Molehill Mountain feasibility study: Protocol for a non-randomised pilot trial of a novel app-based anxiety intervention for autistic people.

Up to 50% of autistic people experience co-occurring anxiety, which significantly impacts their quality of life. Consequently, developing new interventions (and/ or adapting existing ones) that improve anxiety has been indicated as a priority for clinical research and practice by the autistic community. Despite this, there are very few effective, evidence-based therapies available to autistic people that target anxiety; and those that are available (e.g., autism adapted Cognitive Behavioural Therapy; CBT) can be challenging to access. Thus, the current study will provide an early-stage proof of concept for the feasibility and acceptability of a novel app-based therapeutic approach that has been developed with, and adapted for, autistic people to support them in managing anxiety using UK National Institute for Health and Care Excellence (NICE) recommended adapted CBT approaches. This paper describes the design and methodology of an ethically approved (22/LO/0291) ongoing non-randomised pilot trial that aims to enrol approximately 100 participants aged ≥16-years with an existing autism diagnosis and mild-to-severe self-reported anxiety symptoms (trial registration NCT05302167). Participants will be invited to engage with a self-guided app-based intervention-'Molehill Mountain'. Primary (Generalised Anxiety Disorder Assessment, Hospital Anxiety and Depression Scale) and secondary outcomes (medication/ service use and Goal Attainment Scaling) will be assessed at baseline (Week 2 +/- 2), endpoint (Week 15 +/- 2) and three follow-ups (Weeks 24, 32 and 41 +/- 4). Participants will also be invited to complete an app acceptability survey/ interview at the study endpoint. Analyses will address: 1) app acceptability/ useability and feasibility (via survey/ interview and app usage data); and 2) target population, performance of outcome measures and ideal timing/ duration of intervention (via primary/ secondary outcome measures and survey/ interview)-with both objectives further informed by a dedicated stakeholder advisory group. The evidence from this study will inform the future optimisation and implementation of Molehill Mountain in a randomised-controlled trial, to provide a novel tool that can be accessed easily by autistic adults and may improve mental health outcomes.

How do autistic people fare in adult life and can we predict it from childhood?

This study describes social, mental health, and quality of life outcomes in early adulthood, and examines childhood predictors in the Special Needs and Autism Project (SNAP), a longitudinal population-based cohort. Young autistic adults face variable but often substantial challenges across many areas of life. Prediction of outcomes is important to set expectations and could lead to the development of targeted early intervention. Autistic children were enrolled at age 12 and parents reported outcomes 11 years later when their children were age 23 (n = 121). Thirty six percent of autistic adults were in competitive employment or education and 54% had frequent contact with friends. Only 5% of autistic adults were living independently, and 37% required overnight care. Moderate or severe anxiety and depression symptoms were found for 11% and 12% of young adults, respectively. Subjective quality of life was similar to UK averages except for social relationships. Using childhood IQ, autism traits and adaptive functioning meaningful predictions can be made of living situation, employment and education and physical health. Prediction was poor for friendships, mental health outcomes and other aspects of quality of life. Our results suggest that although young autistic adults face challenges across normative, social outcomes, they may be faring better in regard to mental health or quality of life. Childhood IQ, autism traits and adaptive functioning are most useful for predicting outcomes. After accounting for these factors, childhood measurements of behavioral and emotional problems and language offered little improvement in prediction of adult outcomes.

COPD Population in US Primary Care: Data From the Optimum Patient Care DARTNet Research Database and the Advancing the Patient Experience in COPD Registry.

PURPOSE: To describe demographic and clinical characteristics of chronic obstructive pulmonary disease patients managed in US primary care. METHODS: This was an observational registry study using data from the Chronic Obstructive Pulmonary Disease (COPD) Optimum Patient Care DARTNet Research Database from which the Advancing the Patient Experience COPD registry is derived. Registry patients were aged ≥35 years at diagnosis. Electronic health record data were collected from both registries, supplemented with patient-reported information/outcomes from the Advancing the Patient Experience registry from 5 primary care groups in Texas, Ohio, Colorado, New York, and North Carolina (June 2019 through November 2020). RESULTS: Of 17,192 patients included, 1,354 were also in the Advancing the Patient Experience registry. Patients were predominantly female (56%; 9,689/17,192), White (64%; 9,732/15,225), current/ex-smokers (80%; 13,784/17,192), and overweight/obese (69%; 11,628/16,849). The most commonly prescribed maintenance treatments were inhaled corticosteroid with a long-acting ß2-agonist (30%) and inhaled corticosteroid with a long-acting muscarinic antagonist (27%). Although 3% (565/17,192) of patitents were untreated, 9% (1,587/17,192) were on short-acting bronchodilator monotherapy, and 4% (756/17,192) were on inhaled corticosteroid monotherapy. Despite treatment, 38% (6,579/17,192) of patients experienced 1 or more exacerbations in the last 12 months. These findings were mirrored in the Advancing Patient Experience registry with many patients reporting high or very high impact of disease on their health (43%; 580/1,322), a breathlessness score 2 or more (45%; 588/1,315), and 1 or more exacerbation in the last 12 months (50%; 646/1,294). CONCLUSIONS: Our findings highlight the high exacerbation, symptom, and treatment burdens experienced by COPD patients managed in US primary care, and the need for more real-life effectiveness trials to support decision making at the primary care level.

Variation in Demographic and Clinical Characteristics of Patients with COPD Receiving Care in US Primary Care: Data from the Advancing the Patient EXperience (APEX) in COPD Registry.

Introduction: Little is known about the variability in chronic obstructive pulmonary disease (COPD) management and how it may be affected by patient characteristics across different healthcare systems in the US. This study aims to describe demographic and clinical characteristics of people with COPD and compare management across five primary care medical groups in the US. Methods: This is a retrospective observational registry study utilizing electronic health records stored in the Advancing the Patient Experience (APEX) COPD registry. The APEX registry contains data from five US healthcare organizations located in Texas, Ohio, Colorado, New York, and North Carolina. Data on demographic and clinical characteristics of primary care patients with COPD between December 2019 and January 2020 were extracted and compared. Results: A total of 17,192 patients with COPD were included in analysis: Texas (n = 811), Ohio (n = 8722), Colorado (n = 472), New York (n = 1149) and North Carolina (n = 6038). The majority of patients at each location were female (>54%) and overweight/obese (>60%). Inter-location variabilities were noted in terms of age, race/ethnicity, exacerbation frequency, treatment pattern, and prevalence of comorbid conditions. Patients from the Colorado site experienced the lowest number of exacerbations per year while those from the New York site reported the highest number. Hypertension was the most common co-morbidity at 4 of 5 sites with the highest prevalence in New York. Depression was the most common co-morbidity in Ohio. Treatment patterns also varied by site; Colorado had the highest proportion of patients not on any treatment. ICS/LABA was the most commonly prescribed treatment except in Ohio, where ICS/LABA/LAMA was most common. Conclusions and Relevance: Our data show heterogeneity in demographic, clinical, and treatment characteristics of patients diagnosed with COPD who are managed in primary care across different healthcare organizations in the US.

The association of adverse life events and parental mental health with emotional and behavioral outcomes in young adults with autism spectrum disorder.

People with autism spectrum disorder (ASD) are at increased risk of developing co-occurring mental health difficulties across the lifespan. Exposure to adverse life events and parental mental health difficulties are known risk factors for developing a range of mental health difficulties. This study investigates the association of adverse life events, parental stress and mental health with emotional and behavioral problems in young adults with ASD. One hundred and fifteen young adults with ASD derived from a population-based longitudinal study were assessed at three time-points (12-, 16-, and 23-year) on questionnaire measures of emotional and behavioral problems. Parent-reported exposure to adverse life events and parental stress/mental health were measured at age 23. We used structural equation modeling to investigate the stability of emotional and behavioral problems over time, and the association between adverse life events and parental stress and mental health and emotional and behavioral outcomes at 23-year. Our results indicate that exposure to adverse life events was significantly associated with increased emotional and behavioral problems in young adults with ASD, while controlling for symptoms in childhood and adolescence. Higher reported parental stress and mental health difficulties were associated with a higher frequency of behavioral, but not emotional problems, and did not mediate the impact of adverse life events. These results suggest that child and adolescent emotional and behavioral problems, exposure to life events and parent stress and mental health are independently associated, to differing degrees, with emotional or behavioral outcomes in early adulthood. LAY SUMMARY: People with autism experience high rates of mental health difficulties throughout childhood and into adult life. Adverse life events and parental stress and mental health may contribute to poor mental health in adulthood. We used data at three time points (12-, 16-, and 23-year) to understand how these factors relate to symptoms at 23-year. We found that emotional and behavioral problems in childhood, adverse life events and parent mental health were all associated with increased emotional and behavioral problems in adulthood.

Trajectories of emotional and behavioral problems from childhood to early adult life.

LAY ABSTRACT: Although mental health problems are common in autism, relatively little is known about their stability and the factors that influence their persistence or change over the life-course. To address this, we use data from the Special Needs and Autism Project (SNAP) cohort studied at three time-points from 12 to 23 years. Using the parent-reported Strengths and Difficulties Questionnaire (SDQ) domains of conduct, emotional, and ADHD symptoms, we evaluated the role of child, family, and contextual characteristics on these three trajectories. Symptoms decreased significantly over time for all three domains, but many participants still scored above the published disorder cutoffs. Individuals showed high levels of persistence. Higher initial adaptive function and language levels predicted a greater decline in conduct and ADHD symptoms. In contrast, higher language functioning was associated with higher levels of emotional symptoms, as was lower levels of autism symptom severity and higher parental education. Those with higher neighborhood deprivation had higher initial conduct problems but a steeper decline over time. Our findings highlight that it may be possible to accurately predict mental health trajectories over this time period, which could help parents and carers in planning and help professionals target resources more efficiently.

Brief Report: Testing the Psychometric Properties of the Spence Children's Anxiety Scale (SCAS) and the Screen for Child Anxiety Related Emotional Disorders (SCARED) in Autism Spectrum Disorder.

Anxiety is a prevalent and impairing co-morbidity among individuals with autism spectrum disorder (ASD), yet assessment measures, including screening tools, are seldom validated with autism samples. We explored the psychometric properties of the child and parent reports of the Spence Children's Anxiety Scale (SCAS) and the Screen for Anxiety Related Disorder-71 (SCARED-71) with 49 males with ASD (10-16 years, 63% co-occurring anxiety). Both measures had excellent internal consistency and fair-good parent-child agreement. The SCAS has a higher proportion of items evaluating observable behaviors. Predictive power of the measures did not differ. Higher cut-points in the parent reports (SCARED only) and lower cut-points in the child reports may enhance prediction in this sample. Choice of measure and cut-points should be considered alongside intended purpose.

Trajectories in Symptoms of Autism and Cognitive Ability in Autism From Childhood to Adult Life: Findings From a Longitudinal Epidemiological Cohort.

OBJECTIVE: For the first time, we use a longitudinal population-based autism cohort to chart the trajectories of cognition and autism symptoms from childhood to early adulthood and identify features that predict the level of function and change with development. METHOD: Latent growth curve models were fitted to data from the Special Needs and Autism Project cohort at three time points: 12, 16, and 23 years. Outcome measures were IQ and parent-reported Social Responsiveness Scale autism symptoms. Of the 158 participants with an autism spectrum disorder at 12 years, 126 (80%) were reassessed at 23 years. Child, family, and contextual characteristics obtained at 12 years predicted intercept and slope of the trajectories. RESULTS: Both trajectories showed considerable variability. IQ increased significantly by a mean of 7.48 points from 12 to 23 years, whereas autism symptoms remained unchanged. In multivariate analysis, full-scale IQ was predicted by initial language level and school type (mainstream/specialist). Participants with a history of early language regression showed significantly greater IQ gains. Autism symptoms were predicted by Social Communication Questionnaire scores (lifetime version) and emotional and behavioral problems. Participants attending mainstream schools showed significantly fewer autism disorder symptoms at 23 years than those in specialist settings; this finding was robust to propensity score analysis for confounding. CONCLUSION: Our findings suggest continued cognitive increments for many people with autism across the adolescent period, but a lack of improvement in autism symptoms. Our finding of school influences on autism symptoms requires replication in other cohorts and settings before drawing any implications for mechanisms or policy.

Exploring the neurocognitive correlates of challenging behaviours in young people with autism spectrum disorder.

Many young people with autism spectrum disorder display 'challenging behaviours', characterised by externalising behaviour and self-injurious behaviours. These behaviours can have a negative impact on a young person's well-being, family environment and educational achievement. However, the development of effective interventions requires greater knowledge of autism spectrum disorder-specific models of challenging behaviours. Autism spectrum disorder populations are found to demonstrate impairments in different cognitive domains, namely social domains, such as theory of mind and emotion recognition, but also non-social domains such as executive functioning and sensory or perceptual processing. Parent-rated self-injurious behaviour and externalising behaviours, and neurocognitive performance were assessed in a population-derived sample of 100 adolescents with autism spectrum disorder. Structural equation modelling was used to estimate associations between cognitive domains (theory of mind, emotion recognition, executive functioning and perceptual processing) and self-injurious behaviour and externalising behaviours. Poorer theory of mind was associated with increased self-injurious behaviour, whereas poorer perceptual processing was associated with increased externalising behaviours. These associations remained when controlling for language ability. This is the first analysis to examine how a wide range of neurocognitive domains relate to challenging behaviours and suggests specific domains that may be important targets in the development of interventions in adolescents with autism spectrum disorder.

Retail-based healthy food point-of-decision prompts (PDPs) increase healthy food choices in a rural, low-income, minority community.

This study examines the potential for point-of-decision prompts (PDPs) to promote healthier food choices among shoppers in a rural, low-income, minority community. We hypothesized that a narrowly defined PDP (focused on fresh produce) would be easier for shoppers to remember than a broadly defined PDP (focused on any healthy items), resulting in a higher proportion of healthy items purchased. PDPs were placed at the entrance to a supermarket in Mission, South Dakota, United States of America, on the Rosebud Sioux Reservation for alternating time periods, July 9-10, 2017. Sales records from 653 transactions were retrieved from the supermarket, comprising periods in which PDPs were in place and control periods. We examined the proportion of selected items and proportion of total expenditures that were a) any healthy foods and b) fresh fruits and vegetables. Data were analyzed in 2018. The narrowly defined prompt consistently resulted in a higher proportion of items and expenditures on healthy foods than either the broad prompt or the control condition. Shoppers in the narrow prompt condition purchased and spent significantly more on any healthy foods and fresh produce than shoppers in the control condition. While shoppers in the narrow prompt condition purchased more healthy foods and fresh produce than shoppers in the broad prompt condition, the differences were not statistically significant. Shoppers exposed to the narrow PDP consistently purchased more healthy foods than shoppers in a control group, while shoppers in the broad PDP did not, highlighting the importance of considering cognitive processes when designing health promotion messages.

Diagnosing autism spectrum disorder: who will get a DSM-5 diagnosis?

BACKGROUND: Introduction of proposed criteria for DSM-5 Autism Spectrum Disorder (ASD) has raised concerns that some individuals currently meeting diagnostic criteria for Pervasive Developmental Disorder (PDD; DSM-IV-TR/ICD-10) will not qualify for a diagnosis under the proposed changes. To date, reports of sensitivity and specificity of the new criteria have been inconsistent across studies. No study has yet considered how changes at the 'sub domain' level might affect overall sensitivity and specificity, and few have included individuals of different ages and ability levels. METHODS: A set of DSM-5 ASD algorithms were developed using items from the Diagnostic Interview for Social and Communication Disorders (DISCO). The number of items required for each DSM-5 subdomain was defined either according to criteria specified by DSM-5 (Initial Algorithm), a statistical approach (Youden J Algorithm), or to minimise the number of false positives while maximising sensitivity (Modified Algorithm). The algorithms were designed, tested and compared in two independent samples (Sample 1, N = 82; Sample 2, N = 115), while sensitivity was assessed across age and ability levels in an additional dataset of individuals with an ICD-10 PDD diagnosis (Sample 3, N = 190). RESULTS: Sensitivity was highest in the Initial Algorithm, which had the poorest specificity. Although Youden J had excellent specificity, sensitivity was significantly lower than in the Modified Algorithm, which had both good sensitivity and specificity. Relaxing the domain A rules improved sensitivity of the Youden J Algorithm, but it remained less sensitive than the Modified Algorithm. Moreover, this was the only algorithm with variable sensitivity across age. All versions of the algorithm performed well across ability level. CONCLUSIONS: This study demonstrates that good levels of both sensitivity and specificity can be achieved for a diagnostic algorithm adhering to the DSM-5 criteria that is suitable across age and ability level.

Therapeutic peptides: technological advances driving peptides into development.

As potential therapeutics, peptides offer several advantages over small molecules (increased specificity) and antibodies (small size). Nevertheless, a number of key issues have hampered their use as drug candidates. A series of new technologies have recently been developed that allow peptides to be viable drug candidates in areas usually restricted to protein therapeutics, such as monoclonal antibodies. These include the development of various types of peptide-conjugates that have lower rates of clearance and hence the potential to increase the exposure of peptide drug candidates in chronic diseases. Structural additions have also been made to peptides, including the use of unnatural amino acids, mainchain modifications and other novel substitutions, which have helped to improve peptide stability and further their therapeutic potential.

Generation of high-affinity human antibodies by combining donor-derived and synthetic complementarity-determining-region diversity.

Combinatorial libraries of rearranged hypervariable V(H) and V(L) sequences from nonimmunized human donors contain antigen specificities, including anti-self reactivities, created by random pairing of V(H)s and V(L)s. Somatic hypermutation of immunoglobulin genes, however, is critical in the generation of high-affinity antibodies in vivo and occurs only after immunization. Thus, in combinatorial phage display libraries from nonimmunized donors, high-affinity antibodies are rarely found. Lengthy in vitro affinity maturation is often needed to improve antibodies from such libraries. We report the construction of human Fab libraries having a unique combination of immunoglobulin sequences captured from human donors and synthetic diversity in key antigen contact sites in heavy-chain complementarity-determining regions 1 and 2. The success of this strategy is demonstrated by identifying many monovalent Fabs against multiple therapeutic targets that show higher affinities than approved therapeutic antibodies. This very often circumvents the need for affinity maturation, accelerating discovery of antibody drug candidates.

Novel peptide inhibitors of angiotensin-converting enzyme 2.

Angiotensin-converting enzyme 2 (ACE2), a recently identified human homolog of ACE, is a novel metallocarboxypeptidase with specificity, tissue distribution, and function distinct from those of ACE. ACE2 may play a unique role in the renin-angiotensin system and mediate cardiovascular and renal function. Here we report the discovery of ACE2 peptide inhibitors through selection of constrained peptide libraries displayed on phage. Six constrained peptide libraries were constructed and selected against FLAG-tagged ACE2 target. ACE2 peptide binders were identified and classified into five groups, based on their effects on ACE2 activity. Peptides from the first three classes exhibited none, weak, or moderate inhibition on ACE2. Peptides from the fourth class exhibited strong inhibition, with equilibrium inhibition constants (K(i) values) from 0.38 to 1.7 microm. Peptides from the fifth class exhibited very strong inhibition, with K(i) values < 0.14 microm. The most potent inhibitor, DX600, had a K(i) of 2.8 nm. Steady-state enzyme kinetic analysis showed that these potent ACE2 inhibitors exhibited a mixed competitive and non-competitive type of inhibition. They were not hydrolyzed by ACE2. Furthermore, they did not inhibit ACE activity, and thus were specific to ACE2. Finally, they also inhibited ACE2 activity toward its natural substrate angiotensin I, suggesting that they would be functional in vivo. As novel ACE2-specific peptide inhibitors, they should be useful in elucidation of ACE2 in vivo function, thus contributing to our better understanding of the biology of cardiovascular regulation. Our results also demonstrate that library selection by phage display technology can be a rapid and efficient way to discover potent and specific protease inhibitors.

Development of mammalian serum albumin affinity purification media by peptide phage display.

Several phage isolates that bind specifically to human serum albumin (HSA) were isolated from disulfide-constrained cyclic peptide phage-display libraries. The majority of corresponding synthetic peptides bind with micromolar affinity to HSA in low salt at pH 6.2, as determined by fluorescence anisotropy. One of the highest affinity peptides, DX-236, also bound well to several mammalian serum albumins (SA). Immobilized DX-236 quantitatively captures HSA from human serum; mild conditions (100 mM Tris, pH 9.1) allow release of HSA. The DX-236 affinity column bound HSA from human serum with a greater specificity than does Cibacron Blue agarose beads. In addition to its likely utility in HSA and other mammalian SA purifications, this peptide media may be useful in the proteomics and medical research markets for selective removal of mammalian albumin from serum prior to mass spectrometric and other analyses.