Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. METHODS: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1-2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. DISCUSSION: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. TRIAL REGISTRATION: ISRCTN, ISRCTN15984604 . Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

UK adult ADHD services in crisis.

The UK's services for adult attention-deficit hyperactivity disorder (ADHD) are in crisis, with demand outstripping capacity and waiting times reaching unprecedented lengths. Recognition of and treatments for ADHD have expanded over the past two decades, increasing clinical demand. This issue has been exacerbated by the COVID-19 pandemic. Despite an increase in specialist services, resource allocation has not kept pace, leading to extended waiting times. Underfunding has encouraged growth in independent providers, leading to fragmentation of service provision. Treatment delays carry a human and financial cost, imposing a burden on health, social care and the criminal justice system. A rethink of service procurement and delivery is needed, with multiple solutions on the table, including increasing funding, improving system efficiency, altering the service provision model and clinical prioritisation. However, the success of these solutions hinges on fiscal capacity and workforce issues.

Identification and treatment of individuals with attention-deficit/hyperactivity disorder and substance use disorder: An expert consensus statement.

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.

Evaluating the Difference in Neuropsychological Profiles of Individuals with FASD Based on the Number of Sentinel Facial Features: A Service Evaluation of the FASD UK National Clinic Database.

(1) It might be implied that those with Fetal Alcohol Spectrum Disorder (FASD) with fewer sentinel facial features have a "milder" neuropsychological presentation, or present with fewer impairments than those with more sentinel facial features. The aim of this service evaluation was to compare the neuropsychological profile of people with FASD with varying numbers of sentinel facial features. (2) A clinical sample of 150 individuals with FASD, aged between 6 and 37 years, completed various standardised assessments as part of their diagnostic profiling. These included the documented level of risk of prenatal alcohol exposure (4-Digit Diagnostic Code), sensory needs (Short Sensory Profile), cognition (Wechsler Intelligence Scale for Children-4th Edition; WISC-IV), and communication and socialisation adaptive behaviours (Vineland Adaptive Behavior Scale-2nd Edition; VABS-II). As FASD has high comorbidity rates of Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), these were also reviewed. The profiles of the 'FASD with 2 or 3 sentinel facial features' group (n = 41; 28 male, 13 female) were compared with the 'FASD with 0 or 1 sentinel facial features' group (n = 109; 50 male, 59 female) using Chi² tests, independent sample t-tests, and Mann-Whitney U analyses (where appropriate). (3) There were no significant differences between the two comparison groups across any measure included in this service evaluation. (4) Whilst sentinel facial features remain an important aspect in recognising FASD, our service evaluation indicates that there is no significant relationship between the number of sentinel facial features and the neuropsychological profile of people with FASD in terms of severity of presentation.

Fetal alcohol spectrum disorders.

Alcohol readily crosses the placenta and may disrupt fetal development. Harm from prenatal alcohol exposure (PAE) is determined by the dose, pattern, timing and duration of exposure, fetal and maternal genetics, maternal nutrition, concurrent substance use, and epigenetic responses. A safe dose of alcohol use during pregnancy has not been established. PAE can cause fetal alcohol spectrum disorders (FASD), which are characterized by neurodevelopmental impairment with or without facial dysmorphology, congenital anomalies and poor growth. FASD are a leading preventable cause of birth defects and developmental disability. The prevalence of FASD in 76 countries is >1% and is high in individuals living in out-of-home care or engaged in justice and mental health systems. The social and economic effects of FASD are profound, but the diagnosis is often missed or delayed and receives little public recognition. Future research should be informed by people living with FASD and be guided by cultural context, seek consensus on diagnostic criteria and evidence-based treatments, and describe the pathophysiology and lifelong effects of FASD. Imperatives include reducing stigma, equitable access to services, improved quality of life for people with FASD and FASD prevention in future generations.

Autism spectrum disorder and personality disorders: How do clinicians carry out a differential diagnosis?

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.

Foetal alcohol spectrum disorder and Investigative interviewing: A systematic review highlighting clinical and legal implications and recommendations.

Individuals with foetal alcohol spectrum disorders (FASD) are estimated to be 19 times more likely to encounter the criminal justice system (CJS) in comparison to individuals without FASD. During encounters with the CJS, investigative interviews are employed to obtain accurate information from suspects, victims or witnesses of crime. A systematic search using PRISMA guidelines was performed to identify empirical studies published that have explored the questioning of the FASD population within the CJS and the vulnerabilities of FASD-impacted individuals during investigative interviewing. A total of 383 studies were identified from the databases searched and 7 further studies were identified from Google Scholar. After deduplication, abstract and title screening, the full text of 23 studies were assessed for inclusion and 5 were included in the narrative synthesis of results. Two papers were empirical studies focussed on the performance of FASD-impacted individuals during investigative interviewing. Whilst the first study found the FASD population susceptible to suggestions, the second (a case study), identified the ploys employed during investigative interviewing to obtain a confession. Three papers studied the wider vulnerabilities of FASD-impacted individuals and found diminished psycho-legal abilities, increased risk of recidivism and biological, psychological and social factors that render FASD-impacted individuals vulnerable to CJS encounters. Despite the greater likelihood of CJS encounters, the result of this review highlights the slim evidence base useful to establish the vulnerabilities of FASD-impacted individuals within the CJS.

Prevalence of fetal alcohol spectrum disorder in Greater Manchester, UK: An active case ascertainment study.

BACKGROUND: Despite high levels of prenatal alcohol exposure in the UK, evidence on the prevalence of fetal alcohol spectrum disorders (FASD) is lacking. This paper reports on FASD prevalence in a small sample of children in primary school. METHODS: A 2-phase active case ascertainment study was conducted in 3 mainstream primary schools in Greater Manchester, UK. Schools were located in areas that ranged from relatively deprived to relatively affluent. Initial screening of children aged 8-9 years used prespecified criteria for elevated FASD risk (small for age; special educational needs; currently/previously in care; significant social/emotional/mental health symptoms). Screen-positive children were invited for detailed ascertainment of FASD using gold standard measures that included medical history, facial dysmorphology, neurological impairment, executive function, and behavioral difficulties. RESULTS: Of 220 eligible children, 50 (23%) screened positive and 12% (26/220) proceeded to Phase 2 assessment. Twenty had a developmental disorder, of whom 4 had FASD and 4 were assessed as possible FASD. The crude prevalence rate of FASD in these schools was 1.8% (95% CI: 1.0%, 3.4%) and when including possible cases was 3.6% (2.1%, 6.3%). None of these children had previously been identified with a developmental diagnosis. CONCLUSIONS: FASD was found to be common in these schools and most of these children's needs had not previously been identified. A larger, more definitive study that uses a random sampling technique stratified by deprivation level to select schools is needed to make inferences regarding the population prevalence of FASD.

Genetically-encoded discovery of proteolytically stable bicyclic inhibitors for morphogen NODAL.

In this manuscript, we developed a two-fold symmetric linchpin (TSL) that converts readily available phage-displayed peptides libraries made of 20 common amino acids to genetically-encoded libraries of bicyclic peptides displayed on phage. TSL combines an aldehyde-reactive group and two thiol-reactive groups; it bridges two side chains of cysteine [C] with an N-terminal aldehyde group derived from the N-terminal serine [S], yielding a novel bicyclic topology that lacks a free N-terminus. Phage display libraries of SX1CX2X3X4X5X6X7C sequences, where X is any amino acid but Cys, were converted to a library of bicyclic TSL-[S]X1[C]X2X3X4X5X6X7[C] peptides in 45 ± 15% yield. Using this library and protein morphogen NODAL as a target, we discovered bicyclic macrocycles that specifically antagonize NODAL-induced signaling in cancer cells. At a 10 µM concentration, two discovered bicyclic peptides completely suppressed NODAL-induced phosphorylation of SMAD2 in P19 embryonic carcinoma cells. The TSL-[S]Y[C]KRAHKN[C] bicycle inhibited NODAL-induced proliferation of NODAL-TYK-nu ovarian carcinoma cells with apparent IC50 of 1 µM. The same bicycle at 10 µM concentration did not affect the growth of the control TYK-nu cells. TSL-bicycles remained stable over the course of the 72 hour-long assays in a serum-rich cell-culture medium. We further observed general stability in mouse serum and in a mixture of proteases (Pronase™) for 21 diverse bicyclic macrocycles of different ring sizes, amino acid sequences, and cross-linker geometries. TSL-constrained peptides to expand the previously reported repertoire of phage-displayed bicyclic architectures formed by cross-linking Cys side chains. We anticipate that it will aid the discovery of proteolytically stable bicyclic inhibitors for a variety of protein targets.

Genetically Encoded Fragment-Based Discovery from Phage-Displayed Macrocyclic Libraries with Genetically Encoded Unnatural Pharmacophores.

Genetically encoded macrocyclic peptide libraries with unnatural pharmacophores are valuable sources for the discovery of ligands for many targets of interest. Traditionally, generation of such libraries employs "early stage" incorporation of unnatural building blocks into the chemically or translationally produced macrocycles. Here, we describe a divergent late-stage approach to such libraries starting from readily available starting material: genetically encoded libraries of peptides. A diketone linchpin 1,5-dichloropentane-2,4-dione converts peptide libraries displayed on phage to 1,3-diketone bearing macrocyclic peptides (DKMP): shelf-stable precursors for Knorr pyrazole synthesis. Ligation of diverse hydrazine derivatives onto DKMP libraries displayed on phage that carries silent DNA-barcodes yields macrocyclic libraries in which the amino acid sequence and the pharmacophore are encoded by DNA. Selection of this library against carbonic anhydrase enriched macrocycles with benzenesulfonamide pharmacophore and nanomolar Kd. The methodology described in this manuscript can graft diverse pharmacophores into many existing genetically encoded phage libraries and significantly increase the value of such libraries in molecular discoveries.

Fetal alcohol spectrum disorders: an overview of current evidence and activities in the UK.

Estimates for the UK suggest that alcohol consumption during pregnancy and prevalence of fetal alcohol spectrum disorder (FASD)-the most common neurodevelopmental condition-are high. Considering the significant health and social impacts of FASD, there is a public health imperative to prioritise prevention, interventions and support. In this article, we outline the current state of play regarding FASD knowledge and research in the UK, which is characterised by a lack of evidence, a lack of dedicated funding and services, and consequently little policy formulation and strategic direction. We highlight progress made to date, as well as current knowledge and service gaps to propose a way forward for UK research.

Screening prevalence of fetal alcohol spectrum disorders in a region of the United Kingdom: A population-based birth-cohort study.

Fetal alcohol spectrum disorders (FASDs) are lifelong disabilities caused by prenatal alcohol exposure. Prenatal alcohol use is common in the UK, but FASD prevalence was unknown. Prevalence estimates are essential for informing FASD prevention, identification and support. We applied novel screening algorithms to existing data to estimate the screening prevalence of FASD. Data were from a population-based cohort study (ALSPAC), which recruited pregnant women with expected delivery dates between 1991 and 1992 from the Bristol area of the UK. We evaluated different missing data strategies by comparing results from complete case, single imputation (which assumed that missing data indicated no exposure and no impairment), and multiple imputation methods. 6.0% of children screened positive for FASD in the analysis that used the single imputation method (total N = 13,495), 7.2% in complete case analysis (total N = 223) and 17.0% in the analysis with multiply imputed data (total N = 13,495). A positive FASD screen was more common among children of lower socioeconomic status and children from unplanned pregnancies. Our analyses showed that the complete case and single imputation methods that are commonly used in FASD prevalence studies are likely to underestimate FASD prevalence. Although not equivalent to a formal diagnosis, these screening prevalence estimates suggest that FASD is likely to be a significant public health concern in the UK. Given current patterns of alcohol consumption and recent changes in prenatal guidance, active case ascertainment studies are urgently needed to further clarify the current epidemiology of FASD in the general population of the UK.

Comparisons of the BRIEF parental report and neuropsychological clinical tests of executive function in Fetal Alcohol Spectrum Disorders: data from the UK national specialist clinic.

Extant literature is sparse with regards to the relationship between caregiver reports and neuropsychological tests of executive functioning in Fetal Alcohol Spectrum Disorders (FASD). The goal of this paper was determining the clinical utilities of executive functioning measures used in the United Kingdom national FASD clinic. We examined relationships between outcomes on the Behavior Rating Inventory of Executive Function (BRIEF) and the Delis-Kaplan Executive Function System (D-KEFS), as part of an ongoing service evaluation. Profiles of executive functioning measures were reported in order to contribute to delineating a profile of executive dysfunction in FASD. Caregivers of 49 people with FASD completed the Parent BRIEF, and 61 people with FASD were administered the D-KEFS. Pearson's Correlations between all 11 BRIEF scales and the 18 selected D-KEFS subscales showed little relationship. The BRIEF showed a profile of clinically significant elevations in all three Index scores and seven out of the eight Scale scores. Several D-KEFS tests showed below average executive functioning. Both executive function measures have separate clinical utility in demonstrating executive function deficits in FASD. The sample population used in this study also show a similar pattern to FASD populations internationally, suggesting a similar neuropsychological profile is seen in the United Kingdom. However, caregiver reports display little relationship to neuropsychological tests. These measures likely monitor different aspects of executive functioning in different settings. Future research should focus on identifying tests that better relate findings from clinical settings to behavior in daily life.

Diagnosis and management of foetal alcohol specturm disorder.

PURPOSE OF REVIEW: Our understanding of the diagnosis and management of Foetal Alcohol Spectrum Disorders (FASD), has been increasingly refined in the last 45 years: This review highlights current understanding and identifies future areas for research. RECENT FINDINGS: Newer techniques such as three-dimensional facial recognition and advanced brain imaging, have advanced our understanding. Despite this, there remain areas, such as the relationship with other neurodevelopmental disorders, that have been insufficiently explored. Understanding the unique management approaches required is still in its infancy. However, progress is being made to treat specific aspects in FASD. SUMMARY: Foetal alcohol syndrome has progressed from identification primarily through recognition of physical stigmata, to a broad understanding of neurocognitive function in the full spectrum of alcohol exposure. Understanding of neurocognitive functioning has helped to define a specific phenotype to delineate FASD from other neurodevelopmental disorders. This review explores some of these areas and demonstrates how the field has changed since its recognition 45 years ago.

Neurodevelopmental outcomes in individuals with fetal alcohol spectrum disorder (FASD) with and without exposure to neglect: Clinical cohort data from a national FASD diagnostic clinic.

Disentangling the relative developmental impact of prenatal alcohol exposure from postnatal neglect is clinically valuable for informing future service provision. In this study, developmental outcomes across groups are compared in a 'natural experiment'. METHODS: Clinical data from 99 persons with fetal alcohol spectrum disorder (FASD) diagnoses were audited. Developmental outcomes (diagnosis of attention deficit hyperactivity disorder, ADHD; social and communication disorder, SCD; or Autistic Spectrum Disorder, ASD; Short Sensory Profile, SSP; Vineland II Adaptive Behaviour Scales) were compared across two exposure groups: prenatal alcohol only; and mixed prenatal alcohol and neglect. RESULTS: ADHD (74%) and ASD/SCD (68%) were common, with no significant difference between groups (ADHD, p = 0.924; ASD, p = 0.742). Vineland age equivalence scores were lower than chronological age (11.1 years - prenatal alcohol only, and 12.7 years - neglect) across all domains, especially receptive language (3.7 years for both groups). Age equivalence did not differ between groups, with the exception of domestic daily living (neglect: 7.7 years vs. prenatal alcohol only: 5.8 years, p = 0.027). A probable/definite difference on SSP was more common in the prenatal alcohol only (96% vs. 67%, p = 0.006). For the individual subscales of SSP, there were no significant differences by neglect category. DISCUSSION: Postnatal neglect in this group did not make the developmental outcome any worse, suggesting that prenatal alcohol influences these outcomes independently. Professionals who support families looking after a child with both FASD and a history of neglect should be aware that the behavioral difficulties are likely to be related to prenatal alcohol exposure and not necessarily reflective of parenting quality.

Expanding the Scope of Single- and Double-Noncanonical Amino Acid Mutagenesis in Mammalian Cells Using Orthogonal Polyspecific Leucyl-tRNA Synthetases.

Engineered aminoacyl-tRNA synthetase/tRNA pairs that enable site-specific incorporation of noncanonical amino acids (ncAAs) into proteins in living cells have emerged as powerful tools in chemical biology. The Escherichia coli-derived leucyl-tRNA synthetase (EcLeuRS)/tRNA pair is a promising candidate for ncAA mutagenesis in mammalian cells, but it has been engineered to charge only a limited set of ncAAs so far. Here we show that two highly polyspecific EcLeuRS mutants can efficiently charge a large array of useful ncAAs into proteins expressed in mammalian cells, while discriminating against the 20 canonical amino acids. When combined with an opal-suppressing pyrrolysyl pair, these EcLeuRS variants further enabled site-specific incorporation of different combinations of two distinct ncAAs into proteins expressed in mammalian cells.

Defining the current scope and limitations of dual noncanonical amino acid mutagenesis in mammalian cells.

The ability to site-specifically incorporate two distinct noncanonical amino acids (ncAAs) into the proteome of a mammalian cell with high fidelity and efficiency will have many enabling applications. It would require the use of two different engineered aminoacyl-tRNA synthetase (aaRS)/tRNA pairs, each suppressing a distinct nonsense codon, and which cross-react neither with each other, nor with their counterparts from the host cell. Three different aaRS/tRNA pairs have been developed so far to expand the genetic code of mammalian cells, which can be potentially combined in three unique ways to drive site-specific incorporation of two distinct ncAAs. To explore the suitability of using these combinations for suppressing two distinct nonsense codons with high fidelity and efficiency, here we systematically investigate: (1) how efficiently the three available aaRS/tRNA pairs suppress the three different nonsense codons, (2) preexisting cross-reactivities among these pairs that would compromise their simultaneous use, and (3) whether different nonsense-suppressor tRNAs exhibit unwanted suppression of non-cognate stop codons in mammalian cells. From these comprehensive analyses, two unique combinations of aaRS/tRNA pairs emerged as being suitable for high-fidelity dual nonsense suppression. We developed expression systems to validate the use of both combinations for the site-specific incorporation of two different ncAAs into proteins expressed in mammalian cells. Our work lays the foundation for developing powerful applications of dual-ncAA incorporation technology in mammalian cells, and highlights aspects of this nascent technology that need to be addressed to realize its full potential.

Prenatal alcohol exposure and traumatic childhood experiences: A systematic review.

Prenatal alcohol exposure (PAE) and traumatic childhood experiences (trauma) such as abuse or neglect can each cause central nervous system neurobiological changes or structural damage which can manifest as cognitive and behavioural dysfunction. In cases where both exposures have occurred, the risk of neurodevelopmental impairment may be greater, but this interaction has not been well studied. Here we present a systematic review that identified five primary research studies which investigated either the impact of trauma in children with PAE, or of PAE in children with trauma. Due to the heterogeneity of studies, narrative analysis was applied. Children in these cohorts with both exposures were more likely to show deficits in language, attention, memory and intelligence, and exhibit more severe behavioural problems than children with one exposure in absence of the other. However, the current literature is scarce and methodologically flawed. Further studies are required that: assess dual exposure in other neurodevelopmental domains; feature developmentally impaired yet non-exposed controls; and account for the wide spectrum of effects and different diagnostic criteria associated with PAE.