A medical approach towards behavioural problems could make professionals without a medical background, like teachers and other educational professionals feel inapt. In this article, we raise six scientifically grounded considerations regarding ADHD, currently the most prevalent childhood psychiatric diagnosis. These “need to knows” show just how misguided and potentially stigmatizing current conceptualizations of unruly behaviour have become. Some examples are given of how teachers are misinformed, and alternative ways of reporting about neuropsychological research are suggested. A reinvigorated conceptual understanding of ADHD could help educational institutions to avoid the expensive outsourcing of behavioural problems that could also—and justifiably better—be framed as part of education’s primary mission of professionalized socialization. Attention deficit hyperactivity disorder (ADHD) is one of the syndromes defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM). In the DSM-5 .In the USA, the total number of children on ADHD medication skyrocketed from 1.5 million in 1995 . Furthermore, these heritability claims vary strongly and are subject to debate because of methodological issues of twin, familial and adoption studies that are used for calculating the heritability coefficient. For example, the higher co-occurrence of ADHD between monozygotic twins (who share 100% of their genes) compared to their dizygotic counterparts (who share 50% of their genes) cannot rule out the influence of environment, as homozygote twins are often treated more similarly and more often have a physical and psychological closeness than their heterozygotic counterparts . Now Roar has been given his medicine, and consequently I can expect him to behave properly (…) things are going to be normal again. If not, he’ll be moved to “the group for the badly behaved ones”. Berg,  cited byWe addressed six issues that educational professionals should be aware of when confronted with inattention and hyperactivity in the classroom. Often, such behaviours are merely the slightly less occurring variations at the poles of any bell-curved behavioural indicator. It is therefore understandable that they are often confused with normal “young” behaviours (paragraph 1). However, disputable yet pervasive claims of ADHD as a genetic neurodevelopmental disorder (paragraphs 3 and 4) could make teachers and other educational professionals feel inapt and might urge them to find solutions outside the realms of their own skills and facilities. Indeed, previous research indicates that teachers are hesitant to accept responsibility for students with special needs Pijl, . A partiFor educational professionals, but also for medical and behavioural experts and policy makers, these issues have at least the following implications.First, more caution is needed with regard to claims made about the etiology of ADHD in general, particularly information addressed at teachers. Generalizing, pathologizing views on the etiology of ADHD-related behaviours—widely dispersed on the internet and in books—do little justice to the different interacting causes of ADHD related behaviours.Second, we hope that a reinvigorated understanding of ADHD makes us reconsider our own expectations of children. Research indicates that many young children, particularly those diagnosed with ADHD, thrive with more space for physical activity  space to the institution and its professionals we entrusted with the larger part of the socialization of our children.


Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample ( ASD is defined by impaired communication and social interaction as well as repetitive and restricted behaviors and interests.1 ADHD and ASD frequently co-occur, with the presence of ADHD within ASD ranging from 30 to 80%, whereas the presence of ASD in ADHD is estimated at 20–50%.3 Both disorders are highly heritable, with estimates of 90% for ASD and ~76% for ADHD.6 In addition, ~50–70% of the contributing genetic factors are overlapping between ADHD and ASD,7 but also see Lee et al.8 Despite their high heritability, finding genetic risk variants for both disorders has been challenging so far. Several candidate genes have been associated with ADHD and ASD symptoms,12 but genome-wide association studies have not yielded many genome-wide significance findings.13 ADHD and ASD are very heterogeneous and polygenic disorders, which may explain the difficulties in identifying the underlying genetic factors.15 One characteristic that ADHD and ASD have in common is impairments in behavioral inhibition;16 for review see Wang et al.13 This overlapping trait in both disorders is linked to deficits in frontostriatal brain areas. Studying an overlapping trait in ADHD and ASD may complement the search for genetic variants involved in the disorders themselves.17Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by age-inappropriate inattentiveness and/or increased hyperactivity and impulsivity.18 Because of these wide-ranging functions, altered glutamatergic neurotransmission has been implicated in many different nervous system processes.19 Gamma-aminobutyric acid (GABA), on the other hand, is the most abundant inhibitory neurotransmitter of the human brain involved in long-range signaling responsible for inhibition of behavior. Both neurotransmitters are involved in frontostriatal signaling, related to the dysfunctions in inhibition seen in ADHD and ASD.21Glutamate is the most abundant excitatory neurotransmitter in the human brain and is involved in many neuronal functions including synaptic transmission, neuronal migration, excitability, plasticity and long-term potentiation.23 The pathophysiology of ASD has been proposed to be characterized by a glutamate–GABA imbalance.24 Abnormalities in the expression of glutamate transporters, GABA-A and GABA-B receptors have been shown in post-mortem brains of patients.26 In addition, clinical trials of glutamate receptor antagonists and GABA receptor agonists in Fragile X syndrome, which has many characteristics in common with ASD, have shown improvement of social impairments.27 In ADHD, an imbalance in glutamate and GABA signaling has not been reported before. Magnetic reasonance spectroscopy studies investigating GABA and glutamate in ADHD have, however, shown decreased prefrontal GABA levels in children, whereas in another study increased glutamatergic levels were found in comparable prefrontal brain areas.29 A recent study showed a role for GABA in impulsivity and response inhibition.30 In addition, BOLD activity during response inhibition has been related to striatal glutamate levels, mediating the effect of dopamine synthesis on inhibition.31The balance between glutamate and GABA is essential for proper brain development and functioning in these frontostriatal circuits.34 including ADHD and ASD. Deficits in inhibition can be linked to frontostriatal deficits in glutamate and GABA levels, which is consistent with findings in ADHD and ASD showing altered glutamate and GABA signaling.35 Genetic associations have been found for several candidate genes within the glutamatergic system. For instance, associations have been found for variation in the GRIN2B gene with both inattention and hyperactivity symptoms in ADHD,36 and both GRIN2A and GRIN2B have been associated with ASD.37 A genome-wide study investigating rare variants found over-representation of variants belonging to the metabotropic glutamate receptor genes in several ADHD cohorts.38 GABA transporter subtype 1 (GAT1) gene knockout mice have been shown to have decreased attention and increased impulsive behavior, relating this gene to ADHD symptomatology and difficulties in inhibiting impulses.39 In addition, mutations in the GABA-A receptor subunit-encoding genes GABRQ and GABRA3 have been found in two different families with ASD.40Genes encoding glutamate and GABA receptors and transporters are candidate genes for several neuropsychiatric disorders,43 In addition, top findings within genome-wide association studies of psychiatric disorders have been found to converge on common underlying biological processes, suggesting that multiple genetic variants within interacting sets of genes are involved in the etiology of psychiatric disorders.45Both ADHD and ASD are polygenic, with multiple genetic variants with small effects assumed to have a role in a major part of the patient population. Identifying single genetic variants with a small effect size can be challenging. Considering multiple genetic variants within the same analysis can potentially increase the total explained phenotypic variance and thereby boost the power of a genetic study. Earlier studies on cognitive disorders focusing on multiple variants within the same gene or within candidate genetic pathways already showed potential for this approach.46 Such an approach may help to better take into account the heterogeneity of the disorders as well as the extent of overlap between them.47 Complementary, because of the common deficit of inhibitory control in ADHD and ASD and because of its regulation by frontostriatal glutamatergic and GABAergic signaling, we also investigated in a subsample whether the genes for glutamate and GABA neurotransmission are involved in inhibitory control. We made use of the stop-signal reaction time (SSRT) of a behavioral response inhibition task, which is related to excitatory and inhibitory signaling in the frontostriatal circuit. We investigated multiple genetic variants within glutamatergic and GABAergic genes simultaneously using a gene-set approach with the MAGMA software. Subsequently, we investigated gene-wide associations within this data set.In the present study we explored, whether genes for glutamate and GABA neurotransmission are associated with ADHD and ASD traits. This was investigated by looking at the two symptom dimensions hyperactivity/impulsivity and inattention of ADHD. In addition, because of the evidence of a genetic overlap between ADHD and ASD and the glutamate–GABA imbalance hypothesis, we also investigated whether these neurotransmission gene sets moderate symptoms of ASD within an ADHD case-only sample. We used quantitative measures of ADHD and ASD symptom severity to characterize the disorders in terms of continuous distributions.49 The IMAGE study was designed to identify genes that increase ADHD susceptibility. Participants were 5–17 years old and of European Caucasian descent. Exclusion criteria included an IQ below 70, the presence of a classical autism diagnosis, epilepsy, known neurological disorders and any genetic or medical disorder associated with externalizing behaviors that might mimic ADHD. Details of the IMAGE sample have been described elsewhere.50The present study is part of the International Multi-center ADHD Genetics (IMAGE) study, an international collaborative study in seven European countries  and Israel.51) and questionnaires  were used to establish an ADHD diagnosis in children who were clinically diagnosed previously  for the standardized algorithm that was applied to derive the DSM-IV symptoms). To investigate symptom severity, a 4-point scale was used for the questions of the subscales for inattention and hyperactivity/impulsivity of the Conners parent rating scale. Severity was defined as the summed value of the questions per subscale.A semi-structured, standardized, investigator-based interview  reciprocal social interaction, (ii) communication and (iii) restricted, repetitive and stereotyped interests and patterns of behavior. Here, the score (ranging from 0 to 39) was used as a continuous measure of autism symptom severity. As a DSM-IV diagnosis of autistic disorder or Asperger syndrome was an exclusion criterion for the IMAGE study (see Sample), the autism symptoms could not exceed the threshold for clinical diagnosis.Autism spectrum symptoms were determined by administration of the Social Communication Questionnaire20 The latency of the stop process, the SSRT, is a reliable measure of inhibition, which has shown group differences between ASD and ADHD cases compared with controls, whereas unaffected siblings showed an intermediate pattern and SSRT correlates between siblings.20Response inhibition was measured using a Stop task in which participants are required to withhold their response to a stop signal as opposed to the more frequently occurring go-trials. This task was part of a larger neuropsychological assessment battery used in the Dutch part of the IMAGE study.56 An imputation approach was used with the Hapmap II release 22 data set.57 The imputed data underwent quality control, in which SNPs with an imputation score lower than 0.5 and minor allele frequency lower than 0.01 were excluded. After this step, 2 182 904 SNPs across the genome were retained, excluding the X-chromosome.Genome-wide genotyping of the IMAGE probands was performed as part of the Genetics Association Information Network study using the Perlegen genotyping platform, described previously.http://www.ingenuity.com). This is a frequently updated genetic database for genetic pathway analysis. Ingenuity generates these ‘canonical’ pathways based on experimental evidence from the scientific literature and many other sources, including gene expression and gene annotation databases to assign genes to different groups and categories of functionally related genes. We selected genes that are known to have a distinct role in either glutamate or GABA signaling  and for the SNPs within the genes plus the 100 kb flanking region. In addition, we investigated association with genes encoding glutamate/GABA receptors and transporters only because of their most central role in neurotransmitter signaling.62 In this way, we wanted to check whether our results are mainly driven by these genes.Selection of the glutamate (48 genes) and GABA (36 genes) gene sets was based on Ingenuity Pathway Analysis software (n=931) and for autism symptoms (n=922). Post hoc to the analysis of association to symptoms, in a subsample . To accSubsequently, we tested whether the genes in the gene set were jointly associated with the phenotype. This analysis may include a self-contained test, examining association of the set with the phenotype under a null hypothesis of no effect. However, the more valid competitive test examines whether a certain gene set of interest is more strongly associated with a phenotype than all other genes in the genome, correcting for gene size and density. In the competitive test, the effect of the gene set is compared with the background signal of all genes that are not in your gene set. Here, we only report the results of the competitive tests.post hoc in a subsample because of availability of behavioral data only for a small group.Initial testing considered gene-set associations with the phenotypes' inattention severity, hyperactivity/impulsivity severity and autistic symptom severity. The association to inhibition was performed P-value of <0.01 was considered statistically significant (Pcorrected=0.05/#gene-sets/#effective tests). For gene-wide association, a P-value of 0.0003 was considered statistically significant (Pcorrected=0.05/#genes/#effective tests).In addition, gene-wide and single SNP associations were considered. Because of the correlations between the phenotypic variables, corrections for multiple comparisons were based on the effective number of tests calculated by using the eigenvalues of the correlation matrix. Taking the correlations into account, our number of effective tests was 2.5. For the gene sets, a P<0.01) and weak correlations were found between hyperactivity/impulsivity symptom severity and autism symptom severity . No significant correlation was observed between inattention and autism symptom severity . Similarly, no significant correlations were found between any of the clinical ADHD or autism symptom scores and the SSRT .GRIA3 in the glutamate set, GABRA3, GABRE, GABRQ in the GABA set) were not included in the analysis because of unavailability of the X-chromosome variation in this sample. Dependent on whether flanking regions were included, the glutamatergic gene set included 42  or 47 genes, consisting of 9287 and 15 466 SNPs, respectively. For GABA, the gene set without a flanking region consisted of 30 genes and 3047 SNPs , whereas for the 100 kb condition the set consisted of 33 genes (7534 SNPs). See The selection of glutamate and GABA genes yielded a total of 84 genes . Four geP=0.009) shows that the association with the glutamate gene set was stronger compared with genes that were not in the gene set, which also survived correction for multiple comparisons. No significant associations were found for autism symptom severity and inattention symptom severity .The glutamate set showed association with hyperactivity/impulsivity symptom severity, as shown in P-values). In addition, no associations were found at the single variant level (data not shown).Single-gene analyses did not show any significant associations (P=0.044). See also the The more specific association analyses that included only genes encoding for glutamate receptors and transporters showed trend-significant association with hyperactivity/impulsivity symptom severity . In addition, no associations were found at the single variant level (data not shown). P=0.04); however, this did not survive correction for multiple comparisons. The more specific association analyses that included only genes encoding for GABA receptors and transporters also did not demonstrate any significant associations. See also the The GABA gene set was not significantly associated with any of the symptom dimensions. Single-gene analyses also did not show any significant associations  or whether its association to other genes or sets is equally possible (a nonsignificant test) by comparing it to the effect of genes that are not part of your gene set in the entire genome. A significant competitive test emphasizes the association to be specific for the tested gene set, whereas a nonsignificant test indicates that a part of the polygenic nature of the trait was captured. Self-contained tests do not take into account the overall level of association across the genome, the gene size  and the gene density. Competitive testing therefore has more merits.66 Furthermore, glutamate has been related to self-reported impulsivity in other disorders67 and to impulsive behavior in healthy adolescents.68 Previous work in the same sample showed that the hyperactivity/impulsivity domain of ADHD was also associated with candidate genetic pathways involved in dopamine/norepinephrine and serotonin signaling,41 suggesting that several genetic mechanisms contribute to hyperactivity/impulsivity symptoms in ADHD cases.The strongest finding in the current study was for the association of glutamate signaling-linked genetic variation with hyperactivity/impulsivity symptoms. This finding is in accordance with results from studies showing increased glutamate release from the prefrontal cortex of the spontaneously hypertensive rat, an animal model showing ADHD-like hyperactive behavior.24 Our results thus provide an interesting hypothesis for further investigating the underlying mechanism of the overlap between ADHD and ASD. Although symptoms coexist across ADHD and ASD, only weak correlations were found between hyperactivity/impulsivity symptom severity and ASD symptoms, and no correlations were found between inattention and ASD symptoms. The associations found in the current study could, therefore, not be related to the mere correlation between the studied phenotypes.In our study, we investigated the genetic underpinnings of autism symptom severity in an ADHD-only sample. ASD itself has been linked to glutamate and GABA by the excitatory/inhibitory imbalance hypothesis.69 In the present study, GABA was nominally significantly related to inhibition, which may reflect a disturbance of these inhibitory factors. Our finding was, however, limited by the small sample size used and needs replication in an independent data set before any conclusions can be drawn.A previous study indicated excitatory/inhibitory gene expression to be disturbed in ASD, suggesting reduction of the expression of inhibitory genes to be more pronounced compared with genes related to excitation and that the imbalance was mainly due to GABA disturbances.The current results support the hypothesis that glutamate and possibly also GABA are associated with ADHD and ASD traits. Unfortunately, current gene-set association analysis cannot reveal the direction of the observed effects, or whether the directions for the gene sets differ, which makes the interpretation of the findings in this study more difficult in terms of the imbalance theory for GABA and glutamate. In future studies, it would be interesting to add information on the neural mechanisms underlying inhibition by using imaging studies focusing on the frontostriatal circuitry.70 both of which have their drawbacks as well. Therefore, with our approach, we may have missed genes that are involved in glutamatergic and/or GABAergic signaling; however, we are confident that the genes that we included are directly involved in glutamate/GABA signaling.Our findings should be viewed in light of certain strengths and limitations. An important strength of the current study is the combination of multiple genetic variants, which enables us to better take into account the small effect sizes for single variants and genetic heterogeneity. A second strength is the use of a competitive test that tests association of the selected gene set against the background signal of other genes. Gene-set selection is, however, limited by the fact that the currently available databases are still incomplete and/or not sufficiently annotated. For the current study, we took the approach of only including genes that could be selected by using the canonical pathway database from Ingenuity. Other approaches would have been selection based on literature on glutamatergic and GABAergic genes with a possible role in ADHD, or using proteomic studies,61 this flanking region may also include neighboring genes that may dilute effects of variants in the selected genes. We therefore reported both approaches in the current manuscript.As the studied sample consisted of ADHD patients only, the current results should not be viewed as related to disorder risk either for ADHD or ASD. To this end, a case–control study should first be performed. In addition, a diagnosis of autistic disorder or Asperger disorder was an exclusion criterion in the IMAGE study. We could therefore not directly compare overlapping genetic underpinnings, but could only investigate the presence of autism behavior within the ADHD sample. It would be interesting for the future to replicate these findings in an ASD sample and to include patients with ASD with comorbid ADHD. Lastly, differences in results occurred based on the flanking region we used. Although inclusion of the 100 kb flanking regions of selected genes did not seem to lead to more explained variance in most cases, the difference between using the flanking region and not using it should be highlighted. The gene sets without the flanking region capture the SNPs in the genes, whereas in the gene sets with the 100 kb flanking region there were 4487 and 6179 extra SNPs present in the GABA and glutamate set, respectively, which are not part of the gene itself (see In conclusion, the current study supports the hypothesis that genes involved in glutamate neurotransmission are involved in ADHD as they were associated to hyperactivity/impulsivity severity. An overlapping trait between ADHD and ASD, altered response inhibition, may show an association with GABA; however, additional research is necessary to clarify this. In addition the present study shows that studying the aggregated effect of multiple genetic variants may overcome power problems in genetic association testing.


Attention-deficit/hyperactivity disorder (ADHD) is one of the most common disorders in early childhood. However, not many studies have been conducted on the prevalence and effect of ADHD on school performance in Ghana. This study sought to ascertain the prevalence of ADHD and its effect on school performance among primary school pupils in the Hohoe municipality of Ghana.This is a cross-sectional descriptive study that included 400 primary school pupils in the Hohoe Municipality of Ghana. The study adopted the disruptive behaviour disorder rating scale which includes the three subtypes of ADHD among pupils in the form of a close-ended questionnaire for data collection.The results revealed the overall prevalence of ADHD to be 12.8%. The males had a higher prevalence (14.4%) compared to the females (10.5%). For the subtypes, the prevalence was 8.0% for attention-deficit disorder, 8.5% for hyperactivity disorder and 3.8% for the combined subtype. In terms of school performance, the results showed that there was a significant difference in the school performance between ADHD-positive pupils and the negative status pupils among the various core subjects.Attention-deficit/hyperactivity disorder was quite prevalent among primary school pupils in the Hohoe Municipality, and has impacted negatively on their school performance. Screening of pupils for ADHD should be integrated into the school health services to enable early detection and management. Education is an important tool for national development. In the developing countries including Africa, where the literacy level is low, significant efforts are directed toward the need to increase the level of literacy through increasing priority for education . In GhanAttention-deficit/hyperactivity disorder is one of the most common disorders in early childhood . It is cWhile it was previously thought that children eventually outgrow ADHD, recent studies suggest that 30–60% of affected children continue to show significant symptoms of the disorder during adulthood . ADHD caIn spite of the fact that ADHD hinders school development in children and has adulthood negative effects, not much has been done on it. Little information also exists on the prevalence of ADHD and its effects on school children in Ghana. This study, therefore, sought to investigate the prevalence of ADHD and its effect on school performance by comparing the school performance of children diagnosed with ADHD and those without ADHD in the core subjects.The study was conducted in the Hohoe Municipality of the Volta Region, Ghana. It was conducted among pupils in 10 public and private schools between the ages of 6 and 12 in the classes of primary 1 to 6. This target population had no pupils with intellectual disability and their culturally compatible IQ tests would place them in the normal range of intelligence. The study adopted a descriptive cross-sectional study design.Simple random sampling (lottery method) was used to select ten schools for the study. The process was carried out by writing the names of all the primary schools in the municipality on sheets of paper that were folded and then randomly picking 10 out of them. Quota sampling technique was then used to select 400 respondents from all the classes in the schools selected.This study used the parent/teacher disruptive behaviour disorder rating scale (DBDRS) in the form of a close-ended questionnaire for data collection. This explores the prevalence of all three subtypes of ADHD among the pupils. The parent/teacher DBDRS is a standard rating scale used to screen children for the presence of ADHD and other disruptive behaviours diagnosed in early childhood. This rating scale was completed by the class teacher because it was assumed that the teacher might have been with the child for more than 3 months and, therefore, knew the child well enough to complete the rating scale on his or her behalf. The school performance of each pupil in the core subjects such as Mathematics, Science and English was also obtained from the school registers. The performance was, therefore, classified based on a grading of 70–100% for good performance, 40–69 for average and 39 or below for poor performance.The completed questionnaires were cleaned and checked for completeness. Stata version 12 was used to process the data. The results were presented in tables in the form of frequencies, percentages and proportions, while Chi square test was used to examine the effect of ADHD on school performance of the pupils. Pupils diagnosed with the disorder were labelled ‘positive’ while those without the disorder were labelled ‘negative’.A summary of the background characteristics of respondents has been presented in Table The total prevalence of ADHD has been presented in Table Results were also presented for the various subtypes of ADHD by the background characteristics of the respondents. The results for the first subtype, ADD, have been presented in Table A summary of the results for the second subtype, hyperactivity disorder (HD), is also presented in Table For age, the prevalence of the HD subtype was highest (11.7%) among respondents aged 11–12, but was lowest among respondents aged 8–10 (4.6%). However, there was no significant association between age of respondent and the HD subtype. With the classes, the highest (17.3%) prevalence was among class two pupils, followed by class six pupils (15.2%), while the least was observed among class one pupils (2.2%). As such, the results showed a significant association between class of respondent and the HD subtype (PV = 0.004).Table The study also sought to examine the possible effect of ADHD on the school performance of the respondents. Table For science, 49.3% of the respondents performed averagely, 42% had good performance, and only 9.0% performed poorly. Twenty percent of the ADHD-positive respondents had poor performance compared to 8.6% of the ADHD-negative respondents. Likewise, 6.7% of the ADHD-positive respondents attained good performance compared to 43.1% of the ADHD-negative respondents. Therefore, the study found a significant difference in performance in the Science subject between ADHD-positive and the ADHD-negative respondents (PV = 0.014).With regard to English language, 47.5% of the respondents were average performers while 43.7% were good performers with only 8.8% being poor performers. About 13% of the ADHD-positive respondents performed poorly compared to 8.6% for the ADHD-negative respondents who performed poorly. In the same way, none of the ADHD-positive respondents were good performers in English language compared to 45.4% of the ADHD-negative respondents who were good performers in the subject. The study, therefore, showed a significant difference in performance in the English language subject between the ADHD-positive and the negative respondents (PV = 0.002).This study found the total prevalence of ADHD among pupils in the Hohoe municipality to be 12.8%. In the context of the study area, this prevalence may be on the high side. On the other hand, a similar study also came out with a similar prevalence of 11.6% in Jeddah City, Saudi Arabia .Furthermore, the findings of the study showed prevalence of the subtypes as ADD 8.0%, HD 8.5%, and the combined subtype of 3.8%. In a similar study conducted in Lebanon, Bathiche  found thThe study showed a significantly higher prevalence among males compared to females in all the three subtypes of ADHD, making it a common disorder among the males than the females. Also, the results showed that sex and age of respondent had no association with all the three subtypes of the disorder. This could mean that the symptoms may not differ between the sexes and may not diminish as the child grows older. However, class of respondent had a significant association with two of the subtypes except the combined subtype. This may imply that regardless of the child’s sex or age, there were some significant differences among the various classes in terms of the ADD and the HD. It may also mean that the prevalence or the symptoms of ADD and HD may persist with the increase in the class or age of the respondents.The results further revealed that school performance in subjects such as Mathematics, Science and English was poorer among ADHD-positive respondents than the ADHD-negative respondents. Thus, not only was the school performance poor among the ADHD-positive respondents compared to the ADHD-negative respondents, but also, there were significant differences in the school performance of the two categories of respondents in all the three subjects. This means that ADHD has serious implications for the school performance of the respondents. A number of similar studies around the globe have, therefore, come out with similar findings. For instance, Daley and Birchwood  have comThe study showed that ADHD is quite a prevalent disorder among primary school pupils in the Hohoe Municipality, Ghana. The disorder has a dire implication for the school performance of the school pupils in the municipality. Hence, pupils with positive ADHD status are more likely to perform poorly in school compared to their counterparts with negative ADHD status. It is, therefore, imperative to integrate the screening of pupils for ADHD into the school health services in order to enable early detection and management of the disorder. Also, there is the need to intensively educate teachers on ADHD and how they can manage these pupils in order to help to improve their school performance. This can be done by the District Health Directorate through organizing workshops on ADHD for teachers.


Attention Deficit Hyperactivity Disorder (ADHD) is frequently linked with antisocial behaviour, yet less is known about its relationship with sociomoral reasoning, and the possible mediating effect of intelligence. A pilot study was designed to investigate the relationship between antisocial personality traits, intelligence and sociomoral reasoning in adults with ADHD. Twenty two adults with ADHD and 21 healthy controls, matched for age, gender and IQ completed a battery of measures including the National Adult Reading Test, Gough Socialisation Scale and Sociomoral Reflection Measure-Short Form. There was no difference between the groups and levels of sociomoral reasoning, despite the ADHD group reporting greater antisocial personality traits. Sociomoral reasoning was positively correlated with intelligence. Results from a hierarchical multiple regressions indicated that both antisocial traits and IQ were significant predictors of sociomoral reasoning, with IQ proving the most powerful predictor. Whilst antisocial personality traits may explain some of the variance in levels of sociomoral reasoning, a diagnosis of ADHD does not appear to hinder the development of mature moral reasoning. Intellectual functioning appears to facilitate the development of sociomoral reasoning. A further analysis showed that both ADHD and low sociomoral reasoning were significant predictors of antisocial traits. The current findings have important treatment implications. In summary, research to date is inconclusive as to whether those with ADHD  achieve lower levels of sociomoral reasoning than those without, and also whether antisocial traits/behaviours relate directly to immature moral reasoning. There is emerging evidence that a number of factors may intervene in any such relationships, particularly that of intelligence. In this pilot study we assessed whether sociomoral reasoning in adults with ADHD is related to relevant underlying factors, including antisocial personality traits and intelligence. It was hypothesised that (H1) sociomoral scores would be negatively correlated with antisocial personality traits , (H2) sociomoral scores would be positively correlated with estimated full-scale IQ; and (H3) sociomoral scores would be lower in adults with ADHD than healthy controls. A further aim was to explore the relationship between antisocial personality traits, sociomoral reasoning and intellectual functioning. Two hierarchical multiple regressions were conducted to examine, first the incremental contribution of antisocial personality traits and intelligence to sociomoral reasoning, and second, the incremental contribution of sociomoral reasoning and intelligence to antisocial personality traits.2.2.1.The sample consisted of 22 adults with ADHD, recruited from the Maudsley Adult ADHD Service, and 21 healthy controls. The ADHD Service is a UK national and specialist service, providing assessment and treatment for adults with ADHD. Inclusion criteria were aged between 18 and 65 years; IQ > 70 (i.e. no history of learning disability); no history of severe psychiatric disorder  or current major depressive disorder, and agreement to refrain from taking ADHD medication for 48 hours prior to the assessment. Participants were excluded if they had a primary diagnosis of substance abuse, history of autistic disorders, neurological impairment or head injury.Healthy controls were recruited from a University volunteer database and circular email list. Controls were recruited on the basis of the inclusion and exclusion criteria described above, with the additional exclusion criteria of a diagnosis of ADHD (in childhood or adulthood).Demographic information, together with information on ADHD subtype, was recorded from a review of clinical records. Relevant information was obtained from controls in a brief interview.2.2.2.2.1.This is a “production measure” of moral judgment, where participants are asked to verbalise their own reasoning to questions about moral dilemmas. It includes 11 questions . For each question the response choice is “Very important”, “Important” or “Not important” and the participant is asked to rationalise their answer. The response is scored using a set of heuristic rules detailed in the SRM manual Each SRMS can be further classified within a developmental range based on point boundaries as specified in the manual. This classification system includes the four main stages, with two transition stages between each, creating ten Global Stages, as follows: Stage 1: 100–125 (Transition stages between 1 and 2: 126–149 and 150–174); Stage 2: 175–225 (Transition Stages between 2 and 3: 226–249 and 250–274); Stage 3: 275–325 (Transition Stages between 3 and 4: 326–349 and 350–374); and Stage 4: 375–400.The SRM-SF is reported to be a valid measure among both males and females of various age-groups, including university students, adults, and delinquent adolescents r = 0.80 for the SRMS . The intra-class coefficient, based on absolute agreement, was also calculated and indicated good reliability (ICC = 0.78).For the current study, inter-rater reliability was obtained by second rater who randomly selected and blind-rated 10 questionnaires, 5 from each group respectively. Scoring agreement was within recommended parameters on all indices of inter-rater reliability in manual at 2.2.2.This is a 54 item “True” or “False” scale that measures the extent to which the individual has internalised the values of society 2.2.3.The NART was administered as a measure of estimated FSIQ 2.3.Participants gave informed written consent to participate and were informed that results would be anonymous and confidential and would not affect their care. Data reported here was collected as part of a larger battery of measures in a study of decision-making. Participants were informed that the purpose of the study was to examine how people make decisions. Participants with ADHD were asked to refrain from taking stimulant medication for 48 hours prior to the assessment because the current assessment was administered at the same time as a study of a cognitive decision-making task that required patients to be off medication. This request has been used across various studies and there is no evidence to suggestion that discontinuation leads to withdrawal or exacerbation of symptoms 3.3.1.N = 15 Methylphenidate; N = 4 Dexamfetamine; and N = 1 Atomoxetine). The control group consisted of 21 participants, with a mean age of 35.6 years and a mean of 16 years of education. Both ADHD patients and controls were predominantly white British .The ADHD group consisted of 22 participants , with a mean age of 36.9 years, and a mean of 15 years of education. Eleven had primarily inattentive subtype, eight had combined inattentive-hyperactive/impulsive subtype and three had not been classified. Twenty participants (91%) reported taking medication for ADHD (3.2.2(1) = 0.30, P = 0.59, years of education (t(41) = 1.63, P = 0.11), age (t(41) = -0.40, P = 0.69), or intellectual functioning  =1.02, P = 0.31; see (41) = 3.7, P < 0.001), with the ADHD group indicating significantly more antisocial personality traits . Uninsured men are 56% less likely than men with public insurance to agree they are confident in knowing when to get medical care . Men in good and very good/excellent health were 1.57 and 2.11 times more likely to agree they are confident in knowing when to get medical care than those in poor health .3.4.1.N = 43), a significant positive correlation was found between the SRM-SF and the GSS . When the groups were analysed separately, SRM-SF and GSS was significantly correlated for the ADHD group only . See For the whole group (3.4.2.N = 43), a significant positive correlation was found between the SRM-SF and predicted FSIQ . When the groups were analysed separately, SRM-SF and predicted FSIQ was significantly correlated for both the ADHD group  and control group . See For the whole group (3.5.N = 39)  entry method was conducted on the data (N = 39) . Age, geP = 0.83 and P = 0.11, respectively) but Model 3 was significant (P < 0.01). In Model 1, none of the predictors were significant and in Model 2, only the GSS score for antisocial traits was significant (P < 0.05), which explained 10% of the variance in sociomoral reasoning. In Model 3, both the GSS score and IQ were significant predictors  of sociomoral reasoning; the model as a whole accounting for 34% of the variance in moral reasoning.Models 1 and 2 were not significant  were entered in the first block to account for their possible effects; the SRM-SF total was added in the second block, followed by the NART estimated FSIQ in the third block see .P < 0.05, P < 0.001 and P < 0.01 respectively). In Model 1, only group was significant (P < 0.01), accounting for 21% of the variance in antisocial behaviour. In the Model 2, age, group and sociomoral reasoning were significant , explaining 32% of the variance in antisocial behaviour. Adding NART estimated FSIQ in Model 3 did not improve the amount of predictive variance in antisocial behaviour already explained by age, group and sociomoral reasoning.Models 1, 2 and 3 were all significant . The hypothesis of a significant positive correlation between sociomoral reasoning and intelligence (H2) was supported for both groups. The hypothesis that adults with ADHD would obtain lower sociomoral scores than healthy controls (H3) was not supported. The two groups were matched for gender, age and estimated IQ. Results from the first hierarchical multiple regression indicated that when controlling for age, gender and diagnostic classification, both antisocial traits and IQ were significant predictors of sociomoral reasoning, with IQ proving the most powerful predictor. Indeed, IQ added 24% to the variance of sociomoral reasoning above and beyond that of antisocial personality traits. This suggests that IQ has a unique variance in relation to sociomoral reasoning, which should be addressed in future research. Results from the second hierarchical multiple regression indicated that both diagnostic group and sociomoral reasoning were significant predictors of antisocial traits, explaining a similar amount of variance in the final model. Therefore, both appear to be important in explaining the amount of antisocial personality traits among the participants.As hypothesised, intelligence was strongly associated with sociomoral reasoning perhaps reflecting that intellectual function plays a protective role in the development of mature moral reasoning. The finding supports previous research which reported that intellectual functioning was an important mediator between sociomoral reasoning and illegal behaviour Some confounding variables must be acknowledged which were not controlled for in the current study, such as ADHD subtype. As this was a pilot study, the sample size was small. A larger sample size would have allowed the division of subgroups  to assess the relative impact of each on sociomoral reasoning and antisocial personality traits. Whilst participants refrained from taking their medication for 48 hours prior to the assessment, this is unlikely to have unduly influenced their responses to the sociomoral assessment which draws on an individual”s experiential understanding of the world and social values. However the sample were recruited from clinic referrals and most had a history of treatment with ADHD medication; their experiences  may differ from epidemiological samples and those who have not had access to treatment. The assessment relied on self-report methods; hence it is possible that antisocial traits and/or sociomoral responses were not reliably reported. However the “production measure” presentation style of the SRM-SF reduces the risk of socially desirable responding as the individual is asked to expand and rationalise their answers.These findings may have important implications for treatment. In the current pilot study, those attending an ADHD outpatient clinic reported significantly greater antisocial traits compared with the normal population. It is important that psychological treatments are provided to address both ADHD and comorbid problems


The genetic relationships reported by recent studies between Sherpas and Tibetans are controversial. To gain insights into the population history and the genetic basis of high-altitude adaptation of the two groups, we analyzed genome-wide data in 111 Sherpas  and 177 Tibetans (Tibet and Qinghai), together with available data from present-day human populations.Sherpas and Tibetans show considerable genetic differences and can be distinguished as two distinct groups, even though the divergence between them  is much later than that between Han Chinese and either of the two groups . Sub-population structures exist in both Sherpas and Tibetans, corresponding to geographical or linguistic groups. Differentiation of genetic variants between Sherpas and Tibetans associated with adaptation to either high-altitude or ultraviolet radiation were identified and validated by genotyping additional Sherpa and Tibetan samples.Our analyses indicate that both Sherpas and Tibetans are admixed populations, but the findings do not support the previous hypothesis that Tibetans derive their ancestry from Sherpas and Han Chinese. Compared to Tibetans, Sherpas show higher levels of South Asian ancestry, while Tibetans show higher levels of East Asian and Central Asian/Siberian ancestry. We propose a new model to elucidate the differentiated demographic histories and local adaptations of Sherpas and Tibetans.The online version of this article (doi:10.1186/s13059-017-1242-y) contains supplementary material, which is available to authorized users. EPAS1 (MIM 603349) and EGLN1 (MIM 606425), two key genes in the hypoxia inducible factor (HIF) pathway that detect and react to oxygen supply changes ) plays pivotal roles in clearing oxidants like reactive oxygen species (ROS), which greatly increase under hypoxic conditions ) encodes proteins belonging to the family of nitric oxide synthases  and may regulate oxygen delivery by local paracrine control of vasomotor tone and central control over cardiovascular and respiratory responses  for t generations ago with chip array data (panels 1 and 2), where c is the recombination distance between loci in Morgans (M) and t = 1/(2c) [rLD2 values were adjusted as rLD2 – (1/n), where n is the sample size prior to the calculation of Ne. We calculated Ne for each subgroup with recombination distances ranging from 0.01 to 0.25 centimorgan (cM), corresponding to 125 to 5000 years ago, with 25 years per generation. The divergence times measured by TF in generations based on the chip array dataset (panel 2) were also estimated [TF = 2NeFST, where Ne is the harmonic mean Ne of two target populations. Divergence times between SHP, TBN, and HAN were also estimated using G-PhoCS [We applied multiple sequentially Markovian coalescent (MSMC) analysis  to inferce panel . Ne estneration . Besides= 1/(2c) . As expestimated . Here T G-PhoCS  with oneR package REHH [BEAGLE v4.0 [ALDH3A1 and 30 randomly selected variants shared by SHP and non-SHP   and Inteage REHH . Cross-page REHH . PopulatGLE v4.0 . A mediaGLE v4.0 . The hap Project ) residin Project , and GER Project  scores,  Project . Lastly,


Leymus chinensis, the dominant plant species in Inner Mongolia grassland, to various mowing frequencies in a 17‐yr controlled experiment. Affected by mowing, the concentrations of nitrogen (N), phosphorus (P), and carbon (C) in leaves and stems were significantly increased, negatively correlating with plant sizes. Moreover, we found significant trade‐offs between the concentrations and accumulation of N, P, and C in plant tissues. The N:P ratios of L. chinensis aboveground biomass, linearly correlating with plant size, significantly decreased with increased mowing frequencies. The ratios of C:N and C:P of L. chinensis individuals were positively correlated with plant size, showing an exponential pattern. With increased mowing frequencies, L. chinensis size was correlated with the allocation ratios of leaves to stems of N, P, and C by the tendencies of negative parabola, positive, and negative linear. The results of structure equation modeling showed that the N, P, and C allocations were co‐regulated by biomass allocation and nutrient concentration ratios of leaves to stems. In summary, we found a significant decoupling effect between plant traits and nutrient strategies along mowing frequencies. Our results reveal a mechanism for how long‐term mowing‐induced changes in concentrations, accumulations, ecological stoichiometry, and allocations of key elements are mediated by the variations in plant sizes of perennial rhizome grass.While mowing‐induced changes in plant traits and their effects on ecosystem functioning in semi‐arid grassland are well studied, the relations between plant size and nutrient strategies are largely unknown. Mowing may drive the shifts of plant nutrient limitation and allocation. Here, we evaluated the changes in nutrient stoichiometry and allocation with variations in sizes of  We addressed three main questions: (1) How does mowing influence the relationships between L. chinensis size and C, N, and P concentrations in leaves and stems? (2) How does mowing intensity affect the relationship between L. chinensis C:N:P stoichiometry and morphological plasticity? (3) How does mowing intensity affect C, N, and P allocation patterns in L. chinensis with varying plant sizes?In addition, typical steppes dominated by 22.1L. chinensis  and Stipa grandis  typically dominated the grassland communities of our study area  of the Chinese Academy of Sciences in the Xilinhot, Inner Mongolia Autonomous Region, P.R. China. The semi‐arid continental climate of this area is characterized by a mean (1998–2013) precipitation of 253.45 mm and a mean temperature of 13.77°C during grassland growth season (April to August). Maximum precipitation usually falls during the growing season , coinciding with the highest temperatures in this period. The coefficient of variation for precipitation is over 20% because of the inter‐annual variability  M1/1, mowing once a year; and (4) M2/1, mowing twice a year. The mowing was conducted each year on 16 August (or 1–3 days later depending on the weather) for the M1/2 and M1/1 treatments and on 15 June and 15 September for the M2/1 treatment. The lawn mower was used to cut the grass to a 6‐cm stubble height , leaf width (LW), leaf number (LN), stem length (SL), stem diameter (SD), and plant height (PH), has been described in our previous study , stem biomass (SBM), and aboveground biomass (ABM).Using the method described by  was performed to determine the relationships among the phenotypic traits and the effects of different mowing frequencies on these traits  given by the following equation  given by the following equation:L. chinensis N, P, and C allocation patterns were analyzed by structural equation modeling (SEM) method . The utility of each nutrient index within the SEM was compared based on a number of measures, including the power of the particular model to explain the variation in L. chinensis N, P, and C allocation (r2), measures of model significance and fit (χ2), and the significance of the functional trait variables within the model . The exception to this is the increasing of LN per L. chinensis individual under light mowing disturbance . The CV values of plant traits were significantly correlated with PI . The N:P ratios in leaves were significantly higher than those in stems . Ratios of C:N and C:P of the whole L. chinensis individual were positively correlated with plant size, following an exponential pattern . The allocation ratios were as follows: N > P > C (p < .05, Figure L. chinensis were correlated with the allocation ratios of N, P, and C by the tendencies of parabola, positive, and negative, respectively (p < .05, Figure We observed three different response patterns in the allocation ratios of N, P, and C from leaves to stems Figure . Allocat4L. chinensis is sensitive to habitat changes and various disturbances (Li, Liu, et al., L. chinensis.As a dominant species in eastern Eurasian temperate grasslands, L. chinensis phenotypic traits tend to be reduced in response to long‐term mowing, which is consistent with the results from previous studies in many mowing experiments in semi‐arid grasslands (Li, Wu, et al., Our findings show that the majority of The contents of key nutrient elements in aboveground tissues are important for plant growth and development in nutrient‐poor ecosystems (Fay et al., L. chinensis growth through causing N deficiency, that is, increasing N requirement of the plant and decreasing N availability in the soil. Moreover, we detected that the N:P ratios in leaves were significantly higher than those in stems of L. chinensis. We speculate that this is most likely associated with the adaptive changes in allometry between leaves and stems, as shown previous studies (Li, Wu, et al., The stoichiometry of C:N:P in plant tissues is associated with plant growth strategies, which strongly influence its adaptation to various abiotic or abiotic disturbances, such as mowing (Hillebrand & Kahlert, L. chinensis leaves and stems.To some extent, the ratios of C:P and C:N ratios in plant tissues can be a predictive indicator for nitrogen‐ and phosphorus‐use efficiency (Hidaka & Kitayama, L. chinensis at the individual scale, suggesting that an L. chinensis individual invests more of its photosynthetic products in leaves than in stems during plant miniaturization. In general, leaves are among the most important functional organs of a plant and are required for photosynthesis, transpiration, and nutrient use (Bloomfield, Farquhar, & Lloyd, Our results demonstrated that the decrease in plant height after long‐term mowing corresponds with an increased C allocation from leaf to stem of 5L. chinensis populations. In plants affected by mowing, the concentrations of N, P, and C in leaves and stems were significantly increased, negatively correlating with plant individual sizes. Moreover, the results show significant trade‐offs between the concentrations and accumulation of N, P, and C in leaves, stem, and aboveground biomass. The N:P ratios of L. chinensis aboveground biomass, linearly correlating with plant size, significantly decreased with increasing mowing frequencies. In contrast, the C:N and C:P ratios of L. chinensis individuals were positively correlated with plant size and showed an exponential pattern. With increasing mowing intensity, L. chinensis size was correlated with the allocation ratios of N, P, and C by the tendencies of parabola, positive, and negative, respectively. Structure equation modeling showed that the allocation patterns from leaves to stems in N, P, and C were co‐regulated by biomass allocation and nutrient concentration ratios of leaves to stems. Our results reveal a mechanism for long‐term mowing‐induced changes in concentration, accumulation, ecological stoichiometry, and allocation of key elements mediated by the variations in plant sizes of perennial rhizome grass.We conclude that mowing intensity is negatively correlated with phenotypic trait values and positively correlated with variability in plant functional traits in None declared.Z.Y.L., T.B., and X.L.L. designed the study; Z.Y.L., J.S., and X.L.L. analyzed the data; Z.Y.L. and H.M. carried out the experiment; all co‐authors contributed to writing and discussions. Click here for additional data file.


Attention deficit hyperactivity disorder (ADHD) is a debilitating behavioural disorder affecting daily ability to function, learn, and interact with peers. This publication assesses the role of omega-3/6 fatty acids in the treatment and management of ADHD. A systematic review of 16 randomised controlled trials was undertaken. Trials included a total of 1,514 children and young people with ADHD who were allocated to take an omega-3/6 intervention, or a placebo. Of the studies identified, 13 reported favourable benefits on ADHD symptoms including improvements in hyperactivity, impulsivity, attention, visual learning, word reading, and working/short-term memory. Four studies used supplements containing a 9 : 3 : 1 ratio of eicosapentaenoic acid : docosahexaenoic acid : gamma linolenic acid which appeared effective at improving erythrocyte levels. Supplementation with this ratio of fatty acids also showed promise as an adjunctive therapy to traditional medications, lowering the dose and improving the compliance with medications such as methylphenidate. ADHD is a frequent and debilitating childhood condition. Given disparaging feelings towards psychostimulant medications, omega-3/6 fatty acids offer great promise as a suitable adjunctive therapy for ADHD. Attention deficit hyperactivity disorder (ADHD) is a common child-onset neurodevelopmental disorder occurring in children, adolescents, and adults, with an estimated prevalence of 5 to 7 per cent across cultures . ADHD teLong-chain polyunsaturated fatty acids (LCPUFA) and particularly omega-3 fatty acids have been under the spotlight for decades. They are key regulators of brain neurotransmission, neurogenesis, and neuroinflammation, all having an important role in the prevention and treatment of psychological and behavioural dysfunction disorders . EicosapThe omega-6 fatty acid gamma linolenic acid (GLA) is also important in the generation of arachidonic acid (ARA) which is abundantly present in in the brain , 13. A rOmega-3 deficiencies have been found to alter dopaminergic and serotonergic systems, potentially modifying cerebral receptors in specific regions of the brain . EPA andA number of studies have measured LCPUFA status in individuals with ADHD. One study conducted on young adults 22.3 to 24.3 years) found the proportion of omega-3 fatty acids was significantly lower in the plasma phospholipids and red blood cells of ADHD participants compared with controls, whilst levels of saturated fatty acids were higher . Another.3 years Given that the human brain is nearly 60 per cent fat and the central role that EFAs have to play in the structure, synthesis, and functions of brain neurotransmitters , the preThe National Centre for Biotechnology Information (NCBI) search engine (PubMed) was used to extract relevant publications. English-language, human, randomised controlled trials (RCTs) published between 2001 and March 2017 were included. Data files were extracted from the NCBI collection depository and imported into Covidence software used to create systematic reviews.Publications were excluded if they were not a RCT, did not use participants with ADHD, or were conducted on older adults with ADHD. For inclusion studies needed to be conducted on children or young people (up to 18 years of age), participants were considered to have ADHD at baseline and were taking an omega-3/6 supplement, including EPA, DHA, or GLA. Publications were further included if the full text was available or could be purchased.The search terms “attention deficit hyperactivity disorder” or “ADHD” were combined with “long-chain n-3 fatty acids”, “omega-3/6 fatty acids”, “docosahexaenoic acid”, “eicosapentaenoic acid”, and “gamma linoleic acid”. Data extracted from each article included (1) author(s) and country of research, (2) subjects , (3) mean age, (4) study design and methods, (5) dose of supplement, and (6) main findings.The NCBI search identified 77 papers. After a further adjustment for replica papers, 28 articles remained for assessment. Of these, 12 papers were discarded after reviewing the abstracts and article content as they did not meet the inclusion criteria. This left 16 RCTs for general review. As shown in A total of 16 RCTs studied interrelationships between combinations of omega-3/6 fatty acids and ADHD symptoms . Of thesOne of the most recent studies found that children (aged 6 to 12 years) receiving omega-3/6 fatty acids (Equazen) providing 558 mg EPA, 174 mg DHA, and 60 mg GLA in a 9 : 3 : 1 ratio over a period of 12 months did not need such a high dose of MPH to manage and reduce their ADHD symptoms (0.8 mg/kg/day versus 1.0 mg/kg/day). The completion rate was also higher in this group, whilst the withdrawal rate and the incidence of adverse events were significantly lower. These findings indicate that omega-3/6 fatty acids may act as a useful adjunctive therapy to MPH, helping to improve tolerability, dosing, and adherence .A 12-week RCT comprised of 76 male adolescents with ADHD using a similar dose of fatty acids found that supplementation improved blood levels of EPA, DHA, and total omega-3 fatty acids, though no effects on aggression, impulsivity, or anxiety were seen, possibly due to the smaller study sample size and shorter study length of this trial . Two othThree studies used functional foods providing LC3PUFA. In a double-blind RCT, the ingestion of 10 g margarine daily providing 650 mg EPA/DHA improved parent-rated attention in children with ADHD after 16 weeks in 8–14-year-olds who continued with their usual medication. Another trial using “omega eggs” providing EPA and DHA found that daily consumption by 7–12-year-olds over 3 months significantly improved visual acuity and the red blood cell fatty acid profile of children with lower intelligent quotients or ADHD, indicating that the DHA content of ordinary eggs may not be sufficient . Anotherα-linolenic acid ameliorated some ADHD symptoms amongst 7–13-year-olds, although no significant differences were found, possibly because children were unmedicated [Three studies concluded that there were limited associations between omega-3/6 fatty acid supplementation and ADHD outcomes. In one study, Conners' Parent and Teacher Rating Scale was not regarded as being sensitive enough to detect small improvements in the behaviour of male adolescents . Anotheredicated . Earlieredicated .Remaining studies showed general benefits. An Australian study found that children with ADHD who had increased erythrocyte EPA + DHA levels had significantly improved spelling and attention and reduced oppositional behaviour, hyperactivity, and cognitive problems . An omegOther trials showed findings to be more prominent in certain subgroups. For example, a large trial of 200 children found that supplementation with phosphatidylserine-omega-3 reduced ADHD symptoms in a subgroup of hyperactive-impulsive, emotionally and behaviourally dysregulated ADHD children compared with the placebo . AnotherThe aetiology of ADHD is complex and multifactorial though diet, nutrition, and abnormalities in the metabolism of LCPUFA are thought to have underlying roles , 22. TheTaken together, a growing body of clinically proven evidence suggests that dietary supplementation using omega-3/6 PUFAs may help to augment conventional ADHD treatments. Research carried out in Mexico at the National Health Institute with children prescribed with MPH and taking omega-3/6 fatty acids found that they required lower doses of the prescription medicine and experienced fewer medication-related side effects . SimilarThese studies are further supported by evidence from meta-analytical studies. Evidence collated from ten trials comprised of 700 children has shown that omega-3 supplementation, with higher doses of EPA had modest effects in the treatment of ADHD, indicating potential roles in augmenting traditional pharmacological treatments, whilst providing an option for families who may decline other psychopharmacologic options . An earlIn terms of study outcomes, most focused on ADHD symptoms. Whilst reduced hyperactivity and impulsivity were reported in most studies , 38, 40,With regards to dose a 9 : 3 : 1 ratio of EPA (558 mg) to DHA (174 mg) and GLA (60 mg) was used in four studies –34. In tInconsistencies of lack of findings in some trials may have been attributed to interventions being too short. As erythrocytes survive in the body for 120 days, supplementation trials shorter than 12 weeks (84 days) may not be sufficient enough to detect changes in LCPUFA compositions . EquallyIn conclusion, ADHD is a debilitating neurodevelopmental disorder that can impact heavily on children and young people's behaviour, mental health, education, and social/family lives. Whilst conventional medications have a role to play in the management of ADHD symptoms, new clinically trialled evidence indicates that omega-3/6 supplementation programmes can provide a promising adjunctive therapy, lowering the dose of psychopharmacologic medications needed and subsequently improving compliance with these. It also appears that parents are looking for complementary treatments for their children to use alongside traditional treatments.


These findings suggest that health promotion programs aiming to improve children’s diets and active lifestyles may also reduce the public health burden of ADHD.Attention-deficit and hyperactivity disorder (ADHD) in children and adolescents is a global public health burden. Identification of health-related behavioral risk factors including diet quality and physical and sedentary activities for ADHD is important for prioritizing behavioral intervention strategies to improve mental health. This study aimed to examine the association of diet quality, physical activity, and sedentary behaviours in childhood with ADHD throughout adolescence. We linked data from grade five students aged primarily 10 and 11 years old who participated in a population-based lifestyle survey in the Canadian province of Nova Scotia with their administrative health care data. We applied negative binomial regression methods to examine the associations between health behaviours and ADHD. Of the 4875 students, 9.7% had one or more diagnoses of ADHD between the ages of 10/11 and 18 years. The number of primary diagnoses with ADHD was statistically significantly lower among students with better diet quality, higher levels of physical activity, and those that spent less time playing computers and video games ( Attention-deficit and hyperactivity disorder (ADHD) is one of the most frequently diagnosed mental health disorders among children and adolescents, and has been acknowledged as a global public health burden . EpidemiStudies in the etiology of ADHD have predominantly focused on genetic and environmental factors ,20. SomeCross-sectional and systematic review studies that examined the associations between physical activity (PA) and ADHD provide some support for the positive effects of PA on alleviating inattentive and hyperactive symptoms of ADHD ,28,29,30Further investigation of the predictive effect of these health-related behaviours on ADHD will help elucidate prospective relationships between diet quality, specific types of PAs and sedentary behaviours, and the future development of ADHD. The information is important for public health policy makers to allocate scarce resources to the health interventions and preventive actions targeted at promoting healthy diets and active living behaviours among youth to reduce the burden from ADHD and to enhance their mental health.The objective of the present study is to investigate the association between diet quality, physical activity and sedentary behaviours, and physician diagnosed ADHD throughout adolescence in a cohort of grade five students.The 2003 Children’s Lifestyle and School Performance Study (CLASS) is a population-based survey among grade five students who are primarily 10 and 11 years old, and their parents, in the province of Nova Scotia, Canada. Of all 291 provincial public schools with grade five students, 282 schools participated in the study. The participation rate was 51.1% per school. Of the 5517 grade five students in the participating schools who received parental consent to participate in the study, 5200 students (94.3%) completed the surveys .The CLASS study consisted of a home survey that was completed by parents, a student survey that included questions on the frequency of physical activities, self-esteem, and time of sedentary behaviours, and a Canadian version of the Harvard Youth/Adolescent Food Frequency Questionnaire (YAQ) . The YAQThe administrative health data were derived from the Medical Services Insurance (MSI) database and the Canadian Institute for Health Information Discharge Abstract Database (CIHI DAD). The MSI database is administered by Medavie Blue Cross for the province of Nova Scotia and contains records for each insured health service rendered by a physician (including emergency room visits) and paid for by the Nova Scotia provincial health care system. The CIHI DAD contains a comprehensive administrative transcription of each admission to a Nova Scotia hospital facility. Both of these databases contain individual patient-level information including patient demographic characteristics, visiting physicians, and diagnoses received. Data were available from 1992 (when the grade 5 students who participated in 2003 were born) to 2011 (when participating students turned 18 years of age).Of the 5200 students who completed the survey, 4875 (94%) were provided valid health card numbers and were successfully linked with the administrative health data.The exposure variables in the present study were diet quality, PA and sedentary behaviours among grade five students. On the basis of students’ nutrient intake and dietary information from the YAQ  and CanaThe CLASS included questions from the National Longitudinal Survey for Children and Youth  on playiParticipants are considered to have an attention deficit and hyperactivity disorder if they received one or more diagnoses of attention deficit disorder, hyperactivity disorder, hyperkinetic syndrome, or hyperkinetic conduct disorder according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or Tenth Revision, (ICD-10-CA). The ICD-9 and ICD-10 codes for ADHDs in this study include 314.xx (ICD-9-CM) and F90.xx (ICD-10-CA). All the primary diagnoses for ADHDs between 2003 (children’s age 10 to 11 years) and 2011 (participants turned 18 years of age) were considered.We considered gender, household income, parental educational attainment, residential location, body weight status, and self-esteem as potential confounders in the relationship between the health behaviours and ADHD. Each of these variables are established predictors for ADHD ,23,42. TEleven questions on the measurement of self-esteem of the students were included in the CLASS survey, each with three response levels: (1) Never or almost Never; (2) Sometimes and (3) Often or almost Always . By meanWe applied univariate (unadjusted) and multivariable (adjusted) negative binomial regression models (NBMs) to examine the association between diet quality, PA, sedentary behavior, and the diagnosis of ADHD. The multivariable NBM was adjusted for the confounding influence of students’ gender, residency, household income, parental education, body weight, and self-esteem. The multivariable regression was also adjusted for energy intake as per established recommendations for the analysis of food frequency data . The numAs response rates in residential areas with lower household incomes were slightly lower than the average, we weighted the analyses using response weights such that the estimates represent the population of grade five students in the province of Nova Scotia . MissingThe data collection and parental informed consent forms of the CLASS study were approved by the Human Research Ethics Boards of Dalhousie University and the University of Alberta. The data linkage of the CLASS survey data with the administrative health data was approved by the Human Research Ethics Boards of the University of Alberta and Dalhousie University, and by Health Data Nova Scotia, the custodian of the administrative health data.n = 469) had one or more health care provider contacts with a diagnosis of ADHD following the 2003 CLASS survey. Students who reported a poorer diet quality, reported less PA, and reported more time using a computer or playing video games in the 2003 survey, were more likely to be diagnosed with ADHD in subsequent years  and restriction or elimination of the detrimental foods  may help to reduce symptoms of ADHD among child and youth patients . HoweverRecent studies about the associations between dietary or nutrient patterns and ADHD in children and adolescents ,25,26,27Our study adds to the existing research on the physical activity and ADHD relation by revealing a difference in the number of diagnoses for ADHD between children engaged in organized  and unorganized  sports. We found an independent association between PA with a coach, where children who participated in moderate physical activities (one to three times per week) were less likely to seek health care services for ADHD than children who never played sports or undertook PA with a coach. This is consistent with some previous studies showing that PA is inversely related to the diagnosis or symptoms of ADHD ,31. We aThe present study revealed that children who spent excessive time (≥5 h/day) in playing computer and video games were more likely to be diagnosed with ADHD later than children who used the media less than one hour a day. This is consistent with studies showing that playing video games are linked to increased attention problems and ADHD among children and adolescents ,34. EvidThe present study expands the analysis for associations between self-esteem in childhood and ADHD in adolescence. We found that children with more externalizing problems, low self-perception (body esteem and looks for future), and low social-perception (being victims of bullying and lack of friends) were more likely to receive a subsequent diagnosis of ADHD relative to children with high self-esteem on these components. These findings add to the existing literature on the relationship between self-esteem and mental health by addressing the impact of component-specific self-esteem in childhood on future ADHD .We observed gender differences in the diagnosis of ADHD for the background variables of parental education, residency, household income, and the sedentary behaviours of the use of computer and video games and watching TV. These results underscore the importance of integrating gender differences in health promotion efforts to reduce the burden of the mental health disorder from ADHD among children and youth. Additionally, the gender differences in the association between the self-esteem variables and ADHD suggest that the influence of self-esteem of children on ADHD may be different among boys and girls. Poor social-perception is associated with increased diagnoses of ADHD among boys, while low self-esteem on self-perception and more internalizing problems are related to increased diagnoses of ADHD among girls.In the present study, we found that physical activity, diet quality, and the use of a computer or playing video games in childhood had an impact on diagnoses of ADHD during adolescence. As ADHD is usually considered a chronic mental disorder with impairments persisting from childhood to adolescence and adulthood, identification of the onset of ADHD from childhood to early adulthood would be an additional interesting topic in future research. It may also be possible that the diet, physical activity, and sedentary behaviours of children and youth have also been affected by the symptoms of ADHD . For exaThere are several strengths in this study. The analysis was conducted in a large representative sample of grade five students in the Canadian province of Nova Scotia with linked longitudinal administrative health data from childhood to early adulthood over an 8-year follow up period. The prospective design provides more robust evidence than cross-sectional studies for the directionality between the exposures and the mental health disorder outcome. The large sample allowed us to adjust the confounding influence of a variety of socio-demographic and self-esteem variables in the negative binomial regression analysis. The utilisation of health care provider diagnoses of mental health disorders provides valid and clinically meaningful assessments for ADHD.Limitations should also be acknowledged when the study results are interpreted. The child physical activity, sedentary behaviours, and self-esteem were self-reported, subject to recall bias. Dietary assessment was also based on self-reporting which is prone to error, though the Harvard YAQ measure has been validated in this population of children . The stuThis study reveals that diet quality, physical activity, and the use of computer and video games among children are associated with increased diagnoses of attention deficit and hyperactivity behaviours later in adolescence. The findings suggest that broader investments in programs and interventions that promote healthy eating and active lifestyles in childhood may help prevent the development of ADHD and alleviate the public health burden and health care services associated with this mental disorder.


Executive function (EF) deficits are major impairments in adults with attention deficit/hyperactivity disorder (ADHD). Previous studies have shown that the insula is involved in cognitive and EFs. However, the insula is highly heterogeneous in function, and few studies have focused on functional networks which related to specific insular subregions in adults with ADHD. We explored the functional networks of the insular subregions . Furthermore, their correlations with self-ratings of ecological EFs, including inhibition, shifting, and working memory were investigated.Resting-state functional magnetic resonance imaging data in 28 adults with ADHD and 30 matched healthy controls (HCs) were analyzed. The seed-based resting-state functional connectivity (RSFC) of the insular subregions was evaluated. We also investigated their associations with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) inhibition, working memory, and shifting factor scores.Compared with HCs, adults with ADHD showed altered RSFC of the AI, with the precuneus, precentral gyrus, and inferior temporal gyrus extended to the middle temporal gyrus, lingual gyrus, and superior occipital gyrus, respectively. There were no significant differences in RSFC of the MI and PI between the two groups. Within the HC group, working memory scores were associated with the RSFC of AI with precuneus and temporal gyrus. However, there was no correlation between these variables in the ADHD group.The study evaluated RSFC patterns of the insular subregions in adults with ADHD for the first time. Altered RSFC of the AI which is a crucial region of salience network (SN) and part of regions in default mode network (DMN), were detected in adults with ADHD in both results with and without global signal regression (GSR), suggesting that disrupted SN-DMN functional connectivity may be involved in EF impairments in adults with ADHD, especially with respect to working memory. Deficits of the AI which is involved in salient stimuli allocation, might be associated with the pathophysiology of ADHD. The inconsistent results of MI and PI between analyses with and without GSR need further exploration. Attention deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder characterized by developmentally inappropriate symptoms of inattention, hyperactivity, and impulsivity . ADHD haExecutive function (EF) deficits are major impairments in ADHD. They include inhibition, working memory, shifting, and so on –10. On tThe pathophysiology of EF impairments in patients with ADHD is still unclear. Convergent evidence indicated that EF impairment in ADHD was associated with functional and structural abnormalities in large-scale brain networks consisting of the prefrontal cortex, parietal lobe, occipital cortex, temporal lobe, insula, and limbic regions . RecentlPrevious studies have investigated the abnormal function of the entire insula in patients with ADHD. However, the insula is a complicated and functionally heterogeneous structure. Based on previous studies on insular structure and function –31, the To explore the neural networks alterations of the insular subregions and the mechanism correlated with ecological EF from a broader view, the present study utilized the seed-based resting-state functional connectivity (RSFC) to investigate the functional connectivity patterns of AI, MI, and PI. Then, we explored their correlations with ecological EFs, including inhibition, working memory and shifting factor scores. Based on prior literature, we expected that (a) patients with ADHD compared with healthy controls (HCs) would show significantly altered RSFC between the insular subregions and other regions  and (b) altered RSFC in adults with ADHD between the insular subregions and other brain regions would be correlated with inhibition, working memory, and shifting factor scores.Thirty-five right-handed adults with ADHD were recruited from clinics of Peking University Sixth Hospital and advertisements on the Internet when taking part in cognitive behavioral therapy studies and 30 HCs matched for sex, age, and IQ were enrolled in the study. All of the participants were interviewed, underwent diagnosis and were screened for any potential comorbidities according to exclusion criteria using the Structured Clinical Interview for DSM-IV Axis I Disorders [SCID-I ] by a quz-scores of the clusters, which showed differences between the ADHD and HC groups for patients without history, patients with the history and the HCs. There was no difference in mean functional connectivity z-scores of 8 clusters between the two ADHD groups. Furthermore, differences were found between patients with a history and the HCs as well as between patients without a history and the HCs. Therefore, we combined patients with and without medication together to compare with the HC for our final results.Six participants with ADHD had a history of methylphenidate hydrochloride or tomoxetine hydrochloride treatment. Three of the six had stopped the treatment for a long time or had only taken medicine for a short period of time (no >2 months). The other three participants were still being treated with methylphenidate hydrochloride and were required to undergo a washout period of 24 h before the MRI scan. Furthermore, we compared the mean functional connectivity Self-administered scales were completed by all of the participants for diagnostic and correlational purposes.The ADHD Rating Scale-IV [ADHD RS-IV ], a 4-poThe Mandarin version of the BRIEF-A consists of 75 items based on the EFs . The parThis study was approved by the Research Ethics Review Board of Peking University Sixth Hospital. All subjects were fully informed about the research before being asked to sign the informed consent form.Magnetic resonance imaging data were acquired using a Siemens Trio 3 T scanner  at the Imaging Center for Brain Research at Beijing Normal University. During the resting-state functional magnetic resonance imaging (rs-fMRI) scanning, participants lay in the supine position and were instructed to remain still and relaxed with their eyes closed and to keep their mind vacant but without falling asleep. A head strap and foam pads were used to minimize head movements. Functional images were acquired using an echo-planar imaging sequence with the following parameters: repetition time (TR) = 2,000 ms, echo time (TE) = 30 ms, flip angle = 90°, thickness/skip = 3.5/0.7 mm, matrix = 64 × 64, field of view (FOV) = 200 mm × 200 mm, 33 axial slices, and 240 volumes. High-resolution T1-weighted anatomical images were acquired with the following parameters: TR = 2,530 ms, TE = 3.39 ms, inversion time = 1,100 ms, flip angle = 7°, 128 slices, slice thickness = 1.33 mm, FOV = 256 mm × 256 mm, and matrix = 256 × 256.3. Linear detrending of the time series and temporal bandpass filtering (0.01–0.08 Hz) were conducted. Whether preprocessing should include global signal regression (GSR) is controversial  Brain Imaging (DPABI) . First, oversial –53. We cx, y, z): left = −32, 16, 6; right = 32, 16, 6], the bilateral MI , and the bilateral PI . The time course of the ROIs were correlated against all other voxels within the whole brain. Individual RSFC maps of the AI, MI and PI were generated by calculating Pearson’s correlation coefficients between the mean time series of the ROIs and the time series of each voxel in the whole brain. Subject-level correlation maps were then converted to z-value maps using Fisher’s transformation to improve the normality. All figures were displayed using BrainNet Viewer (k = 3) for further analysis to confirm our results  with a radius of 6 mm centered on six MNI coordinates, which were selected based on the previous anatomical and MRI studies , 54: thet Viewer . We used results . The resp = 0.705).Head motion was defined by the mean frame-wise displacement (FD), as described Jenkinson et al. . The meat-tests were performed on z-maps of each ROI to generated maps showing significant positive and negative RSFC by applying a gray matter mask implemented in DPABI template within each insular subregions in the adults with ADHD and the HC. A p < 0.05 uncorrected indicated that the voxel was significantly correlated with the ROIs. Furthermore, the regions with significant correlations with the ROIs in the two groups were combined to produce a mask for the next analysis.One-sample t-tests were conducted between the ADHD and HC groups by applying masks which obtained from the significant regions of the combined one-sample t-test significant regions. Because of the exploratory nature, the significance of the statistical functional connectivity maps was p < 0.05 multiple comparisons using the voxel-wise non-parametric permutation test  with threshold-free cluster enhancement [TFCE  in the ADHD and HC groups. Owing to the exploratory nature of these correlation analyses, the statistical level of significance was set at p < 0.05, uncorrected.Pearson’s correlation analyses were performed between the RSFC The demographics and clinical characteristics of the ADHD and HC groups were given in Table t-tests displayed the within-group functional connectivity patterns in the ADHD and HC group .The RSFC of the other 4 ROIs, including those of the bilateral MI and PI, displayed no significant difference between the two groups in the results with GSR. There were significant differences between two groups within the results without GSR. Decreased RSFC were detected in adults with ADHD of right MI with right precuneus, left PI with right mid cingulate gyrus, right PI with right inferior temporal gyrus, right PI with right cerebellum and right PI with orbital frontal cortex .z-values of the brain regions showing significant differences between the two groups were used for further correlation analyses with the shifting, working memory and inhibition factor scores from the BRIEF-A. In the subjects in the HC group which only 27 participants were calculated the correlations, working memory scores were positively associated with the RSFC between the left AI and right precuneus . The RSFC of the left AI and right inferior temporal gyrus  and that of the left superior occipital gyrus  were negatively associated with the working memory scores. The working memory scores also showed a significant negative correlation with the RSFC of the right AI and left cuneus . However, there was no correlation between these variables in the ADHD group.The RSFC This is the first study on the RSFC of the insular subregions and their correlations with ecological EF performance in adults with ADHD. First, compared with the HCs, adults with ADHD displayed general patterns of widespread altered RSFC between the AI and precuneus, occipital cortex, temporal cortex, lingual gyrus, and cuneus in the results with and without GSR. Second, within the HCs, the working memory scores were correlated with the RSFC of the bilateral AI with other brain regions. There were no significant differences of the RSFC of MI and PI in the results with GSR. However, in the results without GSR, patients with ADHD showed decreased positive functional connectivity in precuneus, temporal gyrus, cerebellum with MI and PI compared with HCs. These findings suggest that the overlapped altered functional connectivity of the AI and regions in the DMN in adults with ADHD in with GSR and without GSR may be involved in the aberrant EFs during daily life.Altered RSFC between the left AI and right precuneus and between the bilateral AI and right medial temporal gyrus extended to the inferior temporal gyrus were observed in adults with ADHD compared with the HCs. Besides, the RSFC AI and right precuneus overlapped in the results with GSR and without GSR. The precuneus and medial temporal gyrus are two critical nodes of the DMN , 61 thatWe still identified an altered RSFC of the bilateral AI with left lingual gyrus. The lingual gyrus participates in visual phonological and word processing , 75. rs-p = 0.062). There was no correlation of these variables in the ADHD group. The results identified that participants with a higher RSFC (positive and negative) had better working memory performance during daily life in the HC group. However, these associations between working memory and the RSFC were disrupted in ADHD group. The disrupted correlation might influence the working memory procedure and therefore suggest working memory impairment. Based on the previous studies . To explore fully how the ADHD subtypes moderate such relationships, a separate study with a much larger sample is needed. Furthermore, the IQs of the participants of the two groups in our study were high. Though the IQs of the two groups had no significant statistical differences, a high IQ may cover up some other differences in adults with ADHD. Next, 6 of the 28 participants in the ADHD group had received medication treatment before the assessment. However, after excluding these six patients, the results did not change substantially and our conclusion was not influenced. Finally, the results of the without GSR analyses  showed different pattern with the results using GSR. Therefore, our findings should be interpreted with some caution and need further replication with regard to the abovementioned limitations.In summary, this study was the first to detect the abnormality of the insular subregions’ functional networks among adults with ADHD and determined that the EF factor scores are associated with the RSFC of the AI with the precuneus and temporal gyrus in the HC group. However, there is no correlation of the EF factor and with the RSFC of the AI in the ADHD group. The normal correlations between the working memory and RSFC of the AI were disrupted in adults with ADHD. The results indicate that disrupted SN-DMN networks might be involved in EF impairment in adults with ADHD, especially working memory. Our findings suggest that deficits of AI particularly, which refer to abnormal salient stimuli allocation, might be involved in working memory impairment in patients with ADHD. The inconsistent results of MI and PI between results with and without GSR need further exploration.This study was approved by the Research Ethics Review Board of Peking University Sixth Hospital. All subjects were fully informed about the research before being asked to sign the informed consent form.QZ and LS contributed to the design of the work. QZ, HL, XY, FH, YW, QQ, LS, LL, and YW were involved in the acquisition of the data. QZ, HL, XY, and LS participated in the analysis and interpretation of the data. QZ and LS drafted the work. LL, YZ, QC, and YW revised it critically.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.