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Non-tuberculous mycobacterium encephalitis is rare. Since 2013, a global outbreak of Mycobacterium chimaera infection has been attributed to point-source contamination of heater cooler units used in cardiac surgery. Disseminated M. chimaera infection has presented many unique challenges, including non-specific clinical presentations with delays in diagnosis, and a high mortality rate among predominantly immunocompetent adults. Here, we describe three patients with fatal disseminated Mycobacterium chimaera infection showing initially non-specific, progressively worsening neurocognitive decline, including confusion, delirium, depression and apathy. Autopsy revealed widespread granulomatous encephalitis of the cerebrum, brain stem and spinal cord, along with granulomatous chorioretinitis. Cerebral involvement and differentiation between mycobacterial granulomas and microangiopathic changes can be assessed best on MRI with contrast enhancement. The prognosis of M. chimaera encephalitis appears to be very poor, but might be improved by increased awareness of this new syndrome and timely antimicrobial treatment.
This presentation will enable the learner to:
1.Describe the clinical, radiological and neuropathological findings of Mycobacterium chimaera encephalitis
2.Be aware of this rare form of encephalitis, and explain its diagnosis, prognosis and management
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Field experiments were conducted in 2016 and 2017 in Champaign County, IL, to study a waterhemp [Amaranthus tuberculatus (Moq.) J. D. Sauer] population (CHR) resistant to 2,4-D and 4-hydroxyphenylpyruvate dioxygenase (HPPD)-, photosystem II–, acetolactate synthase (ALS)-, and protoporphyrinogen oxidase–inhibiting herbicides. Two field experiments were designed to investigate the efficacy of very-long-chain fatty-acid (VLCFA)-inhibiting herbicides, including a comparison of active ingredients at labeled use rates and a rate titration experiment. Amaranthus tuberculatus density and control were evaluated at 28 and 42 d after treatment (DAT). Nonencapsulated acetochlor, alachlor, and pyroxasulfone provided the greatest PRE control of CHR (56% to 75%) at 28 DAT, while metolachlor, S-metolachlor, dimethenamid-P, and encapsulated acetochlor provided less than 27% control. In the rate titration study, nonencapsulated acetochlor controlled CHR more than equivalent field use rates of S-metolachlor. Subsequent dose–response experiments with acetochlor, S-metolachlor, dimethenamid-P, and pyroxasulfone in the greenhouse included three multiple herbicide–resistant (MHR) A. tuberculatus populations: CHR-M6 (progeny generated from CHR), MCR-NH40 (progeny generated from Mclean County, IL), and ACR (Adams County, IL), in comparison with a sensitive population (WUS). Both CHR-M6 and MCR-NH40 are MHR to atrazine and HPPD, and ALS inhibitors and demonstrated higher survival rates (LD50) to S-metolachlor, acetochlor, dimethenamid-P, or pyroxasulfone than ACR (atrazine resistant but HPPD-inhibitor sensitive) and WUS. Based on biomass reduction (GR50), resistant to sensitive (R:S) ratios between CHR-M6 and WUS were 7.5, 6.1, 5.5, and 2.9 for S-metolachlor, acetochlor, dimethenamid-P, and pyroxasulfone, respectively. Values were greater for MCR-NH40 than CHR-M6, and ACR was the most sensitive to all VLCFA inhibitors tested. Complete control of all populations was achieved at or below a field use rate of acetochlor. In summary, field studies demonstrated CHR is not controlled by several VLCFA-inhibiting herbicides. Greenhouse dose–response experiments corroborated field results and generated R:S ratios (LD50) ranging from 4.5 to 64 for CHR-M6 and MCR-NH40 among the four VLCFA-inhibiting herbicides evaluated.
Buoyant jets or forced plumes are discharged into a turbulent ambient in many natural and engineering applications. The background turbulence generally affects the mixing characteristics of the buoyant jet, and the extent of the influence depends on the characteristics of both the jet discharge and ambient. Previous studies focused on the experimental investigation of the problem (for pure jets or plumes), but the findings were difficult to generalize because suitable scales for normalization of results were not known. A model to predict the buoyant jet mixing in the presence of background turbulence, which is essential in many applications, is also hitherto not available even for a background of homogeneous and isotropic turbulence (HIT). We carried out experimental and theoretical investigations of a buoyant jet discharging into background HIT. Buoyant jets were designed to be in the range of
is the momentum length scale, with
representing the asymptotic cases of pure jets and plumes, respectively. The background turbulence was generated using a random synthetic jet array, which produced a region of approximately isotropic and homogeneous field of turbulence to be used in the experiments. The velocity scale of the jet was initially much higher, and the length scale smaller, than that of the background turbulence, which is typical in most applications. Comprehensive measurements of the buoyant jet mixing characteristics were performed up to the distance where jet breakup occurred. Based on the experimental findings, a critical length scale
was identified to be an appropriate normalizing scale. The momentum flux of the buoyant jet in background HIT was found to be conserved only if the second-order turbulence statistics of the jet were accounted for. A general integral jet model including the background HIT was then proposed based on the conservation of mass (using the entrainment assumption), total momentum and buoyancy fluxes, and the decay function of the jet mean momentum downstream. Predictions of jet mixing characteristics from the new model were compared with experimental observation, and found to be generally in agreement with each other.
In the case of X-ray fluorescence analysis of aerosol loaded filters, the X-ray absorption effect Is due to particulate matter absorption and to filter material absorption. The latter contribution is of a predominant importance in many practical cases. It can be calculated from the ratio of the X-ray intensities measured from the front and back side of the filters. The sandwich geometry obtained by folding the filters in two with the loaded side inwards during the measurement renders the filter material absorption correction much simpler and often more accurate, and offers distinct additional advantages.
We sought to define the prevalence of echocardiographic abnormalities in long-term survivors of paediatric hematopoietic stem cell transplantation and determine the utility of screening in asymptomatic patients. We analysed echocardiograms performed on survivors who underwent hematopoietic stem cell transplantation from 1982 to 2006. A total of 389 patients were alive in 2017, with 114 having an echocardiogram obtained ⩾5 years post-infusion. A total of 95 patients had echocardiogram performed for routine surveillance. The mean time post-hematopoietic stem cell transplantation was 13 years. Of 95 patients, 77 (82.1%) had ejection fraction measured, and 10/77 (13.0%) had ejection fraction z-scores ⩽−2.0, which is abnormally low. Those patients with abnormal ejection fraction were significantly more likely to have been exposed to anthracyclines or total body irradiation. Among individuals who received neither anthracyclines nor total body irradiation, only 1/31 (3.2%) was found to have an abnormal ejection fraction of 51.4%, z-score −2.73. In the cohort of 77 patients, the negative predictive value of having a normal ejection fraction given no exposure to total body irradiation or anthracyclines was 96.7% at 95% confidence interval (83.3–99.8%). Systolic dysfunction is relatively common in long-term survivors of paediatric hematopoietic stem cell transplantation who have received anthracyclines or total body irradiation. Survivors who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless otherwise indicated.
OBJECTIVES/SPECIFIC AIMS: Neurological injury remains as the main limiting factor for overall recovery after cardiac arrest (CA). Currently available indicators of neurological injury are inadequate for early prognostication after return of spontaneous circulation (ROSC). High diversification of brain mitochondrial cardiolipins (CL) makes them unique candidates to quantify brain injury and to predict prognosis early after ROSC. METHODS/STUDY POPULATION: CL content in plasma in 39 patients within 6 hours of ROSC and 10 healthy subjects as well as CL content in human heart and brain specimens were quantified using a high-resolution liquid chromatography mass spectrometry method. The quantities of brain-type CL species were correlated with clinical parameters of brain injury severity permitting derivation of a cerebral CL score (C-score) using linear regression. C-score and a single CL species (70:5) were evaluated in patients with varying neurological injury and outcome. Using a rat model of CA, CL was quantified in the plasma and brain of rats using similar methods and results compared with the controls. RESULTS/ANTICIPATED RESULTS: We found that brain and the heart fell on extreme ends of the CL diversity spectrum with 26 species of CL exclusively present in human brain not heart. Nine of these 26 species were present in plasma within 6 hours of ROSC with quantities correlating with greater brain injury. The C-score correlated with early neurologic injury and predicted discharge neurologic/functional outcome. CL (70:5) emerged as a potential point-of-care marker that alone was predictive of injury severity and outcome nearly as well as C-score. Using a rat CA model we showed a significant reduction in hippocampal CL content corresponding to CL released from the brain into systemic circulation. C-score was significantly increased in 10 minute Versus 5 minute no-flow CA and naïve controls. DISCUSSION/SIGNIFICANCE OF IMPACT: CA results in appearance and accumulation of CL in plasma, proportional to injury severity. Quantitation of brain-type CL species in plasma can be used to prognosticate neurological injury within 6 hours after ROSC.
OBJECTIVES/SPECIFIC AIMS: The overall goal of this project is to enhance the use of GCRA in Latina breast cancer survivors at high risk of hereditary breast and ovarian cancer to reduce disparities in GCRA uptake. The aims of the study are to (1) develop a cultural adaptation of an evidence-based TGC intervention that consists of phone genetic counseling and a booklet, (2) evaluate the impact of TGC Versus Usual Care, and (3) explore the communication patterns in TGC and genetic counseling sessions with an interpreter. METHODS/STUDY POPULATION: We are conducting a 2-phase, mixed methods study. In Phase I we will develop a cultural adaption of an evidence-based intervention (TGC) for high-risk Latina breast cancer survivors using the Learner Verification and Revision Framework (n=15). In Phase II we will use a cluster randomized design with four community sites randomized to Spanish TGC (n=2 sites) or usual care (n=2 sites) (n=60; 15 per site). The primary outcome is genetic counseling uptake. Among women who receive genetic counseling either through TGC (n~30) or with an interpreter (n~15), we will assess counseling quality by reviewing 20 randomly selected audiotaped sessions (10 TGC; 10 interpreters). We will evaluate women’s HBOC knowledge and satisfaction with counseling. Communication processes and outcomes will be assessed using gold standard RIAS quantitative coding system and qualitative discourse analysis. RESULTS/ANTICIPATED RESULTS: We elicited input from transdisciplinary team members to develop an initial adaptation of a TGC print booklet and intervention protocol for use with high-risk Latina breast cancer survivors with limited English proficiency. The booklet contains low-literacy information about HBOC, risk factors, pros and cons of testing, and management strategies. Based on these materials and prior work, we anticipate TGC will consist of one 1 hour or less TGC session by phone. Participants interested in pursuing testing will receive a saliva kit and will participate in a second TGC session (30 min) to discuss test results and management options. DISCUSSION/SIGNIFICANCE OF IMPACT: Given access barriers and the shortage of Spanish-speaking genetic counselors, adapting and translating TGC intervention is a promising strategy that could reduce disparities by broadening the reach and accessibility to genetic counseling while enhancing the quality of the service for Latinas with limited English proficiency.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of neurodevelopmental disorder, however, the links between developmental coordination disorder (DCD), intellectual function and psychiatric disorder remain unexplored.
To establish the prevalence of indicative DCD in children with 22q11.2DS and examine associations with IQ, neurocognition and psychopathology.
Neurocognitive assessments and psychiatric interviews of 70 children with 22q11.2DS (mean age 11.2, s.d. = 2.2) and 32 control siblings (mean age 11.5, s.d. = 2.1) were carried out in their homes. Nine children with 22q11.2DS and indicative DCD were subsequently assessed in an occupational therapy clinic.
Indicative DCD was found in 57 (81.4%) children with 22q11.2DS compared with 2 (6.3%) control siblings (odds ratio (OR) = 36.7, P < 0.001). Eight of nine (89%) children with indicative DCD met DSM-5 criteria for DCD. Poorer coordination was associated with increased numbers of anxiety, (P < 0.001), attention-deficit hyperactivity disorder (ADHD) (P < 0.001) and autism-spectrum disorder (ASD) symptoms (P < 0.001) in children with 22q11.2DS. Furthermore, 100% of children with 22q11.2DS and ADHD had indicative DCD (20 of 20), as did 90% of children with anxiety disorder (17 of 19) and 96% of children who screened positive for ASD (22 of 23). The Developmental Coordination Disorder Questionnaire score was related to sustained attention (P = 0.006), even after history of epileptic fits (P = 0.006) and heart problems (P = 0.009) was taken into account.
Clinicians should be aware of the high risk of coordination difficulties in children with 22q11.2DS and its association with risk of mental disorder and specific neurocognitive deficits.
Background: It is well documented that mothers of children with intellectual disabilities experience elevated mental health difficulties and that these are exacerbated by the presence of challenging behaviour. However, comparatively little is known about the effect of specific coping strategies for managing such behaviours. Aims: This paper aims to document coping strategies used by mothers of children showing multiple forms of challenging behaviour and to explore how these relate to positive and negative maternal mental health. Method: Eighty-nine mothers of children with intellectual disabilities completed questionnaires assessing maternal mental health (Hospital Anxiety and Depression Scale, Positive and Negative Affect Scale) and maternal coping strategies (Brief COPE). Results: Coping strategies were not associated with child age or ability, but were associated with maternal mental health. Higher levels of problem- and positive-coping strategies were associated with higher positive affect. Although active-avoidance coping was the least frequently reported, it was associated with higher levels of negative affect and increased anxiety and depression. Moderated mediation analyses identified that active-avoidance coping mediated the relationship between the number of forms of challenging behaviour and poor maternal mental health, but only in mothers with lower levels of problem-focused coping. Conclusions: Active-avoidance coping is associated with poorer negative mental health in mothers of children with intellectual disabilities who have average to low levels of problem-focused coping. This is reflective of that noted within a range of populations, highlighting it as a key area for intervention.
Conjugated linoleic acid (CLA) is a collective term used to represent positional and geometric isomers of linoleic acid with conjugated double bonds. CLAs have been reported to have a wide range of beneficial effects, including: anticarcinogenic, antiatherogenic, antidiabetic and immune stimulatory. They have been shown to alter nutrient partitioning and lipid metabolism, and reduce body fat in a number of different animal species.
To determine the impact of recurrent Clostridium difficile infection (RCDI) on patient behaviors following illness.
Using a computer algorithm, we searched the electronic medical records of 7 Chicago-area hospitals to identify patients with RCDI (2 episodes of CDI within 15 to 56 days of each other). RCDI was validated by medical record review. Patients were asked to complete a telephone survey. The survey included questions regarding general health, social isolation, symptom severity, emotional distress, and prevention behaviors.
In total, 119 patients completed the survey (32%). On average, respondents were 57.4 years old (standard deviation, 16.8); 57% were white, and ~50% reported hospitalization for CDI. At the time of their most recent illness, patients rated their diarrhea as high severity (58.5%) and their exhaustion as extreme (30.7%). Respondents indicated that they were very worried about getting sick again (41.5%) and about infecting others (31%). Almost 50% said that they have washed their hands more frequently (47%) and have increased their use of soap and water (45%) since their illness. Some of these patients (22%–32%) reported eating out less, avoiding certain medications and public areas, and increasing probiotic use. Most behavioral changes were unrelated to disease severity.
Having had RCDI appears to increase prevention-related behaviors in some patients. While some behaviors are appropriate (eg, handwashing), others are not supported by evidence of decreased risk and may negatively impact patient quality of life. Providers should discuss appropriate prevention behaviors with their patients and should clarify that other behaviors (eg, eating out less) will not affect their risk of future illness.
OBJECTIVES/SPECIFIC AIMS: Microarray technology has produced large volumes of gene expression data profiling differences in gene expression in a vast array of conditions, much of which is publicly available. Methods to query these data for similarities in patterns of gene regulation are limited to comparisons between preannotated groups. In response, we developed openSESAME to find experiments where a set of genes is similarly coregulated without regard to experimental design. An important application of openSESAME is drug repositioning: if a pattern associated with disease is reversed by a given drug, the drug might target disease-related processes. METHODS/STUDY POPULATION: Experiments from the Gene Expression Omnibus (GEO) were normalized, signature-association (SA) scores computed for each sample, experiments assigned enrichment scores, and ANOVAs used to assign significance to experimental variables automatically extracted from GEO. SA scores were also generated for hundreds of publicly available signatures, and pairwise correlations used to create a relevance network. RESULTS/ANTICIPATED RESULTS: Using signatures of estrogen and p63, we recovered relevant experimental variables, and with the network approach, we recovered previously reported associations between disease states and/or drug treatments. DISCUSSION/SIGNIFICANCE OF IMPACT: openSESAME has the potential to illuminate “dark data” and discover novel relationships between drugs and diseases on the basis of common patterns of differential gene expression.
Neuroticism, a ‘Big Five’ personality trait, has been associated with sub-clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (rg = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD.