Attention Deficit Hyperactivity disorder (ADHD) is one of the most common and challenging childhood neurobehavioral disorders. ADHD is known to negatively impact children, their families, and their community. About one-third to one-half of patients with ADHD will have persistent symptoms into adulthood. The prevalence in the United States is estimated at 5–11%, representing 6.4 million children nationwide. The variability in the prevalence of ADHD worldwide and within the US may be due to the wide range of factors that affect accurate assessment of children and youth. Because of these obstacles to assessment, ADHD is under-diagnosed, misdiagnosed, and undertreated.We examined factors associated with making and receiving the diagnosis of ADHD. We sought to review the consequences of a lack of diagnosis and treatment for ADHD on children’s and adolescent’s lives and how their families and the community may be involved in these consequences.We reviewed scientific articles looking for factors that impact the identification and diagnosis of ADHD and articles that demonstrate naturalistic outcomes of diagnosis and treatment. The data bases PubMed and Google scholar were searched from the year 1995 to 2015 using the search terms “ADHD, diagnosis, outcomes.” We then reviewed abstracts and reference lists within those articles to rule out or rule in these or other articles.Multiple factors have significant impact in the identification and diagnosis of ADHD including parents, healthcare providers, teachers, and aspects of the environment. Only a few studies detailed the impact of not diagnosing ADHD, with unclear consequences independent of treatment. A more significant number of studies have examined the impact of untreated ADHD. The experience around receiving a diagnosis described by individuals with ADHD provides some additional insights.ADHD diagnosis is influenced by perceptions of many different members of a child’s community. A lack of clear understanding of ADHD and the importance of its diagnosis and treatment still exists among many members of the community including parents, teachers, and healthcare providers. More basic and clinical research will improve methods of diagnosis and information dissemination. Even before further advancements in science, strong partnerships between clinicians and patients with ADHD may be the best way to reduce the negative impacts of this disorder. Faced with controversies from the medical field, parents, and educational authorities, the diagnosis and treatment of ADHD has continued to be a source of debate –3. StudiThe American Academy of Pediatrics and other groups that care for children suggest that ADHD be screened for and diagnosed as early as the preschool years  to afforParents play a major role in early recognition of behavioral problems in their children which may prompt them to seek medical help . ParentaParental exposure to negative information about ADHD, usually from non-healthcare professionals or social media , can alsParents from different cultural and ethnical backgrounds may have different views and perceptions of behavioral norms and when to consider behavior inappropriate or indicative of a clinical disorder such as ADHD . The ratThe level of trust and communication between parents and teachers also has a significant impact in the early diagnosis of ADHD . Given tAccess of the public, children, and their families to healthcare providers and to medical research findings are influential factors in early diagnosis and recognition of ADHD. In the United States, the limited access to mental health clinicians results in the majority of children being diagnosed and treated by primary care physicians (PCP). A study of 60 ADHD patients estimated that 77.8% of the children diagnosed were treated and followed by a PCP and 22.1% were treated and followed by a child psychiatrist . LimitedEven when these difficulties of the assessment process do not exist, the basic definition of ADHD may pose challenges. There are inconsistencies in the definition of ADHD as it is defined in the diagnostic and statistical manual disorders-IV-TR or DSM-5 and in the international statistical classification of disease , 26. TheHowever, challenges for clinical diagnosticians can be addressed by some methods. Detailed prenatal, family, and educational histories are of significant value in aiding the diagnosis of ADHD . When evA supportive environment is an essential part of a child’s life. Children in the US spend a significant portion of their time in school making teachers and the school structure extremely influential for typical development and for the diagnosis of ADHD.In clinical assessment of ADHD, a teacher report of a child’s behavior is often sought. However, teacher ratings of ADHD symptoms in students may have limitations. For example, a discrepancy has been shown in the level of reports of ADHD symptoms in African American students versus same age non-black peers . BecauseNumerous factors intrinsic to a child or youth can affect their diagnosis of ADHD including, gender, age, race, socioeconomic status, and severity of symptoms , 33. WhiA thorough work up for ADHD also incorporates assessment for common comorbid symptoms/diagnosis, including anxiety, depression, oppositional defiant and conduct disorders, developmental and learning disorders or other neurodevelopmental disorders. At times somatic, physical, or syndromic features can overshadow ADHD symptoms , 34. HowGiven the diversity of children in the US, the background history/demographics of the child is important in making an accurate clinical assessment . ChildreThere is an apparent discrepancy between the lack of objective methods for the clinical diagnosis of ADHD and recent advancements in genetic, neuroimaging, and other biological assessment methods . ReliablStrong genetic contributions have been reported for ADHD , 21, 23.EEG and brain imaging have been investigated as a way to support and enhance the diagnosis of ADHD and choices about treatment. In a study of 10 children, medication responders had less Theta/Alpha and more Beta activity on EEG than non-medication responders . HoweverSome studies have examined the role of environmental factors that may predispose an individual to ADHD and thus could be helpful as diagnostic factors or indicators of risk. For example, exposure to nicotine during human prenatal development has been linked with ADHD , perhapsSerum ferritin levels have been found to be low in children with ADHD . Also, bLastly, food additives have been examined for possible roles in ADHD. Some studies have found positive associations but no causal link between hyperactivity and dietary artificial food coloring and sodium benzoate preservative . HoweverAttention Deficit Hyperactivity disorder likely arises from multiple changes in biological, psychological, and social domains from which many etiologies of small effect, both environmental and genetic, interact and result in symptoms . This prThere is need for more research in child psychiatry at the basic biological level, focusing on early human brain development, to help better understand the pathophysiology of ADHD and child psychiatric illnesses in general .Adolescents and youth face challenges during transition to adulthood which can limit their abilities to obtain medical services , 23, 49.As ADHD is regarded as a childhood disorder, there is much less research about ADHD in adults . The worDiagnosis with ADHD matters, in part, because it is often accompanied by recommendations for treatment. Treatment of ADHD has been a source of controversy, especially in relation to the use of psychostimulants like methylphenidate  and mixed amphetamine salts  and non-stimulants, such as atomoxetine, clonidine, and guanfacine for children, each of which has its own limitations , 53, 54.Stimulants used in the treatment of ADHD are thought to act by increasing brain catecholamine levels  and are Evidence suggests there has been an increased use of stimulants in US , 59, 60.The adverse side effects of stimulant use contribute to the ambivalence some patients and families have about treatment initiation and compliance . PossiblOther treatment modalities in addition to pharmacotherapy include: educational modifications, behavioral treatments for parents and teachers to help children modify behavior, and cognitive enhancement interventions . While tOne of the major consequences of ADHD not being diagnosed is a lack of treatment. Untreated ADHD can pose a tremendous amount of psychological, financial, academic, and social burden to the individual and the community, which reflects the importance of diagnosing and treating the disorder , 66. WhiThe consequences of untreated ADHD has been shown in many different domains of functioning.A longitudinal study that examined the impact of stimulant treatment in ADHD to academic outcome during late adolescence found that children treated with stimulants showed academic gains on several measures relative to children who did not receive treatment .Symptoms of hyperactivity that would typically be addressed by treatment are linked, when untreated, to long-term social and peer problems . Poor liMuch work over the past decades suggests that there is a strong link between ADHD and substance/alcohol abuse , 66, 71.Links between ADHD and SUD may be bidirectional . Adults Attention Deficit Hyperactivity disorder, especially when untreated, can lead to financial and employment difficulties , 33, 72.Untreated ADHD is associated with higher rates of criminality, imprisonment, speeding, traffic violation, and motor vehicle accidents , 75, 76.Longitudinal research that followed hyperactive children for 10 years has suggested that hyperactivity is a risk factor for increases in other psychiatric diagnosis . The preMortality rate in a recent study of an ADHD population was 5.85 per 10,000 person-years compared with 2.21 in controls. Interestingly, the highest rate of mortality was found in people diagnosed in adulthood . When diMany of these issues surrounding perception of ADHD and the ability to effectively assess individuals for ADHD influence whether or not accurate diagnoses of ADHD are made. While there are significant data detailing the consequences of ADHD not being treated, fewer studies have been performed to understand whether diagnosis matters independently. ADHD diagnosis and its associated opportunity for psychoeducation and prognostic information may have important effects on development.The few studies that have been done suggest that there are consequences in a variety of domains. First, evidence suggests lower levels of educational attainment in individuals with ADHD who are undiagnosed compared to those diagnosed , 33, 68.Several studies have focused on examining the experience described by individuals with ADHD. Understanding the emotional and psychological burden of this diagnosis and its impact in a child or youth’s quality of life and well-being may help to inform controversies about diagnosis and the basic perception of ADHD.Having ADHD has been shown in multiple studies to be a source of stress, with some individuals recalling a constellation of feelings of loneliness, isolation, low self-esteem, and struggle to get along with their parents and peers at school , 79, 80.On the other hand, some individuals have described that the extra attention from their teachers or parents that accompanied the diagnosis of ADHD helped affirm and build confidence , 80. A qWe have reviewed many of the complexities that lead to and arise from the diagnosis of ADHD. One of the key conclusions from this body of literature is that receiving the diagnosis of ADHD may benefit individuals by creating the possibility for treatment. A significant body of research has demonstrated that treatment is strongly associated with improved outcomes. Outcomes after receiving an ADHD diagnosis independent of treatment are not well understood; however, significant psychological effects of receiving a diagnosis have been described. These latter findings are in line with the complex experience clinicians have as they partner with children, youth and families coping with behavioral problems. It is precisely this partnership that then takes on greater significance when faced with such a double-edged sword in diagnosing and treating ADHD. Medical knowledge about the benefits of treating ADHD, together with the concern that clinicians feel for their patients’ long-term success, will hopefully reduce barriers to diagnosis in the future. This may be accomplished through psychoeducation, greater communication between clinicians, parents, and educators, and more research on biomarkers. Although barriers exist, clinicians who truly partner with their patients also understand that individuals receiving an ADHD diagnosis may experience immediate and complex emotions as well as challenges to their identity. The process of diagnosing ADHD is not unlike the diagnosis of other chronic and serious medical conditions and thus can benefit positively from the medical perspective. This perspective has the potential to positively impact the entire life course of individuals with ADHD as well as their families. The partnership between clinician and patient is one of the most important ways in which this benefit can arise.AH and HS conceived, designed, acquired background material, and drafted this work; AH, AK, and HS interpreted the background material, critically revised, and approved the final version of and agreed to be accountable for this work.The authors declare that this work was completed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Bartonella and Rickettsia spp. in bats and their ectoparasites (Diptera and Siphonaptera) collected across South Africa and Swaziland. We collected 384 blood samples and 14 ectoparasites across 29 different bat species and found positive samples in four insectivorous and two frugivorous bat species, as well as their Nycteribiidae flies. Phylogenetic analyses revealed diverse Bartonella genotypes and one main group of Rickettsia, distinct from those previously reported in bats and their ectoparasites, and for some closely related to human pathogens. Our results suggest a differential pattern of host specificity depending on bat species. Bartonella spp. identified in bat flies and blood were identical supporting that bat flies may serve as vectors. Our results represent the first report of bat-borne Bartonella and Rickettsia spp. in these countries and highlight the potential role of bats as reservoirs of human bacterial pathogens.In addition to several emerging viruses, bats have been reported to host multiple bacteria but their zoonotic threats remain poorly understood, especially in Africa where the diversity of bats is important. Here, we investigated the presence and diversity of  Bartonella and Rickettsia spp. [In recent years, the emergence of bat-borne pathogens has focused interest and stimulated further research. Several studies have shown pathogen spillover from bats to humans, leading in some instances to significant morbidity and mortality, as demonstrated for example with Marburg, Nipah and Hendra viruses . In addisia spp. , as wellBartonella and Rickettsia spp. are intracellular bacteria that are associated with a growing spectrum of emerging diseases in humans, such as life-threatening endocarditis and spotted and typhus fevers [Bartonella species are mainly transmitted to humans through faeces of blood-feeding arthropods, such as fleas, ticks and lice, after superficial scratching of their skin, or directly by the bite of these ectoparasites. These bacteria infect a large range of mammals and are increasingly reported in bats and their ectoparasites [Bartonella mayotimonensis has been associated with bats in the Northern Hemisphere [Rickettsia spp., only serological evidence of infection in bats has been reported [Rickettsia DNA in bat ticks and flies [Bartonella and Rickettsia spp., some of them being identical to the genotypes found in bats, suggesting a vector-borne transmission. Despite these findings, the distribution and diversity of bat-borne Bartonella and Rickettsia spp., as well as the role of bats in transmission to humans remains poorly understood, especially in Africa where the abundance and diversity of bats is high [s fevers ,4. Bartoarasites –10. Recemisphere . For Ricreported  as well nd flies ,13,14. S is high .Bartonella and Rickettsia spp. presence using molecular detection tools in a large range of bat species across South Africa and Swaziland. We further assessed the genetic diversity of bat- and ectoparasite-borne Bartonella and Rickettsia spp. and their relatedness compared to others mammalian strains.To better understand the role of bats and their ectoparasites as reservoirs of bacterial pathogens, we investigated From 2007 to 2012, bat sampling was conducted at nine different locations across South Africa and Swaziland at bat caves and open vegetation . Bats weThe sampling protocol was approved by the University of Pretoria Animal Ethics committee (EC054-14) following guidelines of the South African National Standard (SANS 10386:2008). Catching and collecting was carried out in strict accordance with the terms of research permits issued by national authorities: 000039 NW-07 for Taung, Kgaswane  Department of Agriculture, Conservation, Environment and Tourism, North West province, RB/2010/04 for Pafuri  South African National Parks, OP 500/2010 for Rocktail Bay  Ismangaliso Wetland park authority and Ezemvelo KZN wildlife, CPB6-003767 for Mahune  issued by the Department of Economic Development, Environment & Tourism, and from the Swaziland National Trust Commission for Mlawula Game Reserve, Swaziland.Bartonella spp. was detected using a conventional PCR targeting the partial citrate synthase (gltA) gene [Rickettsia spp., we used a real-time PCR also targeting the gltA gene [Bartonella samples were sequenced using the same primers. Positive Rickettsia samples were further subjected to a nested PCR targeting the partial gltA gene using specific primers PanRick2-for and RpCS1258 [Bartonella henselae and Rickettsia conorii respectively) controls. Molecular identification of ectoparasites was performed using the amplification of the cytochrome oxidase I (COI) fragment [Genomic DNA was extracted from 100 μl anticoagulated blood, or whole ectoparasite specimens cut into small pieces, using the Qiagen DNeasy blood and tissue kit  according to the manufacturer’s instructions. The presence of tA) gene . For RicltA gene . PositivRpCS1258 , and Nglfragment  and a BLBartonella sequences generated in this study with 132 reference sequences representing the major Bartonella species and samples from bats worldwide. For Rickettsia spp., we used all the positive samples as well as 33 reference sequences representing the major Rickettsia species, including sequences from one bat tick [Bartonella and Rickettsia alignments, using the Akaike Information Criterion (AIC) [We used the freeware CLC Sequence Viewer 6 to align the bat tick . JMODELTon (AIC) . Phylogeon (AIC) .Rousettus aegyptiacus in Mahune, were analyzed. Ectoparasites collected from insectivorous bats were not tested. Overall, 13 blood samples were positive for Bartonella spp. and six for Rickettsia spp.  co-infected with both bacteria. Ectoparasites collected from R. aegyptiacus were identified as Nycteribiidae flies  and fleas ; five flies and one non-identified specimen (AA028) were Bartonella-positive and all were Rickettsia-negative. The flea sample was negative for both Bartonella and Rickettsia spp.In total, 384 blood samples were collected from 29 bat species representing eight families, including both insectivorous and frugivorous bat species . Additiosia spp. . Four bagltA gene, for Bartonella and Rickettsia spp. respectively. Bartonella samples. The first group included samples from N. thebaica and M. natalensis , which were closely related to B. grahamii (mean sequence similarity to B. grahamii = 98.2%) but distinct from Bartonella spp. previously reported in other Miniopterus bats and their flies from Kenya, Madagascar and Taiwan. The first group also included a Bartonella genotype detected in E. wahlbergi which grouped with B. elizabethae  and a sequence from an Eucampsipoda fly collected from Rousettus leschenaultii in China, although the bootstrap value at the node was low (i.e. 51%). Moreover, this Bartonella genotype from E. wahlbergi was quite different from Bartonella spp. found in South African rodents [Rousettus aegyptiacus and their flies were infected with a similar Bartonella spp., but this well-supported genetic cluster did not group with any known Bartonella species and was distinct from those previously detected in the same bat species in Kenya [Rousettus obliviosus flies (Eucampsipoda theodori) in the Union of Comoros [After trimming of the sequences for quality and alignment with references, phylogenetic analyses were conducted on a 308-bp and 202-bp fragment of the  rodents  . Moreover, our samples were distinct from the bat-associated Rickettsia spp. described from the tick Argas vespertilionis in France [Rousettus and Miniopterus bats in Madagascar [Analysis of the sia spp. . Despiten France , and frodagascar .Bartonella and Rickettsia spp. infections in different frugivorous and insectivorous bat species and their blood-feeding ectoparasites from South Africa and Swaziland. Our results represent the first report in these countries and highlight the potential role of bats as reservoirs of human bacterial pathogens [We provide evidence of athogens .Bartonella genotypes identified in this study were distantly related to those previously described from bats, especially in other African countries, such as Kenya or Madagascar [B. elizabethae and B. grahamii, which are however associated to only a few reports of endocarditis and neuroretinitis or bilateral retinal artery branch occlusions, respectively [Bartonella species are typically found in rodent hosts, suggesting potential transfer between rodents and bats. However, according to our phylogenetic analyses, the respective genotypes infecting South African rodents [dagascar ,14,17. Sectively –26. Thes rodents  and batsBartonella species within shared roosts of insectivorous bat species may contribute to a lack of host-specificity, as seen in the similarity of the Bartonella spp. found in M. natalensis and N. thebaica, and as previously suggested for bats in Guatemala and Vietnam [Bartonella spp. from R. aegyptiacus bats were distinct and unique from all other Bartonella species. The same result was previously shown for R. aegyptiacus in Kenya [Moreover, different levels of host specificity seem to occur. Active interspecies transmission of  Vietnam ,27. In cin Kenya , but witRickettsia spp. infections in bats is based on serologic surveys [Rickettsia spp. antigens in bats [Rickettsia spp. have been reported in Carios kelleyii and Argas vespertilionis, two tick species that are well adapted to urban areas and can feed on humans in North America and Europe, respectively [Rickettsia spp. infections can also be detected in bat blood. Analysis of the partial gltA sequence data led to identification of bat-associated Rickettsia spp. closely related to R. conorii, and distinct from those previously identified in bat ectoparasites from Europe and Madagascar [Rickettsia spp. and their potential relationship to human pathogens.Available data on  surveys  or detec surveys ,13,14. F in bats . Additioectively ,13. Our dagascar ,14. HoweBartonella and Rickettsia spp. transmission. In Africa, the first report of Bartonella spp. in bat flies was from Cyclopodia greefi greefi collected from the straw-coloured fruit bat Eidelon helvum in Ghana [Bartonella spp. in both bat blood and flies (Cyclopodia dubia) collected in Eidolon dupreanum from Madagascar. More recently, a metagenomic study conducted in Madagascar showed that Bartonella and Rickettsia spp. are main components of the microbiota of different bat fly species [Bartonella spp. in R. aegyptiacus blood and Eucampsipoda flies, showing that these ectoparasites, at least, may probably serve as vectors of Bartonella spp. [Bartonella and Rickettsia spp.Generally, ectoparasite infestation is known as a common mode of in Ghana . Brook ein Ghana  also rep species . Here, wlla spp. . As our Bartonella and Rickettsia spp. infections have been reported in humans and animals [Bartonella prevalences (i.e. 9.5% and 22.5%) in blood of healthy and HIV-positive human subjects, respectively [Bartonella (3.3%) and Rickettsia (1.5%) spp., but 36% of bat flies were PCR-positive for Bartonella spp., although these results need to be confirmed with larger sample size. Bat ectoparasites are generally known to be highly host-specific which may limit the probability of feeding on other hosts [Rickettsia and Bartonella spp. to other animal species, including humans, may be low. However, as a result of greater human activity in caves in Africa, for religious activities especially [Bartonella and Rickettsia spp. in bat species and their ectoparasites highlights the need to study whether these bat-associated bacteria are responsible for the etiology of local undiagnosed illnesses in humans.In southern Africa,  animals ,30. For er hosts ,32, and pecially , there iS1 TableNot all individuals sampled were taken as museum vouchers, and some vouchers have not yet been lodged in a public repository; in such instances identification based on morphology was limited to external features only, and hence identification to species level was not always possible. Acronyms used in Sample ID and Field/Museum number: UP—Virological Research Group, University of Pretoria; ECJS—Ernest Seamark, AfricanBats; NC—Northern Cape, Davis Jacobs, University of Cape Town; TM- Ditsong National Museum of Natural History, Pretoria ; CHIR KNP: Skukuza Biological Reference Collection.(XLSX)Click here for additional data file.


Joseph Conrad – The Shadow-LineBeilstein Journal of Organic Chemistry [Five years have passed since the first publication of the Thematic Series on Olefin Metathesis in the hemistry . During hemistry –3, can eHowever, this does not imply that the research phase is over, that all problems have been solved, that the technology is widely recognized and used, and that catalyst manufacturers have become millionaires. It only means that olefin metathesis is now a full-grown technology, which has already crossed the shadow line – the term coined by the Polish–British novelist Józef Teodor Konrad Korzeniowski (Joseph Conrad) to indicate the point where maturity is gained. This maturity will bring new promise, new expectations, and new challenges. During the application of this technology, new problems on various levels will surely emerge. I am therefore fully convinced that in the forthcoming years scientists dealing with olefin metathesis will have many opportunities for exciting research and for hard work, too.On a personal level, it was for me a great pleasure to serve as the editor of this Thematic Series. I am very thankful to all authors for their first-class contributions. At the same time, I would like to thank the colleagues at the Beilstein-Institut for their professional support and patience.Karol GrelaWarsaw, August 2015


Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder and its impact on cognitive development needs further study. Evidence from neuropsychological, neuroimaging and electrophysiological studies suggests that the decline in tic severity and the ability to suppress tics relate to the development of self-regulatory functions in late childhood and adolescence. Hence, tasks measuring performance monitoring might provide insight into the regulation of tics in children with TS.Method: Twenty-five children with TS, including 14 with comorbid Attention-deficit/ hyperactivity disorder (ADHD), 39 children with ADHD and 35 typically developing children aged 8–12 years were tested with a modified Eriksen-Flanker task during a 34-channel electroencephalography (EEG) recording. Task performance, as well as stimulus-locked and response-locked event-related potentials (ERP) were analyzed and compared across groups.Results: Participants did not differ in their behavioral performance. Children with TS showed higher amplitudes of an early P3 component of the stimulus-locked ERPs in ensemble averages and in separate trial outcomes, suggesting heightened orienting and/or attention during stimulus evaluation. In response-locked averages, children with TS had a slightly higher positive complex before the motor response, likely also reflecting a late P3. Groups did not differ in post-response components, particularly in the error-related negativity (ERN) and error-related positivity (Pe).Conclusions: These findings suggest that children with TS may employ additional attentional resources as a compensatory mechanism to maintain equal behavioral performance. Tourette Syndrome (TS) is a childhood onset neuropsychiatric disorder with multiple motor tics and at least one vocal tic for more than 1 year  in the electroencephalogram (EEG) and outcomes indicate modulations of interference/conflict and control. The stimulus-locked N2 reflects early stages of conflict/mismatch detection  and error positivity (Pe) are detectable. The ERN arises immediately after error commission , inattentive type (n = 11) or hyperactive type (n = 3). Within the study groups, the following comorbid disorders were present: oppositional defiant disorder , and three children with ADHD also had conduct disorder (CD), chronic and transient tics (ADHD n = 3), OCD (TS n = 2), and elimination disorder . Moreover, several children fulfilled criteria for phobia , separation anxiety  and general anxiety . Thirteen children with TS had an additional ADHD diagnosis , 1 of these had an additional OCD diagnosis.One hundred and two participants were recruited for a prospective longitudinal study of children with ADHD, Tourette syndrome, and control children aged 8–12 years. Participants with ADHD and TS were recruited from the Department of Child and Adolescent Psychiatry, Haukeland University Hospital, and from outpatient clinics in the greater Bergen area in the Hordaland County, Norway. Controls were recruited from local schools in the same geographic regions. The Regional Ethics Committee approved the study, and written consent in accordance with the Declaration of Helsinki was obtained from all parents. The diagnostic procedure consisted of a semi-structured interview, the K-SADS . Participants were instructed to fixate a dot presented in the center of a PC screen. Trials began with the presentation of 6 horizontal flanker arrows appearing below fixation. Participants should respond as fast as possible, and as accurate as possible with either a left or a right mouse button press following the direction of a central target arrow that appeared after 100 ms, pointing either into the same direction as the flanker arrows in compatible trials  or in the opposite direction in incompatible trials . The target- and flanker-arrows remained on screen until a response was registered. Trials were terminated by the motor response and followed by an 800-ms interval before onset of the next trial. Stimuli were presented in two blocks with 200 trials that were pseudorandomized separately for each participant. The overall probability of compatible and incompatible trials, as well as left and right responses were kept at 0.5. Performance feedback was given during the experiment when responses were erroneous or slower than an adaptive individual threshold value (mean response time plus 1.5 standard deviations (SD).EEG was recorded continuously in an electromagnetically shielded chamber. Data were sampled at 1000 Hz frequency with a time-constant of 10 s and a high cutoff at 250 Hz with Brain Amp amplifiers . An elastic cap containing 34 Ag/AgCl electrodes placed at Fp1, Fp2, F7, F3, Fz, F4, F8, FT9, FC5, FC1, FC2, FC6, FT10, T7, C3, Cz, C4, T8, TP9, CP5, CP1, CP2, CP6, TP10, P7, P3, Pz, P4, P8, PO9, O1, O2, PO10, Iz was used. Channels were referenced to Fz. Vertical eye movements were recorded with a bipolar derivation between Fp1 and an additional electrode placed below the left eye, horizontal eye movement were recorded with a bipolar derivation between F7 and F8. Additionally, electrocardiogram was monitored. Impedances were kept below 10 kΩ.We preprocessed the EEG in Matlab  using the EEGLAB toolbox , and response-locked epochs (−1 to 0.5 s). The prestimulus period was used as baseline for both epochs. Epochs were excluded when exceeding a ±300 μV amplitude criterion. The remaining epochs were sorted using a summary score of root mean square amplitude across all channels and time points, spatial SD, power spectrum ratio between low and high frequencies, skewness and kurtosis, normalized to unit variance across epochs. Only epochs within ±1 SD were retained for further analysis. These epochs were concatenated and subjected to temporal independent component analysis (ICA) using the infomax algorithm . Repeated measure analyses were conducted to test outcome effects in the behavioral and the ERP data  and “group.” Additional univariate Analysis of Covariance (ANCOVA) were conducted for behavioral measures and ERP components as dependent variable, group as categorical factor and covariates as continuous predictors to test group differences. Significant or trend-significant effects were followed-up with additional t Cohen, . To demoResponse times (RT) and response accuracy (RACC) averages were generated for all possible outcomes. Premature responses faster than 200 ms and slow responses >2000 ms were not considered in the averages. RTs were analyzed with covariates:Age: Because of substantial speeding of RT, and improvement of accuracy with age across the entire sample regardless of group, all analyses included age as a covariate.FSIQ: We decided to analyze the behavioral data with FSIQ as covariate for the sake of consistency across behavioral- and ERP analyses. This appears to be the most sound practice in our case, however see relevant publications for a discussion on this issue  and to compensate for confounders, we conducted a pairwise comparison of post-error and pre-error trials around each error , 64 participants were boys and groups did not differ for age or sex. 15 participants were left-handed. Groups differed in FSIQ, similar to findings reported in other studies  were discarded due to excessive EEG artifact, data from another participant (ADHD) were discarded due to performance on chance level, data from 99 participants thus were included, 39 children with a diagnosis of ADHD, 25 children with TS (11 TS “only” and 14 TS+ADHD), and 35 typically developing children. Children's age ranged from 8 to 12 years (r = −0.29). Slow responses were more frequent in all groups compared with fast responses, also with a significant FSIQ effect, with correlations for lower FSIQ predicting more frequent slower responses (r = −0.34) and age (r = −0.38).  = 2.85, p = 0.06, Post-hoc assessment revealed trend-significant differences for CC responses (p = 0.07) and erroneous responses (p = 0.08) between controls and ADHD and a significant difference in IC trials (p < 0.01) between controls and ADHD. No differences between children with TS and controls.A Repeated Measure Analysis revealed a typical RT pattern for the Flanker task with fast RT in compatible (CC) responses, slower incompatible (IC) responses and faster RT in erroneous trials in all three groups, and trend-significant group differences across all three outcomes [When controlling for covariates in a follow-up ANCOVA, the CC, IC or erroneous RTs did not differ between groups Table .F = 142.14, p < 0.001, F = 2.46, p = 0.09, F = 3.01, p = 0.06, p < 0.01) and TS (p < 0.05) than controls.Errors were defined as incorrect key presses to compatible and incompatible trials. As expected, significantly more errors occurred to incompatible than compatible trials [After controlling for covariates (ANCOVA), groups did not differ in in error rates for either CC or IC responses, or for overall RACC with a significant effect of FSIQ Table .ANCOVA for PES yielded no significant group differences Table .F = 5.68, p < 0.01, A repeated measure analysis of IIV showed smaller IIV for compatible trials, larger IIV in incompatible trials and largest IIV in erroneous trials, and significant group differences across all three outcomes [When controlling for covariates in the follow-up ANCOVA groups did not differ with respect to IIV, but the relevant covariates FSIQ and age reached significance in the overall IIV, as well as in the separate CC, IC and error trials Table .After inspection of the grand averages of the stimulus-locked Figure  and respANCOVA showed no group differences in compatible, incompatible, and error outcomes. A significant effect of RT and IIV was present in incompatible correct outcomes.No group effects were found in ANCOVA for compatible, incompatible, and erroneous P2 amplitudes.F = 4.62, p = 0.01, F = 5.17, p < 0.01, F = 2.82, p = 0.06, post-hoc assessment revealed that, P3 amplitudes across outcomes were higher in children with TS compared to both controls (p < 0.05), and those with ADHD (p < 0.05). No significant differences were found between participants with ADHD and controls.ANCOVA yielded a significant group effect for compatible correct [ANCOVA showed no significant group difference in compatible correct outcomes, there was a significant effect of RACC. Similarly, no differences were present in incompatible correct outcomes, while a significant covariate-effect of IIV was present. No differences were found in erroneous LPC amplitudes.F = 2.5, p = 0.08, Post-hoc tests showed higher amplitudes in TS vs. controls (p = 0.04), and a similar trend between TS and ADHD (p = 0.09), but no difference between controls and ADHD.ANCOVA showed no significant group differences in compatible and erroneous amplitudes. Incompatible amplitudes showed a trend-significant group effect [F = 2.09, p = 0.08, p = 0.03) and similarly for TS compared to ADHD (p = 0.06), whereas no differences were seen between TS and controls. Note though that there is a substantial carry-over of the amplitude modulation from the preceding LPC into this time-window, especially for correct responses.In this sample, we did not observe a distinct negative ERN in this age group, consistent with Davies  = 1.21, p = 0.31, p = 0.99) and controls (p = 0.78). Children with ADHD showed high RTs, but no significant differences to other groups (p > 0.2).For RT, this analysis showed no group difference [F = 1.21, p = 0.31, post-hoc comparison revealed no significant differences between the groups .Also for the IIV, no group differences were found [F = 2.99, p = 0.04, p = 0.63). Children with TS+ADHD showed trends toward higher amplitudes than controls (p = 0.06) and children with ADHD (p = 0.06), whereas TS only had significantly larger amplitudes than ADHD (p = 0.03), and controls (p = 0.02).For the P3 this analysis repeats a significant group difference [Based on these additional analyses, the fact that the sample sizes in analyses of these subsamples are small, and the pattern of results redundant and the high clinical relevance of a comorbid group, we merged all participants with TS into one group.This study investigated electrophysiological differences in a Flanker task in children with TS compared with children with ADHD and with typically developing children. We expected that children with TS would perform comparable or better than controls, whereas children with ADHD would show impairments of behavior and ERP measures.Our results confirmed that children with TS performed behaviorally on the same level as control children. This finding is consistent with previous studies of behavioral performance , and to differences in task selection (passive, active, visual, auditory, response mode; Luck, We found smallest P3/LPC component amplitudes in the ADHD group, albeit not reaching significant difference levels compared with controls. This appears generally consistent with existing literature from several choice response tasks in this age group, including the Flanker task (Johnstone et al., We did not find that children with TS used a different strategy in prioritizing either speed or accuracy in compatible or incompatible trials and with respect to symptoms measured with the YGTSS, nor could we find significant correlations for speed or accuracy.All children were medication-naïve. Age and FSIQ differences did not readily explain group differences because groups were matched for age, as well as age and FSIQ were also used as covariates. The inclusion of children with ADHD is a strength of the study, because it allowed to illustrate the specificity of a higher P3 in children with TS, with and without comorbidity.A limitation here is the relatively small sample size given the incidence, which led us to group TS+ADHD and TS only together. Ideally, the impact of comorbid conditions should be assessed separately, and in more detail, requiring larger sample sizes in future studies, probably best achievable through collaborative multi-site consortia. However, the fact that we did not find any significant differences between these subsamples in the dependent measures reported here justified the inclusion of children with TS only and those with additional ADHD in the same group. The relative lack of negative impact of comorbid ADHD on TS in our sample seems at variance with previous work reporting impaired ERPs (Shephard et al., Many executive tasks are influenced by global changes in response caution, and motivation and error rates might fluctuate. The skills implemented to solve cognitive challenges may differ considerably in typically developing children from children with ADHD or TS. However, we tried to minimize these influences by keeping the time-on-trial to a minimum, and providing individual feedback after slow and after erroneous trials, respectively. During the experiment and upon debriefing there was no reason to suspect differences in motivation, attention or fatigue across groups and order of tasks was counterbalanced. Also, we used a robust estimate of PES (Dutilh et al., These findings provide further evidence that TS is not associated with widespread executive impairments, but presents robust evidence that adaptive changes, such as a heightened attentional capacity, are a core component of the TS disorder. In particular, we report a differential modulation of a P3-subcomponent that has not received much attention so far.Conception and design: HE, TE, IB, LS, KH, KP. Acquisition of data: HE, TE, MH, LS, HW, MW, KP. Analysis and interpretation: HE, TE, KP. Writing of article: HE, TE, KP. Critical review of article: HE, TE, IB, MH, LS, HW, MW, KH, KP. Final approval for publication: HE, TE, IB, MH, LS, HW, MW, KH, KP. Agreement to be accountable for all aspects of the work: HE, TE, IB, MH, LS, HW, MW, KH, KP.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.


Intesis (AS) . It was s of ACS .Encouragingly, similar finding was evident by another study which demonstrated that the circulating Th22 cells were remarkably higher in AMI and UAP patients than those in SAP patients and healthy people. Additionally, there was a positive correlation between the number of Th22 cells and IL-22 levels in AMI and UAP patients . MoreoveTaken together, these findings suggest that frequencies of Th22 cells are greatly increased in patients with ACS, indicating that the potential role of Th22 cells in the progression of ACS. Although large samples of clinical research are needed to further prove Th22 cell as a useful biomarker for ACS, the available evidences explore the close relationship between Th22 cells and the initiation of ACS, presenting a newly diagnostic potential for Th22 at onset of ACS.


With reports of a high prevalence of attention-deficit/hyperactivity disorder (ADHD) in adults, publication of ADHD diagnostic criteria in DSM-5, and the urgent need for a relevant diagnostic instrument conforming to DSM-5, we developed the Assessment System for Individuals with ADHD (ASIA), a Japanese semi-structured diagnostic interview. We report here the reliability and validity of ASIA ADHD diagnostic criteria.ASIA ADHD criterion A corresponds to DSM-5 ADHD criterion A and has 144 original questions assessing nine inattention symptoms and nine hyperactivity–impulsivity symptoms, each having four childhood and four adulthood questions. The 144 questions are evaluated on a 3-point frequency scale. ASIA ADHD criteria B to E correspond to DSM-5 ADHD criteria B to E and are evaluated on a 2-point scale. ASIA was administered to 60 adults .For ASIA ADHD criterion A, values of Cronbach’s α for the adulthood and childhood inattention and hyperactivity–impulsivity symptoms ranged from 0.64 to 0.90. Values of κ for two independent raters ranged from 0.98 to 1.00 for the 144 questions and raw agreement rates ranged from 0.97 to 1.00 for criteria B, C, D, and E. The consensus DSM-5 diagnoses endorsed 59 of the 60 ASIA diagnoses (ADHD and non-ADHD). The ADHD group scored significantly higher on 125 of the 144 questions for criterion A than the non-ADHD group. Correlations between ASIA total and subscale scores in adulthood and corresponding scores on the Japanese version of the Conners’ Adult ADHD Scales-Self Report were high.ASIA ADHD criteria showed acceptable psychometric properties, although further investigation is necessary. The use of ASIA ADHD criteria could facilitate clinical practice and research into adult ADHD in Japan.The online version of this article (doi:10.1186/s12888-015-0525-7) contains supplementary material, which is available to authorized users. There is a high prevalence worldwide of attention-deficit/hyperactivity disorder (ADHD) in adults, children, and adolescents. ADHD symptoms interfere with various aspects of daily life, such as education, work, and social relationships. Current estimates of the prevalence of adult ADHD are as high as 3.4 % 1.2–7.3 %) [.2–7.3 % A relevant diagnosis is imperative for the administration of appropriate interventions for psychiatric or psychological problems. However, there are considerable difficulties in diagnosing adult ADHD, mainly because of high comorbidity rates and uncertainty in the recall of childhood symptoms by potential ADHD patients and their parents. The pattern of comorbidity of ADHD changes from childhood through adolescence . After aSince the publication of DSM-IV , the DSMDSM-5 provides more example symptoms for adult (age ≥17) ADHD than DSM-IV. To our knowledge, there is no diagnostic interview for adult ADHD based on the DSM-5 criteria. Even if such an interview is developed in the near future in Western countries, it may not be readily available in Japan and such an instrument may not be culturally valid in Japan. Therefore, we created the Assessment System for Individuals with ADHD (ASIA) for adult ADHD, a semi-structured interview based on DSM-5 to help Japanese professionals diagnose adult ADHD in a standardized way. The objective of this study was to test the reliability and validity of ADHD diagnostic criteria in the ASIA for adults with and without ADHD.ASIA is a 56-page Japanese instrument consisting of three parts: (1) the semi-structured diagnostic interview for adults (age ≥17) with possible ADHD, (2) a form recording additional participant information, (3) a rating sheet, and (4) a diagnostic algorithm .Part one, the semi-structured ADHD diagnostic interview for which we report reliability and validity in this paper, contains ADHD criteria (A to E) similar to those in DSM-5 as well as questions devised by the authors to quantify in detail the criteria. Criterion A, the most important of the ASIA ADHD criteria, consists of nine inattention symptoms and nine hyperactivity–impulsivity symptoms corresponding to the inattention and hyperactivity–impulsivity symptoms in DSM-5 ADHD criterion A. Each ASIA ADHD criterion A symptom has four questions evaluating present behavior (the average state for the last 6 months) in adulthood age ≥17) and four questions evaluating childhood behavior (the most prominent state before age 12) on a 3-point scale . Of the four questions for each symptom, the first question most faithful to the DSM-5 symptom description; other three questions were devised to obtain further detail about each symptom, using relevant examples of the behavior. A response of “often/always (often or more)” to one or more questions for each symptom in childhood or adulthood constitutes a positive score for that symptom in that period. ASIA ADHD criterion A has a total of 144 questions : (1) demographic data ; (2) prenatal and perinatal history; (3) neonatal history; (4) past medical history; (5) past psychiatric history; (6) current medical conditions; (7) current psychiatric comorbidities; (8) family history ; (9) educational history (academic background and history of drop grade); (10) job history; (11) economic status (income); and (12) collateral information (from parents or from documents such as report cards). As some questions about demographic, psychiatric, familial, or economic issues may be viewed as uncomfortable, especially to Japanese respondents, these questions were placed at the end of the interview.An ASIA interview can last 1–2 h, which is an appropriate and feasible length of time for a personal interview .The interview results are recorded on the rating sheet (part three of ASIA). The ASIA ADHD diagnostic algorithm  and 30 adults who had expressed interest in participating in the research via the webpage of the peer group for adult ADHD/ASD or the first author’s webpage, most of whom considered themselves to have ADHD or another psychiatric disorder. They were recruited from May, 2013–April, 2014. Of the 60 participants , 36  and 24  were subsequently diagnosed with ADHD or non-ADHD, respectively, using consensus diagnoses (see Procedure for detail).n = 5); ASD (n = 3); obsessive–compulsive disorder (n = 2); developmental coordination disorder (n = 2); dysthymic disorder (n = 1); tic disorder (n = 1); post-traumatic stress disorder (n = 1). Of the 24 participants without ADHD, four had major depressive disorder, obsessive–compulsive disorder, ASD, or bipolar II disorder.Of the 36 participants with ADHD, 14 had psychiatric comorbidities (a participant can have one or more comorbidities), as follows: major depressive disorder (t(58) = 0.94) and gender ratio . The mean IQ was significantly lower in the ADHD group (mean = 99.4 ± 12.0) compared to the non-ADHD group (mean = 106.7 ± 10.9) (t(58) = 2.38, p < 0.05).The mean IQ of the 60 participants was 102.3 ± 12.0. The ADHD and non-ADHD groups showed no significant difference in age  using all the available participant information (except for their ASIA criteria data), including data on present behavior and symptoms on the Japanese version of Conners’ Adult ADHD Rating Scales-Self Report (J-CAARS-S) , 21. AddThe first author administered the ASIA to the participants and was blind to participant information, including the J-CAARS-S scores and the additional records used in the consensus diagnoses. This author knew only that participants suspected that they suffered from, or were interested in, ADHD or other psychiatric disorders. The second author (who did not participate in the consensus diagnoses and was blind to any participant information except for the ASIA ratings that she had given) determined the ASIA ADHD diagnoses of the 60 participants on the basis of her ASIA ratings according to the algorithm Fig. .Based on participants’ responses to a question on a 3-point frequency scale rated by the second author, values of Cronbach’s α as a measure of internal consistency reliability were calculated for the nine inattention symptoms and the nine hyperactivity–impulsivity symptoms for both adulthood and childhood. Interrater reliability (κ) was calculated for the 144 questions from data evaluated by the first and second authors. For the criteria B questions (onset prior to age 12), C (pervasiveness in setting), D (impairments), and E , which used “Yes” and “No” responses, only raw agreement rates were calculated because of a lack of variance in one rater’s answers that made κ incalculable.r). The J-CAARS-S is based on DSM-IV, but we considered its use appropriate as ADHD symptom descriptions in DSM-IV and DSM-5 are similar. To test discriminant validity of ASIA ADHD criterion A, the second authors’ ratings of the 144 questions for the ADHD and the non-ADHD groups according to the consensus diagnoses were compared using the Mann–Whitney U test. Statistical analyses were performed using SPSS version 22  with the significance level set at p < 0.05 (two-tailed test).To examine the concurrent validity of the ASIA criteria, the agreement of the diagnoses of ADHD and its subtypes were compared for the ASIA and consensus DSM-5 diagnoses. The association between ASIA ADHD criterion A total and subscale scores in adulthood and childhood and the corresponding J-CAARS-S subscale scores was also examined as a measure of concurrent validity using the Pearson product–moment correlation coefficient  between ASIA ADHD criterion A total and subscale scores in adulthood and childhood and the J-CAARS-S subscale scores ranged from 0.443 to 0.857, except for J-CAARS-S subscale D (ranging from 0.160 to 0.415). In particular, the correlations between scores on the corresponding ASIA ADHD criterion A and the J-CAARS-S subscales  for adulthood hyperactivity–impulsivity (α = 0.64). However, there is some disagreement about the acceptable values of α; these range from 0.70 to 0.95. A low value of α can be a result of a small number of questions, poor interrelatedness between items, or heterogeneous constructs . High vaThe consensus diagnoses agreed with the ASIA ADHD diagnoses (ADHD vs. non-ADHD and subtype diagnoses) in 59 of the 60 cases, indicating acceptable concurrent validity of the ASIA ADHD criteria. In one case, the consensus diagnosis was Other Specified ADHD, whereas the ASIA diagnosis was non-ADHD. This case met the other specified ASIA ADHD diagnosis except for criteria A and D. In the ASIA interview, this case had three positive inattention symptoms and four positive hyperactivity–impulsivity symptoms in childhood, and three positive inattention symptoms and three positive hyperactivity–impulsivity symptoms in adulthood, along with a Global Assessment of Functioning score of 72. The disagreement in diagnoses for this case supports Diller’s point that “although severe and even moderate ADHD might not be too difficult to diagnose, mild ADHD, especially the inattentive type, is wide open to interpretation as to what behavior crosses the line from a variation of normal to the deviancy of disorder .” The dir = 0.44–0.86) and the correlations for the corresponding subscale scores were particularly high (r = 0.66–0.86). We considered the relatively low correlations between ASIA ADHD criterion A scores and the J-CAARS-S subscale D scores reasonable because the subscale D measures problems of self-concept that have no direct relationship with ADHD symptoms. In a similar comparison, correlations between corresponding items on the CAADID DSM-IV ADHD symptom counts and the Conners’ adult ADHD rating scale-Self Report (n = 30) ranged from 0.20 to 0.52 [The correlations between ASIA ADHD criterion A subscale scores and J-CAARS-S subscale scores were moderate to high  failed to show a significant difference between the two groups. This is partly explained by small statistical power resulting from the relatively small number of participants, especially for ADHD with combined presentation. The small number of ADHD combined presentation cases might partly be a result of the attenuating nature of hyperactivity–impulsivity symptoms in adulthood, as described in the DSM-5 ADHD criteria for hyperactivity symptom c, which indicates that “excessive running/climbing may be limited to feeling restless in adolescents or adults [For a diagnosis of Other Specified ADHD, we set an operational rule that four symptoms in adulthood and three to five symptoms in childhood of either inattention or hyperactivity-impulsivity should be present , whereas AISRS employs a 4-point scale. We used a 3-point scale for the ASIA ADHD criterion A questions for the following reasons: to increase the precision of the severity rating of symptoms compared to a 2-point scale, to reduce the number of response choices for Japanese participants who are unfamiliar with frequency responses, and to shed light on subthreshold ADHD  for future research. In the CAADID and DIVA techniques, interviewees are prompted (if necessary) by examples of each symptom, the numbers of which differ from symptom to symptom. For every ASIA ADHD criterion A symptom, the first question (which is most faithful to the DSM-5 symptom description) is followed by three example questions. This unification enables clinicians or researchers to easily measure several psychometric properties.Comorbidity of pervasive developmental disorders (ASD and Rett’s disorder) and ADHD is not permitted in DSM-IV but permitted in DSM-5. There were only three participants in this study diagnosed with both ASD and ADHD. Determining whether there is any symptomatic difference between individuals with ADHD only and those with both ADHD and ASD would be of great clinical interest and should be investigated in a further study.There are some limitations to our study. In the interrater reliability study, the second author rated participants while watching videotaped interviews by the first author instead of directly administering the ASIA, because it would have been time-consuming to administer another assessment. The ratings of the second author, who was blind to any participant information except for her ASIA ratings, were used to diagnose ADHD. However, as the second author rated the interview while watching the videotape of the first author’s interviews, she may have been influenced by the first author’s biases, even though all possible measures were taken to make the first author blind to any information about participants except for the ASIA ratings. This shortcoming needs to be addressed by a further study employing a more rigorous methodology . Even with the inherent methodological problems, it was important to examine interrater reliability in the present study, as this semi-structured diagnostic interview can be administered by a variety of clinicians. Similarly, when confirming concurrent validity, the third and the fourth authors made diagnoses by referring to detailed clinical records of the cases instead of using face-to-face clinical interviews with potential ADHD patients. Although this lessened the participants’ burden, this simplified procedure may have allowed bias in the diagnosis of ADHD in adults. This shortcoming needs to be resolved in a future study.The ASIA ADHD criteria showed acceptable internal consistency reliability; interrater reliability; and concurrent, discriminant, and content validity and could be useful in clinical practice and research. However, further investigation of this instrument is necessary.


Several recent behavioural and behavioural genetic studies have investigated the relationship between attention deficit hyperactivity disorder (ADHD) and mathematical ability. The aim of this systematic review was to provide an overview of these studies to date. An emphasis was placed on reviewing results that explored the association between mathematics and the two ADHD components of attention and hyperactivity-impulsivity separately.A systematic search of quantitative studies investigating the association between mathematics and ADHD was conducted across five databases . A total of 30 cross-sectional and four longitudinal studies were included in this review.Narrative synthesis of the results was provided using PRISMA guidelines. Taken together, the studies pointed at substantial evidence for a negative association between ADHD symptoms and mathematical ability. This association was particularly marked for the inattentive component of ADHD than for the hyperactive-impulsive component. Evidence from twin studies also showed a significant genetic correlation between mathematics and ADHD, which was greater for the inattentive component of ADHD compared to the hyperactive-impulsive component.The differential relationship of the hyperactivity-impulsivity and inattention domains with mathematics emphasises the heterogeneity within the disorder and suggests a partially different aetiology of the two ADHD domains. A better understanding of the aetiology of ADHD could help develop more efficient interventions aimed at the reduction of its symptoms. It could also offer an explanatory framework for shortcomings in achievement and inform the development of non-pharmacological intervention strategies.The online version of this article (doi:10.1186/s12916-015-0414-4) contains supplementary material, which is available to authorized users. Both manuals use a diagnostic criteria consisting of the same 18 symptoms and identify the same two core domains reflecting inattentive and hyperactive-impulsive behaviours. The symptoms are persistent across development and have significant effects in adaptive functioning. The DSM criteria identify a broader range of individuals, including those presenting with predominantly inattentive symptoms and an older age of onset. Depending on the features that are most prominent, three clinical presentations of ADHD are described: predominantly inattentive (ADHD-I), predominantly hyperactive-impulsive (ADHD-H), and combined (ADHD-C) type clinical presentations [Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high global prevalence of 5.29 % , charactAlthough inattention, hyperactivity, and impulsivity represent core symptoms of ADHD, the disorder is highly heterogeneous and is associated with a plethora of different impairments including cognitive and behavioural deficits. Students with ADHD generally show poor academic outcomes relative to their general cognitive abilities, with greater grade repetitions and increased school dropout rates , 4. Due Mathematical training makes up a large portion of school education and it is positively correlated with longer educational duration and higher qualification attainment . FurtherMuch of the existing literature has focused on the links between ADHD and reading disability –10, neglReviews relating to mathematical abilities and ADHD have been sparse in the past due to the limited number of studies focusing on mathematics and ADHD. In this study, we have used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  to preseWe examined existing literature in order to appraise the co-occurrence of mathematical problems and ADHD in all age groups and to explore whether mathematics has a differential relationship with each of the two components of ADHD, namely inattentiveness and hyperactivity-impulsivity.http://www.crd.york.ac.uk/prospero/, reference CRD42015016186).The protocol of this review has been registered with the International Prospective Register of Systematic Reviews  articles published in English in peer-reviewed journals; (2) usage of appropriate empirical research methods, assessed using the quality appraisal criteria ; (3) cases of any age who met the ADHD criteria (DSM-defined ADHD or ICD-defined hyperkinetic disorder) and/or were assessed for symptoms of the disorder on ADHD validated scales (e.g. Conners ); (4) stFive databases, including PsychINFO, EMBASE 1806, Web of Science, PubMed, and were searched for articles. An additional manual search of the literature was performed to identify any publications missed by the database search.The search was conducted on 1 February, 2015 without any constraints on the year of publication to allow for a thorough and complete review of the literature using the following key words: “attention deficit hyperactivity disorder” OR “ADHD” OR “hyperkinetic disorder” AND “mathematical ability” OR “math* achievement” OR “acalculia” OR “mathematics”.The study selection process is illustrated in Fig. Full documents were obtained for the remaining records and checked against the eligibility criteria. Papers were rejected at this stage if 1) no healthy control group was included for comparison ; or (2) individuals with ADHD also had known mathematical disabilities. The papers that met the eligibility requirements, based on the above screening criteria, are summarized in Table  no healtData were extracted by one of the authors and confirmed by a second author; in case of disagreement, a third author was consulted. Extraction was limited to published data; authors of the papers were not contacted for missing information and this is indicated as ‘not reported’ (NR).The following variables were assessed: (1) type of study ; (2) nature of the cases (diagnosis of ADHD in absence of learning disabilities); (3) numbers of cases (ADHD) and, if available, number for each of the ADHD sub-groups, inattention and hyperactivity-impulsivity; (4) nature of the control group  and number of healthy controls where a control group was present; (5) age range and sex by group(s); (6) the response rate to the study; (7) dropout rates for participants recruited ; (8) whether the potential confounding demographic and cognitive factors , socio-economic status, and gender) were accounted for in the design and/or in their analysis; (9) whether cases were on medication during the test or whether the medication was stopped temporarily prior to testing; (10) name of the mathematics test used to test mathematical performance; (11) mean mathematics score with standard deviation for cases and controls and/or other appropriate means of describing the association between ADHD and mathematics ; (12) if longitudinal study scores were available at baseline and follow-up; and (13) whether effects size were included.Risk of bias of individual studies was critically assessed at the study level and taken into account in the quality assessment. The quality assessment of the mixed methods studies reviewed was performed using items provided in the Critical Appraisal Skills Programme, Oxford checklist tool  (see Addt-test), regression coefficients (β), correlation coefficient (r), z-scores, genetic, shared and non-shared environmental correlations , or genetic covariances. The statistical significance  for the results of each analysis was also included in the summary table.Samples descriptive statistics include age range, mean, and standard deviation of age by group, together with total number of cases and controls and whether cases were medicated or not Table . The tabA narrative synthesis of the findings from the studies was performed and reported following PRISMA guidelines.The number of studies emerging from the selection process is illustrated in Fig. Cross-sectional and longitudinal (marked by (*) in Table Data on the risk of bias and quality assessment for each study are presented in Table The most common tests used to asses mathematical performance Table  were theFour studies compared mathematical performance at baseline and follow-up , 38, 46.a, rc, and re, genetic covariance and shared-environmental covariance.Results were evaluated based on the magnitude of the association between mathematics and ADHD and are reported in the sections below using standardised beta coefficients (β) and/or Pearson correlation coefficients (r) and mean difference between cases and controls, where relevant. For genetically sensitive studies, the genetic and environmental correlational coefficients are reported; these are marked as rFollowing quality assessment, all papers were rated as either high or medium with no papers achieving a low-quality rating score.Out of the 24 studies, 20 reported a statistically significant negative association between ADHD symptoms and mathematical performance –48, 50. P = 0.06) during the 8-year period of assessments. However, using a restricted sample of 73 children who exhibited both hyperactive and inattentive symptoms from the first assessment, the association between ADHD-C subtype and mathematics was significant for the same period of time . The other two longitudinal studies [Among the three longitudinal studies with high quality ratings, Massetti et al.  did not  studies , 46 showP <0.001) but did not report results on any analyses looking at differences between males with ADHD and male controls.Rucklidge and Tannock  analysedFour studies with high quality ratings did not show any significant correlation between ADHD or its subtypes and mathematical ability , 39, 49.a), shared (rc), and non-shared (re) environmental correlations between ADHD and mathematics. Greven et al. [a = −0.41; 95 % CI = −0.47, −0.37) compared to hyperactive-impulsive symptoms , suggesting more genetic factors in common between inattention and mathematics compared to hyperactivity-impulsivity and mathematics. The study reported a small significant shared environmental correlation between mathematics and hyperactivity (rc = –0.27) but a non-significant shared environmental correlation with inattention. This may point to a different aetiology of the covariation between mathematics and the two subtypes. Hart et al. [Two behavioural genetic studies used a twin design to explore the genetic  demonstrated a significant association even after controlling for IQ, age, socioeconomic status, and other potential attenuating factors such as psychostimulant medication . RegardlDuring primary school, mathematics education requires increased continuous attention and regular independent seat work, resulting in difficulty in learning for students with ADHD symptoms . In seveThe ADHD clinical subtypes (as described by the DSM-IV criteria) are developmentally unstable and reflect arbitrary cut offs on dimensional measures of inattention and hyperactivity/impulsivity. Some children exhibiting ADHD-C in early childhood would meet the criteria for ADHD-I later on in childhood or adolescence as the hyperactive symptoms decrease overtime in comparison to the inattentive symptoms . AlternaAlthough this review used the differential relationship of ADHD with mathematics to highlight the heterogeneity within the disorder, there are a number of limitations that need to be considered. Several studies had relatively small sample size and different studies controlled for different variables. Moreover, the comorbidity between ADHD and other conduct disorders and behavioural problems are pervasive and this could not be fully appraised within each study. To control for these factors and evaluate bias we used set items provided in the Critical Appraisal Skills Programme checklist tool . Any tooUsing the association of mathematics with ADHD has allowed highlighting the heterogeneity within the disorder. However, studies exploring the association between mathematics and ADHD are fewer compared to other phenotypes. Therefore, the four longitudinal studies identified in this review did not allow to fully capture the developmental aspect of ADHD.Our search for papers was restricted to in-print English articles available in online databases only; articles in other languages could have been missed. Finally, the effect of medications could not be fully accounted for.Overall, the literature reviewed shows a negative association between ADHD and mathematics and that this association is stronger for the inattentive symptoms; the differential relationship of the two ADHD subtypes with mathematics points to a partially different aetiology within the disorder. Due to varying symptomatology found among children with ADHD, it is important to give an accurate diagnosis according to the two subtypes in order to identify which children are more likely to be at risk of mathematical difficulties. The genetic studies reviewed show that the covariation of ADHD and mathematics is partially due to common genetic factors but environmental factors still play a role. These insights are advantageous to our understanding of this complex disorder and they could help develop non-pharmacological interventions that go beyond simply the reduction of ADHD symptoms. These interventions, used solely or in conjunction with pharmacological treatments, could allow children to deal better with the pressures of the general classroom while having the chance to enjoy and thrive in the educational environment. Further research is needed to investigate specific factors that determine the association between ADHD and deficits in mathematical ability and to show the extent to which they share a common neurobiological basis.


Bartonella henselae is a bacterium which can cause a wide range of clinical manifestations, ranging from fever of unknown origin to a potentially fatal endocarditis. We report a case of Bartonella henselae infection in a pediatric-aged patient following a scratch from a kitten. The patient initially presented with a prolonged fever of unknown origin which was unresponsive to antibiotic treatment. The patient was hospitalized with worsening fevers and night sweat. Subsequent ultrasound imaging demonstrated multiple hypoechoic foci within the spleen. A contrast-enhanced CT of the abdomen and pelvis was also obtained which showed hypoattenuating lesions in the spleen and bilateral kidneys. Bartonella henselae IgG and IgM titers were positive, consistent with an acute Bartonella henselae infection. The patient was discharged with a course of oral rifampin and trimethoprim-sulfamethoxazole, and all symptoms had resolved following two weeks of therapy. Bartonella henselae commonly presents as fever and localized lymphadenopathy in children or adolescents with a history of exposure to a scratch from a kitten or cat. The most commonly involved lymph nodes are axillary and epitrochlear, presumably because the majority of contact with cats occurs with the hands [ Bartonella henselae infection have also been reported [ Bartonella henselae on ultrasound and CT in a pediatric patient.he hands . The bache hands , 2. Hepahe hands . Typicalhe hands . More rereported . We repoA previously healthy six-year-old female presented with complaint of fevers up to 101 degrees Fahrenheit, as well as dry cough, intermittent periumbilical abdominal pain, and night sweat. She was taken to her primary care physician, who diagnosed the patient with a urinary tract infection and she was sent home with a 5-day course of oral amoxicillin. The patient returned to the emergency room 2 days after completion of the antibiotics with persistent fevers and cough. Urinalysis and complete blood count were unremarkable. A chest radiograph showed perihilar peribronchial thickening without focal consolidation. The patient was discharged home with a presumed diagnosis of atypical pneumonia and given a 5-day course of oral azithromycin. Following completion of the azithromycin, the patient had improvement in her cough but still had persistent fevers, prompting another visit to the emergency department the day after completing her antibiotic course. A repeat chest radiograph, complete blood count, urinalysis, and renal function panel were normal. C-reactive protein was elevated at 6.65 mg/dL  and erythrocyte sedimentation rate was elevated at 70 mm/h . The patient was hospitalized for further evaluation of her fever.Blood and urine cultures on the date of admission did not demonstrate bacterial growth. Further investigation into the patient's history did not demonstrate any sick contacts but did have exposure to a family member who had been recently incarcerated. The patient did also have recent contacts with new dogs and kittens prior to the onset of fever, and the patient did suffer a scratch to the chest from one of the kittens which did not require medical care.On hospital day 2, a complete abdominal ultrasound demonstrated an echogenic liver which was slightly enlarged to 11 cm in the craniocaudal dimension at the right midclavicular line. The spleen was also enlarged to 7.8 cm and contained several small hypoechoic foci Figures . A contr Bartonella henselae IgG was positive at >1 : 1024, consistent with presence of IgG antibody to Bartonella henselae, suggestive of current or prior infection. Bartonella henselae IgM was also positive at 1 : 128, suggestive of current or recent infection. Given the CT and ultrasound findings, the constellation of findings was consistent with an active Bartonella henselae infection with involvement of the spleen, kidneys, and liver.Epstein-Barr virus, cytomegalovirus, toxoplasmosis, HIV, histoplasmosis titers, and purified protein derivative tests were all negative. On hospital day 3, theFollowing these results, the patient was treated with oral rifampin 150 mg by mouth twice daily for fourteen days and trimethoprim-sulfamethoxazole 150 mg by mouth twice daily for fourteen days, which was well tolerated. The patient's fever and other symptoms resolved during her hospital stay and she was discharged on continuation of the oral antibiotic regimen. At the time of discharge on hospital day 5, the patient had defervesced and her inflammatory markers had decreased, with a C-reactive protein of 2.61 at the time of discharge. Her subsequent outpatient follow-up in the infectious disease clinic 11 days after discharge demonstrated complete resolution of her symptoms. Bartonella henselae is infrequently discussed in the radiology literature. In this report, we present a case of a pediatric patient with Bartonella henselae infection resulting in splenomegaly and microabscesses of the spleen and kidneys as noted on CT and ultrasound; to the best of our knowledge, this is the first report of this constellation of findings on radiologic studies in a pediatric patient.Though well-known as a cause of infection, Bartonella henselae was isolated [ Bartonella henselae is an intracellular bacillus which can be identified on Warthin-Starry silver stains [ Bartonella henselae is cats, with half of pet cats demonstrating antibodies against the bacteria [ Ctenocephalides felis or the “common” cat flea [ Bartonella henselae; however, even 28% of cats without known associations to cat-scratch disease or bacillary angiomatosis have Bartonella henselae bacteremia [It was only as recently as 1992 that the pathogenisolated . Bartonebacteria . The infcat flea . The baccat flea . Cats ascteremia . Prevent Bartonella henselae invasion of endothelial cells in both reservoir and incidental hosts [ Bartonella henselae [Upon infection, the bacteria invade many types of cells; most commonly this involves dendritic cells but also includes CD34+ progenitor cells, erythrocytes, pericytes, and perhaps most importantly endothelial cells , 5. Bartal hosts  results al hosts . This isal hosts  and by shenselae . Bartonella henselae infection is dependent on the immune status of the affected host. Immunocompetent patients most commonly present with fever which may be protracted, localized lymphadenopathy and hepatosplenic disease. Typical cat-scratch disease includes fever and localized lymphadenopathy usually only affecting a single lymph node [ Bartonella henselae can also result in chronic bacteremia, even in immunocompetent patients, who may be entirely asymptomatic or may present with mild or fluctuating symptoms, including fatigue, myalgias, headaches, generalized pains, and insomnia [ Bartonella henselae infection is also one of the most common causes of a fever of unknown origin in a pediatric patient, with some studies showing it to be the third most common cause of a prolonged fever in children [The clinical presentation ofmph node . The patmph node . Althouginsomnia , 12. Barchildren . Bartonella henselae infection in immunocompromised patients, typically those with AIDS [Immunodeficient patients may manifest infection as cutaneous bacillary angiomatosis , with cuith AIDS . It presith AIDS . Bartonella henselae infection can be quite challenging, in part because many of the signs and symptoms are nonspecific and can be seen in other infections including cytomegalovirus infection, HIV infection, toxoplasmosis, and Epstein-Barr virus infection, as well as noninfectious etiologies including malignancies such as lymphoma [ Bartonella henselae infection [ Bartonella henselae infection. In the setting of equivocal serology but a persistent clinical suspicion for Bartonella henselae infection, lymph node biopsy can be performed with polymerase chain reaction to identify DNA fragments [ Bartonella henselae infection [Diagnosinglymphoma . The patlymphoma . The beslymphoma . Unfortulymphoma –17. The lymphoma . Converslymphoma . With thnfection . An addiragments , 16. Thenfection . Bartonella henselae is becoming more widely discovered due to increased use and accuracy of radiological studies. These lesions are seen as hypoattenuating on CT and hypoechoic on ultrasound, which correspond to necrotizing granulomata on pathology [ Bartonella henselae infection, only two had hepatomegaly and two had splenomegaly; all patients in this series had splenic microabscesses and the majority had hepatic microabscesses [On radiologic imaging, hepatosplenic involvement ofathology . These tathology , 6. On cathology . In a stbscesses . Only 64bscesses . Bartonella henselae infection was reported in 2010 [ Bartonella henselae is glomerulonephritis [The first reported case of bilateral renal microabscesses secondary to in 2010 , which p in 2010 . However Bartonella henselae, with incomplete treatment responses to multiple antibiotic agents. Rather, in cats the optimal management is the eradication of fleas [ Bartonella henselae dictate the appropriate therapeutic management; for instance, typical cat-scratch disease is often self-limited and poorly responsive to antimicrobial treatment [ Bartonella henselae infection is also dependent on the patient's immune status, with immunocompetent patients requiring only 2–4 weeks of therapy. In immunocompromised patients, even prolonged antibiotic courses of 6 weeks may subsequently relapse and demonstrate bacteremia [In cats, no antibiotic has proven routinely effective for the treatment ofof fleas . A monthof fleas . Other dof fleas . In humareatment , whereasreatment . Treatmecteremia . As a recteremia .


Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited.We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children.Among 83,389 mother–child pairs enrolled in the Danish National Birth Cohort during 1996–2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child’s sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights.Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother’s PFAS plasma levels and ADHD  or autism . We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise.In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children.http://dx.doi.org/10.1289/ehp.1408412Liew Z, Ritz B, von Ehrenstein OS, Bech BH, Nohr EA, Fei CY, Bossi R, Henriksen TB, Bonefeld-Jørgensen EC, Olsen J. 2015. Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case–control study in the Danish National Birth Cohort. Environ Health Perspect 123:367–373;  Perfluoroalkyl substances (PFASs) are a group of human-made fluorine-containing compounds with unique properties that make materials resistant to stains, oil, and water . PFASs hPFASs can cross the placental barrier and expose the fetus during the most vulnerable period of development . ExperimAttention deficit/hyperactivity disorder (ADHD) is considered one of the most common neurobehavioral disorders worldwide, and is characterized by inattention, hyperactivity, increased impulsivity, and motivational/emotional dysregulation . Autism in utero PFOA levels were associated with higher Full-Scale IQ and decreased ADHD characteristics among children 6–12 years of age  to examine whether prenatal exposure to PFASs is associated with ADHD or autism in children.The DNBC is a nationwide cohort study of pregnancies and health-related outcomes in the children; details have been described elsewhere . BrieflyWritten informed consent was obtained from all participants at recruitment. Study procedures have been approved by the Danish Data Protection Agency and the Institutional Review Board at University of California, Los Angeles.Source population. The source population for this study consisted of live-born singletons along with mothers who participated in the first telephone interview, conducted approximately during the 12th gestational week, and had provided a blood sample at least once either during the first or second pregnancy trimesters. This resulted in 83,389 mother–child pairs, with 42,737 boys and 40,652 girls; we excluded from the original DNBC those with an unsuccessful pregnancy , non-singleton births , births with unknown birth outcomes (n = 25) or missing dates of birth (n = 99), mothers who emigrated (n = 51) or died (n = 3), and women who did not participate in the first telephone interview  or did not provide a prenatal blood sample .Selection of cases and controls. We identified children who were diagnosed with ADHD and autism, respectively, by linking DNBC records to the Danish National Hospital Registry  and included inpatient and outpatient records. A total of 890 ADHD cases and 301 autism cases were identified in the cohort during an average of 10.7 years of follow-up (record linkage was conducted on 1 August 2011). Because of the high costs of measuring PFASs, we randomly selected 220 cases of ADHD and autism each for inclusion in this study.Registry  that conRegistry , which cWe used a case-cohort sampling strategy and randomly selected 550 children  as controls from the source population, frequency matched to cases by sex. The flow chart of subject selection and sampling fractions of cases and controls is shown in PFAS measurements. Details about analytic methods for PFASs have been described previously (r = 0.94 for PFOS and r = 0.95 for PFOA).eviously . Brieflyeviously . For quaOf the 16 different PFASs detected in maternal plasma, we focused on the six PFASs for which at least 90% of all samples were above the lower limit of quantitation (LLOQ): PFOS, 100%; PFOA, 100%; PFHxS, 98%; PFHpS (perfluoroheptane sulfonate), 96%; PFNA, 92%; and PFDA, 90%. The LLOQ for the six PFASs are as follows: PFOS, 0.28 ng/mL; PFOA, 0.20 ng/mL; PFHxS, 0.08 ng/mL; PFHpS, 0.11 ng/mL; PFNA, 0.27 ng/mL; and PFDA, 0.09 ng/mL. The full panel for the LLOQ and distribution of all PFASs was reported previously .Statistical analysis. We used generalized linear models and accounted for the sampling fractions of cases and controls to estimate risk ratios (RR) and 95% confidence intervals (CIs) for prenatal PFAS exposures and ADHD or autism. We also performed unconditional logistic regression to estimate odds ratios (ORs) without applying the sampling weights. PFAS concentrations were first analyzed as continuous variables . The PFAS values were natural-log transformed to reduce the influence of outliers, to improve the model fit, and to make interpretation simpler and more consistent across different PFASs that vary in their ranges of concentration. We also categorized PFAS values into quartiles according to the distribution among controls, using the lowest quartile as the reference group. Moreover, we fitted generalized additive models with a smoothing function of natural-log PFAS values to examine potential nonlinear relations. Five knots were set as the upper limit of number of degrees of freedom, and we compared model fit and visually inspected plots of the smoothed data. We did not find evidence for nonlinearity between natural-log PFAS values and ADHD or autism (data not shown).a priori considering variables that may influence PFAS exposures and previously suggested risk factors of ADHD or autism. We included maternal age at delivery , parity , socioeconomic status (low/medium or high), maternal smoking  and alcohol drinking  during pregnancy, mother’s self-reported psychiatric illnesses , gestational week of blood draw , child’s birth year , and the matching factor child’s sex in the final model. Socioeconomic status was determined based on self-reported maternal and paternal education and occupation using three categories : Higher education (4 years beyond high school) or work in management were classified as high; skilled workers and middle-range education as medium; and unskilled workers and unemployed as low  to ensure that individuals with extreme exposure values did not disproportionately influence our results. Analyses were performed using SAS version 9.2.A Pearson correlation matrix for the considered PFASs is presented in Supplemental Material, Table S1. We constructed a “multiple PFAS” model where we simultaneously included all PFASs in one model to examine whether any single PFAS may be of particular importance. We also evaluated potential effect measure modification by child’s sex; we compared the sex-stratified estimates and examined the p-values ≥ 0.25), but because both diagnoses were more prevalent in boys, estimates for girls were less precise .We generally found no association between ADHD or autism in children and PFAS levels in maternal plasma  . We did When we categorized PFAS values, mothers in the highest quartile of PFOS, PFHxS, PFHpS, and PFDA were less likely to have a child diagnosed with ADHD than mothers in the lowest quartile, after adjustment for potential confounders . When alResults were similar to those from the primary models when we performed additional sensitivity analyses restricting the analyses to children born before 2001 , and excluding extreme PFAS values (results not shown).Overall, our results do not suggest that prenatal exposure to PFASs increases the risk of ADHD or childhood autism in children. We observed some inverse associations between several PFASs and ADHD after controlling for potential confounders. In the “multiple PFAS” model, we found some positive as well as negative associations between PFASs and ADHD but these might be subject to multicollinearity or sparse data bias. Results were mostly close to null for autism in both single and multiple PFAS models.in utero PFOA exposures based on the Clinical Confidence Index  on androgen receptor function . Thus, our subgroup analyses by sex were relatively imprecise for girls, resulting in effect estimates with wide CIs. For autism, the cases were limited to children diagnosed with childhood autism. Although this is the most severe disorder of the autism spectrum, it constitutes only a part of autistic spectrum disorders; specifically children with Asperger’s syndrome and other pervasive development disorders were not studied. Moreover, we have no data for other endocrine-disrupting chemicals, preventing us from evaluating possible correlations or interactions of PFASs with other ubiquitous environmental chemicals with these properties such as polychlorinated biphenyls (PCBs), organophosphates, bisphenol A, and phthalates  PDFClick here for additional data file.