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SUMMARYDetection of the presence of infection and its etiology must be accurate and timely to facilitate appropriate antimicrobial use. Diagnostic strategies that rely solely on pathogen detection often are insufficient due to poor test characteristics, inability to differentiate colonization from infection, or protracted delay to result. Understanding the human response across different pathogens on a clinical and molecular level can provide more accurate, timely, and useful answers, especially in critical illness and diagnostic uncertainty. Improvements in understanding the human immune response including genomics, protein analysis, gene expression, and cellular morphology have led to rapid innovation of new host response-based diagnostic tests. This review describes the limitations of pathogen-focused technology and the benefits of examining the breadth of immune response to diagnose infection. It then explores biomarkers that have been studied for this purpose and scrutinizes the performance of host-based multianalyte testing. Currently cleared diagnostics and those in late-stage development are described in depth, with a focus on the purpose of testing and its utility for clinicians. Finally, it concludes by examining opportunities for further host response-derived diagnostic innovation.

A subset of patients with chronic hepatitis C virus (HCV) infection demonstrate liver enzyme elevation (LEE) after achieving sustained virologic response (SVR). Risk factors for LEE are not well characterised. We conducted a single-centre retrospective cohort study of adults with HCV infection in the Duke University Health System who received direct-acting antiviral therapy and achieved SVR. We performed multivariable logistic regression to assess the relationship between potential risk factors and LEE. We used generalised linear mixed-effects models to explore longitudinal relationships between HIV and LEE. Among 1356 patients, 556 (41.0%) had LEE after achieving SVR. Higher pretreatment alanine aminotransferase (ALT) (adjusted odds ratio [aOR] 1.08 per 10 IU/L increase; 95% confidence interval [CI] 1.05-1.11) and pretreatment cirrhosis (aOR 2.26, 95% CI 1.60-3.21) were associated with higher odds of LEE; male sex was associated with lower odds of LEE (aOR 0.28, 95% CI 0.21-0.38). There was insufficient evidence of an association between HIV and LEE (aOR 0.83, 95% CI 0.47-1.44). Pretreatment ALT, cirrhosis and female sex predicted LEE in this cohort of patients with HCV infection who achieved SVR. These findings can help to identify patients at greatest risk of post-SVR liver injury., (© 2024 John Wiley & Sons Ltd.)

Objectives: To identify the incidence and characteristics of chronic post-surgical pain (CPSP) following total knee arthroplasty and determine peri-operative influencing factors., Methods: A representative, retrospective random sample was taken of patients who underwent total knee arthroplasty in the South Infirmary University Hospital Cork for an 18-month period. Two hundred fourteen patient charts were reviewed out of a total of 507 charts for that period to provide a 90% confidence interval., Results: The incidence of CPSP in an Irish population 6 months after total knee arthroplasty was found to be 36.5%. The following factors were found to be statistically significant with respect to the incidence of CPSP: female sex, lack of multimodal analgesia (consisting of paracetamol, NSAID, and opioids), general anaesthesia, and lower Oxford Knee Scores at 6 months post-surgery. Age, the knee operated on, ASA grade, or greatest acuity pain, were not found to be statistically significant factors in the development of CPSP., Conclusions: CPSP is common after total knee arthroplasty with an incidence of 36.5% at 6 months post procedure. Female sex, lack of multimodal analgesia, and lower Oxford Knee Scores were associated with increased CPSP., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Background: Neurodevelopmental conditions frequently co-occur. The aim of this paper was to determine whether there is a cumulative association between (1) the number of neurodevelopmental conditions, specifically hyperkinetic disorder (hereafter referred to as attention deficit hyperactivity disorder), autism spectrum disorder (hereafter referred to as autism) and intellectual disability, and (2) behavioural and socio-emotional problems and the level of clinician-rated functioning for young males and females., Methods: In this cross-sectional study, diagnostic information, caregiver-rated behavioural and socio-emotional data (as conceptualised by the Strengths and Difficulties Questionnaire) and clinician-rated functioning scores (as conceptualised by the Children's Global Assessment Scale) were extracted from electronic patient records for 2768 young people aged 3-17 years (mean = 11.55, SD = 3.46). All data were extracted at baseline, that is, at the time the young person was diagnosed with attention deficit hyperactivity disorder, autism and/or an intellectual disability. Ordinal regression analyses tested associations between the number of neurodevelopmental conditions met (i.e. 1, 2 or 3) and behavioural and socio-emotional outcomes and functioning., Results: After controlling for age and biological sex, the number of neurodevelopmental conditions was associated with higher levels of inattention/hyperactivity and peer problems, lower levels of prosocial behaviour and poorer clinician-rated functioning. Although these findings were consistent for males, a cumulative association was not identified for females, except for clinician-rated functioning., Conclusions: For young people, the presence of multiple neurodevelopmental conditions may have a cumulative impact across domains, but this may differ between males and females., (© 2024 The Author(s). Journal of Intellectual Disability Research published by John Wiley & Sons and MENCAP.)

Background: Autism spectrum disorder (hereafter referred to as autism) is characterised by difficulties with (i) social communication, social interaction, and (ii) restricted and repetitive interests and behaviours. Estimates of autism prevalence within the criminal justice system (CJS) vary considerably, but there is evidence to suggest that the condition can be missed or misidentified within this population. Autism has implications for an individual's journey through the CJS, from police questioning and engagement in court proceedings through to risk assessment, formulation, therapeutic approaches, engagement with support services, and long-term social and legal outcomes., Methods: This consensus based on professional opinion with input from lived experience aims to provide general principles for consideration by United Kingdom (UK) CJS personnel when working with autistic individuals, focusing on autistic offenders and those suspected of offences. Principles may be transferable to countries beyond the UK. Multidisciplinary professionals and two service users were approached for their input to address the effective identification and support strategies for autistic individuals within the CJS., Results: The authors provide a consensus statement including recommendations on the general principles of effective identification, and support strategies for autistic individuals across different levels of the CJS., Conclusion: Greater attention needs to be given to this population as they navigate the CJS., (© 2024. The Author(s).)

The worldwide pooled prevalence of psychiatric disorders in children is 13.4%. Studying the prevalence of childhood psychiatric disorders across radically different economic systems and social structures could indicate universal factors leading to their development. The prevalence of childhood psychiatric disorders in a mixed-subsistence foraging society has not been studied. The Strengths and Difficulties Questionnaire and the Development and Well-Being Assessment were used to compare the prevalence of behavioural symptoms and psychiatric disorders in Hadza children aged 5-16 years (n = 113) to a nationally representative sample from England (n = 18,029) using a cross-sectional study design. Emotional problems, conduct problems and hyperactivity were lower in the Hadza children. Prosocial behaviour and peer problems were higher in Hadza children. 3.6% of Hadza children met the criteria for a psychiatric disorder compared to 11.8% of English children. All psychiatric disorders in Hadza children were co-morbid with autism spectrum disorder. No child from the Hadza group met the criteria for an emotional, behaviour or eating disorder. Further work should study the factors which lead to the different prevalence of psychiatric disorders in Hadza children., (© 2023. The Author(s).)

Lay Abstract: It is now recognised that autism spectrum disorder (ASD) and personality disorders (PDs) have a variety of factors in common. However, the exact nature of the relationship between ASD and the PDs remains unclear. The overlapping symptom profiles of ASD and PDs can lead to diagnostic uncertainty - features of ASD and PD can be misattributed and easily lead to misdiagnosis of ASD patients. Since differentiating between ASD and PD is such a complex task, it has been argued that there is a need for additional understanding and markers for facilitating diagnostic procedures. There is an urgent need to explore, first, how clinicians make diagnostic decisions and, second, how to effectively deal with the challenges and difficulties they face when making decisions. Also, where there are clear overlaps, how do clinicians choose how to attribute labels in order to understand the person.

Background: The purpose of this paper is to identify the trajectory of conduct and emotional problems for young people within the general population at four time points (between 9 years 7 months and 16 years 6 months), investigate their relationship with hyperactive/inattentive traits and explore the moderating effect of autistic social traits (ASTs)., Methods: Data from 9305 individuals involved in The Avon Longitudinal Study of Parents and Children (ALSPAC) study were included. Conduct and emotional problems and hyperactive/inattentive traits were measured by the Strengths and Difficulties Questionnaire. ASTs were assessed using the Social Communication Disorder Checklist. Individual trajectories for conduct and emotional problems were identified via growth curve modelling. Hyperactive/inattentive traits were included within the growth curve model as a time-varying covariate to determine their effect on these outcomes. Finally, participants were split into two groups (below and above clinical threshold ASTs Groups) and multi-group invariance testing was conducted on the data to identify the moderating effect of ASTs on the relationship between hyperactive/inattentive traits and outcomes (i.e. conduct and emotional problems)., Results: Hyperactive/inattentive traits were associated with higher rates of conduct and emotional problems for both boys and girls. The presence of ASTs moderated these relationships for boys, but not for girls, by increasing the risk of boys with hyperactive/inattentive traits developing greater conduct and emotional problems., Conclusions: These findings underscore the importance of identifying hyperactive/inattentive traits and ASTs in young people and addressing the increased risk of conduct and emotional problems. Research and clinical implications are explored.

Objectives: The current guidelines recommend routine postoperative duplex ultrasound (DUS) screening after endovenous ablation (EVA). This is a grade 2C recommendation, and several contemporary reports have called for revision of this recommendation as there is insufficient evidence to support universal DUS screening after EVA. There are currently no studies that evaluate outcomes among EVA patients who did not have DUS screening. The aim of our study is to present outcomes from our single-center experience among patients who did not have DUS routinely performed after EVA., Methods: We performed a single-center, prospective cohort study that included consecutive patients who underwent EVA of the great saphenous vein at our institution between September 30, 2021, and March 15, 2022. At 30 days after the procedure, electronic medical records were queried to identify patients who may have presented for the evaluation of venous thromboembolism (VTE) symptoms., Results: Over the study period, a total of 80 lower extremity EVA procedures (71 endovenous laser ablation and 9 radiofrequency ablation) were performed among 76 patients. Postoperative DUS was performed on 24 patients, of whom none were identified as having endovenous heat-induced thrombosis. Of the 54 patients who did not have DUS, a 30-day postprocedure chart review revealed that none of these patients were seen for symptoms of VTE. We estimate total cost savings of $14,289 by eliminating routine DUS without impact to clinical outcomes after EVA., Conclusions: Postoperative DUS assessment after EVA comes with associated health care cost and has low yield given that the incidence of clinically significant endovenous heat-induced thrombosis (3 and 4) is rare. In our experience, eliminating routine DUS had no impact on clinical outcomes, improved vascular lab access, and had a positive financial impact in our organization. Limiting DUS screening to EVA patients who exhibit symptoms of VTE can be a cost-effective approach that limits unnecessary imaging, time, and resources with no potential change in clinical outcomes based on our data. Further research is required, and a randomized controlled trial would be ideal to answer this question., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with substance use (SU) and/or substance use disorder (SUD). Individuals with concurrent ADHD and SU/SUD can have complex presentations that may complicate diagnosis and treatment. This can be further complicated by the context in which services are delivered. Also, when working with young people and adults with co-existing ADHD and SU/SUD, there is uncertainty among healthcare practitioners on how best to meet their needs. In February 2022, the United Kingdom ADHD Partnership hosted a meeting attended by multidisciplinary experts to address these issues. Following presentations providing attendees with an overview of the literature, group discussions were held synthesizing research evidence and clinical experience. Topics included: (1) A review of substances and reasons for use/misuse; (2) identification, assessment and treatment of illicit SU/SUD in young people and adults with ADHD presenting in community services; and (3) identification, assessment and treatment of ADHD in adults presenting in SU/SUD community and inpatient services. Dis-cussions highlighted inter-service barriers and fragmentation of care. It was concluded that a multimodal and multi-agency approach is needed. The consensus group generated a table of practice recommendations providing guidance on: identification and assessment; pharmacological and psychological treatment; and multi-agency interventions., Competing Interests: Conflict-of-interest statement: Young S, Abbasian C, Cubbin S, Branney P, Colley B, Deeley Q, Hill P, Hollingdale J, Judge D, Lewis A, Mason P, Johnson J and Woodhouse E are affiliated with consultancy firms/private practices. Over the past five years Young S has received honoraria for consultancy and educational talks years from Janssen, Medice and Takeda. She is author of the ADHD Child Evaluation (ACE) and ACE+ for adults; and lead author of R&R2 for ADHD Youths and Adults. Hill P received honoraria for consultancy and educational talks from Takeda and Flynn Pharma. Cortese S declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD. Mason P has received honoraria for consultancy and educational talks from Takeda, Flynn Pharma and Lily. Nutt D has received honoraria for educational talks from Takeda and Janssen. Lewis A has received honoraria for consultancy to the Association for Child & Adolescent Mental Health (ACAMH) and Takeda and for educational talks to Forensic Treatment Division, Ministry of Justice, Republic of Korea. Mukherjee R has received honoraria for consultancy and talks related to ADHD from Takeda, Flynn Pharma and Janssen. Johnson J has received honoraria for consultancy and educational talks for Flynn Pharma, Takeda and Janssen. The remaining authors (Gudjonsson GH, Cocallis K, Roberts J, Al-Attar Z, Robinson F) declare that the meeting was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The association between attention-deficit/hyperactivity disorder (ADHD) and tuberous sclerosis complex (TSC) is widely reported, with support for the role of epilepsy, yet the mechanisms underlying the association across development are unclear. The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of TSC. In Phase 1 of the study, baseline measures of epilepsy, cortical tuber load, and mutation were obtained with 125 children ages 0-16 years. In Phase 2, at an average of 8 years later, ADHD symptoms were measured for 81 of the participants. Structural equation modeling revealed an indirect pathway from genetic mutation, to cortical tuber load, to epileptic spasm severity in infancy, to ADHD symptoms in middle childhood and adolescence, in addition to a pathway linking current seizure severity to ADHD symptoms. Findings were retained when intelligence quotient (IQ) was entered as a correlated factor. The findings support a cascading developmental pathway to ADHD symptoms mediated by early-onset and severe epilepsy in the first 2 years of life. This warrants detailed investigation of seizure characteristics and cognitive and behavioral sequelae associated with ADHD from early in life, to further the understanding of the association between ADHD and early-onset epilepsy across syndromic and non-syndromic populations., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Self-harm and suicide are major public health concerns among children and adolescents. Many risk and protective factors for suicide and self-harm have been identified and reported in the literature. However, the capacity of these identified risk and protective factors to guide assessment and management is limited due to their great number. This protocol describes an ongoing systematic review and meta-analysis which aims to examine longitudinal studies of risk factors for self-harm and suicide in children and adolescents, to provide a comparison of the strengths of association of the various risk factors for self-harm and suicide and to shed light on those that require further investigation., Methods and Analysis: We perform a systematic search of the literature using the databases EMBASE, PsycINFO, Medline, CINAHL and HMIC from inception up to 28 October 2020, and the search will be updated before the systematic review publication. Additionally, we will contact experts in the field, including principal investigators whose peer-reviewed publications are included in our systematic review as well as investigators from our extensive research network, and we will search the reference lists of relevant reviews to retrieve any articles that were not identified in our search. We will extract relevant data and present a narrative synthesis and combine the results in meta-analyses where there are sufficient data. We will assess the risk of bias for each study using the Newcastle-Ottawa Scale and present a summary of the quantity and the quality of the evidence for each risk or protective factor., Ethics and Dissemination: Ethical approval will not be sought as this is a systematic review of the literature. Results will be published in mental health journals and presented at conferences focused on suicide prevention., Prospero Registration Number: CRD42021228212., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Attempts to link human development and biodiversity conservation goals remain a constant feature of policy and practice related to protected areas (PAs). Underlying these approaches are narratives that simplify assumptions, shaping how interventions are designed and implemented. We examine evidence for five key narratives: 1) conservation is pro-poor; 2) poverty reduction benefits conservation; 3) compensation neutralises costs of conservation; 4) local participation is good for conservation; 5) secure tenure rights for local communities support effective conservation. Through a mixed-method synthesis combining a review of 100 peer-reviewed papers and 25 expert interviews, we examined if and how each narrative is supported or countered by the evidence. The first three narratives are particularly problematic. PAs can reduce material poverty, but exclusion brings substantial local costs to wellbeing, often felt by the poorest. Poverty reduction will not inevitably deliver on conservation goals and trade-offs are common. Compensation (for damage due to human wildlife conflict, or for opportunity costs), is rarely sufficient or commensurate with costs to wellbeing and experienced injustices. There is more support for narratives 4 and 5 on participation and secure tenure rights, highlighting the importance of redistributing power towards Indigenous Peoples and Local Communities in successful conservation. In light of the proposed expansion of PAs under the post-2020 Global Biodiversity Framework, we outline implications of our review for the enhancement and implementation of global targets in order to proactively integrate social equity into conservation and the accountability of conservation actors., Competing Interests: Research ethics statementEthical approval was granted by the Departmental Research Ethics Committee of University College London’s Anthropology Department.Consent for publication statementThe authors declare that research participants’ informed consent to publication of findings – including photos, videos and any personal or identifiable information – was secured prior to publication.Conflicts of interest statementThe co-author Elisa Morgera is an Editorial Board Member of this journal the article is published in, UCL Open: Environment, and the article went through the journals standard open peer review processes – all open peer review reports can be read freely online by following the DOI link of this article https://doi.org/10.14324/111.444/ucloe.000050. All other authors declare no conflicts of interest.The co-author Elisa Morgera is an Editorial Board Member of this journal the article is published in, UCL Open: Environment, and the article went through the journals standard open peer review processes – all open peer review reports can be read freely online by following the DOI link of this article https://doi.org/10.14324/111.444/ucloe.000050. All other authors declare no conflicts of interest., (© 2022 The Authors.)

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca 2+ ) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca 2+ entry is involved in Ca 2+ homeostasis in PASMCs, but its properties in PAH are unclear., Methods: Using a combination of Ca 2+ imaging, molecular biology, in vitro, ex vivo, and in vivo approaches, we investigated the roles of the Orai1 SOC channel in PA remodeling in PAH and determined the consequences of pharmacological Orai1 inhibition in vivo using experimental models of pulmonary hypertension (PH)., Results: Store-operated Ca 2+ entry and Orai1 mRNA and protein were increased in human PASMCs (hPASMCs) from patients with PAH (PAH-hPASMCs). We found that MEK1/2 (mitogen-activated protein kinase kinase 1/2), NFAT (nuclear factor of activated T cells), and NFκB (nuclear factor-kappa B) contribute to the upregulation of Orai1 expression in PAH-hPASMCs. Using small interfering RNA (siRNA) and Orai1 inhibitors, we found that Orai1 inhibition reduced store-operated Ca 2+ entry, mitochondrial Ca 2+ uptake, aberrant proliferation, apoptosis resistance, migration, and excessive calcineurin activity in PAH-hPASMCs. Orai1 inhibitors reduced agonist-evoked constriction in human PAs. In experimental rat models of PH evoked by chronic hypoxia, monocrotaline, or Sugen/hypoxia, administration of Orai1 inhibitors (N-{4-[3,5-bis(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide [BTP2], 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline [JPIII], or 5J4) protected against PH., Conclusions: In human PAH and experimental PH, Orai1 expression and activity are increased. Orai1 inhibition normalizes the PAH-hPASMCs phenotype and attenuates PH in rat models. These results suggest that Orai1 should be considered as a relevant therapeutic target for PAH.

Aim: To examine the association between perinatal adversities and neurodevelopmental outcome in tuberous sclerosis complex (TSC)., Method: The Tuberous Sclerosis 2000 study is a prospective, longitudinal UK study of TSC. In phase 1, mutation type, TSC family history, tuber characteristics, presence of cardiac rhabdomyomas, seizure characteristics, and intellectual ability were assessed in 125 children affected with TSC (64 females, 61 males; median age 39mo, range 4-254). In phase 2, 88 participants (49 females, 39 males; median age 148mo, range 93-323) were assessed for neurodevelopmental outcomes including intellectual ability, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Perinatal histories of 88 participants with TSC and 80 unaffected siblings were collected retrospectively using the Obstetric Enquiry Schedule and coded with a modified Gillberg Optimality Scale to measure levels of perinatal adversity. Data were analysed using Mann-Whitney U tests, Spearman's rank correlation, and linear regression with robust standard errors., Results: Children with familial TSC experienced significantly greater perinatal adversity than unaffected siblings. Perinatal adversity was higher in children with TSC-affected mothers than those with unaffected mothers. There was no significant association between perinatal adversities and neurodevelopmental outcomes after controlling for confounders., Interpretation: Maternal TSC is a significant marker of elevated perinatal risk in addition to risks incurred by fetal genotype. Pregnancies complicated by maternal or fetal TSC require higher vigilance, and mechanisms underlying increased perinatal adversity require further research., What This Paper Adds: Higher perinatal adversity is associated with familial tuberous sclerosis complex (TSC). Maternal TSC was associated with higher frequencies of several perinatal risk markers. Paternal TSC was not associated with higher levels of perinatal adversity. Perinatal adversity levels in TSC1 and TSC2 subgroups did not differ significantly. Perinatal adversities were not associated with neurodevelopmental outcomes., (© 2022 Mac Keith Press.)

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations on the TSC1/TSC2 genes, which result in alterations in molecular signalling pathways involved in neurogenesis and hamartomas in the brain and other organs. TSC carries a high risk for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), although the reasons for this are unclear. One proposal is that TSC-related alterations in molecular signalling during neurogenesis lead to atypical development of neural networks, which are involved in the occurrence of ASD and ADHD in TSC. We investigated this proposal in young people with TSC who have been studied longitudinally since their diagnosis in childhood. Electroencephalography (EEG) was used to examine oscillatory connectivity in functional neural networks and local and global network organisation during three tasks (resting-state, attentional and inhibitory control Go/Nogo task, upright and inverted face processing task) in participants with TSC (n = 48) compared to an age- and sex-matched group of typically developing Controls (n = 20). Compared to Controls, the TSC group showed hypoconnected neural networks in the alpha frequency during the resting-state and in the theta and alpha frequencies during the Go/Nogo task (P ≤ .008), as well as reduced local network organisation in the theta and alpha frequencies during the Go/Nogo task (F = 3.95, P = .010). There were no significant group differences in network metrics during the face processing task. Increased connectivity in the hypoconnected alpha-range resting-state network was associated with greater ASD and inattentive ADHD symptoms (rho≥.40, P ≤ .036). Reduced local network organisation in the theta-range during the Go/Nogo task was significantly associated with higher hyperactive/impulsive ADHD symptoms (rho = -.43, P = .041). These findings suggest that TSC is associated with widespread hypoconnectivity in neural networks and support the proposal that altered network function may be involved in the co-occurrence of ASD and ADHD in TSC., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Over half of young people and adults diagnosed with Attention Deficit Hyperactivity Disorder [ADHD] also have substance use disorder [SUD]. Their use of substances may arise from an attempt to self-medicate and/or to cope with their difficulties. This manuscript reviews key research in the literature and identifies that traditional SUD psychological interventions are an effective treatment for those presenting with a dual diagnosis of ADHD and SUD. However, typically, this is only available to those presenting to specialist SUD services for treatment of harmful use and/or dependency. This misses an opportunity to intervene much earlier, before drug use escalates to these levels. The manuscript aims to provide practical guidance for healthcare practitioners, by detailing a psychological framework for earlier assessment and intervention of problematic drug use in young people and adults with ADHD. Specific techniques are outlined drawing on psychoeducation, motivational interviewing and cognitive behavioural therapy in a phased approach to address factors that motivate initial use of substances and those that maintain use., (© 2020. Springer-Verlag GmbH Austria, part of Springer Nature.)

HIV remains a public health concern in the United States. Although pre-exposure prophylaxis (PrEP) can be expected to reduce HIV incidence, its uptake, adherence, and persistence remain limited, particularly among highest priority groups such as men who have sex with men and transwomen (MSMTW). Using a socioecological framework, we conducted a scoping review to examine PrEP-related stigma to inform future research, policy, and programmatic planning. Using the PRISMA extension for scoping reviews, we conducted database searches from August 2018 to April 2020 for articles addressing PrEP stigma. Studies were independently screened and coded by three authors, resulting in thematic categorization of several types of PrEP stigma on four socioecological levels. Of 557 references, a final sample of 23 studies was coded, 61% qualitative, and 87% focusing exclusively on MSMTW. Most instances of PrEP-related stigma occurred on the interpersonal level and included associations of PrEP with risk promotion, HIV-related stigma, and promiscuity. Other frequent themes across socioecological levels included provider distrust and discrimination, government and pharmaceutical industry distrust, internalized homonegativity, PrEP efficacy distrust, and anticipated homonegativity. Notably, PrEP was also framed positively as having physical and psychological benefits, and assuming responsibility for protecting one's community via PrEP awareness-raising. PrEP-related stigma persists, demanding interventions to modify its impact. Leveraging PrEP-positive discourses to challenge PrEP stigma is an emerging avenue, alongside efforts to increase provider willingness to promote PrEP routinely by reducing provider bias, aligning with the national strategy to End the HIV Epidemic.

Background: Research identifies highly variable prevalence estimates for autism spectrum disorder (ASD) in children and adolescents with attention deficit hyperactivity disorder (ADHD), particularly between community and clinical samples, warranting quantitative meta-analyses to investigate the true prevalence of ASD in children and adolescents with ADHD., Methods: Studies were identified through a systematic literature search of PsycINFO, MEDLINE and Web of Science through January 2018. Twenty-two publications met inclusion criteria (total N = 61 985). Two random effects meta-analyses were conducted: (1) to identify the proportion of children and adolescents with ADHD that met criteria for ASD; and (2) to compare the severity of dimensionally-measured ASD symptomology in children and adolescents with and without ADHD., Results: The overall pooled effect for children and adolescents with ADHD who met threshold for ASD was 21%. There was no significant difference between community samples (19%) and clinical samples (24%) or between US studies v. those from other countries. Children and adolescents with ADHD had substantially more dimensionally-measured ASD traits compared with those who did not have ADHD (d = 1.23)., Conclusion: The findings provide further evidence that ADHD and ASD are associated in nature. Clinical and research implications are discussed.

Background: There is evidence to suggest that the broad discrepancy in the ratio of males to females with diagnosed ADHD is due, at least in part, to lack of recognition and/or referral bias in females. Studies suggest that females with ADHD present with differences in their profile of symptoms, comorbidity and associated functioning compared with males. This consensus aims to provide a better understanding of females with ADHD in order to improve recognition and referral. Comprehensive assessment and appropriate treatment is hoped to enhance longer-term clinical outcomes and patient wellbeing for females with ADHD., Methods: The United Kingdom ADHD Partnership hosted a meeting of experts to discuss symptom presentation, triggers for referral, assessment, treatment and multi-agency liaison for females with ADHD across the lifespan., Results: A consensus was reached offering practical guidance to support medical and mental health practitioners working with females with ADHD. The potential challenges of working with this patient group were identified, as well as specific barriers that may hinder recognition. These included symptomatic differences, gender biases, comorbidities and the compensatory strategies that may mask or overshadow underlying symptoms of ADHD. Furthermore, we determined the broader needs of these patients and considered how multi-agency liaison may provide the support to meet them., Conclusions: This practical approach based upon expert consensus will inform effective identification, treatment and support of girls and women with ADHD. It is important to move away from the prevalent perspective that ADHD is a behavioural disorder and attend to the more subtle and/or internalised presentation that is common in females. It is essential to adopt a lifespan model of care to support the complex transitions experienced by females that occur in parallel to change in clinical presentation and social circumstances. Treatment with pharmacological and psychological interventions is expected to have a positive impact leading to increased productivity, decreased resource utilization and most importantly, improved long-term outcomes for girls and women.

Actigraphy, an objective measure of motor activity, reliably indexes increased movement levels in attention-deficit/hyperactivity disorder (ADHD) and may be useful for diagnosis and treatment-monitoring. However, actigraphy has not been examined in complex neurodevelopmental conditions. This study used actigraphy to objectively measure movement levels in individuals with a complex neurodevelopmental genetic disorder, tuberous sclerosis (TSC). Thirty participants with TSC (11-21 years, 20 females, IQ = 35-108) underwent brief (approximately 1 h) daytime actigraph assessment during two settings: movie viewing and cognitive testing. Multiple linear regressions were used to test associations between movement measurements and parent-rated ADHD symptoms. Correlations were used to examine associations between actigraph measures and parent-rated ADHD symptoms and other characteristics of TSC (symptoms of autism spectrum disorder (ASD), intellectual ability (IQ), epilepsy severity, cortical tuber count). Higher movement levels during movies were associated with higher parent-rated ADHD symptoms. Higher ADHD symptoms and actigraph-measured movement levels during movies were positively associated with ASD symptoms and negatively associated with IQ. Inter-individual variability of movement during movies was not associated with parent-rated hyperactivity or IQ but was negatively associated with ASD symptoms. There were no associations with tuber count or epilepsy. Our findings suggest that actigraph-measured movement provides a useful correlate of ADHD in TSC.

Background: Individuals with co-occurring hyperactivity disorder/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) can have complex presentations that may complicate diagnosis and treatment. There are established guidelines with regard to the identification and treatment of ADHD and ASD as independent conditions. However, ADHD and ASD were not formally recognised diagnostically as co-occurring conditions until the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) was published in 2013. Hence, awareness and understanding of both conditions when they co-occur is less established and there is little guidance in the clinical literature. This has led to uncertainty among healthcare practitioners when working with children, young people and adults who present with co-existing ADHD and ASD. The United Kingdom ADHD Partnership (UKAP) therefore convened a meeting of professional experts that aimed to address this gap and reach expert consensus on the topic that will aid healthcare practitioners and allied professionals when working with this complex and vulnerable population., Method: UK experts from multiple disciplines in the fields of ADHD and ASD convened in London in December 2017. The meeting provided the opportunity to address the complexities of ADHD and ASD as a co-occurring presentation from different perspectives and included presentations, discussion and group work. The authors considered the clinical challenges of working with this complex group of individuals, producing a consensus for a unified approach when working with male and female, children, adolescents and adults with co-occurring ADHD and ASD. This was written up, circulated and endorsed by all authors., Results: The authors reached a consensus of practical recommendations for working across the lifespan with males and females with ADHD and ASD. Consensus was reached on topics of (1) identification and assessment using rating scales, clinical diagnostic interviews and objective supporting assessments; outcomes of assessment, including standards of clinical reporting; (2) non-pharmacological interventions and care management, including psychoeducation, carer interventions/carer training, behavioural/environmental and Cognitive Behavioural Therapy (CBT) approaches; and multi-agency liaison, including educational interventions, career advice, occupational skills and training, and (3) pharmacological treatments., Conclusions: The guidance and practice recommendations (Tables 1, 4, 5, 7, 8 and 10) will support healthcare practitioners and allied professionals to meet the needs of this complex group from a multidisciplinary perspective. Further research is needed to enhance our understanding of the diagnosis, treatment and management of individuals presenting with comorbid ADHD and ASD.

Aim: To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC)., Method: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2., Results: Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence., Interpretation: Early-onset and severe epilepsy in the first 2 years of life are associated with increased risk of long-term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy., What This Paper Adds: Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC). Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings. Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability. Risk pathways through seizures in the first 2 years predict long-term cognitive outcomes in individuals with TSC., (© 2019 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Around 25% of prisoners meet diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD). Because ADHD is associated with increased recidivism and other functional and behavioural problems, appropriate diagnosis and treatment can be a critical intervention to improve outcomes. While ADHD is a treatable condition, best managed by a combination of medication and psychological treatments, among individuals in the criminal justice system ADHD remains both mis- and under-diagnosed and consequently inadequately treated. We aimed to identify barriers within the prison system that prevent appropriate intervention, and provide a practical approach to identify and treat incarcerated offenders with ADHD., Methods: The United Kingdom ADHD Partnership hosted a consensus meeting to discuss practical interventions for youth (< 18 years) and adult (≥18 years) offenders with ADHD. Experts at the meeting addressed prisoners' needs for effective identification, treatment, and multiagency liaison, and considered the requirement of different approaches based on age or gender., Results: The authors developed a consensus statement that offers practical advice to anyone working with prison populations. We identified specific barriers within the prison and criminal justice system such as the lack of adequate: staff and offender awareness of ADHD symptoms and treatments; trained mental health staff; use of appropriate screening and diagnostic tools; appropriate multimodal interventions; care management; supportive services; multiagency liaison; and preparation for prison release. Through discussion, a consensus was reached regarding prisoners' needs, effective identification, treatment and multiagency liaison and considered how this may differ for age and gender., Conclusions: This practical approach based upon expert consensus will inform effective identification and treatment of offenders with ADHD. Appropriate intervention is expected to have a positive impact on the offender and society and lead to increased productivity, decreased resource utilization, and most importantly reduced rates of re-offending. Research is still needed, however, to identify optimal clinical operating models and to monitor their implementation and measure their success. Furthermore, government support will likely be required to effect change in criminal justice and mental health service policies.

Adolescents and adults with autism spectrum disorder (ASD) are at elevated risk of co-occurring mental health problems. These are often undiagnosed, can cause significant impairment, and place a very high burden on family and carers. Detecting co-occurring disorders is extremely important. However, there is no validated screening tool for this purpose. The aim of this pilot study is to test the utility of the strengths and difficulties questionnaire (SDQ) to screen for co-occurring emotional disorders and hyperactivity in adolescents and adults with ASD. The SDQ was completed by 126 parents and 98 individuals with ASD (in 79 cases both parent and self-report were available from the same families). Inter-rater reliability, test-retest stability, internal consistency, and construct validity were examined. SDQ subscales were also compared to clinically utilized measures of emotional disorders and hyperactivity to establish the ability to predict risk of disorder. Inter-rater reliability (r = 0.42), test-retest stability (r = 0.64), internal consistency (α = 0.52-0.81) and construct validity (r = 0.42-0.57) for the SDQ subscales were comparable to general population samples. Parent- and self-report SDQ subscales were significantly associated with measures of anxiety, depression and hyperactivity (62-74% correctly classified). Parent-report performed significantly better than self-report; adults with ASD under-reported difficulties. The SDQ shows promise as a simple and efficient way to screen for emotional disorders and hyperactivity in adolescents and adults with ASD that could help reduce the impact of these disorders on individuals and their families. However, further more systematic attempts at validation are warranted. Autism Res 2016, 9: 1353-1363. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.)

It is unknown whether sex influences the diagnostic evaluation of autism spectrum disorder, or whether male and female adults within the spectrum have different symptom profiles. This study reports sex differences in clinical outcomes for 1244 adults (935 males and 309 females) referred for autism spectrum disorder assessment. Significantly, more males (72%) than females (66%) were diagnosed with an autism spectrum disorder of any subtype (x(2) = 4.09; p = 0.04). In high-functioning autism spectrum disorder adults (IQ > 70; N = 827), there were no significant sex differences in severity of socio-communicative domain symptoms. Males had significantly more repetitive behaviours/restricted interests than females (p = 0.001, d = 0.3). A multivariate analysis of variance indicated a significant interaction between autism spectrum disorder subtype (full-autism spectrum disorder/partial-autism spectrum disorder) and sex: in full-autism spectrum disorder, males had more severe socio-communicative symptoms than females; for partial-autism spectrum disorder, the reverse was true. There were no sex differences in prevalence of co-morbid psychopathologies. Sex influenced diagnostic evaluation in a clinical sample of adults with suspected autism spectrum disorder. The sexes may present with different manifestations of the autism spectrum disorder phenotype and differences vary by diagnostic subtype. Understanding and awareness of adult female repetitive behaviours/restricted interests warrant attention and sex-specific diagnostic assessment tools may need to be considered., (© The Author(s) 2016.)

Background: The association of attention deficit/hyperactivity disorder (ADHD) and fetal alcohol spectrum disorders (FASD) results in a complex constellation of symptoms that complicates the successful diagnosis and treatment of the affected individual. Current literature lacks formal guidelines, randomized control trials, and evidence-based treatment plans for individuals with ADHD and associated FASD. Therefore, a meeting of professional experts was organized with the aim of producing a consensus on identification and treatment guidelines that will aid clinicians in caring for this unique patient population., Methods: Experts from multiple disciplines in the fields of ADHD and FASD convened in London, United Kingdom, for a meeting hosted by the United Kingdom ADHD Partnership (UKAP; www.UKADHD.com ) in June 2015. The meeting provided the opportunity to address the complexities of ADHD and FASD from different perspectives and included presentations, discussions, and group work. The attendees worked towards producing a consensus for a unified approach to ADHD and associated FASD., Results: The authors successfully came to consensus and produced recommended guidelines with specific regards to identification and assessment, interventions and treatments, and multiagency liaisons and care management, highlighting that a lifespan approach to treatment needs to be adopted by all involved. Included in the guidelines are: 1) unique 'red flags', which when identified in the ADHD population can lead to an accurate associated FASD diagnosis, 2) a treatment decision tree, and 3) recommendations for multiagency care management., Conclusions: While clinically useful guidelines were achieved, more research is still needed to contribute to the knowledge base about the diagnosis, treatment, and management of those with ADHD and associated FASD.

Background: Many adults with autism spectrum disorder (ASD) remain undiagnosed. Specialist assessment clinics enable the detection of these cases, but such services are often overstretched. It has been proposed that unnecessary referrals to these services could be reduced by prioritizing individuals who score highly on the Autism-Spectrum Quotient (AQ), a self-report questionnaire measure of autistic traits. However, the ability of the AQ to predict who will go on to receive a diagnosis of ASD in adults is unclear., Method: We studied 476 adults, seen consecutively at a national ASD diagnostic referral service for suspected ASD. We tested AQ scores as predictors of ASD diagnosis made by expert clinicians according to International Classification of Diseases (ICD)-10 criteria, informed by the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and Autism Diagnostic Interview-Revised (ADI-R) assessments., Results: Of the participants, 73% received a clinical diagnosis of ASD. Self-report AQ scores did not significantly predict receipt of a diagnosis. While AQ scores provided high sensitivity of 0.77 [95% confidence interval (CI) 0.72-0.82] and positive predictive value of 0.76 (95% CI 0.70-0.80), the specificity of 0.29 (95% CI 0.20-0.38) and negative predictive value of 0.36 (95% CI 0.22-0.40) were low. Thus, 64% of those who scored below the AQ cut-off were 'false negatives' who did in fact have ASD. Co-morbidity data revealed that generalized anxiety disorder may 'mimic' ASD and inflate AQ scores, leading to false positives., Conclusions: The AQ's utility for screening referrals was limited in this sample. Recommendations supporting the AQ's role in the assessment of adult ASD, e.g. UK NICE guidelines, may need to be reconsidered.

Objective: Recent studies have highlighted the impact of coexisting mental health problems in autism spectrum disorders (ASD). No twin studies to date have reported on individuals meeting diagnostic criteria of ASD. This twin study reports on the etiological overlap between the diagnosis of ASD and emotional symptoms, hyperactivity, and conduct problems measured with the Strengths and Difficulties Questionnaire., Method: Genetic and environmental influences on the covariance between ASD and coexisting problems were estimated, in line with the correlated risks model prediction. Phenotypic causality models were also fitted to explore alternative explanations of comorbidity: namely, that coexisting problems are the result of or result in ASD symptoms; that they increase recognition of ASD; or that they arise due to an over-observation bias/confusion when differentiating between phenotypes., Results: More than 50% of twins with broad spectrum/ASD met the borderline/abnormal levels cut-off criteria for emotional symptoms or hyperactivity, and approximately 25% met these criteria for the 3 reported problems. In comparison, between 13% and 16% of unaffected twins scored above the cut-offs. The phenotypic correlation between ASD and emotional symptoms was explained entirely by genetic influences and accompanied by a moderate genetic correlation (0.42). The opposite was true for the overlap with conduct problems, as nonshared-environmental factors had the strongest impact. For hyperactivity, the best-fitting model suggested a unidirectional phenotypic influence of hyperactivity on ASD., Conclusion: Our findings suggest a possible effect of hyperactivity on identification of ASD. The lack of genetic influences on conduct problems-ASD overlap further supports the genetic independence of these 2 phenotypes. Finally, the co-occurrence of emotional symptoms in ASD, compared to other co-occurring problems, is completely explained by common genetic effects., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Increasing numbers of people are being referred for the assessment of autism spectrum disorder (ASD). The NICE (UK) and the American Academy of Pediatrics recommend gathering a developmental history using a tool that operationalises ICD/DSM criteria. However, the best-established diagnostic interview instruments are time consuming, costly and rarely used outside national specialist centres. What is needed is a brief, cost-effective measure validated in community settings. We tested the Development and Well-Being Assessment (DAWBA) for diagnosing ASD in a sample of children/adolescents representative of those presenting in community mental health settings., Methods: A general population sample of twins (TEDS) was screened and 276 adolescents were selected as at low (CAST score < 12; n = 164) or high risk for ASD (CAST score ≥ 15 and/or parent reported that ASD suspected/previously diagnosed; n = 112). Parents completed the ASD module of the DAWBA interview by telephone or online. Families were visited at home: the ADI-R and autism diagnostic observation schedule (ADOS) were completed to allow a best-estimate research diagnosis of ASD to be made., Results: Development and Well-Being Assessment ASD symptom scores correlated highly with ADI-R algorithm scores (ρ = .82, p < .001). Good sensitivity (0.88) and specificity (0.85) were achieved using DAWBA computerised algorithms. Clinician review of responses to DAWBA questions minimally changed sensitivity (0.86) and specificity (0.87). Positive (0.82-0.95) and negative (0.90) predictive values were high. Eighty-six per cent of children were correctly classified. Performance was improved by using it in conjunction with the ADOS., Conclusions: The DAWBA is a brief structured interview that showed good sensitivity and specificity in this general population sample. It requires little training, is easy to administer (online or by interview) and diagnosis is aided by an algorithm. It holds promise as a tool for assisting with assessment in community settings and may help services implement the recommendations made by NICE and the American Academy of Pediatrics regarding diagnosis of young people on the autism spectrum., (© 2015 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

This study examines the rate of attention-deficit-hyperactivity disorder (ADHD) and associated functional impairments in mentally disordered offenders (MDOs). One hundred and thirty-one male MDOs with a primary diagnosis of either severe mental illness (SMI) or personality disorder (PD) completed screening questionnaires for ADHD. If positive, they were invited for a comprehensive diagnostic interview. Additional data pertaining to self-rated impairments, and objective records of critical incidents and episodes of seclusion were obtained from patient records. Twenty-six patients screened positive (7 with SMI, 19 with PD). On further assessment, no SMI patients met criteria for ADHD. Four PD patients met criteria for persistent 'syndromatic' ADHD, whereas six met 'symptomatic' ADHD criteria, giving overall prevalence estimates of 8.6% and 12.9% respectively. Greater functional impairments were self-reported by the PD+ADHD screener positive group, compared with screener negative peers, with large effect sizes. A significant but small effect was found for spending longer in seclusion. Compared with population norms, a high rate of ADHD and associated impairments are present in MDO's with a primary diagnosis of PD. These individuals have complex needs and both pharmacological and non-pharmacological interventions are required for their rehabilitation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Measures of socio-economic impacts of conservation interventions have largely been restricted to externally defined indicators focused on income, which do not reflect people's priorities. Using a holistic, locally grounded conceptualization of human well-being instead provides a way to understand the multi-faceted impacts of conservation on aspects of people's lives that they value. Conservationists are engaging with well-being for both pragmatic and ethical reasons, yet current guidance on how to operationalize the concept is limited. We present nine guiding principles based around a well-being framework incorporating material, relational and subjective components, and focused on gaining knowledge needed for decision-making. The principles relate to four key components of an impact evaluation: (i) defining well-being indicators, giving primacy to the perceptions of those most impacted by interventions through qualitative research, and considering subjective well-being, which can affect engagement with conservation; (ii) attributing impacts to interventions through quasi-experimental designs, or alternative methods such as theory-based, case study and participatory approaches, depending on the setting and evidence required; (iii) understanding the processes of change including evidence of causal linkages, and consideration of trajectories of change and institutional processes; and (iv) data collection with methods selected and applied with sensitivity to research context, consideration of heterogeneity of impacts along relevant societal divisions, and conducted by evaluators with local expertise and independence from the intervention., (© 2015 The Authors.)

Background: The behavioural symptoms of autism spectrum disorder (ASD) are thought to reflect underlying cognitive deficits/differences. The findings in the literature are somewhat mixed regarding the cognitive features of ASD. This study attempted to address this issue by investigating a range of cognitive deficits and the prevalence of multiple cognitive atypicalities in a large population-based sample comprising children with ASD, their unaffected co-twins, and typically developing comparison children., Methods: Participants included families from the Twins Early Development Study (TEDS) where one or both children met diagnostic criteria for ASD. Overall, 181 adolescents with a diagnosis of ASD and 73 unaffected co-twins were included, plus an additional 160 comparison control participants. An extensive cognitive battery was administered to measure IQ, central coherence, executive function, and theory of mind ability., Results: Differences between groups (ASD, co-twin, control) are reported on tasks assessing theory of mind, executive function, and central coherence. The ASD group performed atypically in significantly more cognitive tasks than the unaffected co-twin and control groups. Nearly a third of the ASD group presented with multiple cognitive atypicalities., Conclusions: Multiple cognitive atypicalities appear to be a characteristic, but not universal feature, of ASD. Further work is needed to investigate whether specific cognitive atypicalities, either alone or together, are related to specific behaviours characteristic of ASD., (© 2014 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Importance: Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population., Objectives: To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD., Design, Setting, and Participants: We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview-Revised (ADI-R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs)., Main Outcomes and Measures: Participants underwent screening using a population-based measure of autistic traits (CAST assessment), structured diagnostic assessments (DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis., Results: On all ASD measures, correlations among monozygotic twins (range, 0.77-0.99) were significantly higher than those for dizygotic twins (range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status (DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors (76%-95%). For the ADI-R only, shared environmental influences were significant (30% [95% CI, 8%-47%]) but smaller than genetic influences (56% [95% CI, 37%-82%])., Conclusions and Relevance: The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD.

Representations of Green Tibetans connected to Buddhism and indigenous wisdom have been deployed by a variety of actors and persist in popular consciousness. Through interviews, participatory mapping and observation, we explored how these ideas relate to people's notions about the natural environment in a rural community on the Eastern Tibetan plateau, in Sichuan Province, China. We found people to be orienting themselves towards the environment by means of three interlinked religious notions: (1) local gods and spirits in the landscape, which have become the focus of conservation efforts in the form of 'sacred natural sites;' (2) sin and karma related to killing animals and plants; (3) Buddhist moral precepts especially non-violence. We highlight the gaps between externally generated representations and local understandings, but also the dynamic, contested and plural nature of local relationships with the environment, which have been influenced and reshaped by capitalist development and commodification of natural resources, state environmental policies, and Buddhist modernist ideas.

Compared with general population rates, prevalence rates of ADHD have been consistently reported to be higher in both male and female offender populations, the latter estimated to range between 10-29%. Research in forensic institutional settings has reported that aggressive behaviour is a particularly prominent source of impairment among men with ADHD. However there is a paucity of research investigating the type of behavioural incidents that may arise in female offenders with ADHD. This pilot study therefore aimed to further our understanding of ADHD within a cohort of female mentally disordered offenders by ascertaining estimated rates of ADHD and associated functional disturbance presenting in this population. Fifty female offenders completed the Barkley ADHD rating scales. Data on aggressive and self-harming behaviours were obtained from patients' clinical records. Almost one-third of patients (28%) screened positive for ADHD, most commonly hyperactive/impulsive and combined subtypes. They were significantly younger than their peers and there were no significant differences in behavioural disturbance records between groups. When controlling for age, hyperactive/impulsive symptoms and combined symptoms were significantly and positively correlated with measures of behavioural disturbance. ADHD symptoms correlated more strongly with self-harm than outward aggression, which is a novel finding. This pilot study has contributed to the knowledge base about the rate and functional problems of female offenders with ADHD. Future research should replicate the study using a larger sample and explore the effect of treatment (pharmacological and psychological) on the reduction of ADHD symptoms, behavioural disturbance, length of stay and quality of life., Competing Interests: Conflict of interest: SY, GG and PA have received honoraria for consultancy, travel, educational talks and/or research from Janssen-Cilag, Eli-Lilly, Shire, Flynn-Pharma, Novatis and/or HB Pharma. All honoraria for PA are paid to Kings College London. SY and PA were members of the NICE guideline development group for ADHD. Other authors have no conflicts of interest in this paper.

Background: Although many children with autism spectrum disorders (ASDs) experience difficulties with anxiety,the manifestation of these difficulties remains unresolved. The current study assessed anxiety in a large population based twin sample, aged 10–15 years. Phenotypic analyses were used to explore anxiety symptoms in children with ASDs, their unaffected co-twins and a control sample., Methods: Participants included 146 families from the Twins Early Development Study (TEDS) where one or both children had a suspected ASD. Eighty control families were also included. The Revised Child Anxiety and Depression scale (Chorpita, Yim, Moffitt, Umemoto & Francis, 2000) was completed (self- and parent-report), along with diagnostic and cognitive tests. Children were categorized into four groups (a) ASD (b) Broader Autism Phenotype (BAP: mainly co-twins of children with ASDs, with high subclinical autistic traits) (c) unaffected co-twins (with neither ASDs nor BAP) (d) controls., Results: Children in the ASD and BAP groups scored significantly higher than controls for all parent-rated (although not child-rated) anxiety subscales.There were no significant differences between the ASD and BAP groups for any of the parent-rated anxiety subscales. Compared with controls, unaffected co-twins showed significantly heightened Social Anxiety, Generalized Anxiety,and Panic symptoms. Significant associations were observed between certain anxiety subscales and both IQ and ASD symptoms. For example, greater parent-rated Social Anxiety was associated with higher IQ and increased social and communicative impairments. Significant interrater correlations were observed for anxiety reports in children with ASDs (r = .27–.54; p < .01), their unaffected co-twins (r = .32–.63; p < .01) and controls (r = .23–.43; p < .01)suggesting that children in this sample with and without ASD symptoms were able to report on their anxiety symptoms with some accuracy., Conclusions: These findings support previous reports of heightened anxiety in children with ASDs, at least on parent-reported measures. Unaffected co-twins of children with ASDs also showed increased anxiety, generating questions about the potential etiological overlap between ASDs and anxiety. Progress in this area now depends on more refined anxiety measurement in ASDs and continued investigation of interrater differences.

Objective: To determine whether multiple-task training of walking is feasible and worthwhile in people with mild to moderate Parkinson's disease., Design: Baseline-controlled pilot study with three-week baseline, training and retention phases., Setting: University research laboratory., Subjects: Five people aged 61 +/-8 years with mild to moderate Parkinson's disease (Hoehn and Yahr stages II-III)., Interventions: Multiple-task training was performed for 30 minutes once a week during the three-week training phase., Main Measures: Participants were tested and trained during the 'on' phase of medication. Feasibility of training was examined using 10 cm visual analogue scales to measure participant perception of mental fatigue, physical fatigue, difficulty, anxiety and confidence. Walking velocity, stride length and cadence under multiple-task conditions were measured., Results: Participants reported low levels of mental fatigue, physical fatigue, difficulty and anxiety as well as high levels of confidence associated with multiple-task training. No adverse effects of training were reported. Multiple-task walking velocity increased by 0.09 +/- 0.06 m/s (95% confidence interval (CI) 0.02 to 0.16) between the baseline and training phase and this increase was maintained in the retention phase., Conclusion: Multiple-task training is feasible in people with mild to moderate Parkinson's disease. The data suggest sustained benefits on multiple-task walking velocity are possible. A randomized controlled trial of multiple-task training efficacy is warranted.

The material properties of the anterior cruciate ligament (ACL) in female rats with normal estrous cycles were compared to those regulated by oral contraceptive steroids. Forty female Sprague-Dawley rats were divided into two groups: an experimental group received daily ethinylestradiol and levonorgestrel in a dosing model designed to simulate a typical oral contraception regime in humans, while a control group received daily oral placebo. After eight cycles, six rats from each group underwent daily phlebotomy to measure serum estradiol and progesterone levels over the course of a single 5-day estrous cycle. Significant differences between groups were found for the area under the curve of blood progesterone levels versus time over the length of the estrous cycle (P=0.02). After 12 cycles, the rats were euthanized and one femur-ACL-tibia complex from each animal was dynamically loaded to failure. The ACLs from the rats in the experimental group had significantly decreased average and tangent stiffness, (P=0.002 and 0.0001, respectively), and significantly increased elongation (P=0.002) and total energy absorbed (P=0.03), or greater toughness than controls. In rats, it appears that the administration of reproductive hormones designed to simulate typical oral contraception in humans alters the mechanical properties of the rat ACL.

Acute traumatic pelvic ring instability causes severe pain and associated hemorrhage. Circumferential pelvic sheeting provides patient comfort and noninvasive, rapid, and temporary pelvic ring stability. A bed sheet is readily available, inexpensive, easily applied around the pelvis, and disposable.

Acute traumatic pelvic ring instability causes severe pain and associated hemorrhage. Circumferential pelvic sheeting provides patient comfort and noninvasive, rapid, and temporary pelvic ring stability. A bed sheet is readily available, inexpensive, easily applied around the pelvis, and disposable.

Approximately 50% of metastatic tumors contain Ras mutations. Ras proteins can activate at least three downstream signaling cascades mediated by the Raf-MEK-extracellular signal-regulated kinase family, phosphatidylinositol-3 (PI3) kinase, and Ral-specific guanine nucleotide exchange factors (RalGEFs). Here we investigated the contribution of RalGEF and ERK activation to the development of experimental metastasis in vivo and associated invasive properties in vitro. Each pathway contributes distinct properties to the metastatic phenotype. Following lateral tail vein injection, 3T3 cells transformed by constitutively active Raf or MEK produced lung metastasis that displayed circumscribed, noninfiltrating borders. In contrast, 3T3 cells transformed by Ras(12V,37G), a Ras effector mutant that activates RalGEF but not Raf or P13 kinase, formed aggressive, infiltrative metastasis. Dominant negative RalB inhibited Ras(12V,37G)-activated invasion and metastasis, demonstrating the necessity of the RalGEF pathway for a fully transformed phenotype. Moreover, 3T3 cells constitutively expressing a membrane-associated form of RalGEF (RalGDS-CAAX) formed invasive tumors as well, demonstrating that activation of a RalGEF pathway is sufficient to initiate the invasive phenotype. Despite the fact that Ras(12V,37G) expression does not elevate ERK activity, inhibition of this kinase by a conditionally expressed ERK phosphatase demonstrated that ERK activity was necessary for Ras(12V,37G)-transformed cells to express matrix-degrading activity in vitro and tissue invasiveness in vivo. Therefore, these experiments have revealed a hitherto-unknown but essential interaction of the RalGEF and ERK pathways to produce a malignant phenotype. The generality of the role of the RalGEF pathway in metastasis is supported by the finding that Ras(12V,37G) increased the invasiveness of epithelial cells as well as fibroblasts.

The activation of endothelial cells during angiogenesis requires cell spreading and migration. These processes are influenced by extracellular signals such as chemoattractants from the local microenvironment. We have shown previously that transmembrane Ca++ influx is necessary for motility and cell spreading, thus we hypothesized that the extracellular divalent cations Mg++ and Ca++ may regulate human umbilical vein endothelial cell (HUVEC) spreading and act as chemoattractants. Studies demonstrated that extracellular Mg++ induced a statistically better spread phenotype when cells were plated on multiple extracellular matrix substrata; Ca++ promoted cell spreading only on vitronectin. Mg++ but not Ca++ acted as a potent chemoattractant when HUVEC migrated on gelatin- and type IV collagen- but not on vitronectin-coated filters. A checkerboard analysis of migration showed that Mg++ induces both chemokinetic and chemotactic migration peaking at 0.1 and 10 mM, respectively. An equivalent effect of oligomycin was seen on motility to Mg++ or to vascular endothelial growth factor (VEGF) in extracellular Mg(++)-free conditions, ruling out an exclusive role for Mg++ as a migration energy producer. The Mg(++)-stimulated chemotaxis was inhibited > 60% by pertussis toxin, d-erythrosphingosine, and tyrphostin B48, but unaffected by cholera toxin exposure. These data suggest that Mg(++)-induced chemotaxis may be promoted through a Gi protein-coupled receptor pathway with a requirement for protein kinase C activity and protein tyrosine phosphorylation. Thus, Mg++ may be a newly recognized receptor-mediated chemoattractant for endothelial cells.

Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine), an analog of creatine and a substrate for creatine kinase (EC 2.7.3.2), inhibits the stimulated motility of tumor cells which possess creatine kinase. A2058-055 human melanoma cells, transfected with a creatine kinase gene, showed an 80-90% reduction in chemotactic response to type IV collagen when incubated overnight in the presence of 10 mM cyclocreatine (p < 0.0001 for n = 8 experiments). This inhibitory effect of cyclocreatine can be partially reversed by addition of creatine to the overnight cell treatment. Non-transfected cells, with very low levels of creatine kinase, were not significantly inhibited. Further experiments utilizing type IV collagen as attractant demonstrated that cyclocreatine inhibited the chemokinetic (91%) and the haptotactic (73%) responses and the in vitro invasion of A2058-055 cells through Matrigel-coated membranes (88%). In addition, motility stimulation of A2058-055 cells by either autotaxin or fibronectin was markedly inhibited by cyclocreatine. DU-145 prostatic tumor cells, which express endogenous creatine kinase, also have a reduced motility response to either autotaxin or epidermal growth factor induced motility in the presence of cyclocreatine.

Cell motility is an essential component of tumor progression and metastasis. A number of factors, both autocrine and paracrine, have been found to influence cell motility. In the present study, adenosine and adenine nucleotides directly stimulated chemotaxis of A2058 melanoma cells in the absence of exogenous factors. Three adenosine receptor agonists stimulated motility in the melanoma cells and two adenosine receptor antagonists strongly inhibited the chemotactic response to both adenosine and AMP. The chemotactic stimulation by adenosine and AMP was pertussis toxin sensitive. Otherwise unresponsive Chinese hamster ovary cells which were transfected with the adenosine A1 receptor cDNA acquired the direct, pertussis toxin sensitive, chemotactic response to adenosine, and this response was inhibited by adenosine receptor antagonists. These findings demonstrate that adenosine and adenine nucleotides are capable of stimulating chemotaxis of tumor cells mediated through an adenosine receptor, probably of the A1 subtype. The possibility of antimetastatic therapies based on inhibition of adenosine receptor activity is raised.