.7%). ADHD and suicidal behaviors relationship was statistically significant but had a very small positive association  after controlling for demographic confounders and comorbidities. There was a significant increase in the number of MDD hospitalization with ADHD for suicidal behaviors from 51.1%  in 2012 to 58.2%  in 2014.ConclusionThere exists a significant but small positive association between suicidal behaviors and comorbid ADHD in MDD adolescents. The suicide rate has increased by 52.2% during the study period in depressed adolescents with ADHD. This calls for early diagnosis and management of ADHD and early-onset depression in adolescents to prevent suicide risk. Depression among adolescents is common psychopathology which may often go unrecognized . With alOne of the major concerning factors seen in depressed individuals is the risk for suicide as it is the foremost cause of increased mortality rates in the United States (US). According to the center of disease control and prevention (CDC), suicide is among the second leading cause of mortality in adolescents . And thrAttention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent pediatric psychiatric illness. As per a national parent survey published in 2016, about six million 9.4%) children have been diagnosed with ADHD, with the majority of the children ranging between the ages of six to 17 years . A study.4% childIn our study, we used the national inpatient data to understand the differences in demographics and psychiatric comorbidities in adolescents with MDD by comorbid ADHD, and assess the risk of suicidal behaviors with comorbid ADHD versus non-ADHD. Also, we studied the trend in adolescent inpatients with MDD and comorbid ADHD in the US hospitals.Data sourceWe conducted a retrospective data analysis using the nationwide inpatient sample  from the healthcare cost and utilization project (HCUP). The NIS provides inpatient data records from about 4,400 non-federal hospitals across 44 states in the US . DiagnosInclusion criteria and outcome variablesWe included patients (age 12 to 18 years) with a primary discharge diagnosis of MDD using the ICD-9 codes 296.20-296.26 or 296.30-296.36 and further grouped by secondary discharge diagnosis of ADHD using the ICD-9 codes 314.00 or 314.01.Demographic variables studied included age, sex , and race  . The comStatistical analysisWe used cross-tabulation and descriptive statistics to discern the demographic and comorbidities differences in MDD by comorbid ADHD diagnoses. Logistic regression analysis was used to measure the demographic predictors for ADHD in adolescents with MDD, and to measure the risk of suicidal behaviors in ADHD versus non-ADHD cohorts after controlling for demographic confounders and psychiatric comorbidities. We used the linear-by-linear association test for measuring the differences in demographics and comorbidities, and the ANOVA test for measuring the changes seen in mean age over the study period in adolescents with MDD and comorbid ADHD. A P-value of less than 0.05 was used to determine the statistical significance and all analysis was done using the statistical package for the social sciences (SPSS) version 26 .Ethical approvalIndividual identifiers were used to protect the patient's identity and health-related information. So, the use of de-identified NIS database in this study does not require approval from the institutional review board .We had a sample of 141,530 adolescent inpatients with a primary diagnosis of MDD, and 16%  had comorbid ADHD. A higher proportion of the ADHD cohort were females (56.8%), but when compared with the non-ADHD cohort, males had 2.3 times higher odds  for comorbid ADHD compared to females. While comparing different races/ethnicities, comorbid ADHD was prevalent in Whites (71.9%), and there exists statistically non-significant difference when compared with Blacks (P = 0.271), while Hispanics and native Americans/Asians were having lower odds. The prevalence of comorbid ADHD increased with median household income, but there was no statistically significant difference in the relationship between household income and the co-diagnosis of ADHD.The most prevalent comorbidities seen in the ADHD cohort were anxiety disorders (46.3%) and substance abuse 20.1%). Patients in the ADHD cohort had 1.5 times higher odds  of comorbid impulse control disorder, and 1.3 times for comorbid substance abuse . ADHD and suicidal behaviors relationship was statistically significant but had a very small positive association  after controlling for demographic confounders and comorbidities as shown in Table %. PatienThe prevalence of comorbid ADHD increased in females from 50.8% in 2012 to 60.4% in 2014, while there is a decrease of 9.6% in the male population (P < 0.001). There is statistically no significant difference seen across the race during the study period. In terms of median household income, there is a bimodal change as there is an increase in prevalence in low-income families below the 25th percentile (20.1% to 23.6%) and a decrease in high-income families above 75th percentile (29.3% to 25.8%) during the study period. There was a significant increase of 52.2% in number of MDD hospitalizations with ADHD for suicidal behaviors . Among comorbidities, the highest increase in prevalence was seen in anxiety disorder (by 8.3%) and impulse control disorders (by 0.7%). There was a statistically significant decrease in alcohol abuse and substance abuse as shown in Table Using a national sample from thousands of hospitals in the US, we were able to find a statistically significant but smaller positive association with suicidal behaviors due to ADHD in adolescents with MDD after controlling for demographic confounders and psychiatric comorbidities including substance abuse.Based on a study conducted by Danielson et al., ADHD was prevalent among adolescents with three million being diagnosed with ADHD in 2016 . So, we We found that depressed adolescents with ADHD have a higher risk of comorbid impulse control disorder and anxiety disorders. Both these disorders are caused by a neurochemical imbalance in serotonergic and dopaminergic systems that slow down inhibitory responses leading to impulsive behavior, and difficult to inhibit intrusive thoughts causing increased anxiety , 15. SubThere was a significant increase in suicidal behaviors among depressed adolescents with ADHD by 52.2% during the study period. Daviss found that MDD and ADHD were independent factors that increase suicide risk among adolescents though there was no correlation between both disorders . Past stOur study had some limitations. Firstly, the NIS lacks patient-level information that is required for evaluating the causal association between suicidal behavior and ADHD in MDD adolescents. Additionally, such cross-sectional database studies are subject to selection bias and moderate sensitivity of diagnostic codes for psychiatric conditions. Yet, using the NIS we were able to draw a population-based perspective on suicidal association due to ADHD after controlling for potential confounders.There exists a significant but small positive association between suicidal behaviors and comorbid ADHD in MDD adolescents. The suicide rate has increased by 52% from 2012 to 2014 in depressed adolescents with ADHD in the US. Due to higher impulsivity in MDD adolescents with ADHD, suicide risk is much higher. This calls for early diagnosis and management of ADHD and early-onset depression in adolescents to prevent suicide risk and mortality, and improve quality of life.


Bartonella spp. are vector-borne pathogens transmitted to humans via blood-sucking arthropods. Rodents such as the black rat (Rattus rattus) and Norway rat (R. norvegicus) are thought to be the main reservoirs. An infection with rodent-associated Bartonella spp. may cause severe symptoms in humans such as endocarditis and neuroretinitis. The current knowledge of Bartonella prevalence in rats from western Europe is scarce.Bartonella spp. by conventional generic polymerase chain reaction (PCR). To determine the Bartonella species, a selected number of amplicons were sequenced and compared with GenBank entries.Rats and a few other rodent by-catches were trapped in the context of a rodenticide resistance study at different sites in Flanders, Belgium. During dissection, biometric data were collected, and spleen tissues were taken. DNA was extracted from spleen samples and tested for R. norvegicus (99.64%). Other rodents trapped included: two water voles ; one colour rat ; and one muskrat . PCR analysis of 1097 rodents resulted in 410  Bartonella spp. DNA-positive samples. Bartonella tribocorum  was the most frequently detected Bartonella species, followed by B. grahamii  and B. doshiae . An uncultured Bartonella species occurred in one water vole . There was a significantly higher Bartonella prevalence in older rats compared to juveniles and a significant difference in Bartonella prevalence concerning the localisation of trapping sites. In contrast, there was no statistically significant difference in Bartonella prevalence regarding sex, degree of urbanisation and season.In total, 1123 rodents were trapped. The predominate species was B. tribocorum in Belgium.Based on the high prevalence found, we conclude that the Norway rat seems to be a key reservoir host for zoonotic  Bartonella consists of haemotropic, facultative intracellular, gram-negative α-proteobacteria, which parasitize endothelial cells and erythrocytes of mammalian hosts [Bartonella spp. may cause different diseases such as cat scratch disease, trench fever and Oroya fever with various symptoms, e.g. endocarditis, regional swelling of lymph nodes and vasoproliferative lesions of the skin and abdominal organs [via fleas , the body louse (Pediculus humanus corporis), sand fly (Lutzomyia verrucarum) or ticks (e.g. Ixodes ricinus) [The genus an hosts , 2. Bartl organs , 4. Thusl organs . Arthropricinus) –10.Bartonella species are known, only a few of them are pathogenic to humans [Bartonella species; however, a majority of these are not zoonotic. The Norway rat (Rattus norvegicus) is known to harbour both non-pathogenic (e.g. B. rattimasiliensis and B. taylorii) as well as pathogenic Bartonella spp. [B. elizabethae, B. vinsonii arupensis and B. washoensis may cause cardiac diseases, B. grahamii is suspected to induce neuroretinitis, and B. tribocorum may cause unspecific symptoms such as fever, apathy and chronic fatigue [Bartonella spp. and other zoonotic agents, rodents are crucial for the transmission and maintenance of vector-borne pathogens [R. rattus) may be of concern. As highly synanthropic rodents they inhabit buildings and households, live in close contact to humans in urban and suburban regions and feed on human spoilage [Bartonella spp. [Although many different o humans , 11–15. lla spp. , 12, 13. fatigue , 12, 13.athogens , 9, 16. spoilage . Therefolla spp. .Bartonella-infection rates in rodents [Bartonella in rodents and their ectoparasites  determine the prevalence of Bartonella spp. in Norway rats from Flanders, Belgium; (ii) identify Bartonella species in these rats; and (iii) analyse Bartonella prevalence rates regarding the sex and age of the rats, seasonal influence, geographical location and degree of urbanisation.Many studies worldwide describe moderate to high  rodents , 20. See: 11–70% –23; Denm: 11–70% ). These e: 30.3% ; Paris, e: 30.3% ), whilstountries . The lat2 and is characterized by a mean human population density of 485 individuals/km2 [Pinus sylvestris) [The trapping sites are located in Flanders, the northern part of Belgium Fig. . This reuals/km2 –29. Belguals/km2 ; 97.9% ouals/km2 . Only 13vestris) , 32.Fig.In 2015 and 2016 rodents were trapped in the context of a rodenticide resistance study for Norway rats conducted by the Belgian Research Institute for Nature and Forest . Detailed information on rodent trapping procedures was published elsewhere . Rodent rpm, twice for 15 s and a break of 10 s in between both runs. Lysis buffer and proteinase K ) were added to each sample, followed by an overnight incubation at 56 °C in a thermomixer . Subsequently, DNA extraction was performed manually with the QIAamp DNA Mini Kit (Qiagen) as recommended by the manufacturer. The quality and quantity of the extracted DNA samples were analysed spectrophotometrically using a NanoDrop ND-1000 (PeqLab Biotechnologie GmbH). Samples with a concentration of > 80 ng/µl DNA were diluted with water  to obtain a DNA concentration of 40–80 ng/µl for each sample.Spleen samples with a size of 1 × 0.5 × 0.2–0.4 cm were homogenized together with 0.6 g sterile ceramic beads  and 500 µl phosphate-buffered saline . Homogenization of the tissues was carried out using a Precellys 24 Tissue Homogenizer (PeqLab Biotechnologie GmbH) at 5500 × Bartonella spp. via conventional polymerase chain reaction (PCR) targeting the gltA gene [® Safe DNA Dye  and analysed under UV light using a Gel Doc 2000 transilluminator .DNA samples were tested for the presence of ltA gene . PositivltA gene , 37. SubBartonella species identification. Based on an overview of species determination of randomly chosen Bartonella-positive samples, a selection algorithm was defined. Nineteen pairs of two females (the lightest and the heaviest) and two males (the lightest and the heaviest) were chosen in order to create an overview of sex as well as weight and accordingly age status. Additionally, Bartonella sequence analysis was performed for all positive muskrats (Ondatra zibethicus) and water voles (Arvicolaamphibius).A selected number of amplicons of the expected size were further processed for ® Gel and PCR clean-up kit  according to the manufacturer’s instructions, analysed for quality and quantity as mentioned above and commercially sequenced with forward (Ba325s: 5′-CTT CAG ATG ATG ATC CCA AGC CTT CTG GCG-3′) and reverse primers (Ba1100as: 5′-GAA CCG ACG ACC CCC TGC TTG CAA AGC-3′) . The obtained sequences were aligned and analyzed with BioNumerics  and compared with sequences in GenBank using BLASTn (https://blast.ncbi.nlm.nih.gov/Blast.cgi). A selection of representative sequences (n = 94) were deposited in the GenBank database under the following accession numbers: MN244575-MN244667.Selected amplicons were purified manually with the NucleoSpincytochrome b gene PCR protocols followed the protocols by Parson et al. [Molecular species identification was completed for rat samples which could not be identified morphologically. The conventional n et al.  and Schln et al. . Moleculn et al. , 41. Vis2) [2); “town” (with 300–1500 inhabitants/km2); and “rural” (with < 300 inhabitants/km2) [Geocoordinates (World Geodetic System 1984) were taken during the capture of almost all rats. Hence, geographical information system (GIS) analyses tools were used to analyse the origin of rats . Census data of human population density (resolution 1 km2)  were addnts/km2) , 44.α = 0.05 for the prevalence of Bartonella spp., sex and species analysis were determined by the Clopper and Pearson method using GraphPad Software . Chi-square test (sample size > 30) was conducted for testing the independence of Bartonella prevalence rates concerning sex, season, location and degree of urbanisation. P-values (probability) < 0.05 were considered to be significant and the degrees of freedom (df) were specified by default. Three aspects were analysed in more detail. Individual infection risk as a function of age was assessed using a generalized additive model  with a weight smoother function. Additionally, a generalized linear model  with a binomial error distribution was used to evaluate if provinces differed within each class of urbanisation (“urban” was excluded due to the low sample size in each province). Estimated marginal means were calculated using the emmeans package and back-transformed for logit-scale to visualize infection probabilities. Analyses were performed using R software [B. tribocorum genotypes were investigated using a Chi-square test on proportions, where the number of positive samples per state for each genotype would be significantly different to equipartition.Confidence intervals (95% CI) with a standard error software . In addiRattus norvegicus f. domestica)  and one muskrat .The vast majority of the 1123 trapped rodents were Norway rats . By-catches represented two water voles , one color rat  were Bartonella DNA-positive  rodents were tested using the Bartonella prevalence between males and females revealed no statistically significant difference .As illustrated in Table Bartonella spp. between individuals from rural areas, towns and urban areas  and no significant difference was found between seasons regarding Bartonella prevalence rates .There was also no significant difference in the prevalence of Bartonella in juvenile rats with a weight < 200 g was significantly lower than in adult rats . This is mirrored in the results of gam . Analysis of differences between provinces for different degrees of urbanisation revealed that this difference was only detected within rural areas. Here, infection probabilities in Antwerp were significantly lower compared to Flemish Brabant, East and West Flanders  resulted in the detection of three Bartonella species  was the predominating species. Eighty-eight rodents positive for B. tribocorum were Norway rats and one additional positive animal was a colour rat  was detected in one muskrat and two Norway rats, while B. doshiae and uncultured Bartonella sp. were each detected in one water vole  , 99% (group II) or 96% (group III) to a sequence (GenBank: HG969192) used as a prototype (Table Bartonella tribocorum genotype I (100% identity to GenBank: HG969192) was normally distributed  in the five areas of Flanders , whereas genotype II  and III  exhibited significant differences, cumulating in East and West Flanders . A lowee: 30.3% ) and othe: 30.3% ; USA: 25e: 30.3% ), South e: 30.3% ) and Asie: 30.3% ).Bartonella tribocorum was the most frequently detected species in this study, with 94.7% of all positive samples sequenced. This result is in line with previous findings (89.6% [B. tribocorum [s (89.6% ) and sugibocorum , at leasBartonella tribocorum is known to be adapted to rats [B. tribocorum is released into the bloodstream again in order to invade new erythrocytes for replication. Thus, B. tribocorum is able to infect about 1% of the erythrocytes in rats, persisting in the host for a long time without seriously harming the host [ to rats , 12 and  to rats . After tthe host , 53.B. tribocorum infections in humans, and no reports of bartonellosis in Belgium. Displaying non-specific symptoms such as fever and apathy, Bartonella-infected humans are probably accidental hosts [B. tribocorum was detected in two of these patients [There are only a few case reports of al hosts , 54. Untpatients .B. grahamii and B. doshiae occurred in a very small number of samples. However, both species have been frequently reported in Europe [Bartonella grahamii was detected in two R. norvegicus and one O. zibethicus in the present study. These results are in line with findings of B. grahamii in voles and mice from Europe [B. grahamii in rats like R. norvegicus is uncommon but not completely unexpected as this pathogen was previously detected in Norway rats from Taiwan [B. grahamii has not yet been identified in rats from Europe. The occurrence of B. grahamii in O. zibethicus was an unexpected finding, as blood parasites have been thus far rarely found in muskrats [Bartonella vectors such as ticks, fleas or lice (Pediculus humanus corporis) [Laelaps multispinosa, Zibethacarus ondatrae and Listrophorus spp. [Bartonella species in a muskrat. As noted above, all Bartonella spp. are rather host-specific, with some Bartonella spp. being more host-specific than others. Host specificity of Bartonella spp. is closely related associated with the ability of  adhering to and invading a host cell [In the present study, n Europe . Bartonem Europe , 10, 11.m Taiwan . Howevermuskrats –60. Furtorporis) . They usrus spp. , 63. Posost cell .Bartonella grahamii possesses a higher number of genes for host-adaptability than human-associated bartonellae. These genes are located in a dynamic region being involved in a phage-derived run-off replication. This results in a high number of amplified genes associated with host-adaptation and a rapid diversification of these genes, enabling rodent-associated Bartonella species like B. grahamii to host shifts [B. grahamii was detected in a muskrat and is adapted to various host species such as Microtus spp., Myodes spp. or Apodemus spp. [B. grahamii is a zoonotic agent causing more specific and severe symptoms such as neuroretinitis [t shifts , 65. Permus spp. . Furtheretinitis , 13.B. doshiae has not been associated with clinical human cases and thus is considered as non-pathogenic to humans [Bartonella doshiae is a common European Bartonella species known to infect different Rattus species [Microtus [Myodes glareolus [B. doshiae in one water vole was not unexpected, although prevalence studies of Bartonella spp. in water voles are lacking.Until now, o humans . Bartone species , voles oMicrotus , 56 and lareolus , 68). HeB. tribocorum (GenBank: HG969192) were detected. Individuals with sequence types II and III cumulated in the western provinces of Flanders  in B. henselae. There are 118 different B. henselae strains, which were classified into 12 to 14 STs [B. henselae and different hosts: most human pathogenic B. henselae isolates (66%) from Europe were identified as ST1, while most feline isolates (27.2%) belong to ST7. Sequence types, however, differed regionally between the UK and Spain  in humans [Three different sequence types I, II and III with 96%, 99%, 100% identity, respectively to the 16S-23S rRNA ITS region reference sequence of o 14 STs . Arvand o 14 STs  confirmen humans .B. henselae seem to depend on the geographical location. Besides, coevolutionary processes have been observed between Bartonella spp. and rodent hosts [The occurrence and host specificity of the sequence types of nt hosts . PossiblBartonella. Kosoy et al. [Bartonella prevalence and sex in a wild cotton rat (Sigmodon hispidus) population from Georgia, USA. In contrast, the age of rats plays an important role for the individual infection status with Bartonella in Norway rats. In the present study, juvenile animals were significantly less frequently Bartonella DNA-positive  showed that juveniles had a significantly higher prevalence of Bartonella than adults [Myodes spp., Apodemus spp., Microtus spp. and Sorex spp.) in central Europe concluded that there is no significant effect of age on individual infection probability in any of the small mammal species [Moreover, we found that the sex of rodents had no influence on the prevalence of y et al.  came to ve Table . In contn adults , 74. Add species . HoweverBartonella DNA-positive could be found in the infectious life-cycle of B. tribocorum. This species can persist in the host until its death without fatally damaging it [A possible explanation as to why older animals are significantly more likely to be aging it , 53.Bartonella prevalence rates according to season were found, although comparable studies demonstrate those for cotton rats from the USA where a very high infection level was reached in autumn (95%) with a lower prevalence in early summer (49%) [In our study, no significant differences in er (49%) . This diBartonella spp. in rural areas compared to East and West Flanders. The reason behind this lower prevalence remains speculative. However, the province of Antwerp, with a gross domestic product of € 80,981 million , is oneBartonella prevalence according to degree of urbanisation was limited . Nevertheless, the results of this study are in line with Obiegala et al. [Bartonella prevalence according to the human population density.The retrospective data analysis of a et al. , who demBartonella spp. (53.5%) in an urban Norway rat population from western Europe .Although other authors have described a high prevalence of e, Paris ), we detYersinia enterocolitica, Y. pseudotuberculosis and Y. pestis, as well as Leptospira interrogans, Rickettsia typhi, Streptobacillus moniliformis and Seoul orthohantavirus [The group size of urban rats was the smallest compared to the town and rural rats but is of particular importance for the transmission of zoonoses . Hence, ntavirus , 76.Bartonella spp. is rarely diagnosed in European countries and bartonellosis became one of Europe’s most neglected diseases. However, the results of the present study and other studies [Bartonella spp. pose a real threat to human health. The high overall prevalence of Bartonella spp. (37.4%) reported here proves that there are human pathogenic Bartonella species in rats from Belgium. Our results suggest that rats of the species R. norvegicus seem to be a major reservoir host for Bartonella spp., especially for B. tribocorum, in Flanders, Belgium.An infection with  studies –24 reinfAdditional file 1: Table S1. PCR results for Bartonella spp. and trapping number with coordinates of trapping sites  per collected rodent, Belgium, 2015–2016.


CRP, a biomarker for inflammation, during early pregnancy in relation to offspring ADHD, we report no significant associations. The lack of any association, when considered with positive findings seen in ASD and schizophrenia, and negative findings in bipolar disorder suggests different pathways linking maternal immune activation and development of various neuropsychiatric disorders.Exposure to infection and inflammation during the fetal period are associated with offspring neuropsychiatric disorders. Few previous studies have examined this association with ADHD with mixed findings. This study aims to examine the association between early gestational maternal C-reactive protein (CRP), prospectively assayed in stored maternal sera and the risk of ADHD in offspring. This study is based on the Finnish Prenatal studies of ADHD (FIPS-ADHD) with a nested case–control design. It includes all singleton-born children in Finland between January 1, 1998 and December 31, 1999 and diagnosed with ADHD. A total of 1079 cases and equal number of controls were matched on date of birth, sex and place of birth. Maternal CRP levels were assessed using a latex immunoassay from archived maternal serum specimens, collected during the first and early second trimester of pregnancy. Elevated maternal CRP when analyzed as a continuous variable was not associated with offspring ADHD . No significant associations were seen in the highest quintile of CRP . The results were similar in both sexes as well as among ADHD cases with or without comorbid ASD or conduct disorder. In this first study examining  Attention deficit hyperactivity disorder (ADHD) is defined as impairment due to behavioral symptoms of inattention, hyperactivity and impulsivity and has an estimated worldwide prevalence of around 5% . DespiteAn exaggerated central nervous system inflammatory response to a pre-/perinatal insult in the developing fetus has been hypothesized as a potential cause of ADHD . Studiesp < 0.01) by mothers of ADHD cases than controls [p = 0.004) [Exposure to infection and inflammation during the fetal period is associated with offspring schizophrenia , bipolarcontrols . A birthcontrols . An Austcontrols . A Daniscontrols . A recencontrols . A Danis= 0.004) .The clinical studies , 13 withC-reactive protein (CRP), primarily synthesized by hepatocytes, is a well-established and reliable general marker of inflammation from both infectious and noninfectious exposures . The aimThis study is based on the Finnish Prenatal studies of ADHD (FIPS-ADHD) with a nested case–control design. The study includes all singleton-born children in Finland between January 1, 1998 and December 31, 1999 and diagnosed with ADHD, as identified from the Finnish Hospital Discharge Register (FHDR) by December 31st, 2011.All offsprings in the FIPS-ADHD were derived from the Finnish Maternity Cohort (FMC). The FMC consists of around 2 million maternal serum samples collected during the first and early second trimester of pregnancy (5th–95th percentile: months 2–4 of pregnancy) from over 950,000 women covering virtually all pregnancies in Finland. Following informed consent, blood samples were collected at the Finnish maternity clinics to screen for congenital infections . The median gestational age of serum collection in this study was 10 weeks (interquartile range 8–12 weeks). After the screening, approximately 1–3 mL of serum from each pregnancy are stored at − 25 °C in a protected biorepository at Biobank Borealis in Oulu, Finland, and can be used for scientific research . The FMCThe Population Information System established by the Finnish Population Register Center (PRC) is a computerized national register containing basic information about Finnish citizens and foreign permanent residents. The personal data included in the system include: name, PIC, address, citizenship and native language, family relations and date of birth and death (if applicable). The Finnish Medical Birth Register (FMBR) includes comprehensive and standardized data on the perinatal period for all live births, and stillbirths of fetuses with birth weight of at least 500 g or gestational age of at least 22 weeks. Statistics Finland is the public authority established particularly for statistical services in Finland. The FHDR contains computerized data on recorded inpatient diagnoses in Finland since 1967 and since 1998, the FHDR also includes outpatient care in public specialized hospital units. The diagnostic classification in Finland is based on the International Classification of Diseases (ICD); the 10th Revision has been used since 1996  and fromThe Finnish public health care system covers both primary health care and specialized health services with children’s mental health care services provided free of charge. ADHD is typically diagnosed based on the assessment of a specialist in psychiatry or neurology in public outpatient services.n = 1079).ADHD cases included in the study were singletons born in Finland between 1998 and 1999 and registered in the FHDR with the ICD-10 codes of hyperkinetic disorders F90.0, F90.1, F90.8, and F90.9 until 2011. Controls were singletons born in Finland without a diagnosis of ADHD, conduct disorder, or severe or profound intellectual disability in the FHDR and matched to the case on date of birth (± 30 days), sex, and place of birth. The controls were required to be alive and living in Finland at the date of diagnosis of the matched case. Since the FMBR was established in 1987, cases and controls were selected from those born 1998–1999 to ensure greater uniformity of the serum specimens with regard to the time of storage. Out of the 1320 total cases and controls identified, sufficient serum was available in the FMC for 1079 cases and matched controls (The CRP assays were performed 18 years after sampling. The precision between series expressed as the coefficient of variation (mean ± SD) was 5.1% ± 2.3% and the systematic error (bias) (mean ± SD) was 2.7% ± 7.4 during the course of the study. Assay sensitivity is 0.10 mg/L.CRP was measured, blind to case/control status, on the clinical chemistry analyzer Architect c8200  using a latex immunoassay . p ≤ 0.1, in accord with standard texts [Potential confounders that have been shown to be associated with both CRP levels and ADHD were initially selected. They included: maternal age , 27, patrd texts .” The avrd texts .Table 1Rn = 1079 per group), a mean value of log-transformed CRP = 1.087 in controls, a standard deviation of 0.5 and alpha set at 5% for two-sided t tests, we had 80% power to detect a mean difference of 0.060 between log-transformed CRP in cases versus controls. That is to say, we had power to detect a mean value of 1.147 in cases (1.087 + 0.060) corresponding to a 6% higher value than in controls. This indicates that we had power to detect even smaller differences than the positive findings of elevated CRP noted in autism [The analysis of the relationship between maternal CRP and offspring ADHD was based on a nested case–control design in which the controls for each case were selected from the population at risk and matched to cases on selected factors, as described in “Case and control identification”. CRP was initially examined as a continuous measure. Due to its skewed distribution, the variable was log-transformed before analysis. To further facilitate data interpretation, we examined maternal CRP categorized into quintiles. The quintiles for the case and control groups in the analyses were derived from the cut-points of maternal CRP levels that defined the quintiles in the control group with the lowest quintile defined as the reference group. With the number of cases and controls , ADHD with and without conduct disorder (CD) and ADHD without ASD or CD.p < 0.05. All the statistical analyses were performed with SAS software .Appropriate to the nested case–control study design, point, and interval estimates of odds ratios were obtained by fitting conditional logistic regression models for matched pairs. Statistical significance was based on The study included 1079 ADHD case–control pairs with the mean age of diagnosis for cases of 7.3 years . As shown in Table The distribution of CRP levels among cases and controls in the sample is shown in Fig. males 1.04, 95% CI 0.95–1.14; ORfemales 1.21, 95% CI 0.93–1.57). There were 70 ADHD cases with comorbid ASD and 211 cases with comorbid conduct disorder (CD). Further analysis was conducted stratifying the sample into ADHD with ASD , ADHD without ASD , ADHD with CD  and ADHD without CD  and ADHD without ASD/CD .Further analysis conducted separately for 922 males and 157 females yielded no association in both the unadjusted and adjusted analyses , our study findings are in line with two previous nationwide studies that did not report any association overall between maternal IDP and offspring ADHD , 17. It Several studies using animal models have demonstrated prenatal infection and subsequent maternal immune activation affecting fetal brain development and producing changes in both gray matter and white matter, similar to that seen among patients with neuropsychiatric disorders , 41. BirWe also comment on results of a few additional analyses. A stratified analysis of ADHD cases separately for males and females was used to evaluate any role of offspring sex in the association. To assess the possible contribution of comorbid disorders on the association between maternal CRP and offspring ADHD, we stratified the cases into lifetime comorbid ASD and CD. There were no significant associations seen in both sex and comorbidity stratified analyses.ASD is also known to be comorbid with ADHD. The findings of this study argue that our previous finding of an association between maternal CRP and ASD  is likelThe strengths of the study include: (1) availability of CRP levels from prospectively drawn maternal serum samples collected during early to mid-gestation that allows a greater focus on prenatal influences. (2) ADHD cases and controls identified from nationwide registers providing a representative study sample, (3) availability of information on several potential confounders including parental psychopathology that was missing in several earlier studies, (4) this is the largest study to date using a biomarker of prenatal inflammation in relation to offspring ADHD.The study does have a few limitations that need to be considered. First, the ADHD cases included only those that were referred to specialized services, and thus likely represent more severe cases. However, a previous study has reported an 88% validity of the ADHD diagnoses in the FHDR examined against DMS-IV criteria for ADHD. Second, the study examined a single marker of infection/inflammation with ADHD. The availability of several inflammatory markers would have possibly enabled examination of more specific markers of inflammation but that was not possible due to the predefined study protocol. Third, the study had maternal CRP measurement at only one time point in early pregnancy and thus the lack of findings seen may not be applicable to infections and inflammation occurring later during pregnancy. Fourth, despite having a wide array of confounders, the study lacks information on an important confounder, maternal body mass index (BMI). In addition, despite the availability of information on parental ADHD diagnosis, the number of parents with ADHD diagnoses in the sample was low, which is a study limitation. The possible reason for underdiagnoses among parents could be the fact that ADHD was not a widely used diagnosis in the parental generation. Furthermore, the FHDR does not cover outpatient diagnoses before 1998, and thus the diagnosis of ADHD among parents is likely underestimated as most of them are likely to have been treated in outpatient care. Lastly, although biodegradation is a theoretical possibility, this is very unlikely. Over the years, CRP analyses have been run from thousands of samples stored in the Finnish Maternity Cohort (FMC) with varying time differences between sampling and laboratory analysis. Our analysis of CRP levels between samples analyzed 10 years after sampling and those analyzed between 15 and 30 years after sampling showed no variation in the CRP levels (unpublished data). In addition, since the sampling from cases and controls was drawn during the same time period and thus stored for equal lengths of time, the case–control design effectively eliminates out any potential effects of storage.This study examined for the first time the association between maternal CRP and offspring ADHD. The lack of any association, in contrast to significant associations of maternal CRP with ASD and schizophrenia suggests different pathways linking maternal immune activation and development of various neuropsychiatric disorders.


No direct effect was found between the ASRS positive screening with the risk of dropout  and worse treatment outcome . These results suggest the relevance of identifying specific treatment approaches for patients with ADHD symptoms and severe eating symptomatology. Attention-deficit/hyperactivity disorder (ADHD) and its symptoms have been shown to be present in patients with eating disorders (EDs) and are associated with increased psychopathology and more dysfunctional personality traits. This study aimed to assess if the presence of ADHD symptoms in patients with EDs affects their short and long-term therapy outcome. A total of 136 consecutively treated ED patients were considered in this study. Baseline pre-treatment evaluation included the Adult ADHD Self-Report Scale (ASRS v1.1) for ADHD symptoms and the assessment of eating symptomatology using the Eating Disorders Inventory (EDI-2). Treatment outcome was evaluated in terms of ED symptoms after cognitive behavioral therapy (CBT) and dropout rate during treatment. Furthermore, we evaluated ED symptoms in treatment completers after a follow-up of 8 years on average. Path analyses assessed the potential mediational role of the EDI-2 total score in the relationship between ADHD and treatment outcome. Results showed that baseline symptoms of ADHD indirectly affected treatment outcome after CBT; the ASRS positive screening was related to higher eating symptomatology (standardized coefficient B = 0.41,  Attention-deficit/hyperactivity disorder (ADHD), which is characterized by symptoms of impulsivity, hyperactivity and inattention, has been described in relation to several psychiatric disorders including eating disorders (EDs) ,2,3,4. AFrom a neurobiological perspective, a recent study examined the genetic factors common to both disorders and observed a stronger genetic association between ADHD and binge-eating behaviors . From a Despite the evidence linking ADHD and EDs, there is a lack of studies investigating whether ADHD symptoms may impact treatment response in patients with EDs, both in terms of treatment adherence  and outcome. To the best of our knowledge, there is only one previous study in female patients with EDs reporting higher ADHD symptoms at baseline as a predictor of non-recovery from eating-related symptomatology one year after treatment, especially for patients with loss of control overeating, bingeing and purging . HoweverThe first aim of the present study was to evaluate if the initial presence of ADHD symptomatology impacts the therapy outcome after a cognitive behavioral therapy (CBT) treatment for EDs and dropout rate during treatment. The second aim was to analyze whether the baseline ADHD symptomatology had an impact on long-term therapy outcome (after eight years on average). Furthermore, we assessed the influence of EDs severity over the relationship between ADHD symptoms and treatment results. n = 191); however, neither online nor paper clinical records were available for 22 out of 158 patients who started treatment. Thus, a final sample of 136 patients was included in the principal analysis. There were no baseline differences between patients who were included in this study and those who were not. Sixty-four participants included in the final sample did not complete treatment sessions (dropout) whereas 72 patients out of 136 completed the treatment   from 16 April 2009 to 31 January 2011. The baseline data of the initial sample was previously reported by Fernández-Aranda et al. (2013). Patients were diagnosed according to the DSM-IV-TR criteria , and diaAdult ADHD Self-Report Scale (ASRS-v1.1) : The ASREating Disorders Inventory-2 (EDI-2) : This se2), they were offered an in-patient treatment with a maximum duration of three months. Patients with AN also had a two-year follow-up period with individual/group sessions. The goals of the treatment were to train patients to implement CBT strategies to reduce eating symptoms and to enable patients to acquire good healthy habits. As described elsewhere ,34, all Patients were re-evaluated at discharge and categorized into the following three categories: full remission, partial remission and non-remission. According to DSM-5 criteria , the defA longitudinal follow-up of the patients was collected during an average period of 8.8 years (SD = 1.5), from the end of the first contact made in our unit to April 2020. This first contact coincided with the assessment using the ASRS screening questionnaire. By searching through centralized Catalonian clinical records and an online shared medical network, we assessed clinical evolution of all ED patients over the time, in terms of symptomatological remission (categorized as positive follow-up) or clinical non-remission of eating symptomatology (categorized as negative follow-up). From the total sample, clinical records were available for 123 patients, while 13 patients were missing (10.5% attrition rate). The present study was carried out in accordance with the latest version of the Declaration of Helsinki. The Bellvitge University Hospital Clinical Research Ethics Committee approved the study and signed informed consent was previously obtained from all participants.χ2).Stata16 for Windows was used to carry out statistical analyses . A compaSurvival function (Kaplan–Meier product-limit estimator) modeled the rate of dropout during the therapy. This procedure is usually used to describe the probability of the patients “living/surviving” for a certain amount of time after one concrete intervention . In thisp > 0.05) in the χ2 test, root mean square error of approximation (RMSEA) < 0.08, Bentler’s comparative fit index (CFI) > 0.90, Tucker–Lewis Index (TLI) > 0.90 and standardized root mean square residual (SRMR) < 0.10. In this study, the relatively low sample size and the high correlations between the EDI-2 scores did not allow the SEM to be included in all the EDI-2 subscales registered for the participants (goodness-of-fit was not achieved). Path analyses assessed the potential mediational role of the ED severity level  in the relationship between ADHD and treatment outcome . This procedure was defined in this work as a case of structural equation modeling (SEM), with the maximum-likelihood estimation method of parameter estimation, adjusting by the covariates participants’ age and the duration of the ED. The goodness-of-fit was evaluated using a standard statistical test, and it was considered adequate fitting for : non-sigχ2 = 0.07, p = 0.982), education level , socioeconomic status , age , duration of the eating problems , onset of the ED , ED-symptom levels  and ADHD-symptom levels .No statistical differences between participants selected for the study and those excluded were found for marital status . Regarding CBT outcomes, the dropout rate in the total sample was 47.0%, non-remission was registered for 11.8%, partial remission for 18.4% and full remission for 22.8%. Within the completers subsample (n = 72), non-remission was registered for 22.2% of the participants, partial remission for 34.7% and full remission for 43.1%.The ADHD level was not directly related to the short-term therapy outcomes in the study; the prevalence of the ASRS positive screening score was statistically equal for completers and dropouts, as well as for participants with partial remission and full remission versus those with dropout and non-remission . No assop = 0.995).χ2 = 0.807 (p = 0.848), RMSEA = 0.001, CFI = 0.999, TLI = 0.998, SRMR = 0.015; better CBT outcome: χ2 = 0.029 (p = 0.864), RMSEA = 0.001, CFI = 0.999, TLI = 0.998, SRMR = 0.004). These results confirmed the indirect effect of ADHD on the therapy outcome; being in the ASRS positive screening group is related to higher ED severity , and this worse ED level contributed to the increase in the risk of dropout and a worse treatment outcome.χ2 = 0.519 (p = 0.771), RMSEA = 0.001, CFI = 0.999, TLI = 0.998, SRMR = 0.016). This new model indicates that the ADHD screening score was not related (through a direct or indirect link) to the clinical condition measured in the follow-up.This study investigated whether the presence of ADHD symptoms in patients with EDs may impact treatment outcome and dropout for EDs. The second aim was to examine the influence of EDs severity on the relationship between ADHD symptoms and treatment outcome/dropout rate. Finally, a long-term follow-up was included to assess the effect of ADHD symptoms at baseline on the clinical evolution of EDs.ADHD screening at baseline did not directly predict treatment outcome or dropout rate in patients attending a CBT for EDs. However, our results highlighted that the severity of eating symptomatology mediates the relation between ADHD and treatment outcome/dropout rate. Specifically, positive screening for ADHD symptoms was directly associated with the severity of EDI-2, which in turn is related to a higher dropout rate and a worse treatment outcome, in terms of dropout during treatment and non-remission of ED symptomatology.The only previous study investigating the effect of ADHD over treatment for ED suggested that patients with higher ADHD symptoms presented a higher risk of poor post-treatment outcome, although the impact of ED severity on this relation was not assessed . InteresIn spite of the higher proportion of dropouts registered within the first two weeks of treatment, the ASRS score does not differ between early or later dropout, suggesting that ADHD symptoms may increase the dropout rate at different stages of treatment. Furthermore, we included a longer follow-up of the majority of the patients, showing that positive screening for ADHD symptoms at baseline did not affect the longer terms evolution of EDs. This is the first retrospective study which allows the evaluation of the impact of ADHD symptoms on EDs with a longitudinal follow-up of roughly 8 years. This study must be interpreted in light of its limitations. First, a self-reporting instrument was used to measure the frequency of adult ADHD symptoms, which may lead to an overestimation of this symptomatology. Therefore, future studies should focus on EDs patients with comorbidity with ADHD, not only taking into account ADHD symptomatology. Furthermore, comorbidity with others psychiatric disorders often associated with EDs  should be addressed by future studies in larger samples. Second, only female EDs patients were included in this study, so further studies would benefit from including male population as men report a higher prevalence of ADHD in adult life . Third, In conclusion, the present findings suggest a higher risk for dropout of treatment  and worse treatment outcomes in patients with more severe ED-symptoms, and an indirect effect of ADHD symptomatology on the treatment outcomes mediated by the ED severity levels. This was the first study to examine the effect of ADHD over the risk of dropout in patients treated for EDs, suggesting the relevance of identifying specific treatment approaches for patients with greater degrees of ADHD symptoms and severe EDs.


To validate the Adult ADHD Self‐Report Scale (ASRS) and the Wender Utah Rating Scale (WURS) in a well‐characterized sample of adult attention‐deficit/hyperactivity disorder (ADHD) patients and population controls.n = 646) and to population controls (n = 908). We performed principal component analyses (PCA) and calculated receiver operating curves (ROC) including area under the curve (AUC) for the full WURS and ASRS, as well as for the PCA generated factors and the ASRS short screener.Both the ASRS and the WURS were administered to clinically diagnosed adult ADHD patients (We found an AUC of 0.956 (95% CI: 0.946–0.965) for the WURS, and 0.904 (95% CI: 0.888–0.921) for the ASRS. The ASRS short screener had an AUC of 0.903 (95%CI: 0.886–0.920). Combining the two full scales gave an AUC of 0.964 (95% CI: 0.955–0.973). We replicated the two‐factor structure of the ASRS and found a three‐factor model for the WURS.The WURS and the ASRS both have high diagnostic accuracy. The short ASRS screener performed equally well as the full ASRS, whereas the WURS had the best discriminatory properties. The increased diagnostic accuracy may be due to the wider symptom range of the WURS and/or the retrospective childhood frame of symptoms. n = 646) and population controls (n = 908). The short ASRS screener performed equally well as the full ASRS, whereas the WURS had the best discriminatory properties.To validate the adult ADHD Self‐Report Scale (ASRS) and the Wender Utah Rating Scale (WURS) in a well‐validated sample of adult attention‐deficit/hyperactivity disorder (ADHD) patients and population controls. Both the ASRS and the WURS was administered to clinically diagnosed adult ADHD patients ( The Norwegian Wender Utah Rating Scale (WURS) and Adult ADHD Self‐Report Scale (ASRS) were validated, both demonstrating excellent screening properties.Retrospective childhood symptoms of aggressiveness and social problems are highly predictive of an adult diagnosis of attention‐deficit hyperactivity disorder.Our results support that emotional regulation problems constitute a large part of ADHD symptomatology in childhood.The use of retrospective self‐report measures might be affected by memory biases and lack of recall.The use of self‐report measures for present ADHD symptoms may be biased by the current health and life situation of the informant.This study was based on a sample diagnosed with ADHD as adults, thus it is uncertain whether the patients included would have obtained a childhood diagnosis of ADHD.1Adult attention‐deficit hyperactivity disorder (ADHD) is a persistent neurodevelopmental disorder with childhood onset, characterized by inattention, hyperactivity, and impulsivity  is the official screening instrument of the World Health Organization . When this protocol was terminated in 2005, the same diagnostic protocol was continued, but without the mandatory extra approval. Experienced clinical psychologists and psychiatrists made the diagnostic assessment in routine practice in outpatient clinics, according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems  is a brief screening instrument to identify current ADHD symptoms  with Varimax rotation was run to establish how the items of the WURS and the ASRS contributed to given components, selecting components with Eigenvalues above one  and negative tests (LH−) and Diagnostic Odds Ratio (DOR) were calculated using formulas from Fischer, Bachmann  years in the ADHD group and 29.4 (SD 7.8) years in the control group (p < .01). There were 48.5% females in the ADHD group and 59.9% females in the control group (p < .01). The total WURS and ASRS scores were strongly correlated . Figure n = 420) or off (n = 125) pharmacological treatment for ADHD, as well as if they had been treated for ADHD as a child (n = 89) or not (n = 530). Adults with ADHD on current pharmacological treatment reported a significantly lower ASRS score than the off treatment group, but there was no difference between these groups on the WURS. Adult patients who had been treated for ADHD as a child scored significantly higher on both the ASRS and the WURS compared to those patients who reported no childhood treatment. Mean scores on the ASRS and WURS for the ADHD group and the control group, as well as for the different subgroups within the ADHD group, are shown in Table The present study included 3.1Aggressiveness and social problems, Learning and attention problems and Dysthymia, respectively. Only the item “Unpopular with other children […]” had ambiguous loading with factor loadings below 0.50 on all factors. Internal consistency measured by Cronbach's alpha was 0.967 for the full WURS, and 0.954 for Aggressiveness and social Problems, 0.919 for Learning and attention problems and 0.897 for Dysthymia, respectively.The Principal Component analysis generated a three‐factor solution for the WURS items in the full sample Table  explainiA two‐factor solution was generated for the ASRS in the full sample Table , explainInternal consistency measured by Cronbach's alpha was 0.952 for the full ASRS score, 0.924 for the Inattentive factor and 0.918 for the Hyperactivity/Impulsivity factor.3.2Learning and attention problems had the highest AUC of 0.95 (95% CI 0.94–0.96), followed by Aggressiveness and social problems with 0.93 (95% CI 0.92–0.94).Figure 4Both the WURS and the ASRS had excellent screening and psychometric properties, with somewhat stronger properties for the WURS. The recommended short screener ASRS performed as well as the full ASRS. A Principal Component analysis confirmed a three‐factor structure of the WURS described in previous studies . Finding that the WURS outperformed the ASRS adds to the ongoing controversy of the defining features of adult ADHD. The factor analysis of the WURS showed that the main factor of the WURS was the Aggressiveness and social problems, indicating that these symptoms play an important role in ADHD. Adler et al. . We found that adult ADHD patients on current pharmacological (mainly stimulant) treatment reported less current symptoms of ADHD on the ASRS compared to those who were not on medication, but there were no statistical differences on the WURS. Furthermore, patients treated for ADHD in childhood reported more symptoms than those who had not been treated in childhood on both the WURS and the ASRS, indicating a more severe and persistent phenotype (Halmoy et al., 4.1The present findings should be viewed in light of some limitations. There are problems related to the use of self‐report measures because measures that employ a retrospective approach might be affected by memory biases and lack of recall. McGough and Barkley  argued tThis study was based on an adult ADHD sample ascertained in adulthood, meaning that it is uncertain whether the patients included would have obtained a childhood diagnosis of ADHD, with the expected symptomatic trajectory. This is potentially an important caveat, as some recent studies have put into question ADHD as a neurodevelopmental disorder, highlighting both discontinuation of childhood symptoms as well as a possible adult onset ADHD phenotype (Agnew‐Blais et al., We used a clinically validated patient sample and a representative population control sample, which strengthens the clinical utility of our findings. Our control sample was randomly recruited from the Norwegian Medical Birth Registry, without any formal exclusion criteria, so there is a potential for some undiagnosed cases of ADHD in the control group. However, screening instruments are generally more useful in at risk populations rather than in the general population, where the performance of the screening tools could be overstated.5The Norwegian translation of both the ASRS and the WURS had excellent psychometric properties and can be used independently for screening and diagnostic assessment for ADHD. We found that the WURS had even better screening properties than the ASRS, in spite of our sample being clinically assessed and diagnosed in adulthood. The wider WURS dimensions of aggression, learning problems and emotional lability were highly relevant to identify adult ADHD in our sample, supporting a broader conceptualization of ADHD. With their different temporal focus and clinically relevant symptom domains, we recommend using the ASRS and the WURS jointly to assess for adult ADHD.JH has received lecture honoraria as part of continuing medical education programs sponsored by Novartis, Eli Lilly and Company, and Janssen‐Cilag. The other authors report no potential conflicts of interest.All authors were involved in the conception and design of the study. JH supervised the data collection for the study. All authors were involved in the data analysis and interpretation, drafting the article and critical revision of the article. All authors approved of the final version to be published.