Using data compiled by the SALURBAL project  we quantified variability in low birth weight (LBW) across cities in Latin America, and evaluated the associations of socio-economic characteristics at various levels  with the prevalence of LBW.The sample included 8 countries, 360 cities, 1321 administrative areas within cities (sub-city units) and birth registers of more than 4.5 million births for the year 2014. We linked maternal education from birth registers to data on socioeconomic characteristics of sub-cities and cities using the closest available national population census in each country. We applied linear and Poisson random-intercept multilevel models for aggregated data.The median prevalence of city LBW by country ranged from a high of 13% in Guatemala to a low of 5% in Peru . Most of the LBW variability across sub-cities was between countries, but there were also significant proportions between cities within a country, and within cities. Low maternal education was associated with higher prevalence of LBW  for less than primary vs. completed secondary or more 1.12 95% CI 1.10, 1.13) in the fully adjusted model. In contrast, higher sub-city education and a better city social environment index were independently associated with higher LBW prevalence after adjustment for maternal education and age, city population size and city gross domestic product . Larger city size was associated with a higher prevalence of LBW .Our findings highlight the presence of heterogeneity in the distribution of LBW and the importance of maternal education, local and broader social environments in shaping LBW in urban settings of Latin America. Implementing context-sensitive interventions guided to improve women’s education is recommended to tackle LBW in the region.The online version contains supplementary material available at 10.1186/s12889-021-10886-7. Low birth weight (LBW) newborns (< 2500 g at birth) have higher risks of adverse health outcomes during childhood and adult life , 2, inclLBW has been linked to maternal, demographic, biologic and behavioral characteristics , 9 as weSeveral mechanisms linking social factors to LBW have been proposed. One example focused on explaining high levels of LBW among African American women in the US is the “weathering hypothesis” that posits that high levels of social stressors resulting from long-term social disadvantage and racism lead to adverse pregnancy outcomes , 19. OthA separate body of work has examined urban-rural differences in LBW. In the U.S., both population-dense urban areas and more isolated rural regions had higher LBW compared to other regions , 26. In Latin America is one of the most urbanized and unequal regions in the world, with great heterogeneity in population socio-economic conditions, health infrastructure, and health outcomes , 33. Undmunicipios, comunas, partidos, delegaciones, cantones, or corregimientos) that are covered, at least in part, by the urban extent of the city. Sub-cities were defined as administrative units nested within cities. In some cases, the city included a single sub-city unit, and in other cases, the city included multiple sub-city units [Data was compiled by the SALURBAL project, an interdisciplinary, multinational and collaborative initiative focused on characterizing the drivers of urban health and urban health inequalities across cities of the region . Cities ty units .n = 158,491) had higher LBW prevalence than those included (8.5% vs 7.8%), were more likely to have maternal education in the intermediate category, and to be births to mothers aged 19 years and younger, but differences between excluded and included births were small , 2011 (Costa Rica), 2010 , 2005 (Colombia), and 2002 . We used a Social environment index (SEI) at the city level  as a proSpearman’s rs = 0.15; p <  0.001) and both were standardized.Additionally, we used a score of population educational attainment at the sub-city level  to captuAnalyses were adjusted for city population size and gross domestic product (GDP) at the city level as both could confound the association of SEI with LBW. City size may be related to health care access  and chanWe first described the proportion of LBW across cities by countries. Then, we calculated the variability in the sub-city prevalence of LBW (hypothesis 1) by using a three-level linear mixed model with percent LBW at the sub-city level as the outcome, and random intercepts for cities and countries. The random part allowed us to evaluate the variation in sub-city LBW within cities, between cities within countries, and between countries. We report the percentage of the variance at each level dividing each variance component by the total variance.Lijk is the number of LBW for cell i in sub-city j in city k; Nijk is the overall number of live births in each cell; γ100 is the coefficient associated with maternal education; γ200 is the coefficient associated with maternal age; γ010 is the coefficient associated with sub-city population educational attainment; γ001 is the coefficient associated with city SEI; γ002 is the coefficient associated with cities GDP; γ003 is the coefficient associated with city population size of cities; Cc corresponds to the fixed effect of countries; ϑjk and ϑk are random effects for sub-cities and cities, respectively.We also examined the distribution of individual and contextual characteristics for births with and without LBW. To test hypotheses 2 and 3 we fitted three-level mixed-effects Poisson models with cross-classified cells of maternal age and education nested within sub-cities, sub-cities nested within cities and country fixed effects. Final models were fitted as follows:To test our hypotheses regarding associations of maternal education, sub-city SES and city social environment with LBW we fitted five models of increasing complexity. First, we estimated an empty model with no explanatory variables and random intercepts for sub-cities and cities. Model 1 added maternal age and education. Model 2 added sub-city population educational attainment (model 2). We then added city SEI as well a potential city-level confounders of city GDP and population size (model 3). Finally, model 4 added country fixed effects. We calculated the change in variance across models by using the proportional change in variance (PCV). PCV expresses the change in the proportion of the sub-city and city variance in a given model explained by adding specific variables in the subsequent model , 45. AllOf the 360 cities in the sample, 42.2% were in Brazil, 25.6% in Mexico, 9.7% in Colombia, 9.2% in Argentina, 6.4% in Peru, 5.8% in Chile, 0.8% in Guatemala and 0.3% in Costa Rica  observed in model 3.We examined variability of LBW prevalence across countries, cities and sub-cities and the associations of LBW with maternal, sub-city and city socioeconomic characteristics in 360 cities from 8 countries in Latin America. We found considerable heterogeneity in the distribution of LBW across cities and sub-cities. We also found that low maternal education was associated with higher prevalence of LBW. In contrast, higher sub-city education and better city social environment were independently associated with higher LBW prevalence after adjustment for maternal characteristics, city size and city GDP.Other work has explored LBW variability at sub-national levels in the U.S. –49, IrelWe found a higher prevalence of LBW among mothers in the lowest category of educational attainment (less than primary school). This is consistent with our hypothesis, with prior work in high-income countries , 53 and In contrast to our hypothesis, higher sub-city education was associated with higher prevalence of LBW. Although the association was not very strong, it is still notable for its consistency across models. A large body of work mostly from higher income countries has shown that higher neighborhood SES is associated with lower prevalence of LBW , 58, 59.Several factors could explain the slightly higher prevalence of LBW that we observed in cities with higher SEI and in sub-city areas with higher education. These include factors occurring to a higher extent in wealthier areas such as late pregnancies   did not substantially change associations of other SES features with LBW. In addition, variability in LBW across cities persisted even after maternal education and age as well as sub-city and city social environment factors were taken into account, suggesting that other city factors may be important to LBW. Additional research is needed in LMICs on how features of urban environments vary across cities and also across communities or neighborhoods.An important limitation of our analyses is that we combined all birthweights under 2500 g which includes a diverse population of live births, from pre-term newborns with adequate birthweight for their gestational age to term newborns that are small for their gestational age (intrauterine growth retardation). Data on gestational age was not available for all countries, and consequently, we were unable to differentiate between these two groups, which have different etiologies and could be differentially related to the factors we studied. The separation of pre-term from small for gestational age births would allow better exploration of the mechanisms that might be involved in generating the patterns that we describe. However, LBW remains a meaningful health outcome in its own right and is often an important metric tracked in perinatal health. An additional limitation is that social environment characteristics retrieved from censuses were at different years and not always consistently aligned with the years for which birth outcomes were obtained. We therefore assumed that social environment measures were relatively stable across the years examined. The use of sub-city units, although capturing some heterogeneity within cities, does not capture neighborhood factors that may also be important in LBW. In addition, there are other important proximal determinants of LBW at both individual or aggregated levels that we were not able to account for due to lack of data. These include important risk factors for LBW such as inadequate or insufficient antenatal care , 64 and In spite of the efforts to reach universal registration, undercounting of births is still an issue in the region (nearly 6% of children under 5 years old have not had their births registered in Latin America and the Caribbean) . AlthougMajor strengths of our study include the large and unique dataset of millions of live births across 8 countries, 360 cities, and the linkage to harmonized maternal, sub-city and city level factors. The multilevel structure allowed us to assess LBW variability across a great number of sub-city units (1321) and city units in different countries, and to simultaneously examine maternal, sub-city and city characteristics. Overall, our study provides a singular perspective on the drivers of LBW within urban social environments in Latin America.In summary, we found that better social environments at both city and sub-city levels, as well as low maternal education were associated with higher prevalence of LBW newborns, independent of maternal age and other features of the social environment of cities like population size and GDP. Furthermore, we found substantial variations in LBW across countries and to a lesser extent across cities within countries and across sub-cities within cities. Our findings add evidence on the relevance of socioeconomic characteristics at both the individual and contextual levels for LBW, based on a large number of Latin American cities.The increasing inequities in health within urban contexts together with the persistent rates of LBW worldwide, highlight the need for public health strategies to prevent LBW in the growing cities of lower- and middle-income countries. Urban health studies exploring the impact of urban environments on health in the global south have recently received increasing attention , 69. OurAdditional file 1: Figure S1. Flow chart describing the sample selection involving eight Latin American countries  for year 2014. Table S1. Study characteristics by country. Table S2. Characteristics of included and excluded cases. Table S3. Variance components for sub-city prevalence of low birth weight in eight Latin American countries  for year 2014.


The World Health Organization working group focused on nutrition as a key component of disease prevention, indicating that “o years” . In theio years” , was devo years” .However, a greater controversy exists in the scientific community regarding the role of nutrition on the onset and progression of mental diseases and behavioral problems, and it is unclear how diet may contribute to therapeutic efficiency regarding patients with diverse psychopathological states. Unfortunately, strategies based on making diet changes and sticking with them are often overlooked in treatments for mental health conditions.In the following sections, we review current studies that analyze the role of specific diet components in the interventions addressed for common mental disorders in developed countries among children and adolescents. Since the psychopathologies considered in this review have elevated risk of comorbid health hazards, the evidence-based interventions for psychiatric patients covering proper nutrition could promote large-scale physical and mental wellbeing. Furthermore, the results of these intervention programs could provide the basis for developing targeted disease prevention programs aimed to reduce modifiable risk factors.Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder whose etiology is the result of complex interactions between multiple factors, including genetic, biological and environmental influences. The disorder is usually diagnosed when a child is of school age, with a worldwide prevalence estimate of 6% during childhood , and perThe standard intervention for ADHD combines pharmacological treatment (largely psychostimulants) with psychological therapy. The beneficial short-term efficacy of such treatments in reducing acute core symptoms is largely verified, but the long-term effects are not clearly evidenced: most patients may still show ADHD symptoms and may not attain normalized behavior even with combined medication and behavioral therapy, which results in frequent medication nonadherence (around 50% within months 12 to 36 of the follow-up). Current studies on alternative interventions for ADHD aim at the prevention of ADHD progression and targeting the underlying triggers . On the basis that making adequate lifestyle changes to minimize these triggers could contribute to better control of ADHD symptoms, studies addressing the efficacy of nutrition on the developmental course of ADHD have observed that deficiencies in certain types of foods can worsen the symptoms of attention deficit, hyperactivity and impulsivity, while adequate dietary plans could optimize brain functions. Most of these treatment studies are focused on exploring the role of vitamins, minerals and polyunsaturated fatty acids , with coResults obtained by a current systematic review reinforce the effectiveness of ADHD treatments with complementary diet interventions, although the benefits could be different for subgroups of patients with different profiles. Concretely, the study of Granero and colleagues  focused The systematic review of Händel et al. was centered around assessing the contribution of using polyunsaturated fatty acids  in the treatment plans of ADHD children and adolescents, obtained from randomized clinical trials . Based oAn open trial conducted by Yorgidis and colleagues explored the role of oligoantigenic diet (OD) as a therapeutic tool within ADHD children  and obseOn the other hand, some studies have also assessed the role of caffeine exposure within the ADHD profile and as a therapeutic tool. Since it was observed that both chronic and acute exposure to caffeine impacts the central nervous system modulating neuronal pathways, the possible existence of a link between the modulation of these neurotransmitters and the development/attenuation of neuropsychiatric outcomes is supposed. Animal research has observed that non-toxic doses of caffeine elicit neuro-pharmacological actions by blocking adenosine A receptors in the brain, which leads to the blockade of adenosine kinase and a decrease in the release of adenosine . Since aStudies have identified a strong link between persistent stress and several adverse effects on the body’s immune, neuroendocrine, cardiovascular and central nervous systems . UntreatMedical intervention (benzodiazepines and antidepressants) plus cognitive behavioral therapy is considered the gold standard intervention for depression and anxiety states. However, in some cases, these treatments are not effective, induce severe side effects (mostly medications) or are not recommended due to the patients’ characteristics . This scenario guided the search for new interventions for assisting in the prevention and management of anxiety-depressive illnesses, with less risk of side effects. Since the prerequisite to developing adequate evidence-based clinical guidelines is to assimilate dietary patterns and identify the biological mechanisms of action of critical nutrients , studiesDietary changes and nutritional supplementation may also be beneficial in improving treatment response and quality of life among patients with depression and anxiety. The comprehensive scoping review conducted by Aucoin and colleagues , with a The meta-analysis of Berthelot and colleagues selecting randomized controlled trials concluded that fasting interventions, compared to control groups, achieved lower anxiety and depression levels, and it was also useful to decrease body mass index levels . The benThis set of results are consistent with established evidence regarding healthy eating patterns and improvements in anxiety and depression states and the benefit of complementing the classic treatments with dietary interventions according to the specific needs of each patient. The low cost and the high effectiveness of these complementary plans may also confer additional benefits to physical aspects of health . It is known that some mental health conditions, such as those included within the autism spectrum, could severely impact the appetite and food choices . Autism A current empirical study aimed to explore the dietary patterns and nutrient intakes of ASD children compared to a healthy control group  observedHowever, most interventions used to treat dysfunctional eating behaviors within the ASD spectrum  are aimed to increase the volume of food consumed, and few consider increasing the variety of foods and addressing protein–energy–micronutrient deficiencies ,37. OtheProblems related to nutrition are often overlooked in patients with common mental health disorders  towards interventions focused on medication complemented by behavior/psychotherapy treatments. Current research within the nutritional psychiatry area provides evidence regarding the role of nutrition and diet on these psychiatric conditions and offers a basis for developing new evidence-based intervention plans from a multidisciplinary perspective. Given the multifaceted and complex nature of mental and neurodevelopmental problems, the onset at early ages of the child (particularly for ADHD and ASD) and its persistent presentation across development stages (from early childhood to older age), the findings of these works could also contribute to the elaboration of guidelines/recommendations for improving the caring capacity of healthcare practitioners and family caregivers. In the end, improving the nutritional status of the patient will contribute to the individuals’ wellbeing and facilitate better progression of medical conditions. However, the design of effective dietary plans is based on the existence of reliable and valid assessment tools. Unfortunately, the current evidence does not propose nutritional assessment instruments specifically developed for individuals with different mental disorders . Nutritional psychiatric research warrants additional attention and effort, combining varied methodologies and analyzing larger groups . Therefore, based on the existing research, dietary markers , biochemical indexes  and anthropometric evaluation  should be key components of these measurement tools.As a final thought, the study of how nutrition and mental health are linked is a growing research area, and the results obtained so far are highly promising. The ultimate objective is to facilitate new strategies for improving the quality of life and health of people with mental illness and to prevent the onset, aggravation and negative impacts of diseases.


Background: Attention deficit hyperactivity disorder (ADHD) is the most common developmental disorder in children. Studies suggest an association between fatty acids composition and ADHD pathogenesis. We aimed to investigate whether children diagnosed with ADHD present unique fatty acid profiles in red blood cells (RBC), as compared to children without ADHD.Method: We examined 60 children aged 6–14 years, out of which 32 were diagnosed with ADHD, and 28 were not. Blood was collected from all children to quantify an array of 26 fatty acids from RBC membranes. Fatty acid methyl esters were generated by acid transesterification and analyzed by gas chromatography.Results: We found that children with ADHD presented unique fatty acid profiles on RBC membranes with significantly higher levels of most of the trans-fatty acids  and lower levels of docosahexaenoic acid (DHA), as compared to controls (4.06 ± 0.79 vs. 4.68 ± 1.37 p = 0.040). Additionally, total trans-fatty acids were higher in children with extremely severe clinical ADHD condition score, as compared to milder ADHD scores and to control children .Conclusion: Children with ADHD have higher levels of trans-fatty acids in RBCs, compared to children without ADHD. This study points to a possible link between trans-fatty acids and ADHD. Understanding these findings and the clinical meaning will potentially contribute to a more targeted dietary intervention. Attention deficit hyperactivity disorder (ADHD) is the most common developmental disorder in school aged children . The preIt has previously been suggested that altered fatty acid composition may be associated with ADHD , 9. Howecis (p = 0.038) . Ano= 0.038) .One of the greatest challenges in research of different central nervous system (CNS) disorders like ADHD is that most CNS tissues are not easily accessible. Therefore, in this study we chose to measure fatty acid profiles from blood. While blood does not fully resemble what occurs within the CNS, it remains the best minimally-invasive source for measuring nutritional components . As fattOur aims were to test the fatty acid composition of RBC membranes in children with vs. without ADHD, and answer whether children with ADHD present a unique fatty acid profile.The study was authorized by the Ziv Helsinki Committee, Israel Ministry of Health, and registered at clinicaltrials.gov under number NCT02391428. Written informed consent was obtained from parents, and verbal assent was received from children before entering the study.n = 24, 75%), predominantly inattentive presentation , and predominantly hyperactive/impulsive presentation . In addition, 28 children without ADHD or related neuropsychiatric syndromes were recruited as a control group. Exclusion criteria for both groups included history of other psychiatric disorders and other severe chronic or autoimmune disorders. Body weight and height of subjects were measured by an electronic balanced beam scale and body mass index (BMI) was calculated.A total of 60 volunteers between 6 to 14 years of age were recruited through the department of child and adolescent psychiatry at the Ziv Medical Center, Israel. Out of these, 32 children were diagnosed with ADHD as confirmed by a children's psychiatrist according to the criteria of Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) . PresentBlood samples (3 ml) were taken from all children by venipuncture into EDTA tubes. RBCs were isolated immediately after collection by centrifugation at 2,500 g for 10 min. and then stored at −80°C for subsequent analyses. Researchers were blinded for the status of samples when performing analysis.Fatty acid composition was analyzed by the omega-3 index methodology previously published . Blood fAll children were clinically evaluated for ADHD symptoms by psychiatric examination according to the DSM-5 definitions, including the commonly used Clinical Global Impression-Severity scale (CGI-S) assessment . The CGIt-test or Mann-Whitney non-parametric tests were applied for testing differences between control and ADHD groups. Kruskal-Wallis non-parametric tests were used to for testing differences according to CGI-S assessment. p-value of 5% or less was considered statistically significant. All data was analyzed using SPSS version 24 .In order to ensure correct use of parametric statistical tests, both the ADHD and the control groups included ~30 participants as minimum size groups in this pilot study. For categorical variables, summary tables are provided giving sample size and absolute frequencies. For continuous variables, summary tables are provided giving arithmetic mean (M) and standard deviation (SD). The independent-sample p = 0.187). Mean age at enrollment was similar among the ADHD group and the control group . The mean BMI-value of the ADHD group was 18.03 (±3.5), and mean BMI percentile was 57.86. In the control group, mean BMI-value was 15.68 (±1.9), and mean BMI percentile was 26.86 (p = 0.046). Both averages and percentiles were within the normal range. Children were diagnosed with ADHD according to the criteria of DSM-5 and the presentation type of ADHD included: combined presentation , predominantly inattentive presentation , and predominantly hyperactive/impulsive presentation . There were no significant changes between the different groups.The study included 32 children with ADHD, along with 28 children without ADHD, as a control group. The male-to-female ratio among ADHD participants was about 2:1 , which in = 19), or consumed only methylphenidate medication , however no significant differences were observed in additional characteristic values between these two sub-groups .We assessed whether children with ADHD present unique fatty acid profiles on RBC membranes, as compared to the non-ADHD healthy controls. We found significant differences in levels of several fatty acids when comparing the overall ADHD group with controls . Out of We next analyzed the levels of trans-fatty acids according to CGI-S scale assessment by psychiatric examination. We found that the percentage of total trans-fats was higher in the extremely severe clinical condition score CGI-S = 6, and CGI-S = 5, as compared to control subjects.Our study aimed to evaluate the association between the RBC fatty acid profile and ADHD symptomatology, as measured in a sample of Israeli children with vs. without ADHD.We identified various alterations in the fatty acid profile of children with ADHD compared to controls. Three types of trans-fatty acids were represented by significantly higher levels in ADHD vs. control children. Additionally, the percentage of total trans-fats was higher in the extremely severe ADHD, and in milder ADHD as compared to control subjects.Concerning the composition of saturated fatty acids, we found higher levels of lignoceric acid (24:0), whereas significantly lower levels of stearic acid (18:0) in children with ADHD. Interestingly, high levels of lignoceric acid in RBCs were previously found to be associated with inflammation in adults with metabolic syndrome . DecreasThe mean omega-3 percentage in healthy Israeli children was found in our study to be 5.06%, which is significantly higher than values reported for healthy children from some other countries , while lower than the index of 5.7% found in adolescents in Norway . This maWhile not reaching significance, we found a lower mean omega-3 index in children with ADHD (4.45%), compared to the non-ADHD control group. We additionally found that levels of the docosahexaenoic acid (DHA) component of the omega-3 index, the main omega-3 in the CNS, were lower in the ADHD group, compared to the control group without ADHD. However, Eicosapentaenoic acid levels did not differ significantly between groups.In relation to the omega-6 family, levels of linoleic acid and docosapentaenoic acid were higher in the ADHD group vs. controls. The only omega-6 that was lower in children with ADHD vs. controls was dihomo-gamma-linolenic acid (DGLA), matching results of a previous study among hyperactive children . AdditioAlthough values of BMI were within the normal range in both study groups, it is important to note that a significant difference in BMI was observed in children with vs. without ADHD, with a higher average within the ADHD group. This result has also been found by others , suggestIn this study, we chose measurements of blood trans-fatty acid levels, as these are generally more reliable and comprehensive than self-reported intake assessment, which are limited in the ability to accurately reflect the nutrient consumption of individuals due to measurement error, recall bias, selective report, and incompleteness of food composition databases . If indeIn general, our results present a unique RBC fatty acid profile for children with vs. without ADHD, highlighting observed differences in specific fatty acids. Due to the numerous differences, it remains difficult to assess the precise clinical effect of each fatty acid separately by this analysis. Additionally, our study is observational, therefore it cannot provide causal evidence of an effect of trans-fatty acids on the development of health outcomes examined; it can only describe associations. However, certain observations, such as the relatively high levels of trans-fatty acids in children with ADHD present potential directions for future research and potential interventions.Our study reveals significant differences in the composition of RBC fatty acids in children with vs. without ADHD. Higher relative levels of most trans-fatty acids were found in children with ADHD vs. control. Future studies should be designed to evaluate the clinical relevance of trans-fatty acids in a larger cohort of ADHD subjects, together with dietary analysis, and perhaps evaluate elimination of trans-fats as a nutritional intervention.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ziv Helsinki Committee, Israel Ministry of Health. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.AA-O, EA, ST, and UY: designed research. AA-O, EA, KS, IM, MS, and UY: conducted research. AA-O and HN: analyzed data and wrote the paper. All authors read and approved the final manuscript.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Addictive-like eating and attention-deficit/hyperactivity disorder (ADHD) are both common among persons seeking treatment for severe obesity. Given that ADHD and addictive-like eating, especially binge eating (BE) and food addiction (FA), are both strongly associated with personality dimensions and emotion dysregulation, it is possible emotional and personality characteristics contribute to the link between addictive-like eating behaviors and ADHD in people with severe obesity. This study aimed to investigate the psychological factors associated with BE and FA in bariatric surgery candidates, and to explore the mediational role of emotional factors  and personality dimensions in the association between ADHD and BE.Method: Two hundred and eighty-two (n = 282) bariatric surgery candidates were recruited during the systematic preoperative psychiatric assessment . We assessed significant BE , probable adult ADHD , FA , emotion dysregulation , alexithymia  and personality dimensions (Big Five Inventory). Mediation analyses were performed using the PROCESS macro for IBM SPSS Statistics 22.Results: Prevalence of probable adult ADHD, significant BE and FA were 8.2, 19.1, and 26.6%, respectively. Participants who screened positive for addictive-like eating showed higher prevalence of probable adult ADHD, as well as higher scores on adult and childhood ADHD symptoms. They also reported lower conscientiousness, but higher emotion dysregulation, higher alexithymia, and higher neuroticism. Only BE (as opposed to FA) was also associated with lower scores on agreeableness and openness. Analysis of the association between adult ADHD and BE suggests that emotion dysregulation, conscientiousness, agreeableness, and neuroticism are total mediators and alexithymia a partial mediator.Conclusion: Our findings suggest a significant association between ADHD and addictive-like eating among bariatric surgery candidates, and also suggest a significant role of emotion dysregulation and personality dimensions in this association. For individuals with ADHD and obesity, eating may be a way to cope with negative emotions, potentially increasing the risk for addictive-like eating behavior. As reported in several reviews , AttentiAccording to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders DSM-5; , binge eAround 60% of individuals with BED also meet criteria for food addiction (FA) . Some auInterestingly, ADHD is linked to addictive-like eating behavior, such as high reward sensitivity, low cognitive control and high negative emotionality. Individuals with ADHD symptomatology are particularly at risk of addictive-like eating , but theBariatric surgery began in the middle of the twentieth century and involves the surgical treatment of severe obesity coupled with multidisciplinary care to help patients lose weight, leading to a reduction in overall mortality  and imprThe aim of this study was thus to investigate for the first time the association between adult ADHD and BE in the specific population of bariatric surgery candidates. More specifically, we aimed to explore the mediational role of emotional factors  and personality dimensions in this association. Secondly, we investigated the sociodemographic, weight-related and psychological factors associated with adult ADHD and addictive-like eating  in this population.We expected that BE and FA would be positively and significantly associated with emotion dysregulation and alexithymia, as well as with some specific personality dimensions . We also expected that these variables would have a mediation effect in the association between adult ADHD and BE. Secondly, we hypothesized that ADHD would be significantly associated with a higher prevalence of addictive-like eating. We also expected that both ADHD and addictive-like-eating behavior would be associated with high levels of emotion dysregulation, alexithymia, and neuroticism and with low levels of extraversion and conscientiousness.How difficult was it for you to understand the questions?” Not at all (0), A little (1), Sometimes (2), Often (3), Very often (4).” We excluded all participants who answered “often” or “very often.” Thus, we excluded patients who had difficulty understanding the questionnaire (n = 23) or did not complete the questionnaire in its entirety (n = 38). Out of 343 eligible patients, we finally recruited 282 participants, of whom 76.6% (n = 216) were women, with a mean age of 43.1 ± 11.2 years and mean BMI of 45.4 ± 7.7 kg/m2 . They completed several self-administered questionnaires providing information about age, gender, marital and professional status, and assessing addictive-like eating behavior (BE and FA), childhood and adulthood ADHD symptoms, emotional factors  and personality dimensions. Inclusion criteria were: age > 18 years, referral for a psychiatric assessment prior to bariatric surgery, and sufficient French reading proficiency. At the end of the self-administered battery, we asked participants to specify their level of comprehension of the questionnaires. The question was the following: “.7 kg/m2 .The 16 items of the French version of the Binge Eating Scale (BES) assess behavior, thoughts emotional states and cognitive symptoms associated with significant BE in patients with obesity . Each itThe Yale Food Addiction Scale 2.0 (YFAS 2.0) was created to assess and diagnose FA, by extrapolating the DSM-5 substance-related and addictive disorder criteria to food . For theThe Wender Utah Render Scale-25 (WURS-25) retrospectively assesses childhood symptoms of ADHD and related problems . The FreThe Adult ADHD Self-Report Scale V1.1 (ASRS) is a self-report screening test of ADHD symptoms in adults, developed by the World Health Organization . This wiAdult ADHD criteria state symptoms include disturbance in attention and or hyperactivity/impulsivity in both childhood (before 12 years old) and adulthood. Thus, in this study, we identified “probable adult ADHD” based on screening positive both for childhood ADHD symptoms (WURS-25 ≥ 46) and for adult ADHD symptoms (number of items with significant severity ≥ 4).The Difficulties in Emotion Regulation Scale (DERS) is a widely used questionnaire assessing emotion regulation difficulties. The previous version of the DERS had 36 items , measuriThe Toronto Alexithymia Scale-20 (TAS-20) is a 20-item questionnaire assessing alexithymia . ParticiBased on the Big Five model of personality, the Big Five Inventory BFI;  evaluate® version 22 . All analyses were two-tailed; p-values ≤ 0.05 were considered statistically significant. Descriptive statistics included percentages for ordinal variables and means and standard deviations for continuous variables. Spearman correlation analyses were conducted between childhood and adult ADHD and BE, FA, emotion dysregulation, alexithymia, and the 5 dimensions of the BFI. As recommended in case of multi-comparisons  were performed using the PROCESS macro (version 3.5.3) for IBM SPSS Statistics 22 . Regressa was the effect of “probable adult ADHD” on M, path b was the effect of M on “significant BE,” path c was the total effect of “probable adult ADHD” on “significant BE,” and path c’ was the direct effect of “probable adult ADHD” on “significant BE.” The indirect effect of “probable adult ADHD” on “significant BE” was the product of a and b.In the mediation model of the effect of X on Y through M, X was “probable adult ADHD” (dichotomous variable), Y was “significant BE” (BES score) and M was the mediator variable. We conducted 2 simple mediations with emotion dysregulation (DERS-16 scores) and alexithymia (TAS-20 scores) as M variables, and a multiple mediation with 5 M variables, namely the 5 BFI dimensions. Unstandardized regression coefficients were identified: path Secondly, we investigated the psychological factors associated with FA in our sample. The prevalence of FA within the whole sample was determined, as well as the prevalence of probable adult ADHD in the subgroup of participants with FA. We used logistic regressions to identify the sociodemographic, weight and psychological factors associated with FA and significant BE: age, gender, marital, and professional status, BMI, significant BE, ADHD symptomatology, emotion dysregulation, alexithymia, and personality dimensions.n = 54). Mean FA score was 2.68 ± 2.91, indicating mild severity. Prevalence of FA was 26.6% (n = 75). Forty-one participants (14.5%) showed both significant BE and FA.r = 0.32, p < 0.001 and r = 0.38, p < 0.001, respectively) and FA .Both childhood and adult ADHD symptoms were positively correlated with BE . Bariatric surgery candidates with significant BE or FA had a higher risk of probable adult ADHD (BE: odd ratio (OR) = 3.759, 95% confidence interval (CI): 1.550–9.116; FA: OR = 4.131, 95% CI: 1726–9.883). The presence of probable adult ADHD was 24.4% (n = 10) among patients who showed both significant BE and FA.The prevalence of probable adult ADHD was significantly higher for individuals with significant BE or FA than individuals without these addictive like eating behaviors , FA (p = 0.001), emotion dysregulation (p < 0.001), alexithymia (p = 0.012) and neuroticism (p < 0.001). They had lower scores for agreeableness (p = 0.002) and conscientiousness (p < 0.001). Details are presented in Bariatric surgery candidates with probable adult ADHD showed higher BE (p = 0.007).Total effect of probable adult ADHD on significant BE was 0.723  = 38.26, p < 0.001; R2 = 0.22]. The direct effect of probable adult ADHD on BE (c’-path) was non-significant (p = 0.706), but effects of probable adult ADHD on emotion dysregulation (a-path) and of emotion dysregulation on BE (b-path) were significant (p < 0.001). Details are presented in Probable adult ADHD and emotion dysregulation significantly predicted BE scores . The direct effect of probable adult ADHD on significant BE (c’-path) was significant (p = 0.037). Moreover, there were significant effects of probable adult ADHD on alexithymia  and of alexithymia on BE . Details are presented in Probable adult ADHD and alexithymia significantly predicted BE scores . The c’-path direct effect was not significant: –0.022 (–0.53 to 0.49), p = 0.933.Probable adult ADHD and the 5 dimensions of the BFI significantly predicted BE scores  (Tours-Poitiers) in 2018 (no. 2018 048). All collected data were in line with the French recommendation regarding use of personal data, with the approval of the French Commission Nationale de l’Informatique et des Libertés (CNIL). The patients/participants provided their written informed consent to participate in this study.AD, RH, and CB-T: data collection. SE: writing—original draft preparation. SE, PB, AD, SC, RH, CB-T, NB, CR, and SB: writing—review and editing. SB and PB: study design, concept, and supervision. All authors have read and agreed to the published version of the manuscript.NB reports personal fees from Lundbeck, Astra-Zeneca and D&A Pharma, unrelated to the submitted work. PB reports personal fees and non-financial support from Lundbeck, personal fees from Astra-Zeneca and D&A Pharma, unrelated to the submitted work. SC declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD. The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


High-dose use of benzodiazepines (BZDs) and Z-drugs was found to be associated with adult attention deficit/hyperactivity disorder (ADHD) and multidomain cognitive deficits, but the interplay between these factors and its effect on quality of life (QoL) is unclear. We explored (a) whether cognitive dysfunction differs in high-dose BZD/Z-drug users with and without adult ADHD and (b) the impact of cognitive deficits and adult ADHD on QoL in this substance-use disorder (SUD). From January 2015 to December 2019, we recruited 207 high-dose BZD/Z-drug users seeking treatment. We assessed the presence of adult ADHD with a screening tool, which was validated in SUD patients, and collected demographic, clinical and QoL data from the 76 included patients. A neuropsychological battery explored five cognitive domains. We found that: (a) screening for adult ADHD was frequently positive; (b) Short Form-36 (SF-36), a self-administered QoL questionnaire, was worse than the general population and worse in patients positive (ADHD+) vs. those negative (ADHD−) to ADHD screening tool; (c) executive function was significantly worse in ADHD+ than ADHD− patients; (d) some SF-36 dimensions were negatively influenced by executive dysfunction; (e) multivariate analysis showed an interplay between adult ADHD and cognitive dysfunction in worsening QoL. We documented a complex interplay between adult ADHD, cognitive dysfunction and QoL in high-dose BZD/Z-drug users. Assessing adult ADHD, neuropsychological measures and QoL may offer a full scenario of these patients, who are frequently impaired in everyday activities. Future research should explore whether pharmacological treatment might improve cognitive dysfunction and QoL in this SUD. Benzodiazepines (BZDs) and related Z-drugs  are positive allosteric modulators of the gamma-amino-butyric acid type A receptor that are prescribed for the treatment of anxiety and insomnia Soyka . DespiteThe estimated prevalence of long-term use of BZDs and Z-drugs at high doses ranges from 0.06 to 0.16% of the population in Europe (Ohayon and Lader Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has 6–9% prevalence in children , who were admitted to the Department of Medicine, Addiction Medicine Unit, Verona University Hospital, Italy from January 2015 to December 2019 for detoxification with slow subcutaneous infusion of flumazenil  age > 18 years, (b) formal education ≥ 8 years, (c) Italian as mother language, (d) normal or corrected-to-normal vision, (e) no hearing loss, (f) no acute drug intoxication, (g) normal overall cognition documented by a Mini Mental State Examination score > 24/30, (h) no neurological diseases that might interfere with cognition, (i) no major psychiatric disorders, and (j) no concurrent alcohol use or other SUD , and/or otherwise problematic use of BZDs/Z-drugs, such as mixing molecules, escalating dosage, obtaining them by illegal means and using them to enhance the effect of other substances , and clinical variables . The dosage of BZD/Z-drug was based on patient’s self-report.The study was conducted according to the Declaration of Helsinki and approved by the Ethics Committee of the Provinces of Verona and Rovigo based at Verona University Hospital . All patients gave written informed consent for participation to the study and for data to be published. All the collected data were anonymized with a coding procedure.Before starting detoxification, patients were screened for adult ADHD with the self-administered World Health Organization Adult six-question ADHD Self-Report Scale version 1.1 (ASRS v1.1) Symptom Checklist Part A , a 21-item self-administered questionnaire , was used to measure the severity of depressive symptoms during the previous 2 weeks .Before detoxification, patients underwent a neuropsychological battery to explore verbal, visuospatial and working memory, attention, and executive function , which measures short-term memory. For DSFT, subjects are asked to repeat progressively longer digit series starting from three up to the longest series they can remember , where subjects are asked to copy a complex bidimensional figure  and then redraw it after a 10-min delay , which is the same as DSFT, but subjects are asked to recall the digit series in reverse of the presented order , which explores selective attention and visuospatial exploration, by asking the subject to draw lines sequentially connecting 25 encircled numbers , which is similar to TMT-A, except that the task evaluates mental flexibility and task switching by asking the subjects to alternate between numbers and letters  and the General Health Questionnaire-12 (GHQ-12).The SF-36 is a generic QoL scale composed of 36 items that are grouped into 8 dimensions: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), mental health (MH), with scores ranging from 0 (worst score) to 100 (best score) for each dimension /standard deviation according to age and/or education. Negative and positive values indicated worse and better performance than the normal population, respectively. Z-scores were computed for tests with normal distribution in the normative sample, i.e., DSFT and TMT-A/B time (s), DSBT, ROCF delayed recall  was taken as the significance threshold for all the tests.All tests were carried with the IBM SPSS version 20.0 statistical package. The normality of variable distribution was analyzed with the Skewness–Kurtosis test. The Pearson’s The ASRS v1.1 Symptom Checklist Part A was positive (ADHD +) in 30 (39.5%) and negative (ADHD−) in 46 (60.5%) of the 76 included patients.Demographic and clinical variables did not differ between ADHD + and ADHD− patients Table .Table 1Dp = 0.024), while the other domains  did not significantly differ between the two groups , while the other domains were not significant .Among neuropsychological measures, only executive function was significantly worse in the ADHD +  than the ADHD− group , with GHQ-12 score ≥ 4 in 24 ADHD + (80.0%) and 35 (76.1%) ADHD− patients (p = 0.69).GHQ-12 score was not significantly different between the two groups  and MH  were significantly correlated with the executive function Z-score , while the other cognitive domains did not influence SF-36 scores.Among SF-36 dimensions, only GH  than in those with GHQ-12 score < 4 .Neuropsychological Z-scores, and variables  that we found to significantly influence QoL in high-dose BZD/Z-drug users in previous studies  PF (working memory), RP , GH (executive function), SF , RE  and MH (executive function); age significantly influenced  all SF-36 dimensions except RE; DDDE negatively influenced  PF  VT, SF, RE and MH; neuropsychological PF Table .Table 2Lp = 0.023) and working memory Z-scores  significantly influenced  the risk of GHQ-12 score ≥ 4, while the remaining covariates were not significant.The multivariate logistic regression model showed that verbal  multivariate analysis showed a complex interplay of adult ADHD and cognitive dysfunction in negatively influencing QoL measures (SF-36 and GHQ-12).The present study confirmed that (a) screening for adult ADHD was frequently positive, (b) QoL (SF-36) was worse than the general population  for all the cognitive domains.Overall, BZD/Z-drug users showed negative Z-score turned out to be significantly worse in ADHD + than ADHD− group. ADHD + group showed significantly worse performances in TMT-B, a cognitive test assessing divided attention and set-shifting. This finding is in keeping with a number of previous neuropsychological studies. Distinct profiles of attentional functioning were reported, with weak differences between ADHD subgroups, indicating gross disturbances of various attention functions in adult ADHD , in keeping with evidence that higher GHQ-12 score is associated with cognitive deficits (Bauermeister and Bunce, The multivariate logistic model indicated that lower verbal and working memory The main limitation is that adult ADHD was detected with the ASRS v1.1 Symptoms Checklist Part A, which is one of the recommended screening tools for adult ADHD in SUD (Crunelle et al. We provided new information on the interplay between adult ADHD, cognitive dysfunction and QoL in in high-dose BZD/Z-drug users. These findings underscore the importance of assessing adult ADHD, neuropsychological measures and QoL in this SUD to offer a full scenario of these patients, who are frequently impaired in everyday activities (Fuermaier et al.


Taijin-Kyofu-sho is an East Asian culture-bound anxiety disorder with similarities to social anxiety disorder. However, few studies have examined these two disorders from the perspective of neurodevelopmental disorders. This study is aimed at examining the association of Taijin-Kyofu-sho and social anxiety disorder with the attention-deficit/hyperactivity disorder (ADHD) trait and autism spectrum disorder (ASD) trait. The Liebowitz Social Anxiety, Taijin-Kyofu-sho, and Adult Attention-Deficit/Hyperactivity Disorder Self-Report scales and the 16-item Autism-Spectrum Quotient were administered to 818 university students. Participants were divided into four groups: control , pure Taijin-Kyofu-sho , pure social anxiety disorder , and mixed Taijin-Kyofu-sho-social anxiety disorder . We used logistic regression analysis to examine whether the ADHD trait and ASD trait were associated with Taijin-Kyofu-sho and social anxiety disorder. ASD trait was significantly associated with pure Taijin-Kyofu-sho . Female sex and ADHD trait were significantly associated with pure social anxiety disorder . Female sex, ADHD trait, and ASD trait were significantly associated with mixed Taijin-Kyofu-sho-social anxiety disorder . Neurodevelopmental disorder traits differed between individuals with Taijin-Kyofu-sho and those with social anxiety disorder. Overall, our study reveals that Japanese individuals with the ADHD or ASD traits are at a heightened risk of developing Taijin-Kyofu-sho or social anxiety disorder. Neurodevelopmental disorders (NDDs) result from impairments in brain growth and development that lead to emotional and behavioral problems that begin in early childhood and persist into adulthood. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM-5), NDDs are characterized by developmental deficits of varying severity in personal, academic, or occupational functioning . Among N, NDDs arSocial anxiety disorder (SAD) is an anxiety disorder characterized by marked fear of social situations in which the individual is exposed to possible scrutiny by others . ExampleTaijin-Kyofu-sho (TK), which literally means disorder (sho) of fear (kyofu) of interpersonal relations (taijin) [Shinkeishitsu in Japanese [SAD was previously known as “social phobia,” a term coined by Janet in the early 1900s . However(taijin) . TK is d(taijin) . It has Japanese  and is rJapanese . In the Japanese .The psychopathologies of TK and SAD have been compared. There are two types of TK: “tension” and “offensive” . In the The offensive type of TK is characterized by fear of offending or disgusting others due to eye contact or body odor. Patients with offensive type TK believe that they are offending others with their physical appearance or that others are avoiding them . PreviouShubo-kyofu, the phobia of a deformed body, and Jikoshu-kyofu, the phobia of one's own foul body odor) [With the publication of the DSM-5, the differences between the features of TK and SAD have become ambiguous. The following sentence was added to the DSM-5 as “criterion B” of SAD: “The individual fears that he or she will act in a way or show anxiety symptoms that will be negatively evaluated ” . The defdy odor) , 29. ThuSince TK and SAD are unlikely to be identical in some respects, we considered it useful to focus on the differences in the causes of these two anxiety disorders. To examine the differences in psychopathology between TK and SAD, we previously compared SAD and TK in terms of ADHD traits . HoweverThis cross-sectional study was conducted at Kyushu University from April 2015 to April 2018. All participants were Japanese students at the Department of Interdisciplinary Graduate School of Engineering Sciences and Faculty of Arts and Science at Kyushu University who volunteered to participate in the study. We obtained informed consent from the students as follows: students were provided with our research manual and received an oral explanation of the study . We then asked students enrolled in psychology, health, and safety courses to volunteer. The questionnaires were completed anonymously, and the answers did not contain any identifying information. Submission of the questionnaire was regarded as consent for participation in the study. Furthermore, the participants were provided opportunities to opt-out from the study. Students who had previously been administered the scales used in the study were excluded to avoid duplication. This study was approved by the Ethics Committee of the Faculty of Arts and Science, Kyushu University, Japan .Taijin-Kyofu-sho scale (TKs), developed by Kleinknecht et al. in 1997, consists of 31 items related to TK symptoms that best differentiate patients with TK from controls [The controls .We used the Japanese version of the LSAS in this study . The LSAThe ASRS version 1.1 is a self-report questionnaire designed to screen for adult ADHD . It consThe AQ, developed by Baron-Cohen et al. , is a 50p values < 0.05 were considered significant.First, we classified the participants into TK+ and TK− groups based on their TKs scores . Similarly, they were classified into SAD+/SAD−, ADHD+/ADHD−, and ASD+/ASD− groups according to the relevant definitions. Second, we compared the prevalence of TK and SAD across the four groups based on ADHD trait/ASD trait, that is, ADHD− ASD−, ADHD+ ASD−, ADHD− ASD+, and ADHD+ ASD+. Third, we used multiple logistic regression analysis to examine the potential contributions of ADHD trait and ASD trait to the occurrence of TK or SAD, with TK  or SAD  as the dependent variable, ADHD trait  and ASD trait  as independent variables, and age (years) and sex  as common covariates. Finally, because some participants had comorbid TK and SAD, we attempted to characterize them based on the differences in symptoms associated with TK and SAD. For this purpose, we further classified them into “pure TK,” “pure SAD,” and “TK-SAD mixed,” where an individual with pure TK only met the criteria for TK but not for SAD (the opposite was true for pure SAD), and an individual with TK-SAD mixed met the criteria for both TK and SAD. We then repeated logistic regression analyses with pure TK, pure SAD, and TK-SAD mixed as dependent variables. The chi-square test or Fisher's exact test was used for comparing categorical variables between groups; the Kruskal-Wallis test was used for the other variables. Data were analyzed using SPSS version 27.0 . Statistical tests were two-sided, and In total, 818 students  completed all the psychological tests. The mean age (standard deviation (SD): range) of the participants was 21.4 years (2.02: 18–40 years). The characteristics of the participants are shown in p < 0.001, (b) p < 0.001, Fisher's exact test).p = 0.032, odds ratio (OR) 1.57; ASD trait: p < 0.001, OR 6.63). Female sex, ADHD trait, and ASD trait were significantly associated with SAD .As shown in p = 0.006; OR 3.99). Female sex and ADHD trait were significantly associated with pure SAD : p = 0.013, OR 2.61; ADHD trait: p = 0.012, OR 2.46). Female sex, ADHD trait, and ASD trait were significantly associated with TK-SAD mixed : p =0.043, OR 2.16; ADHD trait: p = 0.003, OR 2.75; ASD trait: p < 0.001, OR 16.93) (We found that ADHD trait and ASD trait were both significantly associated with TK and SAD . HoweverR 16.93) .In this study, we found that a higher proportion of participants with TK and SAD had ADHD trait and ASD trait than those in the control group. Using logistic regression analysis, we identified ADHD trait and ASD trait as factors associated with TK. In addition to ADHD trait and ASD trait, female sex was significantly associated with SAD. Furthermore, to highlight the differences between the clinical features of TK and SAD, we divided the participants into four groups  and performed logistic regression analyses. ASD trait was associated with pure TK, and female sex and ADHD trait were associated with pure SAD. We believe this is the first study comparing TK and SAD according to NDDs (ADHD and ASD). Our results may provide new insights into the pathogenesis of TK and SAD, which can contribute to the early management of these anxiety disorders.Although few studies have examined the prevalence of TK among patients with developmental disorders, many have shown a relationship between SAD and NDDs in adults. Studies from the U.S. and Norway have reported that 29.3%  and 14.2Adults with ASD have been reported to have a significantly higher prevalence of SAD than those without ASD (21.7% vs. 5.0%) . FurtherLogistic regression analysis identified ADHD trait and ASD trait as common factors associated with TK and SAD. However, the analysis included 47 cases of comorbid TK and SAD. To exclude the effect of TK and SAD on each other, we divided the participants into pure TK and pure SAD groups and performed logistic regression analysis. As a result, ASD trait was identified as a factor associated with pure TK, and ADHD trait and female sex were identified as factors associated with pure SAD.One possible reason for the association between ASD trait and TK is collectivism. Contrary to individualism in Western countries, East Asian societies, including Japan, are characterized by collectivism. In collectivism, people need to sensitively perceive the feelings or thoughts of others because “not bothering others” and “cooperativeness” are regarded as virtues; that is, the fear of being disliked and not accepted plays a prominent role in collectivistic societies like Japan . HoweverHikikomori, which literally means “pulling inward” in Japanese. The definition of Hikikomori is abnormal avoidance of social contact, typically by adolescents [Hikikomori [Hikikomori were more likely to have autistic tendencies than non-Hikikomori individuals [Hikikomori, which was first described in Japan, seems to be closely related to ASD.Another reason for the association between ASD trait and TK may be social withdrawal. Social withdrawal, a maladaptive behavior associated with ASD, is more prevalent among children with ASD than typically developing children and often worsens with age . Meanwhilescents . Indeed,kikomori . Moreoveividuals . Thus, sAccumulating evidence suggests that SAD is closely associated with ADHD. Koyuncu et al. reported that the rate of childhood ADHD in SAD was high (72.3%) . In a crPrevious studies have consistently shown that women are more likely to have SAD, to have more severe clinical symptoms of SAD, and to have greater subjective distress compared to men , 55. HerThis is the first study to examine the association between two types of anxiety disorders (TK and SAD) and developmental disorders (ADHD and ASD) using logistic regression analysis. However, it has some limitations. First, all the participants were recruited from a single university, and 70% of the students were male. Moreover, Kyushu University is ranked as one of the top 10 universities in Japan, due to which the intelligence level of its students is expected to be relatively high. Therefore, our results cannot be generalized to all Japanese young adults. Second, we relied on self-reported assessments to diagnose TK, SAD, ADHD, and ASD. In general, a clinical diagnosis should be made according to the operational diagnostic criteria based on a psychiatric interview. Therefore, a clinical evaluation using structured interviews is required for the accurate diagnosis of these disorders. We also emphasize that our study investigated the traits of each disorder and did not intend to diagnose any of these disorders. Moreover, the TK was developed to evaluate the extent of TK symptoms, and further research is required to ascertain whether it is suitable for diagnosing TK.In this study, we examined the association between anxiety disorders (TK and SAD) and the ADHD and ASD traits. Multivariate logistic regression analyses revealed that ASD was significantly and independently associated with TK, and ADHD trait and female sex were significantly and independently associated with SAD. Differences in ADHD and ASD traits may influence the future onset of TK or SAD in Japanese adults.


The role of environmental chemicals in the etiology of attention deficit hyperactivity disorder (ADHD) has been of interest in recent research. This scoping review aims to summarize known or possible associations between ADHD and environmental exposures to substances selected as priority chemicals of the European Human Biomonitoring Initiative (HBM4EU). Literature searches were performed in PubMed to identify relevant publications. Only meta-analyses and review articles were included, as they provide more extensive evidence compared to individual studies. The collected evidence indicated that lead (Pb), phthalates and bisphenol A (BPA) are moderately to highly associated with ADHD. Limited evidence exists for an association between ADHD and polycyclic aromatic hydrocarbons (PAHs), flame retardants, mercury (Hg), and pesticides. The evidence of association between ADHD and cadmium (Cd) and per- and polyfluoroalkyl substances (PFASs) based on the identified reviews was low but justified further research. The methods of the individual studies included in the reviews and meta-analyses covered in the current paper varied considerably. Making precise conclusions in terms of the strength of evidence on association between certain chemicals and ADHD was not straightforward. More research is needed for stronger evidence of associations or the lack of an association between specific chemical exposures and ADHD. Attention deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterized by persistent inattention and/or hyperactivity-impulsivity, which has a direct negative impact on academic, occupational, or social functioning . The onsSystematic reviews have estimated the worldwide prevalence of ADHD to be between 2% and 7%, averaging around 5% in children and adolescents . ADHD isChildren with ADHD have an increased risk of accidental injuries, worse quality of life, earlier use of tobacco and drugs, and earlier sexual activity. Although ADHD does not directly cause mortality, there is increased mortality among people with ADHD by external and accidental causes . ADHD isWhile pharmacological treatment is the mainstay in ADHD management, nonpharmacological treatments, such as behavioral parent training and social skills training, are also used. They are most commonly recommended for very young children or for mild to moderate ADHD and can also be used in combination with medication. Cognitive behavioral therapy can be useful in adult patients; however, data suggest nonpharmacological treatments are less effective than pharmacological treatments and more research is needed. Psychostimulants (methylphenidate and amphetamines) are the most common pharmaceuticals used in the management of ADHD, followed by atomoxetine, guanfacine, and clonidine. Psychostimulant treatment is efficacious in the short term, but evidence for long-term efficacy is less clear .While there is consistent evidence that ADHD has high heritability, most cases are considered to be multifactorial in origin . Environhttps://www.hbm4eu.eu/) (accessed on 13 January 2022) is a joint European program of 30 countries  and the European Environment Agency, co-funded by the European Commission and national governments . Wh. Wh26]. Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins, which are used in a wide range of consumer products. The presence of BPA is ubiquitous in the environment and can enter the body through ingestion, dermal uptake and inhalation. There is evidence of multi-system toxicity of BPA in humans, with the reproductive system being a key target organ of BPA .A systematic review from 2018 see  found 3 In addition, phthalates and BPA had been analyzed in a combined category in one review and meta-analysis  18]. Th. Th18]. Polycyclic aromatic hydrocarbons (PAHs) are a class of organic compounds that are released into the air during incomplete combustion of organic matter, such as coal, fuel, tobacco and meat. The PAH class is considered carcinogenic and multitoxic to humans . PrimaryTwo systematic reviews showed limited evidence of an association of PAHs and ADHD  31,32].,32.31,32Flame retardants (FR) are chemical compounds that are added to consumer products or materials to reduce flammability and are commonly used in e.g., building materials, textiles, electronics, vehicles, insulation, and appliances. Human exposure occurs via inhalation, ingestion, and dermal exposure.Among the most common FRs since the 1970s were polybrominated diphenyl ethers (PBDEs). PBDEs have been identified as potential causes of neurotoxic, carcinogenic, and endocrine effects. Due to safety concerns surrounding toxicity, persistence, and bioaccumulation, PBDEs are now restricted and being phased out of use. Organophosphate esters (OPE) are now more commonly used, and more data on human toxicity are needed ,39.FRs is a large group of chemicals with a common function but not necessarily common chemical structure. Only sub-categories of FRs have been investigated for their association with ADHD and other cognitive/behavioral conditions, captured in two systematic reviews investigating flame retardants and attention problems . Lam et Doherty (2019) assessed the link between children’s health and organophosphate esters (OPEs) before birth and in childhood in a review of two studies from the USA . While tMercury (Hg) is a heavy metal element which occurs naturally but is also spread as a pollutant as a result of human activity. Coal-fired powerplants, waste incinerators, and small-scale gold mines are significant sources of mercury in the environment . MethylmMercury is neurotoxic, causing a variety of neurological symptoms depending on the level and route of exposure. Children are more susceptible than adults, and transplacental exposure in utero is particularly dangerous. The World Health Organization classifies mercury exposure as a major public health concern .Significant associations between mercury exposure and ADHD were observed in two meta-analyses  18,35].,35.18,35Pesticides are a very large group of chemicals used to control unwanted weeds, insects, various pests and disease carriers, such as rats and mosquitoes ,44. AgriBased on results from a review and meta-analysis including six studies where pesticide exposure was assessed during childhood  and anotThe evidence of the association between ADHD and cadmium (Cd) and per- and polyfluoroalkyl substances (PFASs) was low based on studies identified from the literature review.In a review of studies on the association of perinatal and childhood exposure to cadmium and ADHD or ADHD-like behavior, none of the included five studies reported a significant association .Two studies on perfluoroalkyl compounds (PFCs)  during childhood and ADHD were included in a review by Nilsen and Tulve (2020) . The resThis scoping review demonstrates that there are several chemicals, which children and adults encounter in their living and working environment that may be associated with ADHD outcomes. For certain environmental pollutants, such as lead, phthalates, and bisphenol A, the association is more robust and the evidence stronger. For several other chemicals, the evidence is weaker but warrants more research.https://www.hbm4eu.eu/) (accessed on 13 January 2022) [The starting point for the current review was the list of priority chemicals of the HBM4EU project (ry 2022) . ReviewsThe inclusion criteria and other methods of the included reviews varied. Furthermore, many reviews highlighted the heterogeneity of the individual studies. The quality of the studies included in the reviews was also variable. Sample sizes varied from a few dozen to several thousand and many different study designs were included. Different studies and reviews also used different definitions of ADHD and different methods of diagnosis or measures of outcome, which hindered forming a final conclusion based on their findings. Furthermore, adjusting for confounding factors varied between the original studies and was not consistently reported in all included reviews.n = 5); however, they were analyzed together under the name ‘phthalates/plasticizers’ [The inclusion of published reviews in the current paper was not straightforward in all cases. The categorization of chemicals varied between the reviews. As an example, studies on phthalates and BPA were included in Nilsen and Tulve’s 2020 systematic review and meta-analysis  demonstrated that children born to mothers who had elevated urinary DPHP  in mid-pregnancy had a higher risk of ADHD . The finFor cadmium, none of the studies included in a systematic review that we identified reported a significant association between perinatal and childhood exposure to cadmium and ADHD or ADHD-like behavior . HoweverIt was difficult to make precise conclusions in terms of the strength of evidence of association between certain chemicals and ADHD. It was particularly challenging to distinguish between ‘limited’ and ‘low’ evidence. It is apparent that the chemicals in these categories require more research input. An issue worth mentioning here is that the timing of chemical exposure, e.g., prenatal or during childhood, may be especially important with regards to ADHD development. Thereby, if the exposure was measured during a less relevant time period in a given study, the association may have appeared weaker than it actually is.While not the focus of this paper, the mechanisms by which chemicals may affect the development of ADHD are also of great interest. How much is known about the mechanisms varies depending on the chemical, and the mechanisms and chemical pathways also vary. For example, serotonergic and dopaminergic systems are possible targets through which BPA may exert its neurological effects in humans . PesticiThe focus of this scoping review was only on those selected as the priority substances of the HBM4EU project. Therefore, many substances for which at least suggestive associations with ADHD have been seen, were excluded from the current paper, such as paracetamol, parabens, and dioxin, as well as smoking during pregnancy ,53,54,55Some evidence came from studies designed for other research purposes than assessing possible associations of a particular chemical and ADHD. In future, it would be valuable to implement hypothesis-driven, properly designed studies to collect stronger evidence of associations or the lack of an association between chemical exposures and ADHD.Furthermore, more research is needed in Europe to enhance the understanding of the situation more locally. So far, a large part of the research has been done in North America. Currently, the HBM4EU initiative strives to fill this gap by collecting information on the exposure of European populations to the priority substances and their health effects to support policy decisions for public health protection.Thus far, evidence from epidemiological studies suggests there is an association between ADHD and a number of chemicals, with moderate to high evidence for at least lead, phthalates and bisphenol A.The methods of the individual studies included in the reviews and meta-analyses covered in the current paper varied considerably, which complicated drawing final conclusions.More research is needed for many chemicals to collect stronger evidence of associations or the lack of an association between chemical exposures and ADHD.More European studies are needed. The HBM4EU has prepared standardized operating procedures for collection of data on chemical exposure on humans, and also provides guidelines for standardized collection of health outcomes. The project generates new evidence of chemical exposure and health effects in European countries.


Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder associated with significant morbidity. Current treatment approaches consist of a mixture of pharmacological and psychological approaches. The emergence of digital technology, and mobile gaming applications, represents a promising novel method in potentially augmenting existing interventions for ADHD. In this review, we will map out the use of mobile gaming applications in the management of ADHD and evaluate the effectiveness of these technologies and any areas for future research. Four electronic databases were searched for relevant articles. All articles were screened for abstract and full text by two independent reviewers, and data extracted onto a common data extraction sheet. The data was narratively synthesized and reported in line with the PRISMA-ScR guidelines. A total of 19 studies were included. Studies mostly evaluated the effectiveness of games on male children with ADHD. Most games were focused on the treatment of ADHD, while a minority were focused on the diagnosis and monitoring of ADHD. Some of the common gaming mechanisms employed in games included having participants responding to cures, remembering details, and making associations between different entities. The studies generally showed an improvement in performance of children as they played the games, but evidence for the effectiveness of these modalities remains scarce and mixed. While it is exciting that there is such a wide variety of games available currently in the diagnosis, treatment, and monitoring of ADHD, many of the games lack clinical evidence to prove their effectiveness. Furthermore, most studies contain several limitations including small sample size, limited ages of participants, lack of control group, and lack of comprehensive outcomes. To promote the application of these games to clinical practice, robust clinical trials, collaboration between stakeholders and using a comprehensive set of outcome measurements is essential. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a global prevalence of 5% in children aged 4–17 years old .Conventional treatment strategies for ADHD include a combination of pharmacological and psychological approaches, based on the National Institute for Health and Care Excellence (NICE) guidelines . Howevervia “gamification.” It is proposed that the rewarding feature of games is more attractive to children and thus improves adherence . Five broad classifications of mHealth include health applications, smartphone-connected devices, wearable and wireless devices, handheld-imaging platforms, and miniaturized sensor-based technologies . In thisPeñuelas-Calvo et al.  have preThus, the aim of this review is to map out all existing video games for ADHD, and in determining the specific skill sets that each game targets and their outcomes. It is also the aim of this review in examining the gamification techniques or serious game strategy that has been adopted in existing published ADHD games.The findings arised from this study would have resultant research and clinical implications. In terms of research, this will help researchers understand the effectiveness of ADHD games, and techniques that might help these games be effective. From a clinical perspective, this would help provide guidance for clinicians attempting to use games as a modality of treatment intervention.This scoping review was reported using Preferred Items for Systematic Reviews and Meta-analysis extension for scoping review (PRISMA-ScR) guidelines .The bibliographic databases of Cochrane, MEDLINE, PsycInfo and Scopus were searched for all records published within the past 11 years to identify potentially relevant articles. To identify the relevant articles, the following keywords were used for the search: “Play and Playthings,” “Games,” “Recreational,” “Video Games,” “Cell Phone Use,” “Telemedicine,” “Telerehabilitation,” “Mobile Applications,” “Computers,” “Handheld,” “Attention Deficit Disorder with Hyperactivity.”The details on the search strategy can be found in Articles were included if they were (a) articles on digital games that are used on a mobile or tablet platform, with or without another digital modality, (b) targeted patients with ADHD or caregivers of patients with ADHD, (c) a form of primary research, (d) peer-reviewed articles, pre-prints, or gray literature. Articles were excluded if they were (a) published in a language that is not in English, (b) published before 2010, (c) systematic reviews or other forms of secondary research.The articles were independently screened by two reviewers (RL and RN) using Covidence, who then extracted and categorized data from the selected articles into a spreadsheet. The reviewers sequentially evaluated the titles, abstracts, and then full texts of all publications identified by the searches for potentially relevant articles. If there were any disagreements between the reviewers, this was discussed with a senior study team member.The data extracted from each of the article includes publication details , conduct of the study , and article content . The data was extracted by 4 reviewers  onto a common data extraction sheet on Microsoft Excel. The data was then synthesized into figures and tables and described according to the PRISMA-ScR guidelines.An additional search for games intended for use among children with ADHD was also conducted. The keywords “ADHD” and “game” were entered into the Google Play Store and Apple Store. Games were included if the description of the game included ADHD. General information and features of the highlighted games were used to supplement the data collected from articles in this scoping review to provide enhanced insight on the types of games commercially available on the market.The overview of the selection of the studies are summarized in The general characteristics such as the study design, demographic characteristics, and study sample of various studies are summarized in Developmental research is defined as the systematic study of designing, developing, and evaluating instructional programs, processes, and products that must meet criteria of internal consistency and effectiveness . These sOf the 19 studies included in this review, 6 studies 32%) were purely development research papers with no measured outcomes , 29, 34,% were puAmong the 4 experimental studies, 1 study was an open-label, non-randomized trial , 2 were The studies were conducted in a wide variety of different countries, with most studies being conducted in Spain  or the USA . Four studies (21%) were conducted in low-income countries with the rest being conducted in high-income countries.Excluding the case report, 12 studies (67%) involved ADHD patients with or without other neurodevelopmental disorders such as autism spectrum disorder (ASD) or involved caregivers in the study design. Some studies were primarily developmental but included participants for surveys. The median number of participants was 18. Most studies involved the use of groups of children <16 years old, with only 2 studies (11%) involving the use of participants above the age of 16. Most studies also involved mostly male participants, with only 3 studies (16%) involving more females than males.The games modalities that were observed in the review are summarized in As to where the 18 games were acquired from, 11 games were developed by the research teams, while 7 games were commercially acquired, through the Google Play Store, Apple App Store, or other available sources for mobile games.The 17 games analyzed can be grouped into broad categories, based on the features of their gameplay. Note that there was one game with no game description and some games can fall under more than one category.There were 6 games , 30, 34 There were 4 games , 30, 34 In 7 games , 34, 35 Other, smaller categories include behavioral games , which cA total of 13 studies were experimental or developmental studies that involved the collection of quantitative and qualitative data from a sample population for further analysis. The observations derived from the studies were summarized in n = 4) (n = 3) (n = 5)  , 25, 27, (n = 3) , 21, 30, (n = 5) , 31, 32.n = 4) (The participant performance over the period as they played the game were the most common objective data observed in four studies (n = 4) , 28, 31.n = 4) , 28, 31.n = 4)  and the n = 4)  were usen = 3)  , 27, 32,n = 3) , Test ofn = 2)  , 20, when = 2) , and reaAll studies in this category demonstrated that the use of gamified interventions can prove to be helpful in patients with ADHD in at least one aspect except for Yerys et al.  which fon = 5)  , 31, 32 n = 2), with the Conners Parent and Teacher Rating Scales (CPTRS) and Barkley School Situations Questionnaire (BSSQ) being used by one study  was also provided.Results obtained were mixed, with Tajima-Pozo et al.  suggestiThe themes analyzed by this paper should be considered by future developers who wish to create serious games for children with ADHD.Serious games targeted to treat patients with ADHD, especially children, often rely on the use of colorful visuals to leverage the idea that children tend to be more visual learners, and that knowledge uptake and retention is often better using visuals as opposed to other modalities of learning .The most common features in many of the serious games reviewed, were clear set of objectives, feedback upon the achieving the objectives, internal reward systems , 22 and Another essential feature that was present in the serious games analyzed was portability and location independence. Serious games promote self-management and allow patients to undertake the intervention without constraints on space or time , 17, 20.The games were developed to enhance the attention, memory, and behavioral characteristics. The attention-based games are based on Go/No-Go test concept. The Go/No-Go test essentially requires subjects to respond to a “Go” stimuli, and inhibit a response to a “No-Go” stimuli, and is often used to measure sustained attention and response control . For exaThe game genres were derived from the aims of each respective game. Games that primarily aimed to improve attention amongst subjects with ADHD employed features that required players to focus on a particular task, or execute a task based on a particular cue. Often the features of these games, directed at improving or assessing attention, are based on a Go/No-Go test concept. The Go/No-Go test essentially requires subjects to respond to a “Go” stimuli, and inhibit a response to a “No-Go” stimuli, and is often used to measure sustained attention and response control . For exaIt is important to acknowledge the platforms in which the games have been deployed. As smartphone capabilities improve, the mobile platform is widely used as a range of applications that can be executed on them.The Phygital approach is novel in mobile gaming, which bridges the digital world with real world and provides an extensive immersive experience. An example of a mobile game that utilizes this approach is the Reflex game . The gamAnother innovative modality in the treatment of ADHD with mobile games is the use of Augmented Reality (AR) and Virtual Reality (VR). For example, an AR-based mobile application was used to perform Augmented Reality simulations through interactive “find-the object” game play in one of the included study . The resThe other common gaming platform reported in the literature were personal computer (PC) games. Plan-it-Commander , UVAMat Sensor driven platforms, such as a Brain-Computer Interface (BCI), are increasingly being explored as a possible modality for serious games in the treatment of ADHD, with preliminary evidence suggesting that BCI can be effective at minimizing ADHD symptoms . These sThe greater processing power of PC platforms allows for a greater diversity of performance data to be collected, allowing for an improved assessment of cognitive function and attention to be measured, providing more information to aid clinicians in the management of the child's symptoms.However, a significant shortcoming of PC platforms is the lack of portability, which can significantly impair treatment accessibility and lead to poorer patient compliance should it be administered as part of a treatment plan. Additional hardware such as EEG equipment required to operate complex systems such as the BCI require centralized provision of care, negating the initial advantage of serious games as a treatment modality.There were 2 studies , 27, thaFuture studies attempting to elucidate an association between a gamified approach to the treatment of ADHD and effective management of ADHD can consider using validated tests and designing studies that allow the observation of the long-term impact of the approach.Whilst the use of mobile games in the treatment of ADHD seems interesting, research hints that medication coupled with behavioral therapy may produce better outcomes in the management of ADHD symptoms . This sePreliminary evidence suggests that game-based interventions are positively received by both patients and caregivers, likely a result of games being seen as less invasive than pharmacological therapy and a novel treatment modality. Most caregivers also report visible improvements in the child's ADHD symptoms after exposure to the game. Furthermore, given the likely lower side effect profile of game-based interventions, caregivers are more willing to opt for such modalities given that it is simple to prescribe as well as discontinue use if necessary.There are some limitations of the studies analyzed in this scoping review, some of which significantly impacted the strength of the evidence produced by the studies, resulting in research gaps that cannot be adequately answered.Several flaws in study design were identified. Most studies involved very small sample sizes (median participant size = 18). Only 1 study  exceededBias observed in the demographics of patients studied suggests that the data collected might not be representative of the entire spectrum of patients with ADHD. All but two studies , 26 inclThere is an abundance of mobile game applications available for the diagnosis, management, and education of ADHD patients and their caregivers. The integration of these games with existing treatment options represents an opportunity to extend the management of ADHD beyond geographical boundaries, promote greater self-responsibility, and allow patients to receive treatment at the convenience of their own homes, at any time of the day. Optimizing the applications by reflective evidence from the stake holders is essential, as the evidence could be helpful in developing a robust evidence-based prototype. It is advantageous to use commercially available game applications pertaining their smoother and appealing appearance, however, the drawbacks of these apps should be set before use.Most of the reviewed games had not undergone stringent clinical testing and thus while well-perceived by ADHD patients, their clinical utility remains questioned. Moving forwards, the conduct of some robust clinical trials examining the effectiveness of these applications would help to promote their use further.The original contributions presented in the study are included in the article/MZ and RV jointly conceptualized the study and provided critical inputs to the final manuscript. HJ, RN, YS, and LR were involved in the identification of relevant articles and writing the initial draft, which was revised by HJ, RN, YS, LR, and RV. All authors have read and approved the manuscript prior to submission.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.